US20150150480A1 - Pharma-informatics system - Google Patents

Pharma-informatics system Download PDF

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US20150150480A1
US20150150480A1 US14/596,049 US201514596049A US2015150480A1 US 20150150480 A1 US20150150480 A1 US 20150150480A1 US 201514596049 A US201514596049 A US 201514596049A US 2015150480 A1 US2015150480 A1 US 2015150480A1
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Prior art keywords
signal
battery
partial
electrode
control device
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US14/596,049
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Mark Zdeblick
Andrew Thompson
Aleksandr Pikelny
Timothy Robertson
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Proteus Digital Health Inc
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Proteus Digital Health Inc
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Priority to US14/596,049 priority Critical patent/US20150150480A1/en
Publication of US20150150480A1 publication Critical patent/US20150150480A1/en
Assigned to PROTEUS DIGITAL HEALTH, INC. reassignment PROTEUS DIGITAL HEALTH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAFEZI, HOOMAN
Assigned to PROTEUS BIOMEDICAL, INC. reassignment PROTEUS BIOMEDICAL, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PIKELNY, ALEKSANDR, ZDEBLICK, MARK, ROBERTSON, TIMOTHY, THOMPSON, ANDREW
Assigned to PROTEUS DIGITAL HEALTH, INC. reassignment PROTEUS DIGITAL HEALTH, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: PROTEUS BIOMEDICAL, INC.
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    • A61B5/07Endoradiosondes
    • A61B5/073Intestinal transmitters
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    • A61B5/0002Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0026Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by the transmission medium
    • A61B5/0028Body tissue as transmission medium, i.e. transmission systems where the medium is the human body
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    • A61B5/6846Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
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    • G06K7/10009Methods or arrangements for sensing record carriers, e.g. for reading patterns by electromagnetic radiation, e.g. optical sensing; by corpuscular radiation sensing by radiation using wavelengths larger than 0.1 mm, e.g. radio-waves or microwaves
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    • G06K7/10168Methods or arrangements for sensing record carriers, e.g. for reading patterns by electromagnetic radiation, e.g. optical sensing; by corpuscular radiation sensing by radiation using wavelengths larger than 0.1 mm, e.g. radio-waves or microwaves methods and means used by the interrogation device for reliably powering the wireless record carriers using an electromagnetic interrogation field the powering being adversely affected by environmental influences, e.g. unwanted energy loss in the interrogation signal due to metallic or capacitive objects in the proximity of the interrogation device or in the proximity of the interrogated record carrier
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    • G06K7/10366Methods or arrangements for sensing record carriers, e.g. for reading patterns by electromagnetic radiation, e.g. optical sensing; by corpuscular radiation sensing by radiation using wavelengths larger than 0.1 mm, e.g. radio-waves or microwaves the interrogation device being adapted for miscellaneous applications
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    • G16H20/10ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
    • HELECTRICITY
    • H01ELECTRIC ELEMENTS
    • H01QANTENNAS, i.e. RADIO AERIALS
    • H01Q1/00Details of, or arrangements associated with, antennas
    • H01Q1/27Adaptation for use in or on movable bodies
    • H01Q1/273Adaptation for carrying or wearing by persons or animals
    • HELECTRICITY
    • H04ELECTRIC COMMUNICATION TECHNIQUE
    • H04BTRANSMISSION
    • H04B13/00Transmission systems characterised by the medium used for transmission, not provided for in groups H04B3/00 - H04B11/00
    • H04B13/005Transmission systems in which the medium consists of the human body
    • HELECTRICITY
    • H04ELECTRIC COMMUNICATION TECHNIQUE
    • H04WWIRELESS COMMUNICATION NETWORKS
    • H04W4/00Services specially adapted for wireless communication networks; Facilities therefor
    • H04W4/80Services using short range communication, e.g. near-field communication [NFC], radio-frequency identification [RFID] or low energy communication
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    • A61B2560/02Operational features
    • A61B2560/0204Operational features of power management
    • A61B2560/0214Operational features of power management of power generation or supply
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    • A61B2560/04Constructional details of apparatus
    • A61B2560/0462Apparatus with built-in sensors
    • AHUMAN NECESSITIES
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    • AHUMAN NECESSITIES
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    • A61B2562/16Details of sensor housings or probes; Details of structural supports for sensors
    • A61B2562/162Capsule shaped sensor housings, e.g. for swallowing or implantation
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10T29/49002Electrical device making
    • Y10T29/49117Conductor or circuit manufacturing

Definitions

  • the present Invention relates generally to medical apparatus and methods. More specifically, the present invention relates to apparatus and methods for automatic identification of ingestion or other actual, physical administration of a pharmaceutical material.
  • Prescription medications are effective remedies for many patients when taken properly, e.g., according to instructions.
  • studies have shown that, on average, about 50% of patients do not comply with prescribed medication regimens.
  • a low rate of compliance with medication regimens results in a large number of hospitalizations and admissions to nursing homes every year.
  • it has recently been estimated that the cost to the resulting from patient non-compliance is reaching $100 billion annually.
  • the present invention allows, for the first time, the specific identification of pharmaceutical pills and other types of pharmaceutical delivery systems, such as skin diffusion patches, so that the actual, physical delivery of the pharmaceutical into the body can be automatically detected and this information stored. Because the inventive automatic reporting of physical drug administration does not require patient or clinician input, it avoids many of the inaccuracies which introduce uncertainty in current drug administration monitoring systems. These inventive features are particularly critical when a patient's compliance or mental capacity is a consideration, such as in the administration of psychotropic drugs. The present invention also allows for the identification of sources of illicit drugs for law enforcement purposes.
  • Embodiments of the invention include compositions having: an active agent; an identifier and a pharmaceutically acceptable carrier.
  • an ingestible pill is made identifiable by providing an electronic microchip as part of the pill structure.
  • the electronic microchip is completely encased within the pill.
  • the pill broadcasts a signal when it is dissolved in an ionic solution such as stomach fluids.
  • the broadcasted signal is received by another device, e.g., a receiver, either inside or near the body.
  • the receiver then records that the pill has in fact reached the stomach and is in the process of being dissolved.
  • the signal is an oscillating signal which is picked up by an implanted or topically applied receiver.
  • the implant has one or two electrode(s) that sense the varying signal.
  • the implant is configured so that it can identify the code and record that a specific pill has been ingested at a specific time.
  • FIG. 1 provides a diagrammatic, exemplary representation of the pill embodiment of the present invention.
  • FIGS. 2A and 2B provide a more detailed view of the pill composition shown in FIG. 1 .
  • FIGS. 3A to 3E provide views of different embodiments of signal generation elements of the invention.
  • FIG. 4 shows diagrammatically the effects of the pill ingestion where some of the pill has eroded away.
  • FIG. 5 provides a similar arrangement to FIG. 4 , with a coil rather than two electrodes as the output.
  • FIGS. 6A to 6D provide detail of certain implementations of electronic circuits of various embodiments of the invention.
  • FIG. 7 provides an oscillator and a counter implementation according to an embodiment of the invention.
  • FIG. 8 is an additional embodiment of an oscillator where V control modulates the amount of voltage driving the oscillator.
  • FIG. 9 is an additional embodiment with a simple trickle or asynchronous counter.
  • FIG. 10 provides a schematic representation of a three terminal, monopole signal generation element according to an embodiment of the invention.
  • FIGS. 11A to 13B are diagrams showing a method for fabricating an identifier according to an embodiment of the invention.
  • FIG. 14 shows the multiplexer and the addressing system.
  • FIG. 15 shows a detail of the 4 bit mux of the system shown in FIG. 14 .
  • FIG. 16 shows the 1 bit mux in detail that makes up the 4 bit mux.
  • FIG. 17 is an additional monopole embodiment of a signal generation element.
  • FIG. 18A is an exemplary schematic diagram of a signal-transmission driver circuit that transmits a signal at a fixed frequency, in accordance with one embodiment of the present invention.
  • FIG. 18 B 1 - 18 B 2 provides an exemplary schematic diagram of a receiver circuit, in accordance with one embodiment of the present invention.
  • FIG. 19 shows one exemplary split (i.e., segmented) battery design, in accordance with one embodiment of the present invention.
  • FIG. 20 shows one exemplary design of the driver circuit that uses split battery electrodes for transmission, in accordance with one embodiment of the present invention.
  • FIG. 21 shows one exemplary split battery design with a split cathode, in accordance with one embodiment of the present invention.
  • FIG. 22 shows one exemplary design where the battery electrodes for the driver circuit are coupled to the driver circuit via two external wires, in accordance with one embodiment of the present invention.
  • FIG. 23 shows the principle of an experiment with a split battery configuration.
  • FIG. 24 shows the performance of a pair of split batteries.
  • the present invention provides the clinician an important new tool in their therapeutic armamentarium: automatic detection and identification of pharmaceutical agents actually delivered into the body.
  • the applications of this new information device and system are multi-fold.
  • correlation between drug delivery, batch and dosage can be correlated to a physiological response.
  • optimal pharma-therapeutic regimens may be formulated by the clinician.
  • cardiac stimulating drugs can be titrated to the most appropriate dosages, minimizing side effects such as cardiac muscle exhaustion and rebound effects among others, and optimizing both dosage and timing for each, individual patient.
  • the clinician or care giver is able to verify that the amount of the drug was taken has been taken at approximately the right point and time. Thus, the true efficacy of the drug can be accurately evaluated. Proper administration and patient compliance is especially critical in Alzheimer's, psychiatric, and alcohol aversion drugs, and in the treatment of rest home residents. In the case of accidental and other overdoses situations, the intervening clinician will be able to discern how far the ingestion has proceeded, and how many pills are involved.
  • the present invention allows, in concert with other sensing device developed by some of the present inventors, the measurement and assessment of the cardiac response to those medications.
  • These co-employed sensing devices can be those enumerated below, among others.
  • Other sensing technology developed by some of the present inventors allows measurement of heart health and cardiac efficiency. Using these tools in concert with the present inventive device, the clinician will be able to compare the response of the heart and body to the administered pharmaceutical.
  • the data provided by the present invention can optionally be recorded over time.
  • the recording system records synchrony or conduction velocity of a signal going through cardiac tissue and how that is mediated by the presence of a certain medication. This unique data is made possible by the present invention since it can determine electronically exactly when the pill or other medication was being absorbed into the body.
  • the present invention provides the clinician an accurate dose response curve showing the response to that medication and the timing of the digestion of the pill.
  • the clinician now has the ability to determine which patients have no response to the medicine in the pill.
  • such patients can be removed from a study or a test of the clinical utility of a certain medication.
  • This provides that only people who have a beneficial response to a certain medication are retained in the trail.
  • This feature will improve the efficacy of medications and to reduce the amount of medications that people take that are not being useful. It may also be used in trials to determine which patients actually consumed the medicine, and which did not.
  • the present invention provides a record for emergency room technicians or doctors when a patient is admitted to a hospital so that the patient's status can be accurately ascertained. Dosage events within the last hour or day prior to admission, and the identity of the last medication, will be immediately available.
  • the chips can be fitted with coils, susceptible of interrogation without being dissolved in the body. This is accomplished by transmitting RF energy into the coil in such a way that the inquirer will be apprised of the presence and identity of a pill before it is ingested.
  • a “smart box” is provided that can interrogate each pill and ascertain its address.
  • the box can write a distinctive product number or product code so that every single pill ever made is provided with a unique identifier. Fuses, for example, may be selectively destroyed so the addresses may be detected electrically or optically. Particularly in the case of controlled substances, such as a narcotic, this will be important in limiting the illegal used of previously legitimate medicines.
  • the present invention makes it possible to identify precisely who bought such a pill from the authorized pharmacist. This use of the present invention will rein in the number of illicit uses of controlled substances on the market place.
  • compositions are reviewed first, followed by a discussion of systems including the subject compositions, methods of using the subject compositions and systems and various illustrative applications in which the compositions and methods find use. Also reviewed in greater detail below are kits that include the subject compositions.
  • Embodiments of the invention include active agent compositions having an identifier stably associated therewith.
  • the compositions are disrupted upon administration to a subject.
  • the compositions are physically broken, e.g., dissolved, degraded, eroded, etc., following delivery to a body, e.g., via ingestion, injection, etc.
  • the compositions of these embodiments are distinguished from devices that are configured to be ingested and survive transit through the gastrointestinal tract substantially, if not completely, intact. While the compositions of these embodiments are themselves disrupted upon administration, components of the composition, e.g., the identifier, may survive transit of the gastrointestinal tract, e.g., as described in greater detail below.
  • compositions include an active agent/carrier component and an identifier.
  • active agent/carrier component and an identifier.
  • compositions include an active agent/carrier component.
  • active agent/carrier component is meant a composition, which may be a solid or fluid (e.g., liquid), which has an amount of active agent, e.g., a dosage, present in a pharmaceutically acceptable carrier.
  • the active agent/carrier component may be referred to as a “dosage formulation.”
  • Active agent includes any compound or mixture of compounds which produces a physiological result, e.g., a beneficial or useful result, upon contact with a living organism, e.g., a mammal, such as a human. Active agents are distinguishable from such components as vehicles, carriers, diluents, lubricants, binders and other formulating aids, and encapsulating or otherwise protective components.
  • the active agent may be any molecule, as well as binding portion or fragment thereof, that is capable of modulating a biological process in a living subject.
  • the active agent may be a substance used in the diagnosis, treatment, or prevention of a disease or as a component of a medication.
  • the active agent may be a chemical substance, such as a narcotic or hallucinogen, which affects the central nervous system and causes changes in behavior.
  • the active agent i.e., drug
  • the target may be a number of different types of naturally occurring structures, where targets of interest include both intracellular and extracellular targets.
  • targets of interest include both intracellular and extracellular targets.
  • targets may be proteins, phospholipids, nucleic acids and the like, where proteins are of particular interest.
  • Specific proteinaceous targets of interest include, without limitation, enzymes, e.g. kinases, phosphatases, reductases, cyclooxygenases, proteases and the like, targets comprising domains involved in protein-protein interactions, such as the SH2, SH3.
  • PTB and PDZ domains structural proteins, e.g. actin, tubulin, etc., membrane receptors, immunoglobulins, e.g. IgE, cell adhesion receptors, such as integrins, etc, ion channels, transmembrane pumps, transcription factors, signaling proteins, and the like.
  • the active agent may include one or more functional groups necessary for structural interaction with the target, e.g., groups necessary for hydrophobic, hydrophilic, electrostatic or even covalent interactions, depending on the particular drug and its intended target.
  • the drug moiety may include functional groups necessary for structural interaction with proteins, such as hydrogen bonding, hydrophobic-hydrophobic interactions, electrostatic interactions, etc., and may include at least an amine, amide, sulfhydryl, carbonyl, hydroxyl or carboxyl group, such as at least two of the functional chemical groups.
  • Drugs of interest may include cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups.
  • drug moieties are structures found among biomolecules, including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof. Such compounds may be screened to identify those of interest, where a variety of different screening protocols are known in the art.
  • the drugs may be derived from a naturally occurring or synthetic compound that may be obtained from a wide variety of sources, including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including the preparation of randomized oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means, and may be used to produce combinatorial libraries. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce structural analogs.
  • the drug may be obtained from a library of naturally occurring or synthetic molecules, including a library of compounds produced through combinatorial means, i.e., a compound diversity combinatorial library.
  • a library of compounds produced through combinatorial means i.e., a compound diversity combinatorial library.
  • the drug moiety employed will have demonstrated some desirable activity in an appropriate screening assay for the activity.
  • Combinatorial libraries, as well as methods for producing and screening such libraries, are known in the art and described in: U.S. Pat. Nos.
  • cardiovascular agents include, but are not limited to: cardiovascular agents; pain-relief agents, e.g., analgesics, anesthetics, anti-inflammatory agents, etc.; nerve-acting agents; chemotherapeutic (e.g., antineoplastic) agents; etc.
  • the active agent is a cardiovascular agent, i.e., an agent employed in the treatment of cardiovascular or heart conditions. In certain embodiments, the active agent is a cardiovascular agent, i.e., an agent employed in the treatment of cardiovascular or heart conditions.
  • Cardiovascular agents of interest include, but are not limited to: cardioprotective agents, e.g., Zinecard (dexrazoxane); blood modifiers, including anticoagulants (e.g., coumadin (warfarin sodium), fragmin (dalteparin sodium), heparin, innohep (tinzaparin sodium), lovenox (enoxaparin sodium), orgaran (danaparoid sodium)) antiplatelet agents (e.g., aggrasta (tirofiban hydrochloride), aggrenox (aspirin/extended release dipyridamole), agrylin (anagrelide hydrochloride), ecotrin (acetylsalicylic acid), folan (epoprostenol sodium), halfprin (enteric coated aspirin), integrlilin (eptifibatide), persantine (dipyridamole USP), plavix (clopidogrel bisulfate), pletal (cilostazol), re
  • specific drugs of interest include, but are not limited to: psychopharmacological agents, such as (1) central nervous system depressants, e.g. general anesthetics (barbiturates, benzodiazepines, steroids, cyclohexanone derivatives, and miscellaneous agents), sedative-hypnotics (benzodiazepines, barbiturates, piperidinediones and triones, quinazoline derivatives, carbamates, aldehydes and derivatives, amides, acyclic ureides, benzazepines and related drugs, phenothiazines, etc.), central voluntary muscle tone modifying drugs (anticonvulsants, such as hydantoins, barbiturates, oxazolidinediones, succinimides, acylureides, glutarimides, benzodiazepines, secondary and tertiary alcohols, dibenzazepine derivatives, valproic acid and derivatives, GABA analogs
  • analeptics respiratory stimulants, convulsant stimulants, psychomotor stimulants
  • narcotic antagonists morphine derivatives, oripavine derivatives, 2,6-methane-3-benzoxacine derivatives, morphinan derivatives
  • nootropics e.g.
  • anxiolytic sedatives benzodiazepines, propanediol carbamates
  • antipsychotics phenothiazine derivatives, thioxanthine derivatives, other tricyclic compounds, butyrophenone derivatives and isosteres, diphenylbutylamine derivatives, substituted benzamides, arylpiperazine derivatives, indole derivatives, etc.
  • antidepressants tricyclic compounds, MAO inhibitors, etc.
  • respiratory tract drugs e.g. central antitussives (opium alkaloids and their derivatives);
  • peripheral nervous system drugs e.g. local anesthetics (ester derivatives, amide derivatives)
  • drugs acting at synaptic or neuroeffector junctional sites e.g. cholinergic agents, cholinergic blocking agents, neuromuscular blocking agents, adrenergic agents, antiadrenergic agents, (3) smooth muscle active drugs, e.g. spasmolytics (anticholinergics, musculotropic spasmolytics), vasodilators, smooth muscle stimulants, (4) histamines and antihistamines, e.g.
  • histamine and derivative thereof betazole
  • antihistamines H1-antagonists, H2-antagonists
  • histamine metabolism drugs (5) cardiovascular drugs, e.g. cardiotonics (plant extracts, butenolides, pentadienolids, alkaloids from erythrophleum species, ionophores, -adrenoceptor stimulants, etc), antiarrhythmic drugs, antihypertensive agents, antilipidemic agents (clofibric acid derivatives, nicotinic acid derivatives, hormones and analogs, antibiotics, salicylic acid and derivatives), antivaricose drugs, hemostyptics, (6) blood and hemopoietic system drugs, e.g.
  • antianemia drugs blood coagulation drugs (hemostatics, anticoagulants, antithrombotics, thrombolytics, blood proteins and their fractions), (7) gastrointestinal tract drugs, e.g. digestants (stomachics, choleretics), antiulcer drugs, antidiarrheal agents, (8) locally acting drugs;
  • blood coagulation drugs hemostatics, anticoagulants, antithrombotics, thrombolytics, blood proteins and their fractions
  • gastrointestinal tract drugs e.g. digestants (stomachics, choleretics), antiulcer drugs, antidiarrheal agents, (8) locally acting drugs;
  • chemotherapeutic agents such as (1) anti-infective agents, e.g. ectoparasiticides (chlorinated hydrocarbons, pyrethins, sulfurated compounds), anthelmintics, antiprotozoal agents, antimalarial agents, antiamebic agents, antileiscmanial drugs, antitrichomonal agents, antitrypanosomal agents, sulfonamides, antimycobacterial drugs, antiviral chemotherapeutics, etc., and (2) cytostatics, i.e. antineoplastic agents or cytotoxic drugs, such as alkylating agents, e.g.
  • anti-infective agents e.g. ectoparasiticides (chlorinated hydrocarbons, pyrethins, sulfurated compounds), anthelmintics, antiprotozoal agents, antimalarial agents, antiamebic agents, antileiscmanial drugs, antitrichomonal agents, antitrypanosomal agents, sulfon
  • Mechlorethamine hydrochloride (Nitrogen Mustard, Mustargen, HN2), Cyclophosphamide (Cytovan, Endoxana), Ifosfamide (IFEX), Chlorambucil (Leukeran), Melphalan (Phenylalanine Mustard, L-sarcolysin, Alkeran, L-PAM), Busulfan (Myleran), Thiotepa (Triethylenethiophosphoramide), Carmustine (BiCNU, BCNU), Lomustine (CeeNU, CCNU), Streptozocin (Zanosar) and the like; plant alkaloids, e.g.
  • Vincristine Oncovin
  • Vinblastine Vinblastine
  • Velban Velbe
  • Paclitaxel Taxol
  • antimetabolites e.g. Methotrexate (MTX), Mercaptopurine (Purinethol, 6-MP), Thioguanine (6-TG), Fluorouracil (5-FU), Cytarabine (Cytosar-U, Ara-C), Azacitidine (Mylosar, 5-AZA) and the like
  • antibiotics e.g.
  • Dactinomycin Actinomycin D, Cosmegen
  • Doxorubicin Adriamycin
  • Daunorubicin duanomycin, Cerubidine
  • Idarubicin Idamycin
  • Bleomycin Blenoxane
  • Picamycin Mithramycin, Mithracin
  • Mitomycin Mitomycin (Mutamycin) and the like, and other anticellular proliferative agents, e.g.
  • antibiotics such as: aminoglycosides, e.g. amikacin, apramycin, arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin, fortimicin, gentamicin, isepamicin, kanamycin, micronomcin, neomycin, netilmicin, paromycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin; amphenicols, e.g. azidamfenicol, chloramphenicol, florfenicol, and theimaphenicol; ansamycins, e.g.
  • aminoglycosides e.g. amikacin, apramycin, arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin, fortimicin, gentamicin, isepamicin
  • apicycline, chlortetracycline, clomocycline, etc. synthetic antibacterial agents, such as 2,4-diaminopyrimidines, nitrofurans, quinolones and analogs thereof, sulfonamides, sulfones;
  • antifungal agents such as: polyenes, e.g. amphotericin B, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin, perimycin; synthetic antifungals, such as allylamines, e.g. butenafine, naftifine, terbinafine; imidazoles, e.g. bifonazole, butoconazole, chlordantoin, chlormidazole, etc., thiocarbamates, e.g. tolciclate, triazoles, e.g. fluconazole, itraconazole, terconazole;
  • polyenes e.g. amphotericin B, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartric
  • anthelmintics such as: arecoline, aspidin, aspidinol, dichlorophene, embelin, kosin, napthalene, niclosamide, pelletierine, quinacrine, alantolactone, amocarzine, amoscanate, ascaridole, bephenium, bitoscanate, carbon tetrachloride, carvacrol, cyclobendazole, diethylcarbamazine, etc.;
  • antimalarials such as: acedapsone, amodiaquin, arteether, artemether, artemisinin, artesunate, atovaquone, bebeerine, berberine, chirata, chlorguanide, chloroquine, chlorprogaunil, cinchona, cinchonidine, cinchonine, cycloguanil, gentiopicrin, halofantrine, hydroxychloroquine, mefloquine hydrochloride, 3-methylarsacetin, pamaquine, plasmocid, primaquine, pyrimethamine, quinacrine, quinidine, quinine, quinocide, quinoline, dibasic sodium arsenate;
  • antiprotozoan agents such as: acranil, tinidazole, ipronidazole, ethyistibamine, pentamidine, acetarsone, aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole, suramin, and the like.
  • Name brand drugs of interest include, but are not limited to: Rezulin ⁇ , LovastatinTM, EnalaprilTM, ProzacTM, PrilosecTM, LipotorTM, ClaritinTM, ZocorTM, CiprofloxacinTM, ViagraTM, CrixivanTM, RitalinTM, and the like.
  • Drug compounds of interest are also listed in: Goodman & Gilman's, The Pharmacological Basis of Therapeutics (9th Ed) (Goodman et al. eds) (McGraw-Hill) (1996); and 2001 Physician's Desk Reference.
  • Specific compounds of interest also include, but are not limited to:
  • psycopharmacologicalpsychotropic agents as disclosed in U.S. Pat. Nos. 5,192,799, 5,036,070, 4,778,800, 4,753,951, 4,590,180, 4,690,930, 4,645,773, 4,427,694, 4,424,202, 4,440,781, 5,686,482, 5,478,828, 5,461,062, 5,387,593, 5,387,586, 5,256,664, 5,192,799, 5,120,733, 5,036,070, 4,977,167, 4,904,663, 4,788,188, 4,778,800, 4,753,951, 4,690,930, 4,645,773, 4,631,285, 4,617,314, 4,613,600, 4,590,180, 4,560,684, 4,548,938, 4,529,727, 4,459,306, 4,443,451, 4,440,781, 4,427,694, 4,424,202, 4,397,853, 4,358,451, 4,324,787, 4,314,08
  • cardiovascular agents as disclosed in U.S. Pat. Nos. 4,966,967, 5,661,129, 5,552,411, 5,332,737, 5,389,675, 5,198,449, 5,079,247, 4,966,967, 4,874,760, 4,954,526, 5,051,423, 4,888,335, 4,853,391, 4,906,634, 4,775,757, 4,727,072, 4,542,160, 4,522,949, 4,524,151, 4,525,479, 4,474,804, 4,520,026, 4,520,026, 5,869,478, 5,859,239, 5,837,702, 5,807,889, 5,731,322, 5,726,171, 5,723,457, 5,705,523, 5,696,111, 5,691,332, 5,679,672, 5,661,129, 5,654,294, 5,646,276, 5,637,586, 5,631,251, 5,612,370, 5,612,323, 5,574,037, 5,563,170,
  • immunosuppressive agents as disclosed in U.S. Pat. Nos. 4,450,159, 4,450,159, 5,905,085, 5,883,119, 5,880,280, 5,877,184, 5,874,594, 5,843,452, 5,817,672, 5,817,661, 5,817,660, 5,801,193, 5,776,974, 5,763,478, 5,739,169, 5,723,466, 5,719,176, 5,696,156, 5,695,753, 5,693,648, 5,693,645, 5,691,346, 5,686,469, 5,686,424, 5,679,705, 5,679,640, 5,670,504, 5,665,774, 5,665,772, 5,648,376, 5,639,455, 5,633,277, 5,624,930, 5,622,970, 5,605,903, 5,604,229, 5,574,041, 5,565,560, 5,550,233, 5,545,734, 5,540,931, 5,532,248, 5,527,820, 5,516,7
  • analgesic agents as disclosed in U.S. Pat. Nos. 5,292,736, 5,688,825, 5,554,789, 5,455,230, 5,292,736, 5,298,522, 5,216,165, 5,438,064, 5,204,365, 5,017,578, 4,906,655, 4,906,655, 4,994,450, 4,749,792, 4,980,365, 4,794,110, 4,670,541, 4,737,493, 4,622,326, 4,536,512, 4,719,231, 4,533,671, 4,552,866, 4,539,312, 4,569,942, 4,681,879, 4,511,724, 4,556,672, 4,721,712, 4,474,806, 4,595,686, 4,440,779, 4,434,175, 4,608,374, 4,395,402, 4,400,534, 4,374,139, 4,361,583, 4,252,816, 4,251,530, 5,874,459, 5,688,825, 5,554,789, 5,455,230
  • cholinergic agents as disclosed in U.S. Pat. Nos. 5,219,872, 5,219,873, 5,073,560, 5,073,560, 5,346,911, 5,424,301, 5,073,560, 5,219,872, 4,900,748, 4,786,648, 4,798,841, 4,782,071, 4,710,508, 5,482,938, 5,464,842, 5,378,723, 5,346,911, 5,318,978, 5,219,873, 5,219,872, 5,084,281, 5,073,560, 5,002,955, 4,988,710, 4,900,748, 4,798,841, 4,786,648, 4,782,071, 4,745,123, 4,710,508;
  • adrenergic agents as disclosed in U.S. Pat. Nos. 5,091,528, 5,091,528, 4,835,157, 5,708,015, 5,594,027, 5,580,892, 5,576,332, 5,510,376, 5,482,961, 5,334,601, 5,202,347, 5,135,926, 5,116,867, 5,091,528, 5,017,618, 4,835,157, 4,829,086, 4,579,867, 4,568,679, 4,469,690, 4,395,559, 4,381,309, 4,363,808, 4,343,800, 4,329,289, 4,314,943, 4,311,708, 4,304,721, 4,296,117, 4,285,873, 4,281,189, 4,278,608, 4,247,710, 4,145,550, 4,145,425, 4,139,535, 4,082,843, 4,011,321, 4,001,421, 3,982,010, 3,940,407, 3,852,468, 3,832,470
  • antihistamine agents as disclosed in U.S. Pat. Nos. 5,874,479, 5,863,938, 5,856,364, 5,770,612, 5,702,688, 5,674,912, 5,663,208, 5,658,957, 5,652,274, 5,648,380, 5,646,190, 5,641,814, 5,633,285, 5,614,561, 5,602,183, 4,923,892, 4,782,058, 4,393,210, 4,180,583, 3,965,257, 3,946,022, 3,931,197;
  • the active agents may be present as pharmaceutically acceptable salts.
  • the active agent of the compositions are typically present in a pharmaceutically acceptable vehicle or carrier, e.g., as described below.
  • the active agent is present in an amount of from about 0.1% to about 90% by weight, e.g., from about 1% to about 30% by weight of the active compound.
  • compositions of the invention further include a pharmaceutically acceptable vehicle (i.e., carrier).
  • a pharmaceutically acceptable vehicle i.e., carrier
  • Common carriers and excipients such as corn starch or gelatin, lactose, dextrose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid are of interest.
  • Disintegrators commonly used in the formulations of the invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
  • a liquid composition may comprise a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s), for example, ethanol, glycerine, sorbitol, non-aqueous solvent such as polyethylene glycol, oils or water, with a suspending agent, preservative, surfactant, wetting agent, flavoring or coloring agent.
  • a liquid formulation can be prepared from a reconstitutable powder.
  • a powder containing active compound, suspending agent, sucrose and a sweetener can be reconstituted with water to form a suspension; and a syrup can be prepared from a powder containing active ingredient, sucrose and a sweetener.
  • a composition in the form of a tablet or pill can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid compositions.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example, polyvinylpyrrolidone.
  • the tablet can also be provided with a color film coating, or color included as part of the carrier(s).
  • active compound can be formulated in a controlled release dosage form as a tablet comprising a hydrophilic or hydrophobic matrix.
  • Controlled release “sustained release”, and similar terms are used to denote a mode of active agent delivery that occurs when the active agent is released from the delivery vehicle at an ascertainable and controllable rate over a period of time, rather than dispersed immediately upon application or injection. Controlled or sustained release may extend for hours, days or months, and may vary as a function of numerous factors.
  • the rate of release will depend on the type of the excipient selected and the concentration of the excipient in the composition. Another determinant of the rate of release is the rate of hydrolysis of the linkages between and within the units of the polyorthoester.
  • the rate of hydrolysis in turn may be controlled by the composition of the polyorthoester and the number of hydrolysable bonds in the polyorthoester.
  • Other factors determining the rate of release of an active agent from the present pharmaceutical composition include particle size, acidity of the medium (either internal or external to the matrix) and physical and chemical properties of the active agent in the matrix.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures, for example, by incorporation of active compound and excipients into a hard gelatin capsule.
  • a semi-solid matrix of active compound and high molecular weight polyethylene glycol can be prepared and filled into a hard gelatin capsule; or a solution of active compound in polyethylene glycol or a suspension in edible oil, for example, liquid paraffin or fractionated coconut oil can be prepared and filled into a soft gelatin capsule.
  • Tablet binders that can be included are acacia , methylcellulose, sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.
  • Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
  • Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. Additionally, it may be desirable to add a coloring agent to make the dosage form more attractive in appearance or to help identify the product.
  • the compounds of the invention and their pharmaceutically acceptable salts that are active when given parenterally can be formulated for intramuscular, intrathecal, or intravenous administration.
  • a typical composition for intramuscular or intrathecal administration will be of a suspension or solution of active ingredient in an oil, for example, arachis oil or sesame oil.
  • a typical composition for intravenous or intrathecal administration will be a sterile isotonic aqueous solution containing, for example, active ingredient and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride.
  • Other examples are lactated Ringer's injection, lactated Ringer's plus dextrose injection, Normosol-M and dextrose, Isolyte E, acylated Ringer's injection, and the like.
  • a co-solvent for example, polyethylene glycol
  • a chelating agent for example, ethylenediamine tetraacetic acid
  • an anti-oxidant for example, sodium metabisulphite
  • the solution can be freeze dried and then reconstituted with a suitable solvent just prior to administration.
  • the compounds of the invention and their pharmaceutically acceptable salts which are active on rectal administration can be formulated as suppositories.
  • a typical suppository formulation will generally consist of active ingredient with a binding and/or lubricating agent such as a gelatin or cocoa butter or other low melting vegetable or synthetic wax or fat.
  • transdermal compositions or transdermal delivery devices (“patches”).
  • Such compositions include, for example, a backing, active compound reservoir, a control membrane, liner and contact adhesive.
  • transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. For example, see U.S. Pat. No. 5,023,252, herein incorporated by reference in its entirety. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the pharmaceutical composition may contain other pharmaceutically acceptable components, such a buffers, surfactants, antioxidants, viscosity modifying agents, preservatives and the like.
  • a buffers such as sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium sulfate
  • an identifier may vary depending on the particular embodiment and intended application of the composition.
  • the identifier is a component that emits a signal upon activation by a stimulus, e.g., by interrogation, upon contact with a target physiological location, etc.
  • the identifier may be an identifier that emits a signal when it contacts a target body (i.e., physiological) site.
  • the identifier may be an identifier that emits a signal when interrogated.
  • the identifier is an inert, but identifiable marker, e.g., an engraved identifier (such as one that is fabricated from a material or materials that survive digestion). This marker may then be identified, for example, following an autopsy or forensic examination. It is possible to provide a more internal device within a pill to determine both that its surface has partially been subject to digestion, but also that the inner pill material has also been digested. This application is particularly useful in experimental pharmacological settings.
  • the identifier of these embodiments is one that does not necessarily emit a signal, but which can be optically inspected, e.g., visually or machine read, to obtain information about the composition with which it was associated prior to administration.
  • the identifier may be an identifier that does not emit a signal
  • the identifier is one that does emit a signal.
  • the signal may be a generic signal, e.g., a signal that merely identifies that the composition has contacted the target site, or a unique signal, e.g., a signal which in some way uniquely identifies that a particular composition from a group or plurality of different compositions in a batch has contacted a target physiological site.
  • the identifier may be one that, when employed in a batch of unit dosages, e.g., a batch of tablets, emits a signal which cannot be distinguished from the signal emitted by the identifier of any other unit dosage member of the batch.
  • the identifier emits a signal that uniquely identifies a given unit dosage, even from other identical unit dosages in a given batch. Accordingly, in certain embodiments the identifier emits a unique signal that distinguishes a given type of unit dosage from other types of unit dosages, e.g., a given medication from other types of medications.
  • the identifier emits a unique signal that distinguishes a given unit dosage from other unit dosages of a defined population of unit dosages, e.g., a prescription, a batch or a lifetime production run of dosage formulations.
  • the identifier emits a signal that is unique, i.e., distinguishable, from a signal emitted by any other dosage formulation ever produced, where such a signal may be viewed as a universally unique signal (e.g., analogous to a human fingerprint which is distinct from any other fingerprint of any other individual and therefore uniquely identifies an individual on a universal level).
  • the signal may either directly convey information about the composition, or provide an identifying code, which may be used to retrieve information about the composition from a database, i.e., a database linking identifying codes with compositions.
  • the identifier may be any component or device that is capable of generating a detectable signal following activation in response to a stimulus.
  • the stimulus activates the identifier to emit a signal once the composition comes into contact with a physiological target site, e.g., as summarized above.
  • a patient may ingest a pill that upon contact with the stomach fluids, generates a detectable signal.
  • the target physiological site or location may vary, where representative target physiological sites of interest include, but are not limited to: a location in the gastrointestinal tract (such as the mouth, esophagus, stomach, small intestine, large intestine, etc.); another location inside the body, such as a parental location, vascular location, etc.; or a topical location; etc.
  • a location in the gastrointestinal tract such as the mouth, esophagus, stomach, small intestine, large intestine, etc.
  • another location inside the body such as a parental location, vascular location, etc.
  • a topical location etc.
  • the stimulus that activates the identifier is an interrogation signal, such as a scan or other type of interrogation.
  • the stimulus activates the identifier, thereby emitting a signal which is then received and processed, e.g., to identify the composition in some manner.
  • the identifier may include a power source that transduces broadcast power and a signal generating element that modulates the amount of transduced power, such that a signal is not emitted from the identifier but instead the amount of broadcast power transduced by the identifier is detected and employed as the “signal.”
  • a power source that transduces broadcast power
  • a signal generating element that modulates the amount of transduced power, such that a signal is not emitted from the identifier but instead the amount of broadcast power transduced by the identifier is detected and employed as the “signal.”
  • the identifier is dimensioned to be complexed with the active agent/pharmaceutically acceptable carrier component of the composition so as to produce a composition that can be readily administered to a subject in need thereof.
  • the identifier element is dimensioned to have a width ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mm to about 1 mm, such as from about 0.05 mm to about 0.3 mm, including from about 0.1 mm to about 0.2 mm.
  • the identifier is 1 mm 3 or smaller, such as 0.1 mm 3 or smaller, including 0.2 mm 3 or smaller.
  • the identifier element may take a variety of different configurations, such as but not limited to: a chip configuration, a cylinder configuration, a spherical configuration, a disc configuration, etc, where a particular configuration may be selected based on intended application, method of manufacture, etc.
  • the identifier may generate a variety of different types of signals, including but not limited, RF, magnetic, conductive (near field), acoustic, etc.
  • n is a unit vector in the direction from the center of the dipole source to a location x at a distance r from the source
  • RF communication takes place at distances r ⁇ to r>> ⁇ .
  • implantable medical devices such as pacemakers typically communicate in the 405-MHz frequency band, corresponding to wavelengths of 0.75 meters, somewhat smaller than the scale of a human body.
  • higher frequencies are advantageously not used because structures within the body begin to absorb radiation, leading to undesirable signal loss; substantially lower frequencies (longer wavelengths) are generally regarded as undesirable because much of the energy is redirected into the induction and/or quasi-static field components rather than the far-field component that can be sensed using conventional antennas.
  • RFID applications with a transponder and a base unit typically use wavelengths such that r ⁇ and generally rely on magnetic induction to transmit power from the transponder to the base unit. In certain embodiments, these RF signals are employed.
  • certain embodiments of the present invention advantageously operate at wavelengths much larger than the human body ( ⁇ >>1 meter) to communicate information within the patient's body, e.g., as described in U.S. Provisional Application Ser. No. 60,713,680; the disclosure of which is herein incorporated by reference.
  • frequencies on the order of 100 kHz, corresponding to wavelengths of around 3 km (in air) are advantageously used.
  • the quasi-static electric field term in Eqs. (1) and (2) dominates, and thus the propagating signal is predominantly electrical rather than electromagnetic.
  • Such signals readily propagate in a conductive medium such as the human body.
  • the quasi-static (1/r 3 ) component of Eq. (2) is estimated to be on the order of 10 6 times stronger than the far-field (1/r) component.
  • long-wavelength signaling using near-field coupling is efficient.
  • detectable signals can be transmitted using very small antennas.
  • the transmission frequency is within the “LF” band (low frequency, defined as 30-300 kHz) of the RF spectrum, below the frequency range of AM radio (around 500 to 1700 kHz).
  • the range from 160-190 kHz has been designated by the FCC for experimental use, with specified upper limits on external signal strength. In embodiments of the present invention where the signals are largely confined within the patient's body as described below, this experimental band can be used.
  • the invention is not limited to the 160-190 kHz band or to the LF (30-300 kHz band).
  • Lower bands may also be used; for instance, in the VLF band (3-30 kHz, wavelengths of 10-100 km in air), signals can penetrate water to a distance of 10-40 meters. Since the electrical properties of the human body are similar to those of salt water, it is expected that signals in this band would also readily propagate through the body.
  • a signal strong enough to travel to a receiver within the body can be generated using a very small antenna. For instance, 100 kHz signals generated by a dipole antenna just a few millimeters long can be propagated to a receiver antenna placed 1-2 meters away. This quasi-electrostatic transmission is believed to be aided by the fact that the implanted antenna is directly in contact with a conductive medium, for example, the patient's tissues. For purposes of analyzing electrical properties, human tissue can be approximated as an electrolyte solution with electrical properties comparable to those of salt water.
  • the quasi-electrostatic field created by an oscillating dipole antenna induces an oscillating current in the body.
  • the oscillating current creates oscillating potential variations within the body that can be sensed using a suitable receiver.
  • suitable receivers include the leads of a pacemaker, which create a dipole with an axis of about 20 cm or any other implanted wires with length from 10-100 cm.
  • the patient's skin advantageously acts as a conductive barrier, confining the signals within the patient's body. This confines the signals within the body and also makes it difficult for stray external signals to penetrate the body and create noise or interference in the transmitted signals. Confinement of the signals can mitigate, to some extent, the 1/r falloff of the near-field signal, further reducing power requirements.
  • Such effects have been observed in the laboratory, e.g., in a salt water bath, in which the water/air interface acting as a conductive barrier. Similar effects have been observed in communicating with submarines via RF transmission in the ELF (3-30 Hz) and SLF (30-300 Hz) bands.
  • sonar communications although sonar uses acoustic, rather than electrical or electromagnetic, fields to transmit information, the surface of the water acts as a conductive barrier for acoustic energy and mitigates the fall-off of signal intensity with distance.
  • the antenna can be formed by a pair of electrodes a few millimeters or less in length, spaced apart by a few millimeters, with oscillating voltages of opposite phase applied to create an oscillating electric dipole.
  • Such antennas can be disposed almost anywhere within the body.
  • the frequency, transmitter antenna length, and receiver antenna length are selected such that only microwatts of power are required to produce a detectable signal, where conventional RF communication (e.g., at around 405 MHz) would require at least milliwatts. Accordingly, very compact power supplies that produce only small amounts of power can be used; examples are described in Section IV below.
  • the frequency may range from about 0.1 Hz or lower to about 100 mHz or higher, e.g., from about 1 kHz to about 70 mHz, including from about 5 kHz to about 200 kHz.
  • the signal that is emitted by the identifier is an acoustic signal.
  • any convenient acoustic signal generation element may be present in the identifier, e.g., a piezoelectric element, etc.
  • the transmission time of the identifier may vary, where in certain embodiments the transmission time may range from about 0.1 ⁇ sec to about 4 hours or longer, such as from about 1 sec to about 4 hours.
  • the identifier may transmit a signal once or transmit a signal two or more times, such that the signal may be viewed as a redundant signal.
  • the identifier may be one that is programmable following manufacture, in the sense that the signal generated by the identifier may be determined after the identifier is produced, where the identifier may be field programmable, mass programmable, fuse programmable, and even reprogrammable.
  • the identifier may be field programmable, mass programmable, fuse programmable, and even reprogrammable.
  • Such embodiments are of interest where uncoded identifiers are first produced and following incorporation into a composition are then coded to emit an identifying signal for that composition.
  • Any convenient programming technology may be employed.
  • the programming technology employed is RFID technology.
  • RFID smart tag technology of interest that may be employed in the subject identifiers includes, but is not limited to: that described in U.S. Pat. Nos.
  • a manufacturer/vendor may associate a unique ID code with a given identifier, even after the identifier has been incorporated into the composition.
  • each individual or entity involved in the handling of the composition prior to use may introduce information into the identifier, e.g., in the form of programming with respect to the signal emitted by the identifier, e.g., as described in U.S. Pat. No. 7,031,946 the disclosure of which is herein incorporated by reference.
  • the identifier of certain embodiments includes a memory element, where the memory element may vary with respect to its capacity.
  • the memory element has a capacity ranging from about 1 bit to 1 gigabyte or more, such as 1 bit to 1 megabyte, including from about 1 bit to about 128 bit.
  • the particular capacity employed may vary depending on the application, e.g., whether the signal is a generic signal or coded signal, and where the signal may or may not be annotated with some additional information, e.g., name of active agent, etc.
  • Identifier components of embodiments of the invention have: (a) an activation component and (b) a signal generation component, where the signal generation component is activated by the activation component to produce an identifying signal, e.g., as described above.
  • the activation component is a component that activates the signal generation element to emit a signal upon experience of a stimulus, e.g., contact of the composition with a target physiological site of interest, such as the stomach.
  • the activation component may be configured to be activated in a number of different ways. The following sections detail certain different ways in which the identifier may be activated. As can be seen from the following review, the activation component may or may not be integrated with a power source, e.g., a battery.
  • Illustrative activation approaches include, but are not limited to: Battery Completion, e.g., Battery activated by electrolyte addition and Battery activated by cathode or anode addition; Battery connection, e.g., Battery activated by conductor addition; Transistor-mediated Battery Connection, e.g., Battery activated by transistor gate, Geometry Modification, Detection of Geometry Modification by Resonant Structure, Pressure Detection, Resonant Structure Modification; etc.
  • Battery Completion e.g., Battery activated by electrolyte addition and Battery activated by cathode or anode addition
  • Battery connection e.g., Battery activated by conductor addition
  • Transistor-mediated Battery Connection e.g., Battery activated by transistor gate, Geometry Modification, Detection of Geometry Modification by Resonant Structure, Pressure Detection, Resonant Structure Modification; etc.
  • the battery includes, when completed, a cathode, an anode, and an electrolyte.
  • a cathode e.g., pill
  • an anode e.g., anode
  • an electrolyte e.g., an electrolyte
  • a power source is provided which activates the identifier, e.g., in chip configuration.
  • the data signal is then transmitted. This configuration is described in greater detail below, e.g., in terms FIG. 4 .
  • the system is activated by having the triggering event add a cathode or anode component, with the electrolyte being intrinsic in the partial, pre-battery configuration.
  • the battery is completed, producing power and activating the composition, although not necessarily at the identical point of time.
  • the battery is connected to the circuitry when it enters the stomach.
  • the battery becomes connected, and thus activates the identifier, by conductor addition.
  • these two components are awash in physiological fluid, such as in the stomach, they become electronically connected. This triggering event electrically connects the battery to the signaling microchip, thus activating the smart pill.
  • Another design allowing the battery and the chip together to activate the smart pill has the feature of a transistor gate between the battery and the reporting chip. Once the transistor gate is switched on, such as by activation with the stomach, the reporting signal is transmitted.
  • the gate can be activated by applying a small gate current. This is how, for example, transistors are typically activated.
  • the gate current can be generated in any number of ways well know to the ordinary skilled artisan. Any circuitry which detects the presence of the pill in the environment of interest, such as the stomach, generates the gate current and turns the system on.
  • the gate current can be turned on by detecting a conductivity variation.
  • a circuit can be provided that detects a small change in the conductivity of the stomach. While the stomach is conductive, the pill might not be. As a result, when the conductivity variation is detected, the transistor gate is activated, turning the smart pill on and generating a reporting signal.
  • the conductivity can be modulated by a change in the solution concentration.
  • the system detects a different solution concentration in the stomach in contrast to areas outside the stomach.
  • the solution pH is detected, by a modulation of the conductivity, which turns on the gate, and turn on the pill generating a reporting signal.
  • the stomach contains ionic conductive fluids. Those ionic conductive fluids can be employed to modulate the conductivity of the gate and turn on the smart pill, generating a reporting signal. Individual enzymes can be detected in the stomach. For instance, a chem-FET can be employed that looks for the pepsin content in the stomach, turning the pill on, thus reporting the presence of the enzyme.
  • the stomach is typically a steady 37° C. Areas outside the stomach are more typically 20° C. or less. When the pill enters the stomach and becomes heated up, the pill is so designed that this adjusts the conductivity and turn the identifier on, generating a reporting signal.
  • the conductivity of the transistor can be modified by a microscopic property called carrier mobility.
  • a detection approach using this property uses the transistor itself as a detector.
  • the carrier mobility is modulated by temperature, a well-known phenomenon. In this manner, the transistor is used as a temperature sensor by using that transistor to turn on the smart pill, generating a reporting signal.
  • Another approach is to change the charge on the gate of a MOSFET transistor.
  • the gate charge can be modulated by the factors to be detected. This is again a configuration using the transistor to turn on the circuit, generating a reporting signal.
  • the gate charge is modulated by a material to be detected in the solution.
  • a specific ion would preferentially change the gate charge.
  • This system is modulated by a crystal potential.
  • a crystal potential occurs when crystals generate electric fields under certain circumstances.
  • the electric field can change the charge on the gate, turning on the transistor and generating a reporting signal.
  • This change may be modulated by a chemical potential, resulting from an osmotic or ionic process. This causes charge to accumulate on the gate, thereby, turning it on and generating a reporting signal.
  • a change in the electrical potential can also cause a reporting signal using a variety of potentials.
  • a gravitational potential can detect the change in height of the detector. In the case of a patient swallowing the pill, the change in pill height would indicate ingestion.
  • a transistor gate has associated with it a capacitance. That capacitance is then modulated by certain properties peculiar to the target site, e.g., the stomach.
  • the capacitance is changed by being enveloped in the stomach. This effect on the capacitance is then detected.
  • the gate charge is modulated by change in the carrier concentration.
  • the carrier concentration is modulated by temperature.
  • a transistor structure is also provided that has a geometry that changes. Gate capacitance is determined by a change in geometry which occurs in the stomach, detecting a change in capacitance. These changes can take place in a variety of ways, for example, as further described below.
  • the gate consists of a number of layers, one of which is the dielectric.
  • the enzymes of the stomach dissolve the dielectric, changing the gate capacitance, which is then detected.
  • Various physical and chemical conditions within the stomach dissolve that gate dielectric, thereby activating the circuit.
  • a resonant structure on the gate is provided in other variants.
  • a mechanical structure is provided that has a characteristic frequency. This frequency is excited by the triggering event, and measured. Various interactions with the stomach will cause a change in that resonance.
  • Gate capacitance and resonance with modulation source can also be utilized for detection.
  • an excitation is provided to the resonance structure from a modulation source, such as a sound wave.
  • the gate capacitance of that resonance structure can be used to detecting pressure waves.
  • a resonance structure sits out in the stomach and is hooked up to a detection circuit on a transistor. In the stomach, the resonance circuit detects pressure waves.
  • Pressure waves are also detected by resonant Q factor modulation.
  • Q factor modulation can be accomplished in a number of different manners.
  • the resonance structure has two components, a frequency and a Q factor.
  • the Q factor is modulated by detecting some environmental change.
  • the structure has a very different Q factor in air than it does in the fluid of the stomach.
  • the dampening can be detected by the fluid viscosity.
  • the structure can be configured to be eaten away by the acid or some of the enzymes in the stomach, which changes the cue.
  • Degradation by stomach acid or enzymes also changes the resonant frequency. It is simple to detect the frequency shift of such a structure. The frequency is shifted as this structure is changed in the stomach. There are two approaches to modifying the structure. A catabolic process can occur where the structure gets dissolved, which is easily detectable. Also, an anabolic process would occur where an enzyme from the stomach binds to this structure, making it larger. This effect will also modify the resonance structure. The resonance modification is detected either as a frequency change or a Q factor modulation.
  • the activation element is a power source that is turned on upon contact of the power source with a target site, e.g., a physiological target site, such as the stomach, e.g., stomach acid.
  • a target site e.g., a physiological target site, such as the stomach, e.g., stomach acid.
  • the power source is a battery that is turned on to provide power upon contact with the physiological target site, where the battery is coupled to the signal generation component such that when the battery is turned on, the signal generation component emits the identifying signal.
  • the battery that is employed is one that comprises two dissimilar materials which constitute the two electrodes of the battery.
  • these two materials are shielded from the surrounding environment by an additional layer of material.
  • the shielding material e.g., active agent/carrier matrix
  • the electrode materials are exposed and come in contact with the body fluid, such as stomach acid or other types of electrolyte fluid.
  • a potential difference that is, a voltage
  • a voltaic cell, or battery, can be thereby formed.
  • such batteries are configured such that when the two dissimilar materials are exposed to the target site, e.g., the stomach, the digestive tract, etc., during the physical and chemical erosion of the composition in which the signal generation element is present, a voltage is generated.
  • the power source described above is not a “battery” in the common sense of the word, but rather as defined in the discipline of physics.
  • the two dissimilar materials in an electrolyte are at different potentials, similar to the physics model of a ‘potato battery’. As an example, copper and zinc when put into a cell have different potentials. Similarly, gold and magnesium have different potentials. As a result, a potential difference between the two dissimilar materials is generated.
  • cell-activation approaches include, but are not limited to: activation by presence of electrolyte, activation by presence of a cathode material, activation by presence of a conductive material.
  • the signal generation component can be activated through the activation of the gate of a metal oxide semiconductor (MOS) circuit, such as a CMOS switch.
  • MOS metal oxide semiconductor
  • Activation of the gate of the MOS circuit can be based on one or more parameters, which include but are not limited to: gate current, gate charge, and gate capacitance.
  • the gate current for activation purposes, can be a function of the conductivity of surrounding body fluids or tissues. Such conductivity can further be a function of one or more parameters, which include but are not limited to: solution concentration, solution pH value, ionic content of solution, enzymatic content of solution, temperature, and carrier mobility. Carrier mobility can also be a function of temperature.
  • the gate charge can be a function of one or more parameters, which include but are not limited to: solution composition, crystal potential, electrical potential, gravitational potential, gate capacitance, and carrier concentration.
  • the carrier concentration can also be a function of temperature.
  • the gate capacitance can be a function of the capacitive geometry of the gate, which can further be a function of pressure, a resonant input, or the characteristics of a dielectric material coupled to the gate.
  • the characteristics of the dielectric material can vary with one or more parameters, which include but are not limited to: chemical contents of a digestive tract, chemical character of a physiological location, and amount of dissolution of the dielectric material in body fluids.
  • the battery is one that is made up of active electrode materials, electrolyte, and inactive materials, such as current collectors, packaging, etc.
  • the active materials are any pair of materials with different electrochemical potentials. Suitable materials are not restricted to metals, and in certain embodiments the paired materials are chosen from metals and non-metals, e.g., a pair made up of a metal (such as Mg) and a salt (such as CuI).
  • any pairing of substances—metals, salts, or intercalation compounds—with suitably different electrochemical potentials (voltage) and low interfacial resistance are suitable.
  • electrode materials are chosen to provide for a voltage upon contact with the target physiological site, e.g., the stomach, sufficient to drive the signal generation element of the identifier.
  • the voltage provided by the electrode materials upon contact of the metals of the power source with the target physiological site is 0.001 V or higher, including 0.01 V or higher, such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5 volts or higher, and including 1.0 volts or higher, where in certain embodiments, the voltage ranges from about 0.001 to about 10 volts, such as from about 0.01 to about 10 V.
  • Dissolved oxygen can also serve as a cathode. In this case, the dissolved oxygen in the bodily fluids would be reduced to OH— at a suitable catalytic surface such at Pt or gold. Other catalysts are also possible.
  • one or both of the metals may be doped with a non-metal, e.g., to enhance the voltage output of the battery.
  • Non-metals that may be used as doping agents in certain embodiments include, but are not limited to: sulfur, iodine and the like.
  • the electrode materials are copper iodine (CuI) as the anode and magnesium (Mg) as the cathode.
  • CuI copper iodine
  • Mg magnesium
  • Embodiments of the present invention use electrode materials that are not harmful to the human body.
  • the batteries have a small form factor. Batteries may be 10 mm 3 or smaller, such as 1.0 mm 3 or smaller, including 0.1 mm 3 or smaller, including 0.02 mm 3 or smaller.
  • the battery element is dimensioned to have a width ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mm to about 1 mm, such as from about 0.05 mm to about 0.3 mm, including from about 0.1 mm to about 0.2 mm.
  • the battery has a split or segmented configuration.
  • the battery is one which is free of packaging.
  • the electrodes are exposed and not protected by any protecting or sealing structure.
  • the battery per se does not itself include an protective packaging such that the electrodes are free to contact the electrolyte at the target physiological location.
  • the battery power source may be viewed as a power source that exploits reverse electrolysis in an ionic solution such as gastric fluid, blood, or other bodily fluids and some tissues.
  • FIG. 4 illustrates an identifier 30 having a signal generation element 40 powered by reverse electrolysis.
  • Signal generation element 40 is electrically connected to metal electrodes 32 and 33 , which are made of two different materials and are electrically insulated from each other.
  • metal electrodes 32 and 33 are immersed in an ionic solution 39 , a potential difference develops between them; for instance, electrode 33 rises to a higher potential V+ while electrode 32 falls to a lower potential V ⁇ . This potential difference can be used to power circuitry 40 .
  • Electrodes 32 and 33 can be implemented in various ways; for instance, areas on opposing surfaces of an integrated circuit chip can be coated with two different metals, and the entire chip can be placed in the ionic solution. Alternatively, electrodes 32 and 33 may extend away from element 40 as shown. Other arrangements may also be used.
  • electrodes 32 and 33 can be made of any two materials appropriate to the environment in which the identifier 30 will be operating.
  • electrodes 32 and 33 may be made of a noble metal (e.g., gold, silver, platinum, palladium or the like) so that they do not corrode prematurely.
  • the electrodes can be fabricated of aluminum or any other conductive material whose survival time in the applicable ionic solution is long enough to allow identifier 30 to perform its intended function.
  • the battery may be fabricated in a number of different ways.
  • fabrication protocols which may be categorized as “planar” processing protocols are employed, as developed in greater detail below.
  • acoustic energy e.g., ultrasound
  • a remote device may also be employed in addition to or instead of those described above.
  • chemical or radioisotope batteries with a suitable form factor may be used to power some remote devices.
  • fuel cells that use blood as an energy source can be miniaturized and used to provide electrical energy for a low-power microchip.
  • Piezoelectric crystals that convert mechanical energy (e.g., compression) to electrical energy can be employed for remote devices disposed where suitable mechanical forces can be brought to bear, such as in or around the heart, stomach, joints, or other moving parts of the body.
  • a power source modeled on the cellular energy factory with power being extracted from ATP in the blood so that blood, in effect, “nourishes” the identifier, is employed.
  • acoustic energy e.g., ultrasound
  • the activation element is not an on board power source, but an element that is powered from a separate power source and provides an activation signal to the signal generation component upon contact of the composition with the target site.
  • the activation element may be coupled to a power receiver which is configured to receive broadcast power and transduce the broadcast power into a form suitable for driving the signal generation element.
  • the power receiver may be a coil.
  • the activator component may be powered by a distinct power source, e.g., a sealed battery, a power element that converts mechanical energy of the pill into electrical power, e.g., a piezoelectric power element, etc.
  • the activator may or may not itself be the power source, and in those embodiments where it is not the power source, the identifier may include a distinct power source, such as receiver or power generator.
  • the signal generation component of the identifier element is a structure that, upon activation by the activation component, emits a detectable signal, e.g., that can be received by a receiver, e.g., as described in greater detail below.
  • the signal generation component of certain embodiments can be any convenient device that is capable of producing a detectable signal and/or modulating transduced broadcast power, upon activation by the activation component.
  • Detectable signals of interest include, but are not limited to: conductive signals, acoustic signals, etc.
  • the signals emitted by the signal generator may be generic or unique signals, where representative types of signals of interest include, but are not limited to: frequency shift coded signals; amplitude modulation signals; frequency modulation signals; etc.
  • the signal generation element includes circuitry, as developed in more detail below, which produces or generates the signal.
  • the type of circuitry chosen may depend, at least in part, on the driving power that is supplied by the power source of the identifier. For example, where the driving power is 1.2 volts or above, standard CMOS circuitry may be employed. In other embodiments where the driving power ranges from about 0.7 to about 1.2 V, sub-threshold circuit designs may be employed. For driving powers of about 0.7 V or less, zero-threshold transistor designs may be employed.
  • the signal generation component includes a voltage-controlled oscillator (VCO) that can generate a digital clock signal in response to activation by the activation component.
  • VCO voltage-controlled oscillator
  • the VCO can be controlled by a digital circuit, which is assigned an address and which can control the VCO with a control voltage.
  • This digital control circuit can be embedded onto a chip that includes the activation component and oscillator. Using amplitude modulation or phase shift keying to encode the address, an identifying signal is transmitted.
  • the signal generation component may include a distinct transmitter component that serves to transmit the generated signal to a remote receiver, which may be internal or external to the patient, as reviewed in greater detail below.
  • the transmitter component when present, may take a number of different configurations, e.g., depending on the type of signal that is generated and is to be emitted.
  • the transmitter component is made up of one or more electrodes.
  • the transmitter component is made up of one or more wires, e.g., in the form of antenna(e).
  • the transmitter component is made up of one or more coils.
  • the signal transmitter may include a variety of different transmitters, e.g., electrodes, antennas (e.g., in the form of wires) coils, etc.
  • the signal is transmitted either by one or two electrodes or by one or two wires.
  • a two-electrode transmitter is a dipole; a one electrode transmitter forms a monopole. In certain embodiments, the transmitter only requires one diode drop of power.
  • the transmitter unit uses an electric dipole or electric monopole antenna to transmit signals.
  • FIG. 6A illustrates a dipole antenna.
  • Oscillator 504 provides driving signals ( ⁇ and an inverted signal denoted herein as / ⁇ ) to an electrode driver 506 .
  • FIG. 6C is a circuit diagram showing details of a dipole electrode driver 600 implemented using conventional CMOS driver circuits. Electrode 602 is driven to a potential E 0 by transistors 604 , 606 in response to driving signal ⁇ while electrode 608 is driven to a potential E 1 by transistors 610 , 612 in response to inverted driving signal / ⁇ . Since driving signals ⁇ and / ⁇ oscillate with opposite phase, potentials E 0 and E 1 also oscillate with opposite phase. It will be appreciated that driver 600 and all other electronic circuits described herein can be implemented using sub-micron CMOS processing technologies known in the art; thus, the size of the circuitry is not a limiting factor on the size of a remote device.
  • a monopole antenna can be substituted for the dipole antenna of FIG. 6A .
  • FIG. 6D illustrates a driver circuit for a monopole antenna that can be implemented in conventional CMOS integrated circuits. This antenna driver is generally similar to one half of the driver circuit of FIG. 6C , with driver transistors 702 , 704 driving a single electrode 706 to a potential E m in response to driving signal ⁇ .
  • the driver circuit is powered by a potential difference ( ⁇ V) between terminals V+ and V ⁇ .
  • This potential difference which can be constant or variable, as desired.
  • FIG. 6A is a block diagram of a transmitter signal generation element 500 for an identifier according to an embodiment of the present invention.
  • generation element 500 receives a signal M from the activation component which activates the signal generation element to produce and emit a signal.
  • Signal generation element 500 includes control logic 502 , an oscillator 504 , an electrode driver 506 , and an antenna 508 (in this instance, a pair of electrodes operated as an electric dipole antenna).
  • oscillator 504 generates an oscillating signal (waveform) in response to signals from control logic 502 .
  • the signals from control logic 502 can start or stop the oscillator and in some embodiments can also shape one or more aspects of the oscillatory signal such as amplitude, frequency, and/or phase.
  • Oscillator 504 provides the waveform to electrode driver 506 , which drives current or voltage on antenna 508 to transmit a signal into the conductive medium of body tissues or fluids.
  • the signal may or may not be modulated.
  • the frequency of the signal may be held constant.
  • the signal may be modulated in some manner, e.g., via carrier based modulate schemes, ultra-wide band (or time domain based) modulation schemes, etc.
  • oscillator 504 operates at a constant frequency.
  • the receipt of a constant-frequency signal in and of itself can provide useful information, e.g., that a remote device is present and operational.
  • oscillator 504 modulates its signal to encode additional information.
  • Information can be encoded in various ways, generally by modulating (varying) some property of the transmitted signal, such as frequency, amplitude, phase, or any combination thereof. Modulation techniques known in the art may be employed.
  • information can be transmitted using analog or digital techniques.
  • Analog techniques refers generally to instances in which the modulated property is varied in different degrees, with the degree of variation being correlated to a value representing the information to be transmitted. For instance, suppose that element 500 is transmitting a signal. Oscillator 504 can be designed to operate over some range of frequencies.
  • Digital techniques refers generally to instances in which the information to be transmitted is represented as a sequence of binary digits (bits), and the signal is modulated based on the bit stream. For instance, suppose again that transmitter 500 is transmitting a signal using digital techniques. Oscillator 504 can be designed to operate at least two different frequencies, with one frequency corresponding to bit value 0 and another frequency corresponding to bit value 1. In embodiments of the present invention, either analog techniques, digital techniques, or a combination thereof can be used to transmit information. In addition, various types of modulation may be implemented.
  • Oscillator 504 can be a voltage-controlled oscillator (VCO), an oscillator circuit in which the oscillation frequency depends on an applied voltage.
  • Control logic 502 supplies an appropriate voltage (e.g., reflecting the value of the measurement data, M), and the frequency of the signal indicates the value of the data.
  • amplitude modulation is used; for instance, the amplitude of the driving signals ⁇ and / ⁇ can be varied, or the positive and negative rails of the driver circuit (e.g., V+ and V ⁇ ) can be varied to control the amplitude.
  • phase modulation is used.
  • Oscillator 504 can include a switch circuit that either directly connects or cross-connects the driving signals ⁇ and / ⁇ to the inputs of a driver circuit. Combinations of frequency modulation, amplitude modulation, and/or phase modulation may also be used as desired.
  • the transmitter may transmit a “packet” that includes a unique identifier for the identifier, which in turn is for the composition with which the identifier is associated.
  • the unique identifier may also provide information from the remote device (e.g., the identity of the active agent (i.e., annotation information)).
  • Other techniques for distinguishing different signals may also be used, including: operating different transmitters in different frequency bands, allowing each transmitter to be identified by its frequency and/or configuring different transmitters to transmit at different (and known) times, allowing the transmitter to be identified by when it transmits.
  • the identifier may include a number of different additional components. Some components of interest include, but are not limited, those reviewed below.
  • circuits for enhancing or boosting voltage output of the power source e.g., battery
  • Such voltage enhancing elements may enhance the voltage output by at about 2-fold or more, such as by about 5-fold or more.
  • the activation component includes a power storage element.
  • a duty cycle configuration may be employed, e.g., where slow energy production from a battery is stored in a power storage element, e.g., in a capacitor, which then provides a burst of power that is deployed to the signal generation component.
  • the activation component includes a timing element which modulates, e.g., delays, delivery of power to the signal generation element, e.g., so signals from different compositions, e.g., pills, that are administered at substantially the same time are produced at different times and are therefore distinguishable.
  • the compositions are characterized by having one or more of the following features.
  • the compositions include an identifier which employs a conductive near-field mode of communication in which the body itself is employed as a conductive medium.
  • the compositions include circuitry that, when freed from the composition upon disruption of the composition (e.g., as described above) the circuitry comes into direct contact with the body and does not remain encapsulated or protected in some manner.
  • the signal is not a magnetic signal or high frequency (RF) signal.
  • the systems are ones that include a receiver which is stably associated with the body, e.g., implanted or topically applied to an external location, such that the systems are distinguished from those in which an external device that is not stably associated with the body is employed to collect data.
  • the compositions do not include an imaging system, e.g., camera or other visualization or imaging element, or components thereof, e.g., CCD element, illumination element, etc.
  • the compositions do not include a sensing element, e.g., for sensing a physiological parameter, beyond the activator which detects contact with the targeted physiological site.
  • the compositions do not include a propulsion element.
  • the compositions do not include a sampling element, such as a fluid retrieval element.
  • the compositions do not include an actuatable active agent delivery element, such as an element that retains an active agent with the composition until a signal is received that causes the delivery element to release the active agent.
  • the identifier element includes a semiconductor support component.
  • Any of a variety of different protocols may be employed in manufacturing the identifier structures and components thereof.
  • molding, deposition and material removal e.g., planar processing techniques, such as Micro-Electro-Mechanical Systems (MEMS) fabrication techniques, including surface micromachining and bulk micromachining techniques, may be employed.
  • Deposition techniques that may be employed in certain embodiments of fabricating the structures include, but are not limited to: electroplating, cathodic arc deposition, plasma spray, sputtering, e-beam evaporation, physical vapor deposition, chemical vapor deposition, plasma enhanced chemical vapor deposition, etc.
  • Material removal techniques included, but are not limited to: reactive ion etching, anisotropic chemical etching, isotropic chemical etching, planarization, e.g., via chemical mechanical polishing, laser ablation, electronic discharge machining (EDM), etc.
  • lithographic protocols are also of interest.
  • planar processing protocols in which structures are built up and/or removed from a surface or surfaces of an initially planar substrate using a variety of different material removal and deposition protocols applied to the substrate in a sequential manner.
  • FIGS. 11A to 13B are diagrams showing a method for fabricating an identifier according to an embodiment of the invention.
  • FIG. 11A depicts a cross-section of a semiconductor wafer, 121 , processed by silicon foundry such as IBM or Taiwan Semiconductor Manufacturing Company.
  • the top surface of the wafer, 122 contains numerous electrical contact pads, 123 , and an insulating dielectric layer, 124 .
  • the contact pads can be Al but could also be Cu, Ti, or similar metal; the dielectric may be a combination of SiO 2 and Si 3 N4, but could be other insulators.
  • wafer 121 has been thinned from the back side via grinding or chemical/mechanical polishing to reduce thickness to a desired thickness.
  • a final thickness might be about 300 ⁇ m but it can range from about 10 to about 1000 ⁇ m such as from about 50-about 500 ⁇ m.
  • FIG. 12A shows the second process step, in which a layer of corrosion resistant metal, 125 , has been added to the front side of the wafer to cover the electrical contacts, 123 .
  • the typical metal is platinum but one could also use other corrosion resistant metals such as Au, Ti, Ir, or another platinum group metal.
  • the corrosion resistant metal may be deposited by physical vapor deposition, for example, and may be from about 0.05 to about 100 ⁇ m thick, such as from about 0.5 to about 5 ⁇ m thick.
  • the metal 125 is formed into a desired pattern via photolithography and etching which are standard semiconductor processing techniques.
  • FIG. 12B shows the deposition of the cathode material 126 .
  • Cathode materials of interest include, but are not limited to: Cu or CuI, e.g., as described above. They are deposited by physical vapor deposition, electrodeposition, or plasma deposition, among other protocols.
  • the cathode may be from about 0.05 to about 500 ⁇ m thick, such as from about 5 to about 100 ⁇ m thick.
  • the cathode shape is controlled by shadow mask deposition, or photolithography and etching.
  • Each chip may contain two or more regions, 127 and 127 A, of cathode material as desired.
  • anode material 128 A is deposited as shown in FIG. 12C .
  • Anode materials of interest include, but are not limited: Mg, Zn, or other electronegative metals.
  • Adhesion layer 128 B may be necessary to help anode material to adhere to the silicon.
  • Typical adhesion layers for the anode are Ti, TiW, Cr or similar material.
  • Anode material and the adhesion layer may deposited by physical vapor deposition, electrodeposition or plasma deposition.
  • the cathode may be from about 0.05 to about 500 ⁇ m thick, such as from about 5 to about 100 ⁇ m thick.
  • FIG. 13A shows the optional protection layer 129 A which is deposited and patterned.
  • an insulating layer may be deposited and patterned in such a way that it has openings, 129 B, of limited size. This way the solution reaches the anode or cathode material at a controlled rate.
  • FIG. 13A illustrates the protection layer on the front (cathode) side of the wafer but it could be also deposited on backside (anode side) of wafer.
  • Typical materials for the protection layer are polyimide, or other photo definable polymer any of which may be spin coated or spray coated.
  • a dielectric like SiO 2 , SiC, or SiN may be deposited by physical vapor deposition or chemical vapor deposition.
  • the wafer is then singulated into individual die 115 , 116 , 117 as shown in FIG. 13B .
  • Dicing can be accomplished by dicing with a diamond blade saw or by reactive ion etching. These are standard silicon semiconductor processing techniques. As reviewed above, the chip dimensions may vary.
  • the chip (i.e., identifier) element is dimensioned to have a width ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mm to about 1 mm, such as from about 0.05 mm to about 0.3 mm, including from about 0.1 mm to about 0.2 mm.
  • FIG. 1 provides a diagrammatic, exemplary representation of a pill/capsule embodiment of the present invention, in which the composition is configured as an orally ingestible pharmaceutical formulation in the form of a pill or capsule.
  • the stomach 12 of the patient 10 who ingests the composition 14 is shown.
  • This “smart pill” is shown as it has traveled from the mouth 16 to inside 18 the patient's stomach.
  • the pill/capsule undergoes a dissolving process with both the mechanical action of the stomach and the various chemical materials in the stomach fluids, such as hydrochloric acid and other digestive agents.
  • FIGS. 2A and 2B provide a more detailed view of the pill composition shown in FIG. 1 .
  • FIG. 2A illustrates an identifier 20 disposed inside a pill 14 .
  • Identifier 20 is present as an integrated circuit (IC).
  • the backside (bottom) of circuit 20 is at least partially coated with a first metal 21 , and a portion of the front (top) of circuit 20 is coated with a different metal 22 , allowing circuit 20 to be powered by reverse electrolysis, e.g., as described above connection with FIG. 4 .
  • Also on the top surface are two transmitter electrodes 23 , 24 .
  • the integrated circuit 20 is surrounded by at least one external layer that may include pharmacologically active and/or inert materials in any combination.
  • the external layer dissolves in the stomach through a combination of the mechanical action of the stomach and the action of various chemical constituents (e.g., hydrochloric acid) in stomach fluids.
  • the integrated circuit 20 is attached to, rather than encapsulated in, the pill 14 .
  • circuit 20 might be placed at one end of the pill as the pill is being prepared, in a soluble coating on the surface of the pill, or the like.
  • integrated circuit 20 begins to operate sooner after the pill enters the stomach rather than after the pill dissolves.
  • circuit 20 transmits a signal identifying pill 14 .
  • the identifier may indicate the type (active ingredient(s), brand, etc.) and/or dosage of pill 14 and may also provide a lot number, serial number, or similar identifying information that would allow particular pills to be traced, e.g., as reviewed above.
  • FIG. 2B is a block diagram of one embodiment of electronic circuit 20 .
  • circuit 20 is a transmitter unit that sequentially transmits a predetermined series of address (identifier) bits using frequency shift keying, with a first oscillation frequency corresponding to bit value 0 and a second oscillation frequency corresponding to bit value 1.
  • metal layers 21 and 22 supply power to circuit 20 .
  • the power (not explicitly shown in FIG. 2B ) is supplied to an oscillator 25 , a counter 26 , a readout circuit 27 , and an electrode driver 28 that drives transmitter electrodes 29 A, 29 B to transmit the signal.
  • Oscillator 25 may be of generally conventional design (e.g., a ring oscillator) and is advantageously configured to operate in the quasi-electrostatic frequency region as described above.
  • Oscillator 25 generates a driving signal ⁇ that oscillates between high and low voltage levels and an inverted driving signal / ⁇ that is opposite in phase to driving signal ⁇ .
  • oscillator 25 is a voltage-controlled oscillator (VCO) with an oscillation frequency that depends on a control voltage provided on a signal path 25 A.
  • Counter 26 counts the oscillations of driving signals ⁇ and / ⁇ and provides the current count to readout circuit 27 .
  • VCO voltage-controlled oscillator
  • counter 26 is an eight-bit counter of generally conventional design; other types of counters (including counters with different widths) may also be used.
  • Readout circuit 27 is configured with a set of address (identifier) bits 27 A that are advantageously fixed, e.g., at the time circuit 20 is fabricated. As noted above, the bits can be unique to a particular instance of pill 14 or common to a lot of pills fabricated under the same conditions or common to all pills containing a particular pharmacological agent.
  • Address bits 14 can be stored in nonvolatile storage circuits of generally conventional design, and any number of address bits (e.g., 8, 16, 32, 48, etc.) may be provided.
  • Readout circuit 27 generates an oscillator control signal (e.g., a voltage) on line 25 A that controls the frequency of VCO 25 .
  • readout circuit 27 is configured to select a current address bit, e.g., based on the current count provided by counter 26 , and to generate a control signal on signal line 25 A that selects a frequency corresponding to the value of that bit. After some number of cycles (as determined by counter 26 ), readout circuit 27 selects the next address bit and generates the corresponding control voltage on signal line 25 A.
  • Various frequencies may be used to represent the address bit values “1” and “0.” In one embodiment, frequencies of 100 kHz and 200 kHz may be used to represent values “0” and “1,” respectively.
  • VCO 25 generates complementary signals ⁇ , / ⁇ that oscillate at a frequency determined by the control signal on signal line 25 A.
  • the signals ⁇ , / ⁇ are used to control an electrode driver 28 , which may be implemented, e.g., as shown in FIG. 6D .
  • the near-field component is coupled directly into the conductive medium of the patient's body and can be detected by a suitably configured data collector, e.g., as described below.
  • the collector is configured to log the received address (identifier) and the time of receipt.
  • the data collector can also be configured to retransmit this information to an external device, either in real time or while the patient is in a medical facility.
  • the transmitter described herein is illustrative and that variations and modifications are possible. For instance, other encoding schemes could be used to transmit the data; in one such embodiment, phase shift keying rather than frequency keying is used.
  • multiple address bits can be encoded into a single symbol that is transmitted using various keying schemes known in the art.
  • FIG. 3A provides a detailed depiction of an embodiment of a signal generation element 30 which labels the pharmaceutical material and is encapsulated in the center of the composition.
  • Signal generation element 30 is in the form of IC constructed from a silicon chip where various functional elements, e.g., in the form of one or more layers of circuits, are disposed on a silicon substrate 31 .
  • the chip can be fabricated using standard integrated circuit techniques. An example of such a fabrication approach is a 0.5 ⁇ CMOS process made available by AMI Semiconductor in Idaho, USA. Shown on the backside of the substrate, the bottom of the chip 31 is metal 1 32 which functions as one battery electrode and on the topside of the chip is metal 2 33 which functions as the other battery electrode. Also on the top side of the chip 31 are electrode 1 34 and electrode 2 35 , which constitute a pair of signal-transmission electrodes.
  • electrode 1 34 and electrode 2 35 are fabricated from a material that does not readily corrode in the stomach environment, e.g., they are fabricated from noble metals.
  • the electrodes can be fabricated of a standard aluminum, such as that available from AMI Semiconductor. The criteria for electrode material selection will be readily ascertainable by the ordinary skilled artisan. That is, if the survival time of the electrode is long enough for detection, it is suitable for use. Standard aluminum metals or other lower cost metals if used for electrodes 1 and 2 ( 34 and 35 ) in appropriate applications allow a lower cost for the device. In some cases dissolution of the electrodes, and thus extinction of the reporting signal, can provide a secondary indication of the full dissolution of the pill and incorporated devices.
  • Metal 1 and metal 2 ( 32 and 33 ), in distinction to material selection for the electrode component of the inventive device, are two different metals. Metal 1 and metal 2 are selected so that the potential applied to the silicon is a positive voltage on the top surface and a negative voltage on the bottom surface. In this way the substrate is essentially at the same potential as the cathode, which can be the ground reference for the circuits, and the top surface, with a SiO 2 insulation layer, is coupled to a positive voltage, referenced to that ground on the bottom side.
  • FIG. 3B provides a view of an alternative signal generation element according to an embodiment of the invention.
  • the signal generation element 30 depicted in FIG. 3B includes two antennae 36 and 37 attached to silicon chip 31 .
  • metals 1 and 2 32 and 33 ).
  • the assembly 30 includes circuitry on a silicon chip 31 with either two or four metal structures ( 32 , 33 , 36 and 37 ) attached to it.
  • the two metal structures serve as battery metals, that is metal 1 and metal 2 ( 32 and 33 ).
  • These metal structures can be provided in a variety of forms. For instance, in one embodiment, metal 1 and metal 2 are very thick plated elements on the surface of the chip, front and back (e.g., as shown in FIG.
  • metal 1 and metal 2 are relatively long wires that are simply bonded to the chip at some point, e.g., as shown in FIG. 3B .
  • Metal 1 and metal 2 in some cases are insulated. In this case, the erosion occurs at the tip and then propagates towards the chip 31 . The erosion as it dissolves in the solution starts at the end of the wire and gradually work its way toward the chip 31 . This configuration improves battery life.
  • a metal is plated up on the front and back of the chip, and then the surface disappears.
  • the two wires can also be employed as antennae. In one configuration, a perpendicular pair of antennae ( 36 and 37 ) is provided.
  • metal structures which are typically of the same material.
  • This material can be selected from a variety of metals, such as platinum or gold.
  • These metal structures are attached to the chip and extend some dimension away form the chip. Typically these structures are on the order of a millimeter to a centimeter combined length.
  • a significant portion of the metal structures are insulated so that the dipole created is of maximum dimension.
  • just the battery metals perform that dipole function, e.g., as described below in connection with FIG. 3C , or a separate antenna is provided.
  • the signal generation element does not include antennae and instead uses battery components as antennae, such as shown in FIG. 3C .
  • signal generation element 30 includes silicon support layer 31 positioned between metal 1 layer 32 and metal 2 layer 33 .
  • circuitry layer 38 Also shown is circuitry layer 38 .
  • a switch on the chip e.g., in the circuitry layer
  • a current is produced between the two metals of the battery, which is then detected.
  • a membrane larger then chip which defines a path for the current to travel is provided.
  • FIGS. 3D and 3E Yet another embodiment of a battery which is activated upon contact with a physiological fluid is shown in FIGS. 3D and 3E .
  • the battery comprises top and bottom portions each supporting an electrode, where the top and bottom portions can be brought together to produce a structure comprising a volume bounded by opposing first and second electrodes, where the volume may be filled with an electrolyte, e.g., physiological fluid, when active.
  • FIG. 3D provides a representation of a bottom portion 31 A of the battery in which material 1 32 A is deposited into a recessed chamber 33 A on top of a substrate (e.g., silicon chip) 34 A.
  • Recessed chamber 33 A has one or more ends open to allow electrolyte to enter.
  • Material 2 35 A is deposited on a separate substrate 36 A to produce a second portion 37 A, which is then bonded, e.g. by bonds 38 A and 38 B, to the chip in a “flip chip” type process. All processing can be done at the wafer scale. Where desired, the openings of the recessed chamber are filled with a degradable material, e.g., with a polymer, to control how quickly the battery is activated.
  • Substrates 34 A and 36 A for materials 34 A and 35 A can be silicon, metal, or polymer/plastic.
  • the structure shown in FIGS. 3D and 3E is a battery where the first electrode is deposited into a recessed chamber on the top of the chip.
  • the recessed space has one or two open ends to allow electrolyte flow.
  • the second electrode is deposited on a separate substrate (e.g. a silicon wafer, a metal film or a polymer film), then bonded on top of the wafer with the chips on it in a “flip-chip” type process.
  • the processing is done at a wafer scale and the cells diced as usual.
  • the advantages of this configuration include: protection of the electrode surfaces from being blocked by components present in the stomach or the stomach lining itself; prevention of contact between any species generated on the battery (e.g., Cu) and the stomach lining that could have toxicity risks; 3) provision of uniform consumption of electrode materials across the electrode surface and more uniform current distribution between the electrodes.
  • FIG. 4 provides a diagrammatic representation of the events which occur when the pill is ingested and dissolved to the point that some of the pill has been chemically and/or physically eroded away.
  • Metal 1 and metal 2 ( 32 and 33 ) are now in an ionic solution 39 . This creates a low voltage (V ⁇ ) and a high voltage (V+) as applied to an electronic circuit 40 .
  • the two outputs of that electronic circuit 40 are E0 41 and E1 42 , which are the signal-transmission electrodes on the top surface.
  • the output is E0 41 .
  • FIG. 5 shows a similar arrangement as in FIG. 4 .
  • a coil is provided.
  • Metal 1 and metal 2 ( 32 and 33 ) are applied to the electronic circuit 40 of signal generation element 30 .
  • the outputs of the electronic circuit 40 are coupled to a coil 43 .
  • This configuration provides that a battery is created by metal 1 and metal 2 ( 32 and 33 ) when exposed to ionic solution.
  • This battery drives the circuit 40 , which creates an oscillating frequency.
  • This oscillating current goes through the coil and generates a RF magnetic signal.
  • the RF magnetic signal can be transmitted through body tissues with less attenuation.
  • the RF magnetic signal is then picked up by an external or internal receiver device that has a magnetic-signal detection mechanism. If a broadcast is provided at a high enough frequency, a pager-like device that is worn by the patient will detect whenever a pill is ingested.
  • FIG. 6B shows the detail of one implementation of an electronic circuit that can be employed in a signal generation element.
  • metal 1 and metal 2 32 and 33 .
  • These metals when in contract with an electrolyte, form a battery and provide power to an oscillator 61 , in this case shown as a schematic.
  • the metal 1 32 provides a low voltage, (ground) to the oscillator 61 .
  • Metal 2 33 provides a high voltage (V high ) to the oscillator 61 .
  • V high voltage
  • the oscillator 61 becomes operative, it generates a clock signal 62 and an inverted clock signal 63 , which are opposites of each other.
  • the 8-bit output of counter 64 is coupled to the input of an address multiplexer (mux) 65 .
  • mux 65 contains an address interpreter, which can be hard-wired in the circuit, and generates a control voltage to control the oscillator 61 .
  • Mux 65 uses the output of counter 64 to reproduce the address in a serial bit stream, which is further fed to the signal-transmission driving circuit.
  • Mux 65 can also be used to control the duty-cycle of the signal transmission.
  • mux 65 turns on signal transmission only one sixteenth of the time, using the clock counts generated by counter 64 . Such a low duty cycle conserves power and also allows other devices to transmit without jamming their signals.
  • the address of a given chip can be 8 bits, 16 bits or 32 bits. Typically, more than 8 bits will be used in a product because there are so many different types of pharmaceuticals. Each pharmaceutical will have its own specific address.
  • each pharmaceutical batch can be provided with a batch specific address. This allows identification of where the pill was made, when the pill was made, and in what batch it was made. In some cases, each pill will have a unique identifier. This would be particularly useful when drugs are more likely to be subsequently stolen or used illicitly, and thus should be tracked, or where questions of contamination may arise.
  • mux 65 produces a control voltage, which encodes the address serially and is used to vary the output frequency of oscillator 61 .
  • a control voltage which encodes the address serially and is used to vary the output frequency of oscillator 61 .
  • the control voltage is low, that is, when the serial address bit is at a 0, a 1 megahertz signal is generated by the oscillator.
  • the control voltage is high, that is, when the address bit is a 1, a 2 megahertz signal is generated the oscillator. Alternately, this can be 10 megahertz and 20 megahertz, or a phase shift keying approach where the device is limited to modulating the phase.
  • the purpose of mux 65 is to control the frequency of the oscillator or an AC alternative embodiment of the amplified signal of oscillation.
  • the outputs of mux 65 are coupled to electrode drive 66 which can drive the electrodes to impose a differential potential to the solution, drive an oscillating current through a coil to generate a magnetic signal, or drive a single electrode to push or pull charge to or from the solution.
  • the device broadcasts the sequence of 0's and 1's which constitute the address stored in mux 65 . That address would be broadcast repeatedly, and would continue broadcasting until metal 1 or metal 2 ( 32 and 33 ) is consumed and dissolved in the solution, when the battery no longer operates.
  • FIG. 7 is an alternate embodiment of the present invention.
  • This implementation of the circuit 70 shows the oscillator 71 and a counter 72 .
  • the mux 73 takes 5 bits from counter 72 as its input.
  • On the upper right corner of FIG. 7 is an exemplary circuit diagram for the signal-transmission electrode driver.
  • Two CMOS invertors respectively take the clock and inverted clock signals as their inputs, and drives electrodes e0 and e1.
  • FIG. 8 provides one implementation of an oscillator 80 .
  • V control 81 basically controls the amount of voltage driving the oscillator 80 .
  • V control is low, a 20,000 ohm resistor 82 separates V, 83 , which is the low power-supply voltage, and the oscillator control line, V osc — control 84 .
  • V control is high, the V osc — control goes to V low , putting the maximum voltage across the oscillator circuitry and resulting in a higher frequency coming out of the clock signal and the inverted clock signal ( 85 and 86 ).
  • FIG. 9 shows a simple trickle or asynchronous counter which has in this case four flip flops with some simple inverters that simply count all the way up and then start over again back to zero, and start counting all the way up again.
  • a multiplexer can take A0 and A1, A2, A3, as its address inputs and can compare these inputs with a stored address, and then have the stored address output as the oscillator control signal.
  • the signal generation element may include a single electrode, and therefore have a monopole configuration.
  • a three terminal, monopole signal generation element 100 is provided.
  • the signal generation element 100 of the pill has one electrode 101 which is capacitively coupled to chip 107 .
  • Two metal electrodes 103 and 102 constitute the electrodes for the battery, which provides power for the signal generation element 100 .
  • Electrodes 102 and 103 are coupled to the chip 107 through two resistors 104 and 105 , and an optional storage capacitor 106 .
  • electrode 102 is the ground and electrode 103 provides V high for the signal generation element
  • Electrode 101 is the output of the mono pole signal generation element.
  • electrode 101 will push current into and out of body's fluid at a high frequency.
  • a receiver will detect the pushing and pulling of that charge out of the body's fluids. Note that the biggest difference between this configuration and the configuration described previously is that this configuration provides a mono pole.
  • chip 107 's output changes, capacitor 108 forces the potential on electrode 101 to change instantly, which result a corresponding change in the potential of the body.
  • a receiver that is in contact of the body can thereby detect a large transient voltage change.
  • This inventive design produces an alternating current into and out of the body which is detected by a receiver (not shown).
  • the output coupling capacitors may be optional. However, the presence of these capacitors prevents any DC currents and forces an AC signal.
  • FIG. 14 shows the multiplexer and the addressing system 73 of the circuitry of the signal generation element of FIG. 7 .
  • Each input port of muxes 141 and 142 is coupled to either the high voltage V high or the low voltage V low .
  • This configuration of the present invention will allow for a 32 bit number, which is hard-wired to the 32 inputs of the two muxes, to be converted to a multiplexed serial output 144 .
  • FIG. 15 shows a detail of the 4 bit mux 141 of the system shown in FIG. 14 .
  • the 4 bit mux is constructed from 4 levels of 1 bit muxes.
  • FIG. 16 shows the 1 bit mux in detail that makes up the 4 bit mux 141 .
  • FIG. 17 is an additional mono pole embodiment 170 of a signal generation element.
  • a current source 171 is placed in series with the power supply created by M1 172 and M2 173 . This creates a DC current between M1 172 and M2 173 . This DC current does not compete with the AC signal generated by the electrode 174 . This DC current will then go to one or another capacitor ( 175 and 176 ) and would either charge up the electrode or charge up another capacitor.
  • the concept behind this embodiment is to have a DC current created between M1 and M2 and an AC signal generated at the single electrode.
  • Coupling capacitor 176 is optional.
  • FIG. 18A is an exemplary schematic diagram of a signal-transmission driver circuit.
  • This circuit is based on an 8-pin 555 timer chip.
  • the pin designations of the 555 timer chip are as follows: pin 1 is the ground; pin 2 is the trigger, pin 3 is the output, pin 4 is reset, pin 5 is the control voltage, pin 6 is the threshold, pin 7 is discharge, and pin 8 is the power supply to the chip V dd .
  • the output pin and the ground pin are capacitively coupled to two transmission electrodes, respectively. During operation, this circuit transmits a signal at a fixed frequency.
  • FIG. 18 B 1 to 18 B 2 is an exemplary schematic diagram of a receiver circuit. Shown on the upper left portion of the diagram is a front-end amplification stage, which receives the signal through a pair of electrodes and performs differential amplification to the signal using an instrumentation amplifier.
  • a cascaded four-stage filter In one embodiment, the first two stages are high-pass filters with a cut-off frequency higher than 1 KHz, such as a cut-off frequency at approximately 10 KHz.
  • the high-pass filter removes the low-frequency noises and interferences, such as the 60 Hz power-line noise.
  • the last two stages are low-pass filters with a cut-off frequency lower than 500 KHz, such as a cut-off frequency at approximately 200 KHz.
  • the low-pass filters can remove high-frequency noises and interferences.
  • the filtered and amplified signal is fed to an LED, as is shown on the lower left portion of the diagram. When a signal is detected, the LED is lit indicating presence of the signal.
  • the device described above generally includes two circuits: one is a logic circuit that generates the address bit sequence, and one is a driver circuit that drives the transmission electrodes based on the address bit sequence.
  • the power-consumption characteristics of these two circuits are different.
  • the logic circuit requires a high voltage power supply, e.g., a 1.2 V power supply, to switch the CMOS circuits.
  • the current drawn through the logic circuit is relatively small. For example, in one embodiment, the current drawn through the logic circuits is approximately 5 ⁇ A.
  • the driver circuit may draw a much larger current, because of the power it requires to transmit a sufficiently detectable signal. Consequently, the voltage of the power supply can be pulled down to a lower level.
  • the driver circuit can draw 100 ⁇ A and pull the battery voltage down to 0.5 V.
  • One embodiment of the present invention uses a split battery configuration to decouple the power supplies for the logic and driver circuits.
  • FIG. 19 shows one exemplary split (i.e., segmented) battery design.
  • Two battery electrodes 193 and 194 which are made from copper iodine, constitute the battery anodes for the logic circuit 191 and driver circuit 192 , respectively. Effectively, electrodes 193 and 194 form two separate batteries with a shared common magnesium cathode 195 . In this way, the driver circuit 192 can draw sufficient current to drive transmission electrodes 196 without significantly impairing the power supply for the logic circuit 191 .
  • driver circuit 192 draws a current from the battery formed by electrodes 194 and 195 , and pushes this current through transmission electrodes 196 into the body.
  • the device can avoid the use of separate transmission electrodes by using the battery electrodes for transmission.
  • FIG. 20 shows such a configuration.
  • the driver circuit 206 essentially contains a switch coupled between the anode 204 and the cathode. This switch can be turned on or off by the address signal from the logic circuit 201 . When the switch is turned on, the battery for the driver circuit is effectively short-circuited within the chip. Consequently, a current 207 flows through the body from the cathode to anode 204 . The resistance of the body tissue can thereby generate a voltage difference, which can be readily detected by, for example, a differential amplifier.
  • the size of the cathode could be limited, resulting in coupling between the power supplies for the logic and driver circuits even with split anodes.
  • the cathode can also be split to further decouple the two power supplies.
  • two separate magnesium electrodes 211 and 212 serve as separate cathodes for the two batteries respectively serving the logic and driver circuits. The coupling between the two circuits can thus be minimized.
  • the battery electrodes for the driver circuit can be detached from the chip and coupled to the driver circuit through two external wires, as is shown in FIG. 22 .
  • the battery electrodes for the logic circuit can still be deposited on the chip to provide high-voltage power supply to the logic circuit.
  • the external wires 221 and 222 which can be approximately 1 cm long each, form a long dipole and can provide attendant signal amplification. As a result, the effectiveness of the transmission is not limited by the size of the chip.
  • the wires are initially folded within a pill and can unfold when the pill is digested.
  • a signal generation element is stably associated with the pharmaceutical dosage from in some manner.
  • stably associated is meant that the signal generation element and the dosage form to do separate from each other, at least until administered to the subject in need thereof, e.g., by ingestion.
  • the signal generation element may be stably associated with the pharmaceutical carrier/active agent component of the composition in a number of different ways.
  • the carrier/active agent component is a solid structure, e.g., such as a tablet or pill
  • the carrier/active agent component is produced in a manner that provides a cavity for the signal generation element.
  • the signal generation element is then placed into the cavity and the cavity sealed, e.g., with a biocompatible material, to produce the final composition.
  • a tablet is produced with a die that includes a feature which produces a cavity in the resultant compressed tablet.
  • the signal generation element is placed into the cavity and the cavity sealed to produce the final tablet.
  • the tablet is compressed with a removable element, e.g., in the shape of a rod or other convenient shape. The removable element is then removed to produce a cavity in the tablet.
  • the signal generation element is placed into the cavity and the cavity sealed to produce the final tablet.
  • a tablet without any cavity is first produced and then a cavity is produced in the tablet, e.g., by laser drilling.
  • the signal generation element is placed into the cavity and the cavity sealed to produce the final tablet.
  • a tablet is produced by combining the signal generation element with subparts of the tablet, where the subparts may be pre-made subparts or manufactured sequentially.
  • tablets are produced by first making a bottom half of the tablet, placing the signal generation element on a location of the bottom half of the tablet, and then placing top portion of the tablet over the bottom half and signal generation element to produce the final desired composition.
  • a tablet is produced around a signal generation element such that the signal generation element is located inside of the produced tablet.
  • a signal generation element which may or may not be encapsulated in a biocompatible compliant material, e.g., gelatin (to protect the signal generation element), is combined with carrier/active agent precursor, e.g., powder, and compressed or molded into a tablet in a manner such that the signal generation element is located at an internal position of the tablet.
  • carrier/active agent precursor e.g., powder
  • the carrier/active agent component is, in certain embodiments, sprayed onto the signal generation element in a manner that builds up the tablet structure.
  • the active agent/carrier component precursor may be a liquid formulation which is combined with the signal generation element and then solidified to produce the final composition.
  • pre-made tablets may be fitted with the signal generation element by stably attaching the signal generation element to the tablet.
  • protocols that do not alter the properties of the tablet, e.g., dissolution etc.
  • a gelatin element that snap fits onto one end of a tablet and has the chip integrated with it is employed in certain embodiments.
  • the gelatin element is colored in certain embodiments to readily identify tablets that have been fitted with the signal generation element.
  • the composition has a active agent/carrier composition filled capsule configuration, e.g., such as a gelatin capsule filled configuration
  • the signal generation element may be integrated with a capsule component, e.g., top or bottom capsule, and the capsule filled with the active agent/carrier composition to produce the final composition.
  • the above reviewed methods of manufacture are merely illustrative of the variety of different ways in which the compositions of the invention may be manufactured.
  • Systems of the subject invention include, in certain embodiments, one or more active agent containing compositions, e.g., as reviewed above, as well as a signal detection component, e.g., in the form of a receiver.
  • the signal detection component may vary significantly depending on the nature of the signal that is generated by the signal generation element of the composition, e.g., as reviewed above.
  • the signal detection component is an implantable component.
  • implantable component is meant that the signal detection component is designed, i.e., configured, for implantation into a subject, e.g., on a semi-permanent or permanent basis.
  • the signal detection component is in vivo during use.
  • the signal detection component is ex vivo, by which is meant that the detection component is present outside of the body during use.
  • either separate from or integrated with the ex vivo detection component may be a dosage dispenser element, e.g., for dispensing dosages of the compositions based on signal detected from the signal generation element of the detector.
  • Such features may also be present in implantable detection components, e.g., to provide a closed loop administration system that administers a subsequent dosage based on input about ingestion of a previous dosage.
  • the signal generation element of the composition is activated upon contact with a target body site.
  • the signal detection component is activated upon detection of a signal from the signal generation element.
  • the composition generates an intermittent signal.
  • the detection element is capable of simultaneously detecting multiple compositions.
  • the signal detection component may include a variety of different types of signal receiver elements, where the nature of the receiver element necessarily varies depending on the nature of the signal produced by the signal generation element.
  • the signal detection component may include one or more electrodes for detecting signal emitted by the signal generation element.
  • the receiver device will be provided with two electrodes that are dispersed at some distance. This distance allows the electrodes to detect a differential voltage.
  • the first electrode is in contact with an electrically conductive body element, e.g., blood
  • the second electrode is in contact with an electrically insulative body element relative to said conductive body element, e.g., adipose tissue (fat).
  • the signal detection component may include one or more coils for detecting signal emitted by the signal generation element.
  • the signal detection component includes an acoustic detection element for detecting signal emitted by the signal generation element.
  • the receiver of the present systems may also be viewed as “data collectors.”
  • a “data collector” is any device equipped with receiving antenna to detect the potential differences created in the body by a transmitter as described above, thus receiving the information transmitted.
  • a data collector may handle received data in various ways. In some embodiments, the collector simply retransmits the data to an external device (e.g., using conventional RF communication).
  • the data collector processes the received data to determine whether to take some action such as operating an effector that is under its control, activating a visible or audible alarm, transmitting a control signal to an effector located elsewhere in the body, or the like.
  • the data collector stores the received data for subsequent retransmission to an external device or for use in processing of subsequent data (e.g., detecting a change in some parameter over time). It is to be understood that data collectors may perform any combination of these and/or other operations using received data.
  • an implanted collector may include conventional RF circuitry (operating, e.g., in the 405-MHz medical device band) with which a practitioner can communicate, e.g., using a data retrieval device, such as a wand as is known in the art.
  • the data collector includes an external component
  • that component may have output devices for providing, e.g., audio and/or visual feedback; examples include audible alarms, LEDs, display screens, or the like.
  • the external component may also include an interface port via which the component can be connected to a computer for reading out data stored therein.
  • the data collector is implanted.
  • pacemaker leads provide a suitably sized receiving antenna.
  • Typical pacemakers include a control unit (referred to as a “can”) that incorporates logic circuits configured to perform various data collection and processing operations.
  • the can is also connected to RF transmitter/receiver circuitry that allows communication between the pacemaker and an external wand operated by a health care practitioner.
  • leveraging the existing unit as a data collector may be an efficient choice.
  • the system further includes an element for storing data, i.e., a data storage element.
  • the data storage element is a computer readable medium.
  • computer readable medium refers to any storage or transmission medium that participates in providing instructions and/or data to a computer for execution and/or processing. Examples of storage media include floppy disks, magnetic tape, CD-ROM, a hard disk drive, a ROM or integrated circuit, a magneto-optical disk, or a computer readable card such as a PCMCIA card and the like, whether or not such devices are internal or external to the computer.
  • a file containing information may be “stored” on computer readable medium, where “storing” means recording information such that it is accessible and retrievable at a later date by a computer.
  • “permanent memory” refers to memory that is permanent. Permanent memory is not erased by termination of the electrical supply to a computer or processor. Computer hard-drive ROM (i.e. ROM not used as virtual memory), CD-ROM, floppy disk and DVD are all examples of permanent memory. Random Access Memory (RAM) is an example of non-permanent memory.
  • a file in permanent memory may be editable and re-writable.
  • the data that is recorded on the data storage element includes at least one of, if not all of, time, date, and an identifier of each composition administered to a patient, where the identifier may be the common name of the composition or a coded version thereof.
  • the data of interest includes hemodynamic measurements.
  • the data of interest includes cardiac tissue properties.
  • the data of interest includes pressure or volume measurements.
  • the invention also provides computer executable instructions (i.e., programming) for performing the above methods.
  • the computer executable instructions are present on a computer readable medium. Accordingly, the invention provides a computer readable medium containing programming for use in detecting and processing a signal generated by a composition of the invention, e.g., as reviewed above.
  • the systems include one or more of: a data storage element, a data processing element, a data display element, data transmission element, a notification mechanism, and a user interface.
  • a data storage element e.g., a hard disk drive, a solid state drive, etc.
  • the signal detection component includes a cardiac monitoring element, such as shown in the system of FIG. 1 .
  • FIG. 1 shows a human 10 who has an implanted cardiovascular device “can” 8 and a lead 6 , which components are employed to monitor and detect the signal emitted from pill 14 .
  • the monitoring device can be positioned in other locations as well, such as subcutaneously, in the heart, or in the waist near the stomach, for example. Positioning may be suggested by a particular application.
  • the inventive monitoring system can also be positioned as an external device. By example, it could be positioned by a harness that is worn outside the body and has one or more electrodes that attach to the skin at different locations.
  • the inventive construct can be linked to a portable device, for example a watch that has one or two electrodes dispersed on the wrist.
  • a receiving electrode system could be placed and created such as, hearing aids that beep, necklace, belt, shoes (PZT—powered), or earrings.
  • the systems include an external device which is distinct from the receiver (which may be implanted or topically applied in certain embodiments), where this external device provides a number of functionalities.
  • an apparatus can include the capacity to provide feedback and appropriate clinical regulation to the patient.
  • Such a device can take any of a number of forms.
  • the device can be configured to sit on the bed next to the patient.
  • the device can read out the information described in more detail in other sections of the subject patent application, both from pharmaceutical ingestion reporting and from psychological sensing devices, such as is produced internally by a pacemaker device or a dedicated implant for detection of the pill.
  • the purpose of the external apparatus is to get the data out of the patient and into an external device.
  • One feature of external apparatus is its ability to provide pharmacologic and physiologic information in a form that can be transmitted through a transmission medium, such as a telephone line, to a remote location such as a clinician or to a central monitoring agency.
  • the cardiac monitoring element includes a conduction velocity measurement element. In certain embodiments, the cardiac monitoring element includes a pressure sensor. In certain embodiments, the cardiac monitoring element includes a dimension sensor.
  • Embodiments of the present invention can be used in various systems. Such systems may include various types of sensors. Such sensors and systems have been described in various applications by some of the present inventors. These applications also describe multiplexing systems previously developed by some of the present inventors with which the present invention can be employed. These applications include: U.S. patent application Ser. No. 10/734,490 published as 20040193021 titled: “Method And System For Monitoring And Treating Hemodynamic Parameters”; U.S. patent application Ser. No. 11/219,305 published as 20060058588 titled: “Methods And Apparatus For Tissue Activation And Monitoring”; International Application No.
  • the above described systems are reviewed in terms of communication between an identifier on a pharmaceutical composition and a receiver.
  • the systems are not so limited.
  • the systems are composed of two or more different modules that communicate with each other, e.g., using the transmitter/receiver functionalities as reviewed above, e.g., using the monopole transmitter (e.g., antenna) structures as described above.
  • the above identifier elements may be incorporated into any of a plurality of different devices, e.g., to provide a communications system between two self-powered devices in the body, where the self-powered devices may be sensors, data receivers and storage elements, effectors, etc.
  • one of these devices may be a sensor and the other may be a communication hub for communication to the outside world.
  • This inventive embodiment may take a number of forms. There can be many sensors, many senders and one receiver. They can be transceivers so both of these can take turns sending and receiving according to known communication protocols.
  • the means of communication between the two or more individual devices is the mono polar system, e.g., as described above.
  • each of these senders may be configured to take turns sending a high frequency signal into the body using a monopole pulling charge into and out of the body which is a large capacitor and a conductor.
  • the receiver a monopole receiver is detecting at that frequency the charge going into and out of the body and decoding an encrypted signal such as an amplitude modulated signal or frequency modulated signal.
  • This embodiment of the present invention has broad uses. For example, multiple sensors can be placed and implanted on various parts of the body that measure position or acceleration. Without having wires connecting to a central hub, they can communicate that information through a communication medium.
  • an effective amount of a composition of the invention is administered to a subject in need of the active agent present in the composition, where “effective amount” means a dosage sufficient to produce the desired result, e.g. an improvement in a disease condition or the symptoms associated therewith, the accomplishment of a desired physiological change, etc.
  • the amount that is administered may also be viewed as a therapeutically effective amount.
  • a “therapeutically effective amount” means the amount that, when administered to an subject for treating a disease, is sufficient to effect treatment for that disease.
  • compositions may be administered to the subject using any convenient means capable of producing the desired result, where the administration route depends, at least in part, on the particular format of the composition, e.g., as reviewed above.
  • the compositions can be formatted into a variety of formulations for therapeutic administration, including but not limited to solid, semi solid or liquid, such as tablets, capsules, powders, granules, ointments, solutions, suppositories and injections.
  • administration of the compositions can be achieved in various ways, including, but not limited to: oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intracheal, etc., administration.
  • a given composition may be administered alone or in combination with other pharmaceutically active compounds, e.g., which may also be compositions having signal generation elements stably associated therewith.
  • disease conditions include, but are not limited to: cardiovascular diseases, cellular proliferative diseases, such as neoplastic diseases, autoimmune diseases, hormonal abnormality diseases, infectious diseases, pain management, and the like.
  • treatment is meant at least an amelioration of the symptoms associated with the disease condition afflicting the subject, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. symptom, associated with the pathological condition being treated.
  • amelioration also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g. prevented from happening, or stopped, e.g. terminated, such that the subject no longer suffers from the pathological condition, or at least the symptoms that characterize the pathological condition.
  • treating” or “treatment” of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).
  • a “disease” includes pain.
  • mammals or “mammalian,” where these terms are used broadly to describe organisms which are within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In representative embodiments, the subjects will be humans.
  • carnivore e.g., dogs and cats
  • rodentia e.g., mice, guinea pigs, and rats
  • primates e.g., humans, chimpanzees, and monkeys.
  • the subjects will be humans.
  • the subject methods are methods of managing a disease condition, e.g., over an extended period of time, such as 1 week or longer, 1 month or longer, 6 months or longer, 1 year or longer, 2 years or longer, 5 years or longer, etc.
  • the subject methods may be employed in conjunction with one or more additional disease management protocols, e.g., electrostimulation based protocols in cardiovascular disease management, such as pacing protocols, cardiac resynchronization protocols, etc; lifestyle, such a diet and/or exercise regimens for a variety of different disease conditions; etc.
  • the methods include modulating a therapeutic regimen based data obtained from the compositions.
  • data may be obtained which includes information about patient compliance with a prescribed therapeutic regimen.
  • This data with or without additional physiological data, e.g., obtained using one or more sensors, such as the sensor devices described above, may be employed, e.g., with appropriate decision tools as desired, to make determinations of whether a given treatment regimen should be maintained or modified in some way, e.g., by modification of a medication regimen and/or implant activity regimen.
  • methods of invention include methods in which a therapeutic regimen is modified based on signals obtained from the composition(s).
  • compositions include an active agent, an identifier element and a pharmaceutically acceptable carrier.
  • the identifier emits a signal in response to an interrogation
  • the identifier is interrogate, e.g., by a wand or other suitable interrogation device, to obtain a signal.
  • the obtained signal is then employed to determine historical information about the composition, e.g., source, chain of custody, etc.
  • the methods generally include obtaining the signal generation element of the composition, e.g., by retrieving it from a subject that has ingested the composition, and then determining the history of the composition from obtained signal generation element.
  • the signal generation element includes an engraved identifier, e.g., barcode or other type of identifier
  • the engraved identifier may be retrieved from a subject that has ingested the composition and then read to identify at least some aspect of the history of the composition, such as last known purchaser, additional purchasers in the chain of custody of the composition, manufacturer, handling history, etc.
  • this determining step may include accessing a database or analogous compilation of stored history for the composition.
  • the present invention provides the clinician an important new tool in their therapeutic armamentarium: automatic detection and identification of pharmaceutical agents actually delivered into the body.
  • the applications of this new information device and system are multi-fold. Applications include, but are not limited to: (1) monitoring patient compliance with prescribed therapeutic regimens; (2) tailoring therapeutic regimens based on patient compliance; (3) monitoring patient compliance in clinical trials; (4) monitoring usage of controlled substances; and the like. Each of these different illustrative applications is now reviewed in greater detail below.
  • monitoring patient compliance is meant tracking whether a patient is actually taking medication in the manner prescribed to the patient.
  • the present invention provides accurate data of when a pill has been taken and which pill has been taken. This allows the precise determination of which pill was taken at a specific point in time. Such monitoring capability assures patients are taking the prescribed medication correctly. This information avoids the potential for over prescription of medications that are not actually being taken.
  • pain killers are intended to be administered to a patient, it is possible to verify with the present invention that the patient did in fact take those pain killers in a certain period of time.
  • correct, timely ingestion of the drugs will automatically trigger a prescription refill signal which is forwarded to a pharmacy data system, and in some cases the refill will be automatically delivered directly to the patient's home, or released by a device in the patient's home some period of time later.
  • This feature is particularly valuable in patients with compromised mental capacity and/or limited physical mobility.
  • the invention is particularly useful in complex administration regimens, such as when multiple pharmaceuticals are being taken, and confusion is more likely to occur.
  • inventive pills can have multiple external layers, with only correct dosage allowing dissolution and absorption of the pharmaceutical component.
  • Specific indicators such as electrical conduction velocity in the heart or electrolytic levels in the blood in response to pharmaceutical can also be titrated.
  • a patient can be alerted when the patient is in some way non-compliant with a given treatment regimen. For example, by a sound, visual, or computer reminder, if the pharmacological regimen is not being accurately adhered to, a reminder is provided. If that reminder is not accurately responded to, the system can provide an alert to family members, caregivers, or clinicians in order to remedy the gap in treatment or overdose.
  • the device may also automatically modify the dosage and timing of the regimen to compensate for prior non-standard dosing.
  • one type of application in which the subject compositions and systems find use is in tailoring therapeutic regimens based on patient compliance.
  • data obtained about whether a patient has or has not taken a particular dosage is employed to determine future dosages and/or timing of such dosages.
  • data concerning patient compliance is combined with additional data, e.g., sensed physiological data, to make customized changes or modifications to a given therapeutic regimen.
  • additional data e.g., sensed physiological data
  • data about dosage compliance obtained according to the invention is used in concert with other medical sensing devices, correlation between drug delivery, batch and dosage can be correlated to a physiological response.
  • optimal pharma-therapeutic regimens may be formulated by the clinician.
  • cardiac stimulating drugs can be titrated to the most appropriate dosages, minimizing side effects such as cardiac muscle exhaustion and rebound effects among others, and optimizing both dosage and timing for each individual patient.
  • the present invention allows, in concert with other sensing devices developed by some of the present inventors, the measurement and assessment of the cardiac response to those medications.
  • These co-employed sensing devices can be those enumerated below, among others.
  • Other sensing technology e.g., as mentioned above, developed by some of the present inventors allows measurement of heart health and cardiac efficiency.
  • the clinician will be able to compare the response of the heart and body to the administered pharmaceutical.
  • the data provided by the present invention can optionally be recorded over time.
  • the recording system records synchrony or conduction velocity of a signal going through cardiac tissue and how that is mediated by the presence of a certain medication. This unique data is made possible by the present invention since it can determine electronically exactly when the pill or other medication was being absorbed into the body.
  • the present invention provides a record for emergency room technicians or doctors when a patient is admitted to a hospital so that the patient's status can be accurately ascertained. Dosage events within the last hour or day prior to admission, and the identity of the last medication, will be immediately available. As such, future therapeutic regimens can be made based on accurate records of patient drug medication history.
  • the clinician obtains this information through simple interrogation of the implanted or portable device. This device would tell them without any uncertainty what pills have been taken. As the inventive technology becomes more wide spread, this data will become more regularly available.
  • the present inventive microchips are sufficiently inexpensive such that when they are put into standard production, most or all pharmaceuticals will be fitted with them as a matter of course.
  • the patient monitoring capacity of the external reporting apparatus is an importation function which the inventive device can provide.
  • the device can read out the physiological response of the patient to the ingestion of medication, and then transmit this information back to the clinician.
  • the clinician can then modify therapy to optimal effectiveness, as indicated by the new data in response to the modified therapy, and so forth.
  • the dosage adjustment function within certain parameters, can be performed by an intelligence circuit in the apparatus.
  • an intelligence circuit in the apparatus By example, for a blood pressure medication, the patient takes their blood pressure pill. 20 minutes later, the internal monitoring circuitry in the implantable device registers a drop in blood pressure. The circuitry quantifies this drop, and transmits it to this bedside apparatus. The apparatus then can adjust the dosage of the pill to optimally treat the patient. Similarly, when the patient is connected to an IV, the dosage can be dispensed directly into the IV fluid.
  • the closed-loop system is provided as a fully implantable device.
  • physiological reactions to specific dosages and time intervals would also be continually monitored.
  • the level of drug in the blood stream is monitored, allowing for individual and time of day variations in drug metabolism.
  • This aspect of the present invention effectively minimizes underdosing or overdosing the controlled substances, in some cases addressing these changes before they produce external symptoms apparent to the patient or clinician.
  • the drug dosage can be automatically titrated so that, by example, the smallest appropriate level to quell anxiety due to pain, other physiologic reactions to pain, or provide steady or gradually diminishing blood levels of the drug would be dispensed.
  • This feature of the present invention provides an automatic, appropriately gradual, weaning off of the drug, lessening the chance of serious addiction or severe, adverse withdrawal reactions.
  • An important application of the invention is to provide immediate feedback of physiological data response to administration of a pharmaceutical agent in clinical drug trails.
  • a current challenge is that the experimental drug is administered broadly to a population without a comprehensive foreknowledge of which sub-groups within this population are most likely to benefit from the treatment.
  • Another challenge is monitoring patient compliance with the treatment regimen, by determining if the tests subjects are taking the medicine as indicated. The later challenge is addressed in the sections above. Both patient non-compliance levels and actual response to drug ingestion can thus be determined. As such, compliance intervention can then be addressed early in the study.
  • clinical researchers are provided with immediate access to physiological data.
  • the clinical researchers are able to identify the subset for which the drug is most likely effective from within the original test population of possible participants in the trial.
  • the example above of a patient receiving blood pressure medication and getting feedback immediately demonstrates how effectiveness of a novel medicine can be quickly determined.
  • the present invention provides the clinician an accurate dose response curve showing the response to that medication and the timing of the digestion of the pill.
  • the clinician now has the ability to determine which patients have no response to the medicine in the pill. In a study situation, such patients can be removed from a study or a test of the clinical utility of a certain medication. This ability provides that only people who have a beneficial response to a certain medication are retained in the trail. This feature will improve the efficacy of medications and to reduce the amount of medications that people take that are not being useful. It may also be used in trials to determine which patients actually consumed the medicine, and which did not.
  • the present invention allows identification of physiological proxies for the efficacy of a drug.
  • physiological proxies for a drug which has a long term administration prior to the development of overt clinical changes, there are typically certain short term physiological factors which appear immediately after ingestion of the drug.
  • cancer medication which requires many months to show an effect, can have shorter term indicia of its efficacy in one or a constellation of physiologic factors. Changes, both local or throughout the whole body, in blood pressure, body temperature, internal chemical enzymes or other factors will serve as proxies for the longer term desired effects. A precise correlation of these factors with the time of the pills ingestion enhances the ability to find meaningful indicia.
  • the invention provides a way to determine very quickly whether a patient should be taking the medication or not, whether it will be effective or not, and allow its appropriate titration. Synergies between medications, both helpful and adverse, will also become more readily apparent.
  • the identifiers can be fitted with coils, susceptible of interrogation without being dissolved in the body. This is accomplished by transmitting RF energy into the coil in such a way that the inquirer will be apprised of the presence and identity of a pill before it is ingested.
  • a “smart box” is provided that can interrogate each pill and ascertain its address.
  • the box can write a distinctive product number or product code so that every single pill ever made is provided with a unique identifier. Fuses, for example, may be selectively destroyed so the addresses may be detected electrically or optically. Particularly in the case of controlled substances, such as a narcotic, this will be important in limiting the illegal used of previously legitimate medicines.
  • the present invention makes it possible to identify precisely who bought such a pill from the authorized pharmacist. This use of the present invention will rein in the number of illicit uses of controlled substances on the market place.
  • An important application for the external apparatus aspect of the present invention is in monitoring and regulating the use of controlled pharmaceutical substances.
  • a serious risk when patients are prescribed heavy narcotics for pain control is the possibility of addiction.
  • addiction occurs from the ingestion of too much of the controlled medication by inadvertent overdosing, purposeful misuse, or through inexact dosage prescription.
  • individual serial number are provided on such pharmaceuticals to track the legitimate distribution of the drug before the illicit distribution of such drugs.
  • a means for locking and regulating the dosage of a potential addictive drug is provided.
  • An example of this capacity of the present invention is when a patient takes their narcotic pill, in which the ingestion of the medication is registered by the internal device. This information is then automatically transmitted to the external apparatus.
  • the inventive apparatus is so configured that only after the patient has taken the pill and at the appropriate time has elapsed does this accessory apparatus dispense a further pill.
  • this accessory apparatus dispenses a further pill.
  • the addiction rate for the drug is dramatically lowered by limiting legal drug availability by dispensing exactly the prescribed dosage at precisely the appropriate time interval.
  • the external apparatus can also be effectively employed in mandatory medication forensic applications.
  • the criminal in the case of a convicted criminal, the criminal can be required to take court ordered medication as a condition of release from jail.
  • the court or probation officer has access to a real-time record of the administration of this drug as this information is fed back through the accessory apparatus to the appropriate official.
  • court mandated psychotropic or chemical sterilization drug maintenance for sex offenders which would be addressed by this aspect of the present invention.
  • This use of the present invention is analogous to house arrests where physical position monitoring bands are worn on the ankle of the offender.
  • Kits may include one or more compositions of the invention, as described above.
  • the dosage amount of the one or more pharmacological agents provided in a kit may be sufficient for a single application or for multiple applications. Accordingly, in certain embodiments of the subject kits a single dosage amount of a pharmacological agent is present and in certain other embodiments multiple dosage amounts of a pharmacological agent may be present in a kit.
  • a single dosage amount of a pharmacological agent such may be packaged in a single container, e.g., a single tube, bottle, vial, and the like, or one or more dosage amounts may be individually packaged such that certain kits may have more than one container of a pharmacological agent.
  • Suitable means for delivering one or more pharmacological agents to a subject may also be provided in a subject kit.
  • the particular delivery means provided in a kit is dictated by the particular pharmacological agent employed, as describe above, e.g., the particular form of the agent such as whether the pharmacological agent is formulated into preparations in solid, semi solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols, and the like, and the particular mode of administration of the agent, e.g., whether oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intracheal, etc. Accordingly, certain systems may include a suppository applicator, syringe, I.V. bag and tubing, electrode, etc.
  • kits may also include a signal receiving element, as reviewed above.
  • the kits may also include an external monitor device, e.g., as described above, which may provide for communication with a remote location, e.g., a doctor's office, a central facility etc., which obtains and processes data obtained about the usage of the composition.
  • the subject kits may also include instructions for how to practice the subject methods using the components of the kit.
  • the instructions may be recorded on a suitable recording medium or substrate.
  • the instructions may be printed on a substrate, such as paper or plastic, etc.
  • the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub-packaging) etc.
  • the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, etc.
  • the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided.
  • An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate.
  • kits may be packaged in suitable packaging to maintain sterility.
  • the components of the kit are packaged in a kit containment element to make a single, easily handled unit, where the kit containment element, e.g., box or analogous structure, may or may not be an airtight container, e.g., to further preserve the sterility of some or all of the components of the kit.
  • Tx transmitter
  • Rx receiver
  • the Tx and Rx float in a bath of saline, and an LED glows on the Rx when the Tx is placed in the bath. Both Tx and Rx are completely isolated from the outside world.
  • the Tx representing the compositions of the present application, e.g., a pill composition having an active agent and signal generation element, is an oscillator circuit based on a CMOS timer chip. It produces a square wave at about 80 kHz of 3V amplitude from a Lithium battery. A tightly twisted pair of wires extends from the circuit, out of the container, and into the bath. At the end of the twisted pair, the wires are striped of insulation by about 1 mm and separated to form a dipole antenna. The signal amplitude was found to scale linearly with the separation distance characterizing this dipole. The signal was easily detectable with this setup when the dipole was 5 mm in extent.
  • the Rx is a filtered amplifier circuit with outputs to detect the transmitted signal.
  • the differential signal was coupled into the inputs of a gain 100 instrumentation amplifier through 0.1 uF series capacitors.
  • the output of the instrumentation amplifier was fed into a 4-pole high-pass filter, with gain of 100 and cutoff frequency 5 kHz. This output was fed into a 2-pole low-pass filter with gain 20 and cutoff frequency 100 kHz.
  • the overall gain of the circuit is 200,000. This output signal is applied across an LED and resistor in series, which glows when the output signal exceeds a few volts.
  • the Rx LED When not in the bath, the Rx LED was on all the time as it picked up interference and power line noise from the environment. When the pacing lead was shorted to the mock can the LED turned off.
  • the LED When placed in solution, the LED turned off.
  • the Rx LED When the Tx was also placed in solution, the Rx LED turned on and the dependence on position and orientation was investigated. The intensity of the LED was found to depend on the cosine of the angle between the Rx and Tx dipole, with a null for perpendicular orientation and sign inversion as the sense of the dipole was reversed, as observed with an external oscilloscope. The intensity of the LED was found to vary directly with position, with a bright, saturated glow observed for spacing less than 5 cm and a dim, diffuse glow observed for the maximum spacing allowed by the bath, about 50 cm.
  • the key to making the detection robust is differentiating the desired signal from spurious interference. Such was accomplished in this experiment by restricting the frequency band of sensitivity to between 5 and 100 kHz. To the extent this band can be narrowed, the more robust the system will be.
  • the challenge here is to match the frequency of the Tx and Rx circuits, in light of the fact that the Tx frequency may vary by 30% due to manufacturing variation.
  • the Rx circuit can be very narrow through the use of a narrow bandpass or by using demodulation techniques from the radio.
  • the Rx circuit can be swept across a tuning frequency range to detect the presence of the pill. The presence of the pill can be confirmed by encoding an unlikely bit sequence in the digital information transmitted by the pill.
  • the Tx may be readily powered off a chemical battery, such as a Pt/Mg system.
  • digital information is readily encoded in the signal using a variety of encoding techniques to eliminate errors and improve the overall reliability of the system.
  • a transmitter according to the subject invention was set up as follows.
  • the circuit was powered off a 9V battery and floated on a bath of saline.
  • the circuit was an oscillator based on the TLC551 chip, a CMOS version of the popular 555 timer.
  • the oscillator was run at ⁇ 7 kHz, with a duty cycle of perhaps 15%.
  • the outputs of the oscillator were each capacitively coupled through 7 uF to a twisted pair, which was terminated in a small “Y” shaped dipole, with the arms separated by ⁇ 1 mm, and ⁇ 2 mm of bare wire exposed to the saline bath.
  • the signal was received through two Cu electrodes, each with ⁇ 1 cm 2 exposed to the bath. This was routed to the input of a Stanford pre-amp operated off batteries, set to a gain of 1000 with a pass band between 3 kHz and 30 kHz. The output of the pre-amp was observed on a battery powered oscilloscope.
  • a maximum signal of ⁇ 200 uV referenced to the amplifier input was observed for an Rx electrode separation of ⁇ 20 cm.
  • a dipolar coupling strength was observed, displaying a sinusoidal angular dependence, with a null in received signal for perpendicular orientation; phase inversion was seen between parallel and anti-parallel orientations.
  • the received signal strength was seen to scale linearly with separation of the Rx electrodes.
  • a prototype smart pill microchip which broadcasts a fixed code using frequency shift keying, was first powered by a 1.5V AA battery.
  • the conductive signal was applied to a physiological saline bath with a twisted pair T-shaped dipole, approximately 1 cm across with 1 mm of conductor exposed on each arm of the T.
  • the signal was detected by two copper electrodes, spaced approximately 10 cm apart, which feed into a battery powered, isolated differential pre-amp.
  • the signal was observed on an oscilloscope.
  • An oscillatory signal clearly representative of the transmitted data, was observed with a frequency of about 300 kHz and an input-referenced amplitude of about 10 mV.
  • a dependence of the received signal strength on the cosine of the angle between the transmit and receive conductors, as is characteristic of a dipolar interaction was observed.
  • a Mg—CuI water-activated battery, with each electrode having an exposed surface area of ⁇ 1 mm 2 was constructed.
  • the Mg electrode was formed by simply potting commercial grade Mg ribbon in epoxy and polishing the end flat with sandpaper.
  • the CuI electrode was produced by first polishing the end of Cu wire potted in epoxy.
  • the CuI—Mg battery was connected to the power terminals of the chip, and the output terminals were connected to the dipole conductor described above in a physiological saline bath.
  • the battery was activated by dropping the electrodes in the bath, and a signal of amplitude ⁇ 2 mV at a frequency of 20 kHz was observed for at least a minute.
  • the output terminals of the chip were shorted together, effectively configuring the chip for the 2-terminal operation described above.
  • An output signal was observed, but its amplitude was much weaker, probably because of the decreased effective transmitter dipole length in this configuration. That is, in the 4-terminal configuration, the effective transmit conductor size is determined by the spacing between the battery and dipolar T, which was several centimeters; in the 2-terminal mode, the effective dipole length is reduced to the separation between the Mg and CuI electrodes, which was less than 1 cm.
  • the observed signal was perhaps a few hundred ⁇ V, and could be quantified using averaging to overcome an interfering signal amplified by the broadband receiver. More sophisticated detection schemes will have little problem detecting such a signal reliably.
  • a pill composition as described above prior to ingestion may be composed of two main components, an address generating logic circuit and a signal transmission circuit.
  • the address generation circuit is powered with low current adequate to the required tasks. However, if the voltage supplied to the address generation circuit changes, the frequency of the oscillator therein will also change. This may produce changes in signal transmission, introduce noise into the transmission, and cause other undesired effects.
  • embodiments of the system are powered with two voltage sources.
  • the receivers are powered with one battery, and the servos are powered with another battery. With this configuration, whatever occurs in the servo does not affect the receiver. As such, a more stable remote control results, thereby improving the performance of the complete system.
  • a common cathode is provided.
  • one part of the battery will power the address generation circuit, and the other will power the transmission circuit.
  • This configuration provides a stable voltage to the address generation circuit.
  • the transmitter section of the device is turned on, only the voltage on the transmitter will change, but no change of voltage will occur in the address generation section of the device. Hence, the changes will typically cause a change in signal amplitude, but not in the frequency. As a result, the transition will be more stable, and the frequency of RF transmission will be unaffected, or minimally effected.
  • the surface preparation before the copper iodine is forming is of interest.
  • One approach is to use copper wire embedded in epoxy. This can be plated with electrolytic copper. After the copper is polarized in solution of potassium iodide, copper iodine is formed on the tip of the electrode. Copper iodine can also be formed by chemically deposition. Other means are also available.
  • 10 ⁇ m is a typical range for thickness of copper iodide to produce an adequate amount of electricity to accomplish the activity of the device for a 15 minute period. If less thickness is employed, the transmission will last a shorter time. Thus, the thickness of copper iodide is determined by the time required to produce electricity to provide the results needed for a particular application. For several seconds of transmission, less than 1 ⁇ m of copper iodide would be adequate. For one microsecond of transmission, a few nanometers of copper iodine thickness, such as in the range of about 10-100 nanometers, more specifically, about 20-50 nanometers is sufficient.

Abstract

An apparatus that includes a partial power source including a first material and a second material, the partial power source configured to generate, upon contact with a conducting medium, a potential difference between the first material and the second material to provide power to a control device, and generate, using the first material and the second material, a current flow within the conducting medium, the current flow including information encoded based on a variable conductance between the first material and the second material.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims priority to U.S. application Ser. No. 12/949,720 filed on Nov. 18, 2010, which claims priority to U.S. application Ser. No. 11/912,475, filed on Jun. 23, 2008, which is the U.S. National Stage entry of International Application No. PCT/US2006/016370, filed on Apr. 28, 2006 which, pursuant to 35 U.S.C. §119 (e), claims priority to the filing dates of: U.S. Provisional Patent Application Ser. No. 60/676,145 filed Apr. 28, 2005; U.S. Provisional Patent Application Ser. No. 60/694,078 filed Jun. 24, 2005; U.S. Provisional Patent Application Ser. No. 60/713,680 filed Sep. 1, 2005 and U.S. Provisional Patent Application Ser. No. 60/790,335 filed Apr. 7, 2006 and entitled “Pharma-Informatics System”; the disclosures of which are herein incorporated by reference.
  • BACKGROUND
  • The present Invention relates generally to medical apparatus and methods. More specifically, the present invention relates to apparatus and methods for automatic identification of ingestion or other actual, physical administration of a pharmaceutical material.
  • Prescription medications are effective remedies for many patients when taken properly, e.g., according to instructions. However, studies have shown that, on average, about 50% of patients do not comply with prescribed medication regimens. A low rate of compliance with medication regimens results in a large number of hospitalizations and admissions to nursing homes every year. In the United States alone, it has recently been estimated that the cost to the resulting from patient non-compliance is reaching $100 billion annually.
  • Consequently, various methods and apparatus have been made available to improve patient compliance with prescribed regimens in efforts to improve patient health. To date, many different types of “smart” packaging devices have been developed. In some cases, such devices automatically dispense the appropriate pill. In other cases, there are electronic controls that detect and record when the pill is taken out of the box.
  • While devices and protocols have been developed for improving patient compliance, there is continued interest in the development of new ways of monitoring patient compliance.
  • SUMMARY
  • The present invention allows, for the first time, the specific identification of pharmaceutical pills and other types of pharmaceutical delivery systems, such as skin diffusion patches, so that the actual, physical delivery of the pharmaceutical into the body can be automatically detected and this information stored. Because the inventive automatic reporting of physical drug administration does not require patient or clinician input, it avoids many of the inaccuracies which introduce uncertainty in current drug administration monitoring systems. These inventive features are particularly critical when a patient's compliance or mental capacity is a consideration, such as in the administration of psychotropic drugs. The present invention also allows for the identification of sources of illicit drugs for law enforcement purposes.
  • Embodiments of the invention include compositions having: an active agent; an identifier and a pharmaceutically acceptable carrier. In one embodiment of the present invention, an ingestible pill is made identifiable by providing an electronic microchip as part of the pill structure. In some aspects, the electronic microchip is completely encased within the pill. In this embodiment, the pill broadcasts a signal when it is dissolved in an ionic solution such as stomach fluids. The broadcasted signal is received by another device, e.g., a receiver, either inside or near the body. In turn, the receiver then records that the pill has in fact reached the stomach and is in the process of being dissolved.
  • In certain of these embodiments, the signal is an oscillating signal which is picked up by an implanted or topically applied receiver. The implant has one or two electrode(s) that sense the varying signal. The implant is configured so that it can identify the code and record that a specific pill has been ingested at a specific time.
  • BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 provides a diagrammatic, exemplary representation of the pill embodiment of the present invention.
  • FIGS. 2A and 2B provide a more detailed view of the pill composition shown in FIG. 1.
  • FIGS. 3A to 3E provide views of different embodiments of signal generation elements of the invention.
  • FIG. 4 shows diagrammatically the effects of the pill ingestion where some of the pill has eroded away.
  • FIG. 5 provides a similar arrangement to FIG. 4, with a coil rather than two electrodes as the output.
  • FIGS. 6A to 6D provide detail of certain implementations of electronic circuits of various embodiments of the invention.
  • FIG. 7 provides an oscillator and a counter implementation according to an embodiment of the invention.
  • FIG. 8 is an additional embodiment of an oscillator where V control modulates the amount of voltage driving the oscillator.
  • FIG. 9 is an additional embodiment with a simple trickle or asynchronous counter.
  • FIG. 10 provides a schematic representation of a three terminal, monopole signal generation element according to an embodiment of the invention.
  • FIGS. 11A to 13B are diagrams showing a method for fabricating an identifier according to an embodiment of the invention.
  • FIG. 14 shows the multiplexer and the addressing system.
  • FIG. 15 shows a detail of the 4 bit mux of the system shown in FIG. 14.
  • FIG. 16 shows the 1 bit mux in detail that makes up the 4 bit mux.
  • FIG. 17 is an additional monopole embodiment of a signal generation element.
  • FIG. 18A is an exemplary schematic diagram of a signal-transmission driver circuit that transmits a signal at a fixed frequency, in accordance with one embodiment of the present invention.
  • FIG. 18B1-18B2 provides an exemplary schematic diagram of a receiver circuit, in accordance with one embodiment of the present invention.
  • FIG. 19 shows one exemplary split (i.e., segmented) battery design, in accordance with one embodiment of the present invention.
  • FIG. 20 shows one exemplary design of the driver circuit that uses split battery electrodes for transmission, in accordance with one embodiment of the present invention.
  • FIG. 21 shows one exemplary split battery design with a split cathode, in accordance with one embodiment of the present invention.
  • FIG. 22 shows one exemplary design where the battery electrodes for the driver circuit are coupled to the driver circuit via two external wires, in accordance with one embodiment of the present invention.
  • FIG. 23 shows the principle of an experiment with a split battery configuration.
  • FIG. 24 shows the performance of a pair of split batteries.
  • DETAILED DESCRIPTION
  • The present invention provides the clinician an important new tool in their therapeutic armamentarium: automatic detection and identification of pharmaceutical agents actually delivered into the body. The applications of this new information device and system are multi-fold. By example, when used in concert with other medical sensing devices, correlation between drug delivery, batch and dosage can be correlated to a physiological response. In this manner, optimal pharma-therapeutic regimens may be formulated by the clinician. By example, cardiac stimulating drugs can be titrated to the most appropriate dosages, minimizing side effects such as cardiac muscle exhaustion and rebound effects among others, and optimizing both dosage and timing for each, individual patient.
  • Assessment of a range of alternate medications is made possible by the present invention without resort to awaiting overt clinical sequel of treatment, many of which can be seriously adverse. By example, positive effects would be quickly ascertainable without being obscured by more random factors. Negative responses, such as changes in blood pressure, would become clearly evident as drug related or independent above background physiologic variation.
  • The ability to document the ingestion of a drug or other actual exposure of the body to a medication has many important clinical applications. In the simplest form, this technique provides accurate data of when a pill has been taken and which pill has been taken. This allows the precise determination of which pill was taken at a specific point in time. Such monitoring capability assures patients are taking the prescribed medication correctly. This information avoids the potential for over prescription of medications that are not actually being taken. By example, if pain killers are intended to be administered to a patient, it is possible to verify that the patient did in fact take those pain killers in a certain period of time. This is an important tool in limiting the illicit sale of unconsumed drugs to an unintended party. In the case of cardio vascular pills, the clinician or care giver is able to verify that the amount of the drug was taken has been taken at approximately the right point and time. Thus, the true efficacy of the drug can be accurately evaluated. Proper administration and patient compliance is especially critical in Alzheimer's, psychiatric, and alcohol aversion drugs, and in the treatment of rest home residents. In the case of accidental and other overdoses situations, the intervening clinician will be able to discern how far the ingestion has proceeded, and how many pills are involved.
  • In one clinical arena, the present invention allows, in concert with other sensing device developed by some of the present inventors, the measurement and assessment of the cardiac response to those medications. These co-employed sensing devices can be those enumerated below, among others. Other sensing technology developed by some of the present inventors allows measurement of heart health and cardiac efficiency. Using these tools in concert with the present inventive device, the clinician will be able to compare the response of the heart and body to the administered pharmaceutical.
  • The data provided by the present invention can optionally be recorded over time. The recording system records synchrony or conduction velocity of a signal going through cardiac tissue and how that is mediated by the presence of a certain medication. This unique data is made possible by the present invention since it can determine electronically exactly when the pill or other medication was being absorbed into the body.
  • From this innovative data, the present invention provides the clinician an accurate dose response curve showing the response to that medication and the timing of the digestion of the pill. Such innovative data has many applications. For instance, the clinician now has the ability to determine which patients have no response to the medicine in the pill. In a study situation, such patients can be removed from a study or a test of the clinical utility of a certain medication. This provides that only people who have a beneficial response to a certain medication are retained in the trail. This feature will improve the efficacy of medications and to reduce the amount of medications that people take that are not being useful. It may also be used in trials to determine which patients actually consumed the medicine, and which did not.
  • In more standard clinical environments, this unique data allows careful selection and titration of drug administration without resort to more overt physical symptoms to ascertain contraindications, efficacy, and optimal dosage levels. The present invention provides a record for emergency room technicians or doctors when a patient is admitted to a hospital so that the patient's status can be accurately ascertained. Dosage events within the last hour or day prior to admission, and the identity of the last medication, will be immediately available.
  • The clinician obtains this information through simple interrogation of the implanted or portable device. This device would tell them without any uncertainty what pills have been taken. As the inventive technology becomes more wide spread, this data will become more regularly available. The present inventive microchips described below are sufficiently inexpensive when put into standard production that most or all pharmaceuticals will be fitted with them as a matter of course.
  • In other embodiments of the inventive microchips, the chips can be fitted with coils, susceptible of interrogation without being dissolved in the body. This is accomplished by transmitting RF energy into the coil in such a way that the inquirer will be apprised of the presence and identity of a pill before it is ingested.
  • In an additional embodiment of the present invention, a “smart box” is provided that can interrogate each pill and ascertain its address. The box can write a distinctive product number or product code so that every single pill ever made is provided with a unique identifier. Fuses, for example, may be selectively destroyed so the addresses may be detected electrically or optically. Particularly in the case of controlled substances, such as a narcotic, this will be important in limiting the illegal used of previously legitimate medicines. The present invention makes it possible to identify precisely who bought such a pill from the authorized pharmacist. This use of the present invention will rein in the number of illicit uses of controlled substances on the market place.
  • In further describing the invention in greater detail, embodiments of the compositions are reviewed first, followed by a discussion of systems including the subject compositions, methods of using the subject compositions and systems and various illustrative applications in which the compositions and methods find use. Also reviewed in greater detail below are kits that include the subject compositions.
  • Compositions
  • Embodiments of the invention include active agent compositions having an identifier stably associated therewith. In certain embodiments, the compositions are disrupted upon administration to a subject. As such, in certain embodiments, the compositions are physically broken, e.g., dissolved, degraded, eroded, etc., following delivery to a body, e.g., via ingestion, injection, etc. The compositions of these embodiments are distinguished from devices that are configured to be ingested and survive transit through the gastrointestinal tract substantially, if not completely, intact. While the compositions of these embodiments are themselves disrupted upon administration, components of the composition, e.g., the identifier, may survive transit of the gastrointestinal tract, e.g., as described in greater detail below.
  • In certain embodiments, the compositions include an active agent/carrier component and an identifier. Each of these different components is reviewed separately in greater detail below.
  • Active Agent/Carrier Component
  • The subject compositions include an active agent/carrier component. By “active agent/carrier component” is meant a composition, which may be a solid or fluid (e.g., liquid), which has an amount of active agent, e.g., a dosage, present in a pharmaceutically acceptable carrier. The active agent/carrier component may be referred to as a “dosage formulation.”
  • Active Agent
  • “Active agent” includes any compound or mixture of compounds which produces a physiological result, e.g., a beneficial or useful result, upon contact with a living organism, e.g., a mammal, such as a human. Active agents are distinguishable from such components as vehicles, carriers, diluents, lubricants, binders and other formulating aids, and encapsulating or otherwise protective components. The active agent may be any molecule, as well as binding portion or fragment thereof, that is capable of modulating a biological process in a living subject. In certain embodiments, the active agent may be a substance used in the diagnosis, treatment, or prevention of a disease or as a component of a medication. In certain embodiments, the active agent may be a chemical substance, such as a narcotic or hallucinogen, which affects the central nervous system and causes changes in behavior.
  • The active agent (i.e., drug) is capable of interacting with a target in a living subject. The target may be a number of different types of naturally occurring structures, where targets of interest include both intracellular and extracellular targets. Such targets may be proteins, phospholipids, nucleic acids and the like, where proteins are of particular interest. Specific proteinaceous targets of interest include, without limitation, enzymes, e.g. kinases, phosphatases, reductases, cyclooxygenases, proteases and the like, targets comprising domains involved in protein-protein interactions, such as the SH2, SH3. PTB and PDZ domains, structural proteins, e.g. actin, tubulin, etc., membrane receptors, immunoglobulins, e.g. IgE, cell adhesion receptors, such as integrins, etc, ion channels, transmembrane pumps, transcription factors, signaling proteins, and the like.
  • The active agent (i.e., drug) may include one or more functional groups necessary for structural interaction with the target, e.g., groups necessary for hydrophobic, hydrophilic, electrostatic or even covalent interactions, depending on the particular drug and its intended target. Where the target is a protein, the drug moiety may include functional groups necessary for structural interaction with proteins, such as hydrogen bonding, hydrophobic-hydrophobic interactions, electrostatic interactions, etc., and may include at least an amine, amide, sulfhydryl, carbonyl, hydroxyl or carboxyl group, such as at least two of the functional chemical groups.
  • Drugs of interest may include cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Also of interest as drug moieties are structures found among biomolecules, including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof. Such compounds may be screened to identify those of interest, where a variety of different screening protocols are known in the art.
  • The drugs may be derived from a naturally occurring or synthetic compound that may be obtained from a wide variety of sources, including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including the preparation of randomized oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means, and may be used to produce combinatorial libraries. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce structural analogs.
  • As such, the drug may be obtained from a library of naturally occurring or synthetic molecules, including a library of compounds produced through combinatorial means, i.e., a compound diversity combinatorial library. When obtained from such libraries, the drug moiety employed will have demonstrated some desirable activity in an appropriate screening assay for the activity. Combinatorial libraries, as well as methods for producing and screening such libraries, are known in the art and described in: U.S. Pat. Nos. 5,741,713; 5,734,018; 5,731,423; 5,721,099; 5,708,153; 5,698,673; 5,688,997; 5,688,696; 5,684,711; 5,641,862; 5,639,603; 5,593,853; 5,574,656; 5,571,698; 5,565,324; 5,549,974; 5,545,568; 5,541,061; 5,525,735; 5,463,564; 5,440,016; 5,438,119; 5,223,409, the disclosures of which are herein incorporated by reference.
  • Broad categories of active agents of interest include, but are not limited to: cardiovascular agents; pain-relief agents, e.g., analgesics, anesthetics, anti-inflammatory agents, etc.; nerve-acting agents; chemotherapeutic (e.g., antineoplastic) agents; etc.
  • In certain embodiments, the active agent is a cardiovascular agent, i.e., an agent employed in the treatment of cardiovascular or heart conditions. In certain embodiments, the active agent is a cardiovascular agent, i.e., an agent employed in the treatment of cardiovascular or heart conditions. Cardiovascular agents of interest include, but are not limited to: cardioprotective agents, e.g., Zinecard (dexrazoxane); blood modifiers, including anticoagulants (e.g., coumadin (warfarin sodium), fragmin (dalteparin sodium), heparin, innohep (tinzaparin sodium), lovenox (enoxaparin sodium), orgaran (danaparoid sodium)) antiplatelet agents (e.g., aggrasta (tirofiban hydrochloride), aggrenox (aspirin/extended release dipyridamole), agrylin (anagrelide hydrochloride), ecotrin (acetylsalicylic acid), folan (epoprostenol sodium), halfprin (enteric coated aspirin), integrlilin (eptifibatide), persantine (dipyridamole USP), plavix (clopidogrel bisulfate), pletal (cilostazol), reopro (abciximab), ticlid (ticlopidine hydrochloride)), thrombolytic agents (activase (alteplase), retavase (reteplase), streptase (streptokinase)); adrenergic blockers, such as cardura (doxazosin mesylate), dibenzyline (phenoxybenzamine hydrochloride), hytrin (terazosin hydrochloride), minipress (prazosin hydrochloride), minizide (prazosin hydrochloride/polythiazide); adrenergic stimulants, such as aldoclor (methyldopa—chlorothiazide), aldomet (methyldopa, methyldopate HCl), aldoril (methyldopa—hydrochlorothiazide), catapres (clonidine hydrochloride USP, clonidine), clorpres (clonidine hydrochloride and chlorthalidone), combipres (clonidine hydrochloride/chlorthalidone), tenex (guanfacine hydrochloride); alpha/bet adrenergic blockers, such as coreg (carvedilol), normodyne (labetalol hydrochloride); angiotensin converting enzyme (ACE) inhibitors, such as accupril (quinapril hydrochloride), aceon (perindopril erbumine), altace (ramipril), captopril, lotensin (benazepril hydrochloride), mavik (trandolapril), monopril (fosinopril sodium tablets), prinivil (lisinopril), univasc (moexipril hydrochloride), vasotec (enalaprilat, enalapril maleate), zestril (lisinopril); angiotensin converting enzyme (ACE) inhibitors with calcium channel blockers, such as lexxel (enalapril maleate—felodipine ER), lotrel (amlodipine and benazepril hydrochloride), tarka (trandolapril/verapamil hydrochloride ER); angiotensin converting enzyme (ACE) inhibitors with diuretics, such as accuretic (quinapril HCl/hydroclorothiazide), lotensin (benazepril hydrochloride and hydrochlorothiazide USP), prinizide (lisinopril-hydrochlorothiazide), uniretic (moexipril hydrochloride/hydrochlorothiazide), vaseretic (enalapril maleate—hydrochlorothiazide), zestoretic (lisinopril and hydrochlorothiazide); angiotensin II receptor antagonists, such as atacand (candesartan cilexetil), avapro (irbesartan), cozaar (losartan potassium), diovan (valsartan), micardis (telmisartan), teveten (eprosartan mesylate); angiotensin II receptor antagonists with diuretics, such as avalide (irbesartan—hydrochlorothiazide), diovan (valsartan and hydrochlorothiazide), hyzaar (losartan potassium—hydrochlorothiazide); antiarrhythmics, such as Group I (e.g., mexitil (mexiletine hydrochloride, USP), norpace (disopyramide phosphate), procanbid (procainamide hydrochloride), quinaglute (quinidine gluconate), quinidex (quinidine sulfate), quinidine (quinidine gluconate injection, USP), rythmol (propafenone hydrochloride), tambocor (flecainide acetate), tonocard (tocainide HCl)), Group II (e.g., betapace (sotalol HCl), brevibloc (esmolol hydrochloride), inderal (propranolol hydrochloride), sectral (acebutolol hydrochloride)), Group III (e.g., betapace (sotalol HCl), cordarone (amiodarone hydrochloride), corvert (ibutilide fumarate injection), pacerone (amiodarone HCl), tikosyn (dofetilide)), Group IV (e.g., calan (verapamil hydrochloride), cardizem (diltiazem HCl), as well as adenocard (adenosine), lanoxicaps (digoxin), lanoxin (digoxin)); antilipemic acids, including bile acid sequestrants (e.g., colestid (micronized colestipol hydrochloride), welchol (colesevelam hydrochloride)), fibric acid derivatives (e.g., atromid (clofibrate), lopid (gemfibrozal tablets, USP), tricor (fenofibrate capsules)), HMG-CoA reductase inhibitors (e.g., baycol (cerivastatin sodium tablets), lescol (fluvastatin sodium), lipitor (atorvastatin calcium), mevacor (lovastatin), pravachol (pravastatin sodium), zocor (simvastatin)), Nicotinic Acid (e.g., Niaspan (niacin extended release tablets)); beta adrenergic blocking agents, e.g., betapace (sotalol HCl), blocadren (timolol maleate), brevibloc (esmolol hydrochloride), cartrol (carteolol hydrochloride), inderal (propranolol hydrochloride), kerlone (betaxolol hydrochloride), nadolol, sectral (acebutolol hydrochloride), tenormin (atenolol), toprol (metoprolol succinate), zebeta (bisoprolol fumarate); beta adrenergic blocking agents with diuretics, e.g., corzide (nadolol and bendroflumethiazide tablets), inderide (propranolol hydrochloride and hydroclorothiazide), tenoretic (atenolol and chlorthalidone), timolide (timolol maleate—hydrochlorothiazide), ziac (bisoprolol fumarate and hydrochlorothiazide); calcium channel blockers, e.g., adalat (nifedipine), calan (verapamil hydrochloride), cardene (nicardipine hydrochloride), cardizem (diltiazem HCl), covera (verapamil hydrochloride), isoptin (verapamil hydrochloride), nimotop (nimodipine), norvasc (amlodipine besylate), plendil (felodipine), procardia (nifedipine), sular (nisoldipine), tiazac (diltiazem hydrochloride), vascor (bepridil hydrochloride), verelan (verapamil hydrochloride); diuretics, including carbonic anhydrase inhibitors (e.g., daranide (dichlorphenamide)), combination diuretics (e.g., aldactazide (spironolactone with hydrochlorothiazide), dyazide (triamterene and hydrochlorothiazide), maxzide (triamterene and hydrochlorothiazide), moduretic (amiloride HCl—hydrochlorothiazide)), loop diuretics (demadex (torsemide), edecrin (ethacrynic acid, ethacrynate sodium), furosemide), potassium-sparing diuretics (aldactone (spironolactone), dyrenium (triamterene), midamor (amiloride HCl)), thiazides & related diuretics (e.g., diucardin (hydroflumethiazide), diuril (chlorothiazide, chlorothiazide sodium), enduron (methyclothiazide), hydrodiuril hydrochlorothiazide), indapamide, microzide (hydrochlorothiazide) mykrox (metolazone tablets), renese (polythi-azide), thalitone (chlorthalidone, USP), zaroxolyn (metolazone)); inotropic agents, e.g., digitek (digoxin), dobutrex (dobutamine), lanoxicaps (digoxin), lanoxin (digoxin), primacor (milrinone lactate); activase (alteplase recombinant); adrenaline chloride (epinephrine injection, USP); demser (metyrosine), inversine (mecamylamine HCl), reopro (abciximab), retavase (reteplase), streptase (streptokinase), tnkase (tenecteplase); vasodilators, including coronary vasodilators (e.g., imdur (isosorbide mononitrate), ismo (isosorbide mononitrate), isordil (isosorbide dinitrate), nitrodur (nitroglycerin), nitrolingual (nitroglycerin lingual spray), nitrostat (nitroglycerin tablets, USP), sorbitrate (isosorbide dinitrate)), peripheral vasodilators & combinations (e.g., corlopam (fenoldopam mesylate), fiolan (epoprostenol sodium), primacor (milrinone lactate)), vasopressors, e.g., aramine (metaraminol bitartrate), epipen (EpiPen 0.3 mg brand of epinephrine auto injector, EpiPen Jr. 0.15 mg brand of epinephrine auto injector), proamatine (midodrine hydrochloride); etc.
  • In certain embodiments, specific drugs of interest include, but are not limited to: psychopharmacological agents, such as (1) central nervous system depressants, e.g. general anesthetics (barbiturates, benzodiazepines, steroids, cyclohexanone derivatives, and miscellaneous agents), sedative-hypnotics (benzodiazepines, barbiturates, piperidinediones and triones, quinazoline derivatives, carbamates, aldehydes and derivatives, amides, acyclic ureides, benzazepines and related drugs, phenothiazines, etc.), central voluntary muscle tone modifying drugs (anticonvulsants, such as hydantoins, barbiturates, oxazolidinediones, succinimides, acylureides, glutarimides, benzodiazepines, secondary and tertiary alcohols, dibenzazepine derivatives, valproic acid and derivatives, GABA analogs, etc.), analgesics (morphine and derivatives, oripavine derivatives, morphinan derivatives, phenylpiperidines, 2,6-methane-3-benzazocaine derivatives, diphenylpropylamines and isosteres, salicylates, p-aminophenol derivatives, 5-pyrazolone derivatives, arylacetic acid derivatives, fenamates and isosteres, etc.) and antiemetics (anticholinergics, antihistamines, antidopaminergics, etc.), (2) central nervous system stimulants, e.g. analeptics (respiratory stimulants, convulsant stimulants, psychomotor stimulants), narcotic antagonists (morphine derivatives, oripavine derivatives, 2,6-methane-3-benzoxacine derivatives, morphinan derivatives) nootropics, (3) psychopharmacologicals, e.g. anxiolytic sedatives (benzodiazepines, propanediol carbamates) antipsychotics (phenothiazine derivatives, thioxanthine derivatives, other tricyclic compounds, butyrophenone derivatives and isosteres, diphenylbutylamine derivatives, substituted benzamides, arylpiperazine derivatives, indole derivatives, etc.), antidepressants (tricyclic compounds, MAO inhibitors, etc.), (4) respiratory tract drugs, e.g. central antitussives (opium alkaloids and their derivatives);
  • pharmacodynamic agents, such as (1) peripheral nervous system drugs, e.g. local anesthetics (ester derivatives, amide derivatives), (2) drugs acting at synaptic or neuroeffector junctional sites, e.g. cholinergic agents, cholinergic blocking agents, neuromuscular blocking agents, adrenergic agents, antiadrenergic agents, (3) smooth muscle active drugs, e.g. spasmolytics (anticholinergics, musculotropic spasmolytics), vasodilators, smooth muscle stimulants, (4) histamines and antihistamines, e.g. histamine and derivative thereof (betazole), antihistamines (H1-antagonists, H2-antagonists), histamine metabolism drugs, (5) cardiovascular drugs, e.g. cardiotonics (plant extracts, butenolides, pentadienolids, alkaloids from erythrophleum species, ionophores, -adrenoceptor stimulants, etc), antiarrhythmic drugs, antihypertensive agents, antilipidemic agents (clofibric acid derivatives, nicotinic acid derivatives, hormones and analogs, antibiotics, salicylic acid and derivatives), antivaricose drugs, hemostyptics, (6) blood and hemopoietic system drugs, e.g. antianemia drugs, blood coagulation drugs (hemostatics, anticoagulants, antithrombotics, thrombolytics, blood proteins and their fractions), (7) gastrointestinal tract drugs, e.g. digestants (stomachics, choleretics), antiulcer drugs, antidiarrheal agents, (8) locally acting drugs;
  • chemotherapeutic agents, such as (1) anti-infective agents, e.g. ectoparasiticides (chlorinated hydrocarbons, pyrethins, sulfurated compounds), anthelmintics, antiprotozoal agents, antimalarial agents, antiamebic agents, antileiscmanial drugs, antitrichomonal agents, antitrypanosomal agents, sulfonamides, antimycobacterial drugs, antiviral chemotherapeutics, etc., and (2) cytostatics, i.e. antineoplastic agents or cytotoxic drugs, such as alkylating agents, e.g. Mechlorethamine hydrochloride (Nitrogen Mustard, Mustargen, HN2), Cyclophosphamide (Cytovan, Endoxana), Ifosfamide (IFEX), Chlorambucil (Leukeran), Melphalan (Phenylalanine Mustard, L-sarcolysin, Alkeran, L-PAM), Busulfan (Myleran), Thiotepa (Triethylenethiophosphoramide), Carmustine (BiCNU, BCNU), Lomustine (CeeNU, CCNU), Streptozocin (Zanosar) and the like; plant alkaloids, e.g. Vincristine (Oncovin), Vinblastine (Velban, Velbe), Paclitaxel (Taxol), and the like; antimetabolites, e.g. Methotrexate (MTX), Mercaptopurine (Purinethol, 6-MP), Thioguanine (6-TG), Fluorouracil (5-FU), Cytarabine (Cytosar-U, Ara-C), Azacitidine (Mylosar, 5-AZA) and the like; antibiotics, e.g. Dactinomycin (Actinomycin D, Cosmegen), Doxorubicin (Adriamycin), Daunorubicin (duanomycin, Cerubidine), Idarubicin (Idamycin), Bleomycin (Blenoxane), Picamycin (Mithramycin, Mithracin), Mitomycin (Mutamycin) and the like, and other anticellular proliferative agents, e.g. Hydroxyurea (Hydrea), Procarbazine (Mutalane), Dacarbazine (DTIC-Dome), Cisplatin (Platinol) Carboplatin (Paraplatin), Asparaginase (Elspar) Etoposide (VePesid, VP-16-213), Amsarcrine (AMSA, m-AMSA), Mitotane (Lysodren), Mitoxantrone (Novatrone), and the like;
  • antibiotics, such as: aminoglycosides, e.g. amikacin, apramycin, arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin, fortimicin, gentamicin, isepamicin, kanamycin, micronomcin, neomycin, netilmicin, paromycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin; amphenicols, e.g. azidamfenicol, chloramphenicol, florfenicol, and theimaphenicol; ansamycins, e.g. rifamide, rifampin, rifamycin, rifapentine, rifaximin; b-lactams, e.g. carbacephems, carbapenems, cephalosporins, cehpamycins, monobactams, oxaphems, penicillins; lincosamides, e.g. clinamycin, lincomycin; macrolides, e.g. clarithromycin, dirthromycin, erythromycin, etc.; polypeptides, e.g. amphomycin, bacitracin, capreomycin, etc.; tetracyclines, e.g. apicycline, chlortetracycline, clomocycline, etc.; synthetic antibacterial agents, such as 2,4-diaminopyrimidines, nitrofurans, quinolones and analogs thereof, sulfonamides, sulfones;
  • antifungal agents, such as: polyenes, e.g. amphotericin B, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin, perimycin; synthetic antifungals, such as allylamines, e.g. butenafine, naftifine, terbinafine; imidazoles, e.g. bifonazole, butoconazole, chlordantoin, chlormidazole, etc., thiocarbamates, e.g. tolciclate, triazoles, e.g. fluconazole, itraconazole, terconazole;
  • anthelmintics, such as: arecoline, aspidin, aspidinol, dichlorophene, embelin, kosin, napthalene, niclosamide, pelletierine, quinacrine, alantolactone, amocarzine, amoscanate, ascaridole, bephenium, bitoscanate, carbon tetrachloride, carvacrol, cyclobendazole, diethylcarbamazine, etc.;
  • antimalarials, such as: acedapsone, amodiaquin, arteether, artemether, artemisinin, artesunate, atovaquone, bebeerine, berberine, chirata, chlorguanide, chloroquine, chlorprogaunil, cinchona, cinchonidine, cinchonine, cycloguanil, gentiopicrin, halofantrine, hydroxychloroquine, mefloquine hydrochloride, 3-methylarsacetin, pamaquine, plasmocid, primaquine, pyrimethamine, quinacrine, quinidine, quinine, quinocide, quinoline, dibasic sodium arsenate;
  • antiprotozoan agents, such as: acranil, tinidazole, ipronidazole, ethyistibamine, pentamidine, acetarsone, aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole, suramin, and the like.
  • Name brand drugs of interest include, but are not limited to: RezulinÔ, Lovastatin™, Enalapril™, Prozac™, Prilosec™, Lipotor™, Claritin™, Zocor™, Ciprofloxacin™, Viagra™, Crixivan™, Ritalin™, and the like.
  • Drug compounds of interest are also listed in: Goodman & Gilman's, The Pharmacological Basis of Therapeutics (9th Ed) (Goodman et al. eds) (McGraw-Hill) (1996); and 2001 Physician's Desk Reference.
  • Specific compounds of interest also include, but are not limited to:
  • antineoplastic agents, as disclosed in U.S. Pat. Nos. 5,880,161, 5,877,206, 5,786,344, 5,760,041, 5,753,668, 5,698,529, 5,684,004, 5,665,715, 5,654,484, 5,624,924, 5,618,813, 5,610,292, 5,597,831, 5,530,026, 5,525,633, 5,525,606, 5,512,678, 5,508,277, 5,463,181, 5,409,893, 5,358,952, 5,318,965, 5,223,503, 5,214,068, 5,196,424, 5,109,024, 5,106,996, 5,101,072, 5,077,404, 5,071,848, 5,066,493, 5,019,390, 4,996,229, 4,996,206, 4,970,318, 4,968,800, 4,962,114, 4,927,828, 4,892,887, 4,889,859, 4,886,790, 4,882,334, 4,882,333, 4,871,746, 4,863,955, 4,849,563, 4,845,216, 4,833,145, 4,824,955, 4,785,085, 476925, 4,684,747, 4,618,685, 4,611,066, 4,550,187, 4,550,186, 4,544,501, 4,541,956, 4,532,327, 4,490,540, 4,399,283, 4,391,982, 4,383,994, 4,294,763, 4,283,394, 4,246,411, 4,214,089, 4,150,231, 4,147,798, 4,056,673, 4,029,661, 4,012,448;
  • psycopharmacologicalpsychotropic agents, as disclosed in U.S. Pat. Nos. 5,192,799, 5,036,070, 4,778,800, 4,753,951, 4,590,180, 4,690,930, 4,645,773, 4,427,694, 4,424,202, 4,440,781, 5,686,482, 5,478,828, 5,461,062, 5,387,593, 5,387,586, 5,256,664, 5,192,799, 5,120,733, 5,036,070, 4,977,167, 4,904,663, 4,788,188, 4,778,800, 4,753,951, 4,690,930, 4,645,773, 4,631,285, 4,617,314, 4,613,600, 4,590,180, 4,560,684, 4,548,938, 4,529,727, 4,459,306, 4,443,451, 4,440,781, 4,427,694, 4,424,202, 4,397,853, 4,358,451, 4,324,787, 4,314,081, 4,313,896, 4,294,828, 4,277,476, 4,267,328, 4,264,499, 4,231,930, 4,194,009, 4,188,388, 4,148,796, 4,128,717, 4,062,858, 4,031,226, 4,020,072, 4,018,895, 4,018,779, 4,013,672, 3,994,898, 3,968,125, 3,939,152, 3,928,356, 3,880,834, 3,668,210;
  • cardiovascular agents, as disclosed in U.S. Pat. Nos. 4,966,967, 5,661,129, 5,552,411, 5,332,737, 5,389,675, 5,198,449, 5,079,247, 4,966,967, 4,874,760, 4,954,526, 5,051,423, 4,888,335, 4,853,391, 4,906,634, 4,775,757, 4,727,072, 4,542,160, 4,522,949, 4,524,151, 4,525,479, 4,474,804, 4,520,026, 4,520,026, 5,869,478, 5,859,239, 5,837,702, 5,807,889, 5,731,322, 5,726,171, 5,723,457, 5,705,523, 5,696,111, 5,691,332, 5,679,672, 5,661,129, 5,654,294, 5,646,276, 5,637,586, 5,631,251, 5,612,370, 5,612,323, 5,574,037, 5,563,170, 5,552,411, 5,552,397, 5,547,966, 5,482,925, 5,457,118, 5,414,017, 5,414,013, 5,401,758, 5,393,771, 5,362,902, 5,332,737, 5,310,731, 5,260,444, 5,223,516, 5,217,958, 5,208,245, 5,202,330, 5,198,449, 5,189,036, 5,185,362, 5,140,031, 5,128,349, 5,116,861, 5,079,247, 5,070,099, 5,061,813, 5,055,466, 5,051,423, 5,036,065, 5,026,712, 5,011,931, 5,006,542, 4,981,843, 4,977,144, 4,971,984, 4,966,967, 4,959,383, 4,954,526, 4,952,692, 4,939,137, 4,906,634, 4,889,866, 4,888,335, 4,883,872, 4,883,811, 4,847,379, 4,835,157, 4,824,831, 4,780,538, 4,775,757, 4,774,239, 4,771,047, 4,769,371, 4,767,756, 4,762,837, 4,753,946, 4,752,616, 4,749,715, 4,738,978, 4,735,962, 4,734,426, 4,734,425, 4,734,424, 4,730,052, 4,727,072, 4,721,796, 4,707,550, 4,704,382, 4,703,120, 4,681,970, 4,681,882, 4,670,560, 4,670,453, 4,668,787, 4,663,337, 4,663,336, 4,661,506, 4,656,267, 4,656,185, 4,654,357, 4,654,356, 4,654,355, 4,654,335, 4,652,578, 4,652,576, 4,650,874, 4,650,797, 4,649,139, 4,647,585, 4,647,573, 4,647,565, 4,647,561, 4,645,836, 4,639,461, 4,638,012, 4,638,011, 4,632,931, 4,631,283, 4,628,095, 4,626,548, 4,614,825, 4,611,007, 4,611,006, 4,611,005, 4,609,671, 4,608,386, 4,607,049, 4,607,048, 4,595,692, 4,593,042, 4,593,029, 4,591,603, 4,588,743, 4,588,742, 4,588,741, 4,582,854, 4,575,512, 4,568,762, 4,560,698, 4,556,739, 4,556,675, 4,555,571, 4,555,570, 4,555,523, 4,550,120, 4,542,160, 4,542,157, 4,542,156, 4,542,155, 4,542,151, 4,537,981, 4,537,904, 4,536,514, 4,536,513, 4,533,673, 4,526,901, 4,526,900, 4,525,479, 4,524,151, 4,522,949, 4,521,539, 4,520,026, 4,517,188, 4,482,562, 4,474,804, 4,474,803, 4,472,411, 4,466,979, 4,463,015, 4,456,617, 4,456,616, 4,456,615, 4,418,076, 4,416,896, 4,252,815, 4,220,594, 4,190,587, 4,177,280, 4,164,586, 4,151,297, 4,145,443, 4,143,054, 4,123,550, 4,083,968, 4,076,834, 4,064,259, 4,064,258, 4,064,257, 4,058,620, 4,001,421, 3,993,639, 3,991,057, 3,982,010, 3,980,652, 3,968,117, 3,959,296, 3,951,950, 3,933,834, 3,925,369, 3,923,818, 3,898,210, 3,897,442, 3,897,441, 3,886,157, 3,883,540, 3,873,715, 3,867,383, 3,873,715, 3,867,383, 3,691,216, 3,624,126;
  • antimicrobial agents as disclosed in U.S. Pat. Nos. 5,902,594, 5,874,476, 5,874,436, 5,859,027, 5,856,320, 5,854,242, 5,811,091, 5,786,350, 5,783,177, 5,773,469, 5,762,919, 5,753,715, 5,741,526, 5,709,870, 5,707,990, 5,696,117, 5,684,042, 5,683,709, 5,656,591, 5,643,971, 5,643,950, 5,610,196, 5,608,056, 5,604,262, 5,595,742, 5,576,341, 5,554,373, 5,541,233, 5,534,546, 5,534,508, 5,514,715, 5,508,417, 5,464,832, 5,428,073, 5,428,016, 5,424,396, 5,399,553, 5,391,544, 5,385,902, 5,359,066, 5,356,803, 5,354,862, 5,346,913, 5,302,592, 5,288,693, 5,266,567, 5,254,685, 5,252,745, 5,209,930, 5,196,441, 5,190,961, 5,175,160, 5,157,051, 5,096,700, 5,093,342, 5,089,251, 5,073,570, 5,061,702, 5,037,809, 5,036,077, 5,010,109, 4,970,226, 4,916,156, 4,888,434, 4,870,093, 4,855,318, 4,784,991, 4,746,504, 4,686,221, 4,599,228, 4,552,882, 4,492,700, 4,489,098, 4,489,085, 4,487,776, 4,479,953, 4,477,448, 4,474,807, 4,470,994, 4,370,484, 4,337,199, 4,311,709, 4,308,283, 4,304,910, 4,260,634, 4,233,311, 4,215,131, 4,166,122, 4,141,981, 4,130,664, 4,089,977, 4,089,900, 4,069,341, 4,055,655, 4,049,665, 4,044,139, 4,002,775, 3,991,201, 3,966,968, 3,954,868, 3,936,393, 3,917,476, 3,915,889, 3,867,548, 3,865,748, 3,867,548, 3,865,748, 3,783,160, 3,764,676, 3,764,677;
  • anti-inflammatory agents as disclosed in U.S. Pat. Nos. 5,872,109, 5,837,735, 5,827,837, 5,821,250, 5,814,648, 5,780,026, 5,776,946, 5,760,002, 5,750,543, 5,741,798, 5,739,279, 5,733,939, 5,723,481, 5,716,967, 5,688,949, 5,686,488, 5,686,471, 5,686,434, 5,684,204, 5,684,041, 5,684,031, 5,684,002, 5,677,318, 5,674,891, 5,672,620 5,665,752, 5,656,661, 5,635,516, 5,631,283, 5,622,948, 5,618,835, 5,607,959, 5,593,980, 5,593,960, 5,580,888, 5,552,424, 5,552,422 5,516,764, 5,510,361, 5,508,026, 5,500,417, 5,498,405, 5,494,927: 5,476,876 5,472,973 5,470,885, 5,470,842, 5,464,856, 5,464,849 5,462,952, 5,459,151, 5,451,686, 5,444,043 5,436,265, 5,432,181, RE034918, 5,393,756, 5,380,738, 5,376,670, 5,360,811, 5,354,768, 5,348,957, 5,347,029, 5,340,815, 5,338,753, 5,324,648, 5,319,099, 5,318,971, 5,312,821, 5,302,597, 5,298,633, 5,298,522, 5,298,498, 5,290,800, 5,290,788, 5,284,949, 5,280,045, 5,270,319, 5,266,562, 5,256,680, 5,250,700, 5,250,552, 5,248,682, 5,244,917, 5,240,929, 5,234,939, 5,234,937, 5,232,939, 5,225,571, 5,225,418, 5,220,025, 5,212,189, 5,212,172, 5,208,250, 5,204,365, 5,202,350, 5,196,431, 5,191,084, 5,187,175, 5,185,326, 5,183,906, 5,177,079, 5,171,864, 5,169,963, 5,155,122, 5,143,929, 5,143,928, 5,143,927, 5,124,455, 5,124,347, 5,114,958, 5,112,846, 5,104,656, 5,098,613, 5,095,037, 5,095,019, 5,086,064, 5,081,261, 5,081,147, 5,081,126, 5,075,330, 5,066,668, 5,059,602, 5,043,457, 5,037,835, 5,037,811, 5,036,088, 5,013,850, 5,013,751, 5,013,736, 500,654, 4,992,448, 4,992,447, 4,988,733, 4,988,728, 4,981,865, 4,962,119, 4,959,378, 4,954,519, 4,945,099, 4,942,236, 4,931,457, 4,927,835, 4,912,248, 4,910,192, 4,904,786, 4,904,685, 4,904,674, 4,904,671, 4,897,397, 4,895,953, 4,891,370, 4,870,210, 4,859,686, 4,857,644, 4,853,392, 4,851,412, 4,847,303, 4,847,290, 4,845,242, 4,835,166, 4,826,990, 4,803,216, 4,801,598, 4,791,129, 4,788,205, 4,778,818, 4,775,679, 4,772,703, 4,767,776, 4,764,525, 4,760,051, 4,748,153, 4,725,616, 4,721,712, 4,713,393, 4,708,966, 4,695,571, 4,686,235, 4,686,224, 4,680,298, 4,678,802, 4,652,564, 4,644,005, 4,632,923, 4,629,793, 4,614,741, 4,599,360, 4,596,828, 4,595,694, 4,595,686, 4,594,357, 4,585,755, 4,579,866, 4,578,390, 4,569,942, 4,567,201, 4,563,476, 4,559,348, 4,558,067, 4,556,672, 4,556,669, 4,539,326, 4,537,903, 4,536,503, 4,518,608, 4,514,415, 4,512,990, 4,501,755, 4,495,197, 4,493,839, 4,465,687, 4,440,779, 4,440,763, 4,435,420, 4,412,995, 4,400,534, 4,355,034, 4,335,141, 4,322,420, 4,275,064, 4,244,963, 4,235,908, 4,234,593, 4,226,887, 4,201,778, 4,181,720, 4,173,650, 4,173,634, 4,145,444, 4,128,664, 4,125,612, 4,124,726, 4,124,707, 4,117,135, 4,027,031, 4,024,284, 4,021,553, 4,021,550, 4,018,923, 4,012,527, 4,011,326, 3,998,970, 3,998,954, 3,993,763, 3,991,212, 3,984,405, 3,978,227, 3,978,219, 3,978,202, 3,975,543, 3,968,224, 3,959,368, 3,949,082, 3,949,081, 3,947,475, 3,936,450, 3,934,018, 3,930,005, 3,857,955, 3,856,962, 3,821,377, 3,821,401, 3,789,121, 3,789,123, 3,726,978, 3,694,471, 3,691,214, 3,678,169, 3,624,216;
  • immunosuppressive agents, as disclosed in U.S. Pat. Nos. 4,450,159, 4,450,159, 5,905,085, 5,883,119, 5,880,280, 5,877,184, 5,874,594, 5,843,452, 5,817,672, 5,817,661, 5,817,660, 5,801,193, 5,776,974, 5,763,478, 5,739,169, 5,723,466, 5,719,176, 5,696,156, 5,695,753, 5,693,648, 5,693,645, 5,691,346, 5,686,469, 5,686,424, 5,679,705, 5,679,640, 5,670,504, 5,665,774, 5,665,772, 5,648,376, 5,639,455, 5,633,277, 5,624,930, 5,622,970, 5,605,903, 5,604,229, 5,574,041, 5,565,560, 5,550,233, 5,545,734, 5,540,931, 5,532,248, 5,527,820, 5,516,797, 5,514,688, 5,512,687, 5,506,233, 5,506,228, 5,494,895, 5,484,788, 5,470,857, 5,464,615, 5,432,183, 5,431,896, 5,385,918, 5,349,061, 5,344,925, 5,330,993, 5,308,837, 5,290,783, 5,290,772, 5,284,877, 5,284,840, 5,273,979, 5,262,533, 5,260,300, 5,252,732, 5,250,678, 5,247,076, 5,244,896, 5,238,689, 5,219,884, 5,208,241, 5,208,228, 5,202,332, 5,192,773, 5,189,042, 5,169,851, 5,162,334, 5,151,413, 5,149,701, 5,147,877, 5,143,918, 5,138,051, 5,093,338, 5,091,389, 5,068,323, 5,068,247, 5,064,835, 5,061,728, 5,055,290, 4,981,792, 4,810,692, 4,410,696, 4,346,096, 4,342,769, 4,317,825, 4,256,766, 4,180,588, 4,000,275, 3,759,921;
  • analgesic agents, as disclosed in U.S. Pat. Nos. 5,292,736, 5,688,825, 5,554,789, 5,455,230, 5,292,736, 5,298,522, 5,216,165, 5,438,064, 5,204,365, 5,017,578, 4,906,655, 4,906,655, 4,994,450, 4,749,792, 4,980,365, 4,794,110, 4,670,541, 4,737,493, 4,622,326, 4,536,512, 4,719,231, 4,533,671, 4,552,866, 4,539,312, 4,569,942, 4,681,879, 4,511,724, 4,556,672, 4,721,712, 4,474,806, 4,595,686, 4,440,779, 4,434,175, 4,608,374, 4,395,402, 4,400,534, 4,374,139, 4,361,583, 4,252,816, 4,251,530, 5,874,459, 5,688,825, 5,554,789, 5,455,230, 5,438,064, 5,298,522, 5,216,165, 5,204,365, 5,030,639, 5,017,578, 5,008,264, 4,994,450, 4,980,365, 4,906,655, 4,847,290, 4,844,907, 4,794,110, 4,791,129, 4,774,256, 4,749,792, 4,737,493, 4,721,712, 4,719,231, 4,681,879, 4,670,541, 4,667,039, 4,658,037, 4,634,708, 4,623,648, 4,622,326, 4,608,374, 4,595,686, 4,594,188, 4,569,942, 4,556,672, 4,552,866, 4,539,312, 4,536,512, 4,533,671, 4,511,724, 4,440,779, 4,434,175, 4,400,534, 4,395,402, 4,391,827, 4,374,139, 4,361,583, 4,322,420, 4,306,097, 4,252,816, 4,251,530, 4,244,955, 4,232,018, 4,209,520, 4,164,514 4,147,872, 4,133,819, 4,124,713, 4,117,012, 4,064,272, 4,022,836, 3,966,944;
  • cholinergic agents, as disclosed in U.S. Pat. Nos. 5,219,872, 5,219,873, 5,073,560, 5,073,560, 5,346,911, 5,424,301, 5,073,560, 5,219,872, 4,900,748, 4,786,648, 4,798,841, 4,782,071, 4,710,508, 5,482,938, 5,464,842, 5,378,723, 5,346,911, 5,318,978, 5,219,873, 5,219,872, 5,084,281, 5,073,560, 5,002,955, 4,988,710, 4,900,748, 4,798,841, 4,786,648, 4,782,071, 4,745,123, 4,710,508;
  • adrenergic agents, as disclosed in U.S. Pat. Nos. 5,091,528, 5,091,528, 4,835,157, 5,708,015, 5,594,027, 5,580,892, 5,576,332, 5,510,376, 5,482,961, 5,334,601, 5,202,347, 5,135,926, 5,116,867, 5,091,528, 5,017,618, 4,835,157, 4,829,086, 4,579,867, 4,568,679, 4,469,690, 4,395,559, 4,381,309, 4,363,808, 4,343,800, 4,329,289, 4,314,943, 4,311,708, 4,304,721, 4,296,117, 4,285,873, 4,281,189, 4,278,608, 4,247,710, 4,145,550, 4,145,425, 4,139,535, 4,082,843, 4,011,321, 4,001,421, 3,982,010, 3,940,407, 3,852,468, 3,832,470;
  • antihistamine agents, as disclosed in U.S. Pat. Nos. 5,874,479, 5,863,938, 5,856,364, 5,770,612, 5,702,688, 5,674,912, 5,663,208, 5,658,957, 5,652,274, 5,648,380, 5,646,190, 5,641,814, 5,633,285, 5,614,561, 5,602,183, 4,923,892, 4,782,058, 4,393,210, 4,180,583, 3,965,257, 3,946,022, 3,931,197;
  • steroidal agents, as disclosed in U.S. Pat. Nos. 5,863,538, 5,855,907, 5,855,866, 5,780,592, 5,776,427, 5,651,987, 5,346,887, 5,256,408, 5,252,319, 5,209,926, 4,996,335, 4,927,807, 4,910,192, 4,710,495, 4,049,805, 4,004,005, 3,670,079, 3,608,076, 5,892,028, 5,888,995, 5,883,087, 5,880,115, 5,869,475, 5,866,558, 5,861,390, 5,861,388, 5,854,235, 5,837,698, 5,834,452, 5,830,886, 5,792,758, 5,792,757, 5,763,361, 5,744,462, 5,741,787, 5,741,786, 5,733,899, 5,731,345, 5,723,638, 5,721,226, 5,712,264, 5,712,263, 5,710,144, 5,707,984, 5,705,494, 5,700,793, 5,698,720, 5,698,545, 5,696,106, 5,677,293, 5,674,861, 5,661,141, 5,656,621, 5,646,136, 5,637,691, 5,616,574, 5,614,514, 5,604,215, 5,604,213, 5,599,807, 5,585,482, 5,565,588, 5,563,259, 5,563,131, 5,561,124, 5,556,845, 5,547,949, 5,536,714, 5,527,806, 5,506,354, 5,506,221, 5,494,907, 5,491,136, 5,478,956, 5,426,179, 5,422,262, 5,391,776, 5,382,661, 5,380,841, 5,380,840, 5,380,839, 5,373,095, 5,371,078, 5,352,809, 5,344,827, 5,344,826, 5,338,837, 5,336,686, 5,292,906, 5,292,878, 5,281,587, 5,272,140, 5,244,886, 5,236,912, 5,232,915, 5,219,879, 5,218,109, 5,215,972, 5,212,166, 5,206,415, 5,194,602, 5,166,201, 5,166,055, 5,126,488, 5,116,829, 5,108,996, 5,099,037, 5,096,892, 5,093,502, 5,086,047, 5,084,450, 5,082,835, 5,081,114, 5,053,404, 5,041,433, 5,041,432, 5,034,548, 5,032,586, 5,026,882, 4,996,335, 4,975,537, 4,970,205, 4,954,446, 4,950,428, 4,946,834, 4,937,237, 4,921,846, 4,920,099, 4,910,226, 4,900,725, 4,892,867, 4,888,336, 4,885,280, 4,882,322, 4,882,319, 4,882,315, 4,874,855, 4,868,167, 4,865,767, 4,861,875, 4,861,765, 4,861,763, 4,847,014, 4,774,236, 4,753,932, 4,711,856, 4,710,495, 4,701,450, 4,701,449, 4,689,410, 4,680,290, 4,670,551, 4,664,850, 4,659,516, 4,647,410, 4,634,695, 4,634,693, 4,588,530, 4,567,000, 4,560,557, 4,558,041, 4,552,871, 4,552,868, 4,541,956, 4,519,946, 4,515,787, 4,512,986, 4,502,989, 4,495,102; the disclosures of which are herein incorporated by reference.
  • Also of interest are analogs of the above compounds.
  • For all of the above active agents, the active agents may be present as pharmaceutically acceptable salts.
  • As indicated above, the active agent of the compositions are typically present in a pharmaceutically acceptable vehicle or carrier, e.g., as described below. In certain embodiments, the active agent is present in an amount of from about 0.1% to about 90% by weight, e.g., from about 1% to about 30% by weight of the active compound.
  • Pharmaceutically Acceptable Carrier
  • As summarized above, the compositions of the invention further include a pharmaceutically acceptable vehicle (i.e., carrier). Common carriers and excipients, such as corn starch or gelatin, lactose, dextrose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid are of interest. Disintegrators commonly used in the formulations of the invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
  • A liquid composition may comprise a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s), for example, ethanol, glycerine, sorbitol, non-aqueous solvent such as polyethylene glycol, oils or water, with a suspending agent, preservative, surfactant, wetting agent, flavoring or coloring agent. Alternatively, a liquid formulation can be prepared from a reconstitutable powder. For example, a powder containing active compound, suspending agent, sucrose and a sweetener can be reconstituted with water to form a suspension; and a syrup can be prepared from a powder containing active ingredient, sucrose and a sweetener.
  • A composition in the form of a tablet or pill can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example, polyvinylpyrrolidone. The tablet can also be provided with a color film coating, or color included as part of the carrier(s). In addition, active compound can be formulated in a controlled release dosage form as a tablet comprising a hydrophilic or hydrophobic matrix.
  • “Controlled release”, “sustained release”, and similar terms are used to denote a mode of active agent delivery that occurs when the active agent is released from the delivery vehicle at an ascertainable and controllable rate over a period of time, rather than dispersed immediately upon application or injection. Controlled or sustained release may extend for hours, days or months, and may vary as a function of numerous factors. For the pharmaceutical composition of the present invention, the rate of release will depend on the type of the excipient selected and the concentration of the excipient in the composition. Another determinant of the rate of release is the rate of hydrolysis of the linkages between and within the units of the polyorthoester. The rate of hydrolysis in turn may be controlled by the composition of the polyorthoester and the number of hydrolysable bonds in the polyorthoester. Other factors determining the rate of release of an active agent from the present pharmaceutical composition include particle size, acidity of the medium (either internal or external to the matrix) and physical and chemical properties of the active agent in the matrix.
  • A composition in the form of a capsule can be prepared using routine encapsulation procedures, for example, by incorporation of active compound and excipients into a hard gelatin capsule. Alternatively, a semi-solid matrix of active compound and high molecular weight polyethylene glycol can be prepared and filled into a hard gelatin capsule; or a solution of active compound in polyethylene glycol or a suspension in edible oil, for example, liquid paraffin or fractionated coconut oil can be prepared and filled into a soft gelatin capsule.
  • Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose. Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
  • Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. Additionally, it may be desirable to add a coloring agent to make the dosage form more attractive in appearance or to help identify the product.
  • The compounds of the invention and their pharmaceutically acceptable salts that are active when given parenterally can be formulated for intramuscular, intrathecal, or intravenous administration.
  • A typical composition for intramuscular or intrathecal administration will be of a suspension or solution of active ingredient in an oil, for example, arachis oil or sesame oil. A typical composition for intravenous or intrathecal administration will be a sterile isotonic aqueous solution containing, for example, active ingredient and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride. Other examples are lactated Ringer's injection, lactated Ringer's plus dextrose injection, Normosol-M and dextrose, Isolyte E, acylated Ringer's injection, and the like. Optionally, a co-solvent, for example, polyethylene glycol, a chelating agent, for example, ethylenediamine tetraacetic acid, and an anti-oxidant, for example, sodium metabisulphite may be included in the formulation. Alternatively, the solution can be freeze dried and then reconstituted with a suitable solvent just prior to administration.
  • The compounds of the invention and their pharmaceutically acceptable salts which are active on rectal administration can be formulated as suppositories. A typical suppository formulation will generally consist of active ingredient with a binding and/or lubricating agent such as a gelatin or cocoa butter or other low melting vegetable or synthetic wax or fat.
  • The compounds of this invention and their pharmaceutically acceptable salts which are active on topical administration can be formulated as transdermal compositions or transdermal delivery devices (“patches”). Such compositions include, for example, a backing, active compound reservoir, a control membrane, liner and contact adhesive. Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. For example, see U.S. Pat. No. 5,023,252, herein incorporated by reference in its entirety. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Optionally, the pharmaceutical composition may contain other pharmaceutically acceptable components, such a buffers, surfactants, antioxidants, viscosity modifying agents, preservatives and the like. Each of these components is well-known in the art. For example, see U.S. Pat. No. 5,985,310, the disclosure of which is herein incorporated by reference.
  • Other components suitable for use in the formulations of the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985).
  • Identifiers
  • Also present in the subject compositions is an identifier. The identifier may vary depending on the particular embodiment and intended application of the composition. In certain embodiments, the identifier is a component that emits a signal upon activation by a stimulus, e.g., by interrogation, upon contact with a target physiological location, etc. As such, the identifier may be an identifier that emits a signal when it contacts a target body (i.e., physiological) site. In addition or alternatively, the identifier may be an identifier that emits a signal when interrogated.
  • In yet other embodiments, the identifier is an inert, but identifiable marker, e.g., an engraved identifier (such as one that is fabricated from a material or materials that survive digestion). This marker may then be identified, for example, following an autopsy or forensic examination. It is possible to provide a more internal device within a pill to determine both that its surface has partially been subject to digestion, but also that the inner pill material has also been digested. This application is particularly useful in experimental pharmacological settings. The identifier of these embodiments is one that does not necessarily emit a signal, but which can be optically inspected, e.g., visually or machine read, to obtain information about the composition with which it was associated prior to administration.
  • While the identifier may be an identifier that does not emit a signal, in certain embodiments (as summarized above) the identifier is one that does emit a signal. Depending on the needs of a particular application, the signal may be a generic signal, e.g., a signal that merely identifies that the composition has contacted the target site, or a unique signal, e.g., a signal which in some way uniquely identifies that a particular composition from a group or plurality of different compositions in a batch has contacted a target physiological site. As such, the identifier may be one that, when employed in a batch of unit dosages, e.g., a batch of tablets, emits a signal which cannot be distinguished from the signal emitted by the identifier of any other unit dosage member of the batch. In yet other embodiments, the identifier emits a signal that uniquely identifies a given unit dosage, even from other identical unit dosages in a given batch. Accordingly, in certain embodiments the identifier emits a unique signal that distinguishes a given type of unit dosage from other types of unit dosages, e.g., a given medication from other types of medications. In certain embodiments, the identifier emits a unique signal that distinguishes a given unit dosage from other unit dosages of a defined population of unit dosages, e.g., a prescription, a batch or a lifetime production run of dosage formulations. In certain embodiments, the identifier emits a signal that is unique, i.e., distinguishable, from a signal emitted by any other dosage formulation ever produced, where such a signal may be viewed as a universally unique signal (e.g., analogous to a human fingerprint which is distinct from any other fingerprint of any other individual and therefore uniquely identifies an individual on a universal level). In one embodiment, the signal may either directly convey information about the composition, or provide an identifying code, which may be used to retrieve information about the composition from a database, i.e., a database linking identifying codes with compositions.
  • The identifier may be any component or device that is capable of generating a detectable signal following activation in response to a stimulus. In certain embodiments, the stimulus activates the identifier to emit a signal once the composition comes into contact with a physiological target site, e.g., as summarized above. For example, a patient may ingest a pill that upon contact with the stomach fluids, generates a detectable signal. Depending on the embodiment, the target physiological site or location may vary, where representative target physiological sites of interest include, but are not limited to: a location in the gastrointestinal tract (such as the mouth, esophagus, stomach, small intestine, large intestine, etc.); another location inside the body, such as a parental location, vascular location, etc.; or a topical location; etc.
  • In certain embodiments the stimulus that activates the identifier is an interrogation signal, such as a scan or other type of interrogation. In these embodiments, the stimulus activates the identifier, thereby emitting a signal which is then received and processed, e.g., to identify the composition in some manner.
  • In certain of these embodiments, the identifier may include a power source that transduces broadcast power and a signal generating element that modulates the amount of transduced power, such that a signal is not emitted from the identifier but instead the amount of broadcast power transduced by the identifier is detected and employed as the “signal.” Such embodiments are useful in a variety of applications, such as applications where the history of a given composition is of interest, e.g., as reviewed in greater detail below.
  • In certain embodiments, the identifier is dimensioned to be complexed with the active agent/pharmaceutically acceptable carrier component of the composition so as to produce a composition that can be readily administered to a subject in need thereof. As such, in certain embodiments, the identifier element is dimensioned to have a width ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mm to about 1 mm, such as from about 0.05 mm to about 0.3 mm, including from about 0.1 mm to about 0.2 mm. In certain embodiments the identifier is 1 mm3 or smaller, such as 0.1 mm3 or smaller, including 0.2 mm3 or smaller. The identifier element may take a variety of different configurations, such as but not limited to: a chip configuration, a cylinder configuration, a spherical configuration, a disc configuration, etc, where a particular configuration may be selected based on intended application, method of manufacture, etc.
  • The identifier may generate a variety of different types of signals, including but not limited, RF, magnetic, conductive (near field), acoustic, etc.
  • As is known in the art (see, e.g., J. D. Jackson, Classical Electrodynamics, 2nd Edition, pp. 394-396 (1975)), the electric (E) and magnetic (B) fields for radiation of an oscillating electric dipole antenna with an angular frequency ω and corresponding wave number k (where k=ω/c, with c being the speed of light in the relevant medium) are given by the equations:
  • B = k 2 ( n × p ) kr r ( 1 - 1 kr ) ; and ( 1 ) E = k 2 ( n × p ) × n kr r + [ 3 n ( n · p ) - p ] ( 1 r 3 - k r 2 ) kr , ( 2 )
  • where n is a unit vector in the direction from the center of the dipole source to a location x at a distance r from the source, and p is a space-integrated density of electric charge given by (p=∫x′ρ(x′)d3x′).
  • As can be seen from Eqs. (1) and (2), in the “far field” region, where r>>λ (where the wavelength λ=2π/k), the electric and magnetic fields are dominated by terms that decrease with distance as 1/r. In this region, mutually perpendicular electric and magnetic fields feed off one another to propagate the signal through space. Where λ˜r, the 1/r2 (“induction”) terms in Eqs. (1) and (2) become significant, and where λ>>r, an additional quasi-electrostatic term that varies as 1/r3 also becomes significant.
  • Conventional RF communication takes place at distances r˜λ to r>>λ. For instance, implantable medical devices such as pacemakers typically communicate in the 405-MHz frequency band, corresponding to wavelengths of 0.75 meters, somewhat smaller than the scale of a human body. As is known in the art, higher frequencies are advantageously not used because structures within the body begin to absorb radiation, leading to undesirable signal loss; substantially lower frequencies (longer wavelengths) are generally regarded as undesirable because much of the energy is redirected into the induction and/or quasi-static field components rather than the far-field component that can be sensed using conventional antennas. It should also be noted that RFID applications with a transponder and a base unit typically use wavelengths such that r˜λ and generally rely on magnetic induction to transmit power from the transponder to the base unit. In certain embodiments, these RF signals are employed.
  • In contrast to these approaches, certain embodiments of the present invention advantageously operate at wavelengths much larger than the human body (λ>>1 meter) to communicate information within the patient's body, e.g., as described in U.S. Provisional Application Ser. No. 60,713,680; the disclosure of which is herein incorporated by reference. For instance, in some embodiments, frequencies on the order of 100 kHz, corresponding to wavelengths of around 3 km (in air), are advantageously used. At distances r that are short as compared to the wavelength λ, the quasi-static electric field term in Eqs. (1) and (2) dominates, and thus the propagating signal is predominantly electrical rather than electromagnetic. Such signals readily propagate in a conductive medium such as the human body. For instance, at a frequency of 100 kHz and distances on the order of 1-2 meters, the quasi-static (1/r3) component of Eq. (2) is estimated to be on the order of 106 times stronger than the far-field (1/r) component. Thus, long-wavelength signaling using near-field coupling is efficient. Further, because the signals are required to travel relatively short distances (typically 2 meters or less), detectable signals can be transmitted using very small antennas.
  • A wide range of frequencies may be used for transmission of signals. In some embodiments, the transmission frequency is within the “LF” band (low frequency, defined as 30-300 kHz) of the RF spectrum, below the frequency range of AM radio (around 500 to 1700 kHz). Within the LF band, the range from 160-190 kHz has been designated by the FCC for experimental use, with specified upper limits on external signal strength. In embodiments of the present invention where the signals are largely confined within the patient's body as described below, this experimental band can be used.
  • However, the invention is not limited to the 160-190 kHz band or to the LF (30-300 kHz band). Lower bands may also be used; for instance, in the VLF band (3-30 kHz, wavelengths of 10-100 km in air), signals can penetrate water to a distance of 10-40 meters. Since the electrical properties of the human body are similar to those of salt water, it is expected that signals in this band would also readily propagate through the body. Thus, any frequency band corresponding to a wavelength that is at least an order of magnitude larger than the human body—e.g., λ˜10 m or longer, or frequencies on the order of 30 MHz or below—can be used.
  • While there is no necessary lower limit on the frequency of signals used, several practical considerations may affect the choice of frequency. For instance, it is well known that the human body carries low-level oscillating signals induced by nearby AC-powered devices, which operate at ˜60 Hz (US) or similar frequencies in other parts of the world. To avoid interference caused by AC electrical power systems, frequencies near 60 Hz are advantageously not used. In addition, as is known in the art, longer wavelengths correlate with lower information transfer rates, and the information-transfer capacity at long wavelengths (e.g., below the 3 kHz-30 kHz VLF band) may be too small for the amount of information that is to be transferred in a particular system. Further, longer wavelengths generally require longer dipole antennas to produce a detectable signal, and at some point the antenna size may become a limiting factor in frequency selection.
  • According to some embodiments of the invention, given a suitable choice of frequency, a signal strong enough to travel to a receiver within the body can be generated using a very small antenna. For instance, 100 kHz signals generated by a dipole antenna just a few millimeters long can be propagated to a receiver antenna placed 1-2 meters away. This quasi-electrostatic transmission is believed to be aided by the fact that the implanted antenna is directly in contact with a conductive medium, for example, the patient's tissues. For purposes of analyzing electrical properties, human tissue can be approximated as an electrolyte solution with electrical properties comparable to those of salt water. Thus, as in an electrolyte bath, the quasi-electrostatic field created by an oscillating dipole antenna induces an oscillating current in the body. As a result of the inherent electrical resistivity of the body (comparable to salt water), the oscillating current creates oscillating potential variations within the body that can be sensed using a suitable receiver. (See, e.g., L. D. Landau et al. Electro-dynamics of Continuous Media, Ch. 3 (1960)). Examples of suitable receivers include the leads of a pacemaker, which create a dipole with an axis of about 20 cm or any other implanted wires with length from 10-100 cm.
  • It should be noted that these currents are undesirable in the context of conventional RF communication, in which current flow in the near field leads to power loss in the far-field. In fact, many RF transmitters include devices designed to minimize near-field current leakage. In near-field transmitters of these embodiments of the present invention, maximizing such currents is desirable.
  • Further, for quasi-electrostatic signals, the patient's skin advantageously acts as a conductive barrier, confining the signals within the patient's body. This confines the signals within the body and also makes it difficult for stray external signals to penetrate the body and create noise or interference in the transmitted signals. Confinement of the signals can mitigate, to some extent, the 1/r falloff of the near-field signal, further reducing power requirements. Such effects have been observed in the laboratory, e.g., in a salt water bath, in which the water/air interface acting as a conductive barrier. Similar effects have been observed in communicating with submarines via RF transmission in the ELF (3-30 Hz) and SLF (30-300 Hz) bands. These effects have also been observed in sonar communications; although sonar uses acoustic, rather than electrical or electromagnetic, fields to transmit information, the surface of the water acts as a conductive barrier for acoustic energy and mitigates the fall-off of signal intensity with distance.
  • As a result of these phenomena, a transmitter with a very small antenna and a small power source are sufficient to create a near-field signal that is detectable within the patient's body. For instance, the antenna can be formed by a pair of electrodes a few millimeters or less in length, spaced apart by a few millimeters, with oscillating voltages of opposite phase applied to create an oscillating electric dipole. Such antennas can be disposed almost anywhere within the body.
  • Further, in some embodiments, the frequency, transmitter antenna length, and receiver antenna length are selected such that only microwatts of power are required to produce a detectable signal, where conventional RF communication (e.g., at around 405 MHz) would require at least milliwatts. Accordingly, very compact power supplies that produce only small amounts of power can be used; examples are described in Section IV below.
  • As such, depending on the particular embodiment of interest, the frequency may range from about 0.1 Hz or lower to about 100 mHz or higher, e.g., from about 1 kHz to about 70 mHz, including from about 5 kHz to about 200 kHz.
  • In certain embodiment, the signal that is emitted by the identifier is an acoustic signal. In these embodiments, any convenient acoustic signal generation element may be present in the identifier, e.g., a piezoelectric element, etc.
  • The transmission time of the identifier may vary, where in certain embodiments the transmission time may range from about 0.1 μsec to about 4 hours or longer, such as from about 1 sec to about 4 hours. Depending on the given embodiment, the identifier may transmit a signal once or transmit a signal two or more times, such that the signal may be viewed as a redundant signal.
  • In certain embodiments, the identifier may be one that is programmable following manufacture, in the sense that the signal generated by the identifier may be determined after the identifier is produced, where the identifier may be field programmable, mass programmable, fuse programmable, and even reprogrammable. Such embodiments are of interest where uncoded identifiers are first produced and following incorporation into a composition are then coded to emit an identifying signal for that composition. Any convenient programming technology may be employed. In certain embodiments, the programming technology employed is RFID technology. RFID smart tag technology of interest that may be employed in the subject identifiers includes, but is not limited to: that described in U.S. Pat. Nos. 7,035,877; 7,035,818; 7,032,822; 7,031,946, as well as published application no. 20050131281, and the like, the disclosures of which are herein incorporated by reference. With RFID or other smart tag technology, a manufacturer/vendor may associate a unique ID code with a given identifier, even after the identifier has been incorporated into the composition. In certain embodiments, each individual or entity involved in the handling of the composition prior to use may introduce information into the identifier, e.g., in the form of programming with respect to the signal emitted by the identifier, e.g., as described in U.S. Pat. No. 7,031,946 the disclosure of which is herein incorporated by reference.
  • The identifier of certain embodiments includes a memory element, where the memory element may vary with respect to its capacity. In certain embodiments, the memory element has a capacity ranging from about 1 bit to 1 gigabyte or more, such as 1 bit to 1 megabyte, including from about 1 bit to about 128 bit. The particular capacity employed may vary depending on the application, e.g., whether the signal is a generic signal or coded signal, and where the signal may or may not be annotated with some additional information, e.g., name of active agent, etc.
  • Identifier components of embodiments of the invention have: (a) an activation component and (b) a signal generation component, where the signal generation component is activated by the activation component to produce an identifying signal, e.g., as described above.
  • Activation Component
  • The activation component is a component that activates the signal generation element to emit a signal upon experience of a stimulus, e.g., contact of the composition with a target physiological site of interest, such as the stomach. The activation component may be configured to be activated in a number of different ways. The following sections detail certain different ways in which the identifier may be activated. As can be seen from the following review, the activation component may or may not be integrated with a power source, e.g., a battery. Illustrative activation approaches include, but are not limited to: Battery Completion, e.g., Battery activated by electrolyte addition and Battery activated by cathode or anode addition; Battery connection, e.g., Battery activated by conductor addition; Transistor-mediated Battery Connection, e.g., Battery activated by transistor gate, Geometry Modification, Detection of Geometry Modification by Resonant Structure, Pressure Detection, Resonant Structure Modification; etc. Each of these illustrative activation approaches is now reviewed in greater detail.
  • Battery Completion Battery Activated by Electrolyte Addition
  • In these embodiments, the battery includes, when completed, a cathode, an anode, and an electrolyte. When the composition (e.g., pill) is administered, e.g., ingested, and travels through the esophagus, it proceeds to enter the stomach. The cathode and anode provided within the composition do not constitute a full battery. However, as the composition dissolves to expose the cathode and anode, the stomach fluid acts as the electrolyte component of the battery. The added component of the stomach fluid thus completes the battery. Therefore, as the composition contacts the target site, e.g., by entering the stomach and dissolving to the point of cathode and anode exposure, a power source is provided which activates the identifier, e.g., in chip configuration. The data signal is then transmitted. This configuration is described in greater detail below, e.g., in terms FIG. 4.
  • Battery Activated by Cathode or Anode Addition
  • In an extension of this approach, the system is activated by having the triggering event add a cathode or anode component, with the electrolyte being intrinsic in the partial, pre-battery configuration. The battery is completed, producing power and activating the composition, although not necessarily at the identical point of time.
  • Battery Connection Battery Activated by Conductor Addition
  • In another embodiment of the present invention, the battery is connected to the circuitry when it enters the stomach. The battery becomes connected, and thus activates the identifier, by conductor addition. In this case, there is a physically complete battery and a complete chip. When these two components are awash in physiological fluid, such as in the stomach, they become electronically connected. This triggering event electrically connects the battery to the signaling microchip, thus activating the smart pill.
  • Transistor-Mediated Battery Connection Battery Activated by Transistor Gate
  • Another design allowing the battery and the chip together to activate the smart pill has the feature of a transistor gate between the battery and the reporting chip. Once the transistor gate is switched on, such as by activation with the stomach, the reporting signal is transmitted.
  • There are numerous methods well know to the ordinary skilled artisan for turning on a transistor gate. Most of them involve activating the gate by closing a switch, which can include a transistor switch or other types of switches.
  • The gate can be activated by applying a small gate current. This is how, for example, transistors are typically activated. The gate current can be generated in any number of ways well know to the ordinary skilled artisan. Any circuitry which detects the presence of the pill in the environment of interest, such as the stomach, generates the gate current and turns the system on.
  • The gate current can be turned on by detecting a conductivity variation. For instance, a circuit can be provided that detects a small change in the conductivity of the stomach. While the stomach is conductive, the pill might not be. As a result, when the conductivity variation is detected, the transistor gate is activated, turning the smart pill on and generating a reporting signal.
  • The conductivity can be modulated by a change in the solution concentration. By example, the system detects a different solution concentration in the stomach in contrast to areas outside the stomach. The solution pH is detected, by a modulation of the conductivity, which turns on the gate, and turn on the pill generating a reporting signal.
  • The stomach contains ionic conductive fluids. Those ionic conductive fluids can be employed to modulate the conductivity of the gate and turn on the smart pill, generating a reporting signal. Individual enzymes can be detected in the stomach. For instance, a chem-FET can be employed that looks for the pepsin content in the stomach, turning the pill on, thus reporting the presence of the enzyme.
  • Temperature change can also be detected using the innovations of the present invention. The stomach is typically a steady 37° C. Areas outside the stomach are more typically 20° C. or less. When the pill enters the stomach and becomes heated up, the pill is so designed that this adjusts the conductivity and turn the identifier on, generating a reporting signal.
  • The conductivity of the transistor can be modified by a microscopic property called carrier mobility. A detection approach using this property uses the transistor itself as a detector. The carrier mobility is modulated by temperature, a well-known phenomenon. In this manner, the transistor is used as a temperature sensor by using that transistor to turn on the smart pill, generating a reporting signal.
  • Another approach is to change the charge on the gate of a MOSFET transistor. The gate charge can be modulated by the factors to be detected. This is again a configuration using the transistor to turn on the circuit, generating a reporting signal.
  • In another configuration, the gate charge is modulated by a material to be detected in the solution. A specific ion would preferentially change the gate charge. This system is modulated by a crystal potential. A crystal potential occurs when crystals generate electric fields under certain circumstances.
  • The electric field can change the charge on the gate, turning on the transistor and generating a reporting signal. This change may be modulated by a chemical potential, resulting from an osmotic or ionic process. This causes charge to accumulate on the gate, thereby, turning it on and generating a reporting signal.
  • A change in the electrical potential can also cause a reporting signal using a variety of potentials. For example, a gravitational potential can detect the change in height of the detector. In the case of a patient swallowing the pill, the change in pill height would indicate ingestion.
  • In another embodiment, a transistor gate has associated with it a capacitance. That capacitance is then modulated by certain properties peculiar to the target site, e.g., the stomach.
  • In one case, the capacitance is changed by being enveloped in the stomach. This effect on the capacitance is then detected. The gate charge is modulated by change in the carrier concentration. The carrier concentration is modulated by temperature. This approach provides a slightly different approach, but similar in concept to using the transistor as a temperature sensor as above.
  • Geometry Modification
  • A transistor structure is also provided that has a geometry that changes. Gate capacitance is determined by a change in geometry which occurs in the stomach, detecting a change in capacitance. These changes can take place in a variety of ways, for example, as further described below.
  • A variety of physiologic factors change the geometry. Pressure in the stomach different than pressure outside occurs with the natural squeezing during the production of chyme, as well as at other times. This changes the gate capacitance. The change is detected by having a dielectric on the gate. In this case, the gate consists of a number of layers, one of which is the dielectric.
  • In an additional embodiment, the enzymes of the stomach dissolve the dielectric, changing the gate capacitance, which is then detected. Various physical and chemical conditions within the stomach dissolve that gate dielectric, thereby activating the circuit.
  • Detection of Geometry Modification by Resonant Structure
  • A resonant structure on the gate is provided in other variants. In this case, a mechanical structure is provided that has a characteristic frequency. This frequency is excited by the triggering event, and measured. Various interactions with the stomach will cause a change in that resonance.
  • Pressure Detection
  • Gate capacitance and resonance with modulation source can also be utilized for detection. In this case, an excitation is provided to the resonance structure from a modulation source, such as a sound wave. The gate capacitance of that resonance structure can be used to detecting pressure waves. A resonance structure sits out in the stomach and is hooked up to a detection circuit on a transistor. In the stomach, the resonance circuit detects pressure waves.
  • Of pressure sound waves within the body, there are particular sounds that are characteristic, such as the heart beat and respiration. These sounds are detected and used to turn the circuit on.
  • Pressure waves are also detected by resonant Q factor modulation. Q factor modulation can be accomplished in a number of different manners. The resonance structure has two components, a frequency and a Q factor. The Q factor is modulated by detecting some environmental change.
  • Resonant Structure Modification
  • By example, the structure has a very different Q factor in air than it does in the fluid of the stomach. Thus, the dampening can be detected by the fluid viscosity. Additionally, the structure can be configured to be eaten away by the acid or some of the enzymes in the stomach, which changes the cue.
  • Degradation by stomach acid or enzymes also changes the resonant frequency. It is simple to detect the frequency shift of such a structure. The frequency is shifted as this structure is changed in the stomach. There are two approaches to modifying the structure. A catabolic process can occur where the structure gets dissolved, which is easily detectable. Also, an anabolic process would occur where an enzyme from the stomach binds to this structure, making it larger. This effect will also modify the resonance structure. The resonance modification is detected either as a frequency change or a Q factor modulation.
  • Battery Power Sources
  • As reviewed above, in certain embodiments, the activation element is a power source that is turned on upon contact of the power source with a target site, e.g., a physiological target site, such as the stomach, e.g., stomach acid. In certain embodiments, the power source is a battery that is turned on to provide power upon contact with the physiological target site, where the battery is coupled to the signal generation component such that when the battery is turned on, the signal generation component emits the identifying signal.
  • In certain embodiments, the battery that is employed is one that comprises two dissimilar materials which constitute the two electrodes of the battery. In certain embodiments, these two materials are shielded from the surrounding environment by an additional layer of material. When the shielding material (e.g., active agent/carrier matrix), is dissolved or eroded by the surrounding fluid, the electrode materials are exposed and come in contact with the body fluid, such as stomach acid or other types of electrolyte fluid. A potential difference, that is, a voltage, is generated between the electrodes as a result of the respective oxidation and reduction reactions incurred to the two electrode materials. A voltaic cell, or battery, can be thereby formed. Accordingly, in embodiments of the invention, such batteries are configured such that when the two dissimilar materials are exposed to the target site, e.g., the stomach, the digestive tract, etc., during the physical and chemical erosion of the composition in which the signal generation element is present, a voltage is generated. In such embodiments, the power source described above is not a “battery” in the common sense of the word, but rather as defined in the discipline of physics. The two dissimilar materials in an electrolyte are at different potentials, similar to the physics model of a ‘potato battery’. As an example, copper and zinc when put into a cell have different potentials. Similarly, gold and magnesium have different potentials. As a result, a potential difference between the two dissimilar materials is generated.
  • Various battery-activation configurations are possible. Representative types of cell-activation approaches include, but are not limited to: activation by presence of electrolyte, activation by presence of a cathode material, activation by presence of a conductive material.
  • After the battery is activated, further activation configurations can be employed to activate the signal generation component. For example, the signal generation component can be activated through the activation of the gate of a metal oxide semiconductor (MOS) circuit, such as a CMOS switch. Activation of the gate of the MOS circuit can be based on one or more parameters, which include but are not limited to: gate current, gate charge, and gate capacitance.
  • The gate current, for activation purposes, can be a function of the conductivity of surrounding body fluids or tissues. Such conductivity can further be a function of one or more parameters, which include but are not limited to: solution concentration, solution pH value, ionic content of solution, enzymatic content of solution, temperature, and carrier mobility. Carrier mobility can also be a function of temperature.
  • Similarly, the gate charge can be a function of one or more parameters, which include but are not limited to: solution composition, crystal potential, electrical potential, gravitational potential, gate capacitance, and carrier concentration. The carrier concentration can also be a function of temperature.
  • The gate capacitance can be a function of the capacitive geometry of the gate, which can further be a function of pressure, a resonant input, or the characteristics of a dielectric material coupled to the gate. The characteristics of the dielectric material can vary with one or more parameters, which include but are not limited to: chemical contents of a digestive tract, chemical character of a physiological location, and amount of dissolution of the dielectric material in body fluids.
  • In certain embodiments, the battery is one that is made up of active electrode materials, electrolyte, and inactive materials, such as current collectors, packaging, etc. The active materials are any pair of materials with different electrochemical potentials. Suitable materials are not restricted to metals, and in certain embodiments the paired materials are chosen from metals and non-metals, e.g., a pair made up of a metal (such as Mg) and a salt (such as CuI). With respect to the active electrode materials, any pairing of substances—metals, salts, or intercalation compounds—with suitably different electrochemical potentials (voltage) and low interfacial resistance are suitable.
  • A variety of different materials may be employed as the battery electrodes. In certain embodiments, electrode materials are chosen to provide for a voltage upon contact with the target physiological site, e.g., the stomach, sufficient to drive the signal generation element of the identifier. In certain embodiments, the voltage provided by the electrode materials upon contact of the metals of the power source with the target physiological site is 0.001 V or higher, including 0.01 V or higher, such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5 volts or higher, and including 1.0 volts or higher, where in certain embodiments, the voltage ranges from about 0.001 to about 10 volts, such as from about 0.01 to about 10 V.
  • Materials and pairings of interest include, but are not limited to those reported in Table 1 below.
  • TABLE 1
    Anode Cathode
    Metals Magnesium, Zinc
    Sodium (†),
    Lithium (†) Iron
    Salts Copper salts: iodide, chloride, bromide,
    sulfate, formate, (other anions possible)
    Fe3+ salts: e.g. orthophosphate,
    pyrophosphate, (other anions possible)
    Oxygen (††) on platinum, gold or other
    catalytic surfaces
    Intercalation Graphite with Li, Vanadium oxide
    compounds K, Ca, Na, Mg Manganese oxide
    (†) Protected anodes: certain high energy anode material such as Li, Na, and other alkali metals are unstable in their pure form in the presence of water or oxygen. These may however be used in an aqueous environment if stabilized. One example of this stabilization is the so-called “protected lithium anode” developed by Polyplus Corporation (Berkeley, CA), where a polymer film is deposited on the surface of lithium metal to protect it from rapid oxidation and allow its use in aqueous environment or air ambient. (Polyplus has IP pending on this).
    (††) Dissolved oxygen can also serve as a cathode. In this case, the dissolved oxygen in the bodily fluids would be reduced to OH— at a suitable catalytic surface such at Pt or gold. Other catalysts are also possible.
  • In certain embodiments, one or both of the metals may be doped with a non-metal, e.g., to enhance the voltage output of the battery. Non-metals that may be used as doping agents in certain embodiments include, but are not limited to: sulfur, iodine and the like.
  • In certain embodiments, the electrode materials are copper iodine (CuI) as the anode and magnesium (Mg) as the cathode. Embodiments of the present invention use electrode materials that are not harmful to the human body.
  • In certain embodiments, the batteries have a small form factor. Batteries may be 10 mm3 or smaller, such as 1.0 mm3 or smaller, including 0.1 mm3 or smaller, including 0.02 mm3 or smaller. As such, in certain embodiments, the battery element is dimensioned to have a width ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mm to about 1 mm, such as from about 0.05 mm to about 0.3 mm, including from about 0.1 mm to about 0.2 mm.
  • As reviewed below, in certain embodiments the battery has a split or segmented configuration.
  • In certain embodiments, the battery is one which is free of packaging. As such, the electrodes are exposed and not protected by any protecting or sealing structure. As such, following removal of the active agent/carrier matrix material with which the battery may be associated, the battery per se does not itself include an protective packaging such that the electrodes are free to contact the electrolyte at the target physiological location.
  • In certain of these embodiments, the battery power source may be viewed as a power source that exploits reverse electrolysis in an ionic solution such as gastric fluid, blood, or other bodily fluids and some tissues. FIG. 4 illustrates an identifier 30 having a signal generation element 40 powered by reverse electrolysis. Signal generation element 40 is electrically connected to metal electrodes 32 and 33, which are made of two different materials and are electrically insulated from each other. When metal electrodes 32 and 33 are immersed in an ionic solution 39, a potential difference develops between them; for instance, electrode 33 rises to a higher potential V+ while electrode 32 falls to a lower potential V−. This potential difference can be used to power circuitry 40.
  • Electrodes 32 and 33 can be implemented in various ways; for instance, areas on opposing surfaces of an integrated circuit chip can be coated with two different metals, and the entire chip can be placed in the ionic solution. Alternatively, electrodes 32 and 33 may extend away from element 40 as shown. Other arrangements may also be used.
  • As illustrated above, electrodes 32 and 33 can be made of any two materials appropriate to the environment in which the identifier 30 will be operating. For instance, in some embodiments where ionic solution 39 comprises stomach acids, electrodes 32 and 33 may be made of a noble metal (e.g., gold, silver, platinum, palladium or the like) so that they do not corrode prematurely. Alternatively, the electrodes can be fabricated of aluminum or any other conductive material whose survival time in the applicable ionic solution is long enough to allow identifier 30 to perform its intended function.
  • Where the power source is a battery, the battery may be fabricated in a number of different ways. In certain embodiments, fabrication protocols which may be categorized as “planar” processing protocols are employed, as developed in greater detail below.
  • Additional Power Sources
  • Other sources, internal or external to the remote device, may also be employed in addition to or instead of those described above. For example, chemical or radioisotope batteries with a suitable form factor may be used to power some remote devices. Recently-developed fuel cells that use blood as an energy source can be miniaturized and used to provide electrical energy for a low-power microchip. Piezoelectric crystals that convert mechanical energy (e.g., compression) to electrical energy can be employed for remote devices disposed where suitable mechanical forces can be brought to bear, such as in or around the heart, stomach, joints, or other moving parts of the body. In yet other embodiments, a power source modeled on the cellular energy factory, with power being extracted from ATP in the blood so that blood, in effect, “nourishes” the identifier, is employed. In other embodiments, acoustic energy (e.g., ultrasound) can be coupled into a remote device through piezoelectric or similar converters.
  • In yet other embodiments, the activation element is not an on board power source, but an element that is powered from a separate power source and provides an activation signal to the signal generation component upon contact of the composition with the target site. For example, the activation element may be coupled to a power receiver which is configured to receive broadcast power and transduce the broadcast power into a form suitable for driving the signal generation element. In certain embodiments, the power receiver may be a coil. Alternatively, the activator component may be powered by a distinct power source, e.g., a sealed battery, a power element that converts mechanical energy of the pill into electrical power, e.g., a piezoelectric power element, etc. As such, the activator may or may not itself be the power source, and in those embodiments where it is not the power source, the identifier may include a distinct power source, such as receiver or power generator.
  • Signal Generation Component
  • The signal generation component of the identifier element is a structure that, upon activation by the activation component, emits a detectable signal, e.g., that can be received by a receiver, e.g., as described in greater detail below. The signal generation component of certain embodiments can be any convenient device that is capable of producing a detectable signal and/or modulating transduced broadcast power, upon activation by the activation component. Detectable signals of interest include, but are not limited to: conductive signals, acoustic signals, etc. As reviewed above, the signals emitted by the signal generator may be generic or unique signals, where representative types of signals of interest include, but are not limited to: frequency shift coded signals; amplitude modulation signals; frequency modulation signals; etc.
  • In certain embodiments, the signal generation element includes circuitry, as developed in more detail below, which produces or generates the signal. The type of circuitry chosen may depend, at least in part, on the driving power that is supplied by the power source of the identifier. For example, where the driving power is 1.2 volts or above, standard CMOS circuitry may be employed. In other embodiments where the driving power ranges from about 0.7 to about 1.2 V, sub-threshold circuit designs may be employed. For driving powers of about 0.7 V or less, zero-threshold transistor designs may be employed.
  • In certain embodiments, the signal generation component includes a voltage-controlled oscillator (VCO) that can generate a digital clock signal in response to activation by the activation component. The VCO can be controlled by a digital circuit, which is assigned an address and which can control the VCO with a control voltage. This digital control circuit can be embedded onto a chip that includes the activation component and oscillator. Using amplitude modulation or phase shift keying to encode the address, an identifying signal is transmitted.
  • The signal generation component may include a distinct transmitter component that serves to transmit the generated signal to a remote receiver, which may be internal or external to the patient, as reviewed in greater detail below. The transmitter component, when present, may take a number of different configurations, e.g., depending on the type of signal that is generated and is to be emitted. In certain embodiments, the transmitter component is made up of one or more electrodes. In certain embodiments, the transmitter component is made up of one or more wires, e.g., in the form of antenna(e). In certain embodiments, the transmitter component is made up of one or more coils. As such, the signal transmitter may include a variety of different transmitters, e.g., electrodes, antennas (e.g., in the form of wires) coils, etc. In certain embodiments, the signal is transmitted either by one or two electrodes or by one or two wires. A two-electrode transmitter is a dipole; a one electrode transmitter forms a monopole. In certain embodiments, the transmitter only requires one diode drop of power.
  • In some embodiments, the transmitter unit uses an electric dipole or electric monopole antenna to transmit signals. FIG. 6A illustrates a dipole antenna. Oscillator 504 provides driving signals (φ and an inverted signal denoted herein as /φ) to an electrode driver 506. FIG. 6C is a circuit diagram showing details of a dipole electrode driver 600 implemented using conventional CMOS driver circuits. Electrode 602 is driven to a potential E0 by transistors 604, 606 in response to driving signal φ while electrode 608 is driven to a potential E1 by transistors 610, 612 in response to inverted driving signal /φ. Since driving signals φ and /φ oscillate with opposite phase, potentials E0 and E1 also oscillate with opposite phase. It will be appreciated that driver 600 and all other electronic circuits described herein can be implemented using sub-micron CMOS processing technologies known in the art; thus, the size of the circuitry is not a limiting factor on the size of a remote device.
  • In some embodiments, a monopole antenna can be substituted for the dipole antenna of FIG. 6A. FIG. 6D illustrates a driver circuit for a monopole antenna that can be implemented in conventional CMOS integrated circuits. This antenna driver is generally similar to one half of the driver circuit of FIG. 6C, with driver transistors 702, 704 driving a single electrode 706 to a potential Em in response to driving signal φ.
  • In either the dipole or monopole case, the driver circuit is powered by a potential difference (ΔV) between terminals V+ and V−. This potential difference, which can be constant or variable, as desired.
  • FIG. 6A is a block diagram of a transmitter signal generation element 500 for an identifier according to an embodiment of the present invention. In this embodiment, generation element 500 receives a signal M from the activation component which activates the signal generation element to produce and emit a signal. Signal generation element 500 includes control logic 502, an oscillator 504, an electrode driver 506, and an antenna 508 (in this instance, a pair of electrodes operated as an electric dipole antenna). In operation, oscillator 504 generates an oscillating signal (waveform) in response to signals from control logic 502. The signals from control logic 502 can start or stop the oscillator and in some embodiments can also shape one or more aspects of the oscillatory signal such as amplitude, frequency, and/or phase. Oscillator 504 provides the waveform to electrode driver 506, which drives current or voltage on antenna 508 to transmit a signal into the conductive medium of body tissues or fluids.
  • Depending on a given embodiment, the signal may or may not be modulated. For example, in certain embodiments the frequency of the signal may be held constant. In yet other embodiments, the signal may be modulated in some manner, e.g., via carrier based modulate schemes, ultra-wide band (or time domain based) modulation schemes, etc.
  • Referring again to FIG. 6A, in some embodiments, oscillator 504 operates at a constant frequency. The receipt of a constant-frequency signal in and of itself can provide useful information, e.g., that a remote device is present and operational. In some embodiments, oscillator 504 modulates its signal to encode additional information.
  • Information can be encoded in various ways, generally by modulating (varying) some property of the transmitted signal, such as frequency, amplitude, phase, or any combination thereof. Modulation techniques known in the art may be employed.
  • In general, information can be transmitted using analog or digital techniques. “Analog techniques” refers generally to instances in which the modulated property is varied in different degrees, with the degree of variation being correlated to a value representing the information to be transmitted. For instance, suppose that element 500 is transmitting a signal. Oscillator 504 can be designed to operate over some range of frequencies. “Digital techniques” refers generally to instances in which the information to be transmitted is represented as a sequence of binary digits (bits), and the signal is modulated based on the bit stream. For instance, suppose again that transmitter 500 is transmitting a signal using digital techniques. Oscillator 504 can be designed to operate at least two different frequencies, with one frequency corresponding to bit value 0 and another frequency corresponding to bit value 1. In embodiments of the present invention, either analog techniques, digital techniques, or a combination thereof can be used to transmit information. In addition, various types of modulation may be implemented.
  • For instance, in one embodiment, frequency modulation is used. Oscillator 504 can be a voltage-controlled oscillator (VCO), an oscillator circuit in which the oscillation frequency depends on an applied voltage. Control logic 502 supplies an appropriate voltage (e.g., reflecting the value of the measurement data, M), and the frequency of the signal indicates the value of the data. In another embodiment, amplitude modulation is used; for instance, the amplitude of the driving signals φ and /φ can be varied, or the positive and negative rails of the driver circuit (e.g., V+ and V−) can be varied to control the amplitude. In another embodiment, phase modulation is used. For instance, in digital signal transmission, one phase corresponds to bit value 0, an opposite phase corresponds to bit value 1, and the phase shifts represent transitions. Oscillator 504 can include a switch circuit that either directly connects or cross-connects the driving signals φ and /φ to the inputs of a driver circuit. Combinations of frequency modulation, amplitude modulation, and/or phase modulation may also be used as desired.
  • In some embodiments, the transmitter may transmit a “packet” that includes a unique identifier for the identifier, which in turn is for the composition with which the identifier is associated. The unique identifier may also provide information from the remote device (e.g., the identity of the active agent (i.e., annotation information)). Other techniques for distinguishing different signals may also be used, including: operating different transmitters in different frequency bands, allowing each transmitter to be identified by its frequency and/or configuring different transmitters to transmit at different (and known) times, allowing the transmitter to be identified by when it transmits.
  • Additional Components
  • Depending on the particular embodiment, the identifier may include a number of different additional components. Some components of interest include, but are not limited, those reviewed below.
  • Power Enhancers
  • Where the activator is a power source that is turned on upon contact with a target physiological site, in certain embodiments, circuits for enhancing or boosting voltage output of the power source, e.g., battery, are provided, e.g., charge pumping circuits, charge doublers, etc. Such voltage enhancing elements may enhance the voltage output by at about 2-fold or more, such as by about 5-fold or more.
  • Power Storage
  • In certain embodiments, the activation component includes a power storage element. For example, a duty cycle configuration may be employed, e.g., where slow energy production from a battery is stored in a power storage element, e.g., in a capacitor, which then provides a burst of power that is deployed to the signal generation component. In certain embodiments, the activation component includes a timing element which modulates, e.g., delays, delivery of power to the signal generation element, e.g., so signals from different compositions, e.g., pills, that are administered at substantially the same time are produced at different times and are therefore distinguishable.
  • Additional Features
  • In certain embodiments, the compositions are characterized by having one or more of the following features. In certain embodiments, the compositions include an identifier which employs a conductive near-field mode of communication in which the body itself is employed as a conductive medium. In such embodiments, the compositions include circuitry that, when freed from the composition upon disruption of the composition (e.g., as described above) the circuitry comes into direct contact with the body and does not remain encapsulated or protected in some manner. In these embodiments, the signal is not a magnetic signal or high frequency (RF) signal. In certain embodiments, the systems are ones that include a receiver which is stably associated with the body, e.g., implanted or topically applied to an external location, such that the systems are distinguished from those in which an external device that is not stably associated with the body is employed to collect data. In certain embodiments, the compositions do not include an imaging system, e.g., camera or other visualization or imaging element, or components thereof, e.g., CCD element, illumination element, etc. In certain embodiments, the compositions do not include a sensing element, e.g., for sensing a physiological parameter, beyond the activator which detects contact with the targeted physiological site. In certain embodiments, the compositions do not include a propulsion element. In certain embodiments, the compositions do not include a sampling element, such as a fluid retrieval element. In certain embodiments, the compositions do not include an actuatable active agent delivery element, such as an element that retains an active agent with the composition until a signal is received that causes the delivery element to release the active agent.
  • Identifier Fabrication
  • In certain embodiments of interest, the identifier element includes a semiconductor support component. Any of a variety of different protocols may be employed in manufacturing the identifier structures and components thereof. For example, molding, deposition and material removal, e.g., planar processing techniques, such as Micro-Electro-Mechanical Systems (MEMS) fabrication techniques, including surface micromachining and bulk micromachining techniques, may be employed. Deposition techniques that may be employed in certain embodiments of fabricating the structures include, but are not limited to: electroplating, cathodic arc deposition, plasma spray, sputtering, e-beam evaporation, physical vapor deposition, chemical vapor deposition, plasma enhanced chemical vapor deposition, etc. Material removal techniques included, but are not limited to: reactive ion etching, anisotropic chemical etching, isotropic chemical etching, planarization, e.g., via chemical mechanical polishing, laser ablation, electronic discharge machining (EDM), etc. Also of interest are lithographic protocols. Of interest in certain embodiments is the use of planar processing protocols, in which structures are built up and/or removed from a surface or surfaces of an initially planar substrate using a variety of different material removal and deposition protocols applied to the substrate in a sequential manner.
  • FIGS. 11A to 13B are diagrams showing a method for fabricating an identifier according to an embodiment of the invention. FIG. 11A depicts a cross-section of a semiconductor wafer, 121, processed by silicon foundry such as IBM or Taiwan Semiconductor Manufacturing Company. The top surface of the wafer, 122, contains numerous electrical contact pads, 123, and an insulating dielectric layer, 124. The contact pads can be Al but could also be Cu, Ti, or similar metal; the dielectric may be a combination of SiO2 and Si3N4, but could be other insulators. In the first process step, shown in FIG. 11B, wafer 121 has been thinned from the back side via grinding or chemical/mechanical polishing to reduce thickness to a desired thickness. A final thickness might be about 300 μm but it can range from about 10 to about 1000 μm such as from about 50-about 500 μm.
  • FIG. 12A shows the second process step, in which a layer of corrosion resistant metal, 125, has been added to the front side of the wafer to cover the electrical contacts, 123. The typical metal is platinum but one could also use other corrosion resistant metals such as Au, Ti, Ir, or another platinum group metal. The corrosion resistant metal may be deposited by physical vapor deposition, for example, and may be from about 0.05 to about 100 μm thick, such as from about 0.5 to about 5 μm thick. The metal 125 is formed into a desired pattern via photolithography and etching which are standard semiconductor processing techniques.
  • FIG. 12B shows the deposition of the cathode material 126. Cathode materials of interest include, but are not limited to: Cu or CuI, e.g., as described above. They are deposited by physical vapor deposition, electrodeposition, or plasma deposition, among other protocols. The cathode may be from about 0.05 to about 500 μm thick, such as from about 5 to about 100 μm thick. The cathode shape is controlled by shadow mask deposition, or photolithography and etching. Each chip may contain two or more regions, 127 and 127A, of cathode material as desired.
  • Next anode material 128A is deposited as shown in FIG. 12C. Anode materials of interest include, but are not limited: Mg, Zn, or other electronegative metals. Adhesion layer 128B may be necessary to help anode material to adhere to the silicon. Typical adhesion layers for the anode are Ti, TiW, Cr or similar material. Anode material and the adhesion layer may deposited by physical vapor deposition, electrodeposition or plasma deposition. The cathode may be from about 0.05 to about 500 μm thick, such as from about 5 to about 100 μm thick.
  • FIG. 13A shows the optional protection layer 129A which is deposited and patterned. In some applications it maybe advantageous to control the rate of anode or cathode exposure to the electrolyte environment, so an insulating layer may be deposited and patterned in such a way that it has openings, 129B, of limited size. This way the solution reaches the anode or cathode material at a controlled rate. FIG. 13A illustrates the protection layer on the front (cathode) side of the wafer but it could be also deposited on backside (anode side) of wafer. Typical materials for the protection layer are polyimide, or other photo definable polymer any of which may be spin coated or spray coated. Alternatively a dielectric like SiO2, SiC, or SiN may be deposited by physical vapor deposition or chemical vapor deposition.
  • The wafer is then singulated into individual die 115, 116, 117 as shown in FIG. 13B. Dicing can be accomplished by dicing with a diamond blade saw or by reactive ion etching. These are standard silicon semiconductor processing techniques. As reviewed above, the chip dimensions may vary. As such, in certain embodiments, the chip (i.e., identifier) element is dimensioned to have a width ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mm to about 1 mm, such as from about 0.05 mm to about 0.3 mm, including from about 0.1 mm to about 0.2 mm.
  • Specific Pill Embodiments
  • In further describing various embodiments of the compositions of the invention, specific embodiments are now described in greater detail in view of the figures. FIG. 1 provides a diagrammatic, exemplary representation of a pill/capsule embodiment of the present invention, in which the composition is configured as an orally ingestible pharmaceutical formulation in the form of a pill or capsule. The stomach 12 of the patient 10 who ingests the composition 14 is shown. This “smart pill” is shown as it has traveled from the mouth 16 to inside 18 the patient's stomach. Upon reaching the stomach, the pill/capsule undergoes a dissolving process with both the mechanical action of the stomach and the various chemical materials in the stomach fluids, such as hydrochloric acid and other digestive agents.
  • FIGS. 2A and 2B provide a more detailed view of the pill composition shown in FIG. 1. FIG. 2A illustrates an identifier 20 disposed inside a pill 14. Identifier 20 is present as an integrated circuit (IC). The backside (bottom) of circuit 20 is at least partially coated with a first metal 21, and a portion of the front (top) of circuit 20 is coated with a different metal 22, allowing circuit 20 to be powered by reverse electrolysis, e.g., as described above connection with FIG. 4. Also on the top surface are two transmitter electrodes 23, 24.
  • When pill 14 is fabricated, the integrated circuit 20 is surrounded by at least one external layer that may include pharmacologically active and/or inert materials in any combination. The external layer dissolves in the stomach through a combination of the mechanical action of the stomach and the action of various chemical constituents (e.g., hydrochloric acid) in stomach fluids.
  • As pill 14 is dissolved, areas of integrated circuit 20 become exposed to the stomach contents, which for present purposes can be regarded as an electrolyte solution. As dissolution of the pill exposes metal layers 21 and 22, power is supplied to circuit 20, which begins to operate and continues to operate until metal layers 21 and 22 or the circuit itself are sufficiently dissolved by digestive processes and acids to become non-functional. Eventually, the remains of the chip are excreted from the body.
  • In an alternative embodiment, the integrated circuit 20 is attached to, rather than encapsulated in, the pill 14. For instance, circuit 20 might be placed at one end of the pill as the pill is being prepared, in a soluble coating on the surface of the pill, or the like. In embodiments where circuit 20 is wholly or partially exposed, integrated circuit 20 begins to operate sooner after the pill enters the stomach rather than after the pill dissolves.
  • In one embodiment, circuit 20 transmits a signal identifying pill 14. The identifier may indicate the type (active ingredient(s), brand, etc.) and/or dosage of pill 14 and may also provide a lot number, serial number, or similar identifying information that would allow particular pills to be traced, e.g., as reviewed above.
  • FIG. 2B is a block diagram of one embodiment of electronic circuit 20. In this embodiment, circuit 20 is a transmitter unit that sequentially transmits a predetermined series of address (identifier) bits using frequency shift keying, with a first oscillation frequency corresponding to bit value 0 and a second oscillation frequency corresponding to bit value 1. As described above, metal layers 21 and 22 supply power to circuit 20. The power (not explicitly shown in FIG. 2B) is supplied to an oscillator 25, a counter 26, a readout circuit 27, and an electrode driver 28 that drives transmitter electrodes 29A, 29B to transmit the signal. Oscillator 25 may be of generally conventional design (e.g., a ring oscillator) and is advantageously configured to operate in the quasi-electrostatic frequency region as described above. Oscillator 25 generates a driving signal φ that oscillates between high and low voltage levels and an inverted driving signal /φ that is opposite in phase to driving signal φ. In one embodiment, oscillator 25 is a voltage-controlled oscillator (VCO) with an oscillation frequency that depends on a control voltage provided on a signal path 25A. Counter 26 counts the oscillations of driving signals φ and /φ and provides the current count to readout circuit 27. In one embodiment, counter 26 is an eight-bit counter of generally conventional design; other types of counters (including counters with different widths) may also be used. Readout circuit 27 is configured with a set of address (identifier) bits 27A that are advantageously fixed, e.g., at the time circuit 20 is fabricated. As noted above, the bits can be unique to a particular instance of pill 14 or common to a lot of pills fabricated under the same conditions or common to all pills containing a particular pharmacological agent. Address bits 14 can be stored in nonvolatile storage circuits of generally conventional design, and any number of address bits (e.g., 8, 16, 32, 48, etc.) may be provided. Readout circuit 27 generates an oscillator control signal (e.g., a voltage) on line 25A that controls the frequency of VCO 25. In one embodiment, readout circuit 27 is configured to select a current address bit, e.g., based on the current count provided by counter 26, and to generate a control signal on signal line 25A that selects a frequency corresponding to the value of that bit. After some number of cycles (as determined by counter 26), readout circuit 27 selects the next address bit and generates the corresponding control voltage on signal line 25A. Various frequencies may be used to represent the address bit values “1” and “0.” In one embodiment, frequencies of 100 kHz and 200 kHz may be used to represent values “0” and “1,” respectively. Other values (e.g., 1 MHz and 2 MHz or 1 kHz and 5 kHz) may also be used. The chosen frequencies advantageously are well below the absorption modes of human tissues, which are typically above 400 MHz. As described above, VCO 25 generates complementary signals φ, /φ that oscillate at a frequency determined by the control signal on signal line 25A. The signals φ, /φ are used to control an electrode driver 28, which may be implemented, e.g., as shown in FIG. 6D. It should be noted that since electrodes 21 and 22 are in contact with stomach fluids when circuit 20 is operative, the near-field component is coupled directly into the conductive medium of the patient's body and can be detected by a suitably configured data collector, e.g., as described below. In one embodiment, the collector is configured to log the received address (identifier) and the time of receipt. The data collector can also be configured to retransmit this information to an external device, either in real time or while the patient is in a medical facility. It will be appreciated that the transmitter described herein is illustrative and that variations and modifications are possible. For instance, other encoding schemes could be used to transmit the data; in one such embodiment, phase shift keying rather than frequency keying is used. In some embodiments, multiple address bits can be encoded into a single symbol that is transmitted using various keying schemes known in the art.
  • FIG. 3A provides a detailed depiction of an embodiment of a signal generation element 30 which labels the pharmaceutical material and is encapsulated in the center of the composition. Signal generation element 30 is in the form of IC constructed from a silicon chip where various functional elements, e.g., in the form of one or more layers of circuits, are disposed on a silicon substrate 31. The chip can be fabricated using standard integrated circuit techniques. An example of such a fabrication approach is a 0.5μ CMOS process made available by AMI Semiconductor in Idaho, USA. Shown on the backside of the substrate, the bottom of the chip 31 is metal 1 32 which functions as one battery electrode and on the topside of the chip is metal 2 33 which functions as the other battery electrode. Also on the top side of the chip 31 are electrode 1 34 and electrode 2 35, which constitute a pair of signal-transmission electrodes.
  • In certain embodiments, electrode 1 34 and electrode 2 35 are fabricated from a material that does not readily corrode in the stomach environment, e.g., they are fabricated from noble metals. Alternatively, in some cases the electrodes can be fabricated of a standard aluminum, such as that available from AMI Semiconductor. The criteria for electrode material selection will be readily ascertainable by the ordinary skilled artisan. That is, if the survival time of the electrode is long enough for detection, it is suitable for use. Standard aluminum metals or other lower cost metals if used for electrodes 1 and 2 (34 and 35) in appropriate applications allow a lower cost for the device. In some cases dissolution of the electrodes, and thus extinction of the reporting signal, can provide a secondary indication of the full dissolution of the pill and incorporated devices.
  • Metal 1 and metal 2 (32 and 33), in distinction to material selection for the electrode component of the inventive device, are two different metals. Metal 1 and metal 2 are selected so that the potential applied to the silicon is a positive voltage on the top surface and a negative voltage on the bottom surface. In this way the substrate is essentially at the same potential as the cathode, which can be the ground reference for the circuits, and the top surface, with a SiO2 insulation layer, is coupled to a positive voltage, referenced to that ground on the bottom side.
  • FIG. 3B provides a view of an alternative signal generation element according to an embodiment of the invention. Instead of electrodes, the signal generation element 30 depicted in FIG. 3B includes two antennae 36 and 37 attached to silicon chip 31. Also shown are metals 1 and 2 (32 and 33). The assembly 30 includes circuitry on a silicon chip 31 with either two or four metal structures (32, 33, 36 and 37) attached to it. In embodiments where two different metals are employed, the two metal structures serve as battery metals, that is metal 1 and metal 2 (32 and 33). These metal structures can be provided in a variety of forms. For instance, in one embodiment, metal 1 and metal 2 are very thick plated elements on the surface of the chip, front and back (e.g., as shown in FIG. 3C described below). In another embodiment, metal 1 and metal 2 are relatively long wires that are simply bonded to the chip at some point, e.g., as shown in FIG. 3B. Metal 1 and metal 2 in some cases are insulated. In this case, the erosion occurs at the tip and then propagates towards the chip 31. The erosion as it dissolves in the solution starts at the end of the wire and gradually work its way toward the chip 31. This configuration improves battery life. In another configuration, a metal is plated up on the front and back of the chip, and then the surface disappears. The two wires can also be employed as antennae. In one configuration, a perpendicular pair of antennae (36 and 37) is provided. In this implementation, there would be two other metal structures which are typically of the same material. This material can be selected from a variety of metals, such as platinum or gold. These metal structures are attached to the chip and extend some dimension away form the chip. Typically these structures are on the order of a millimeter to a centimeter combined length. In some configurations, a significant portion of the metal structures are insulated so that the dipole created is of maximum dimension. In other configurations, just the battery metals perform that dipole function, e.g., as described below in connection with FIG. 3C, or a separate antenna is provided.
  • In certain embodiments, the signal generation element does not include antennae and instead uses battery components as antennae, such as shown in FIG. 3C. In FIG. 3C, signal generation element 30 includes silicon support layer 31 positioned between metal 1 layer 32 and metal 2 layer 33. Also shown is circuitry layer 38. In such embodiments, when a switch on the chip, e.g., in the circuitry layer, is closed, a current is produced between the two metals of the battery, which is then detected. In certain embodiments, a membrane larger then chip which defines a path for the current to travel is provided.
  • Yet another embodiment of a battery which is activated upon contact with a physiological fluid is shown in FIGS. 3D and 3E. In the structure shown in these figures, the battery comprises top and bottom portions each supporting an electrode, where the top and bottom portions can be brought together to produce a structure comprising a volume bounded by opposing first and second electrodes, where the volume may be filled with an electrolyte, e.g., physiological fluid, when active. FIG. 3D provides a representation of a bottom portion 31A of the battery in which material 1 32A is deposited into a recessed chamber 33A on top of a substrate (e.g., silicon chip) 34A. Recessed chamber 33A has one or more ends open to allow electrolyte to enter. Material 2 35A is deposited on a separate substrate 36A to produce a second portion 37A, which is then bonded, e.g. by bonds 38A and 38B, to the chip in a “flip chip” type process. All processing can be done at the wafer scale. Where desired, the openings of the recessed chamber are filled with a degradable material, e.g., with a polymer, to control how quickly the battery is activated. Substrates 34A and 36A for materials 34A and 35A can be silicon, metal, or polymer/plastic. In certain embodiments, the structure shown in FIGS. 3D and 3E is a battery where the first electrode is deposited into a recessed chamber on the top of the chip. The recessed space has one or two open ends to allow electrolyte flow. The second electrode is deposited on a separate substrate (e.g. a silicon wafer, a metal film or a polymer film), then bonded on top of the wafer with the chips on it in a “flip-chip” type process. The processing is done at a wafer scale and the cells diced as usual. The advantages of this configuration include: protection of the electrode surfaces from being blocked by components present in the stomach or the stomach lining itself; prevention of contact between any species generated on the battery (e.g., Cu) and the stomach lining that could have toxicity risks; 3) provision of uniform consumption of electrode materials across the electrode surface and more uniform current distribution between the electrodes.
  • FIG. 4 provides a diagrammatic representation of the events which occur when the pill is ingested and dissolved to the point that some of the pill has been chemically and/or physically eroded away. Metal 1 and metal 2 (32 and 33) are now in an ionic solution 39. This creates a low voltage (V−) and a high voltage (V+) as applied to an electronic circuit 40. The two outputs of that electronic circuit 40 are E0 41 and E1 42, which are the signal-transmission electrodes on the top surface. In an alternate embodiment no shown in FIG. 4 where the signal generation element 30 includes a single electrode, the output is E0 41.
  • FIG. 5 shows a similar arrangement as in FIG. 4. However, instead of having two electrodes as the output, a coil is provided. Metal 1 and metal 2 (32 and 33) are applied to the electronic circuit 40 of signal generation element 30. The outputs of the electronic circuit 40 are coupled to a coil 43. This configuration provides that a battery is created by metal 1 and metal 2 (32 and 33) when exposed to ionic solution. This battery drives the circuit 40, which creates an oscillating frequency. This oscillating current goes through the coil and generates a RF magnetic signal. Unlike near-field quasi-static electrical signals, which may suffer from significant attenuation through body tissues, the RF magnetic signal can be transmitted through body tissues with less attenuation. The RF magnetic signal is then picked up by an external or internal receiver device that has a magnetic-signal detection mechanism. If a broadcast is provided at a high enough frequency, a pager-like device that is worn by the patient will detect whenever a pill is ingested.
  • FIG. 6B shows the detail of one implementation of an electronic circuit that can be employed in a signal generation element. On the left side are the two battery electrodes, metal 1 and metal 2 (32 and 33). These metals, when in contract with an electrolyte, form a battery and provide power to an oscillator 61, in this case shown as a schematic. The metal 1 32 provides a low voltage, (ground) to the oscillator 61. Metal 2 33 provides a high voltage (Vhigh) to the oscillator 61. As the oscillator 61 becomes operative, it generates a clock signal 62 and an inverted clock signal 63, which are opposites of each other. These two clock signals go into the counter 64 which simply counts the number of clock cycles and stores the count in a number of registers. In the example shown here, an 8 bit counter is employed. Thus, the output of counter 64 begins with a value of “00000000,” changes to “00000001” at the first clock cycle, and continues up to “11111111.” The 8-bit output of counter 64 is coupled to the input of an address multiplexer (mux) 65. In one embodiment, mux 65 contains an address interpreter, which can be hard-wired in the circuit, and generates a control voltage to control the oscillator 61. Mux 65 uses the output of counter 64 to reproduce the address in a serial bit stream, which is further fed to the signal-transmission driving circuit. Mux 65 can also be used to control the duty-cycle of the signal transmission. In one embodiment, mux 65 turns on signal transmission only one sixteenth of the time, using the clock counts generated by counter 64. Such a low duty cycle conserves power and also allows other devices to transmit without jamming their signals. The address of a given chip can be 8 bits, 16 bits or 32 bits. Typically, more than 8 bits will be used in a product because there are so many different types of pharmaceuticals. Each pharmaceutical will have its own specific address.
  • The present invention also allows the possibility that, where appropriate, each pharmaceutical batch can be provided with a batch specific address. This allows identification of where the pill was made, when the pill was made, and in what batch it was made. In some cases, each pill will have a unique identifier. This would be particularly useful when drugs are more likely to be subsequently stolen or used illicitly, and thus should be tracked, or where questions of contamination may arise.
  • According to one embodiment, mux 65 produces a control voltage, which encodes the address serially and is used to vary the output frequency of oscillator 61. By example, when the control voltage is low, that is, when the serial address bit is at a 0, a 1 megahertz signal is generated by the oscillator. When the control voltage is high, that is, when the address bit is a 1, a 2 megahertz signal is generated the oscillator. Alternately, this can be 10 megahertz and 20 megahertz, or a phase shift keying approach where the device is limited to modulating the phase. The purpose of mux 65 is to control the frequency of the oscillator or an AC alternative embodiment of the amplified signal of oscillation.
  • The outputs of mux 65 are coupled to electrode drive 66 which can drive the electrodes to impose a differential potential to the solution, drive an oscillating current through a coil to generate a magnetic signal, or drive a single electrode to push or pull charge to or from the solution.
  • In this manner, the device broadcasts the sequence of 0's and 1's which constitute the address stored in mux 65. That address would be broadcast repeatedly, and would continue broadcasting until metal 1 or metal 2 (32 and 33) is consumed and dissolved in the solution, when the battery no longer operates.
  • FIG. 7 is an alternate embodiment of the present invention. This implementation of the circuit 70 shows the oscillator 71 and a counter 72. The mux 73 takes 5 bits from counter 72 as its input. On the upper right corner of FIG. 7 is an exemplary circuit diagram for the signal-transmission electrode driver. Two CMOS invertors respectively take the clock and inverted clock signals as their inputs, and drives electrodes e0 and e1.
  • FIG. 8 provides one implementation of an oscillator 80. In this case, V control 81 basically controls the amount of voltage driving the oscillator 80. When Vcontrol is low, a 20,000 ohm resistor 82 separates V, 83, which is the low power-supply voltage, and the oscillator control line, V osc control 84. When Vcontrol is high, the Vosc control goes to Vlow, putting the maximum voltage across the oscillator circuitry and resulting in a higher frequency coming out of the clock signal and the inverted clock signal (85 and 86).
  • FIG. 9 shows a simple trickle or asynchronous counter which has in this case four flip flops with some simple inverters that simply count all the way up and then start over again back to zero, and start counting all the way up again. In one embodiment, a multiplexer can take A0 and A1, A2, A3, as its address inputs and can compare these inputs with a stored address, and then have the stored address output as the oscillator control signal.
  • As indicated above, in certain embodiments the signal generation element may include a single electrode, and therefore have a monopole configuration. In one embodiment of the present invention, as shown in FIG. 10, a three terminal, monopole signal generation element 100 is provided. In this embodiment, the signal generation element 100 of the pill has one electrode 101 which is capacitively coupled to chip 107. Two metal electrodes 103 and 102 constitute the electrodes for the battery, which provides power for the signal generation element 100. Electrodes 102 and 103 are coupled to the chip 107 through two resistors 104 and 105, and an optional storage capacitor 106. In one embodiment, electrode 102 is the ground and electrode 103 provides Vhigh for the signal generation element Electrode 101 is the output of the mono pole signal generation element. During operation, electrode 101 will push current into and out of body's fluid at a high frequency. A receiver will detect the pushing and pulling of that charge out of the body's fluids. Note that the biggest difference between this configuration and the configuration described previously is that this configuration provides a mono pole. When chip 107's output changes, capacitor 108 forces the potential on electrode 101 to change instantly, which result a corresponding change in the potential of the body. A receiver that is in contact of the body can thereby detect a large transient voltage change.
  • This inventive design produces an alternating current into and out of the body which is detected by a receiver (not shown). The output coupling capacitors may be optional. However, the presence of these capacitors prevents any DC currents and forces an AC signal.
  • FIG. 14 shows the multiplexer and the addressing system 73 of the circuitry of the signal generation element of FIG. 7. In this case, there are two 4 bit muxes (141 and 142) and a 1 bit mux 143, wherein the 1 bit mux 143 takes the outputs of the two 4 bit muxes 141 and 142 as its input. Each input port of muxes 141 and 142 is coupled to either the high voltage Vhigh or the low voltage Vlow. This configuration of the present invention will allow for a 32 bit number, which is hard-wired to the 32 inputs of the two muxes, to be converted to a multiplexed serial output 144. As the counter goes through the 5 bits of counting, the output of mux 144 sequentially selects the inputs of muxes 141 and 142. When the 5 bit counter reaches “11111,” the sequence will start over from the beginning again. This way the 16 bit address is repeatedly sent. An alternative approach is to send 16 bits of zeros and 16 bits of address alternatively, so that the receiving circuitry can be waken up and synchronized.
  • FIG. 15 shows a detail of the 4 bit mux 141 of the system shown in FIG. 14. The 4 bit mux is constructed from 4 levels of 1 bit muxes.
  • FIG. 16 shows the 1 bit mux in detail that makes up the 4 bit mux 141.
  • FIG. 17 is an additional mono pole embodiment 170 of a signal generation element. The biggest difference from the prior described embodiments is that a current source 171 is placed in series with the power supply created by M1 172 and M2 173. This creates a DC current between M1 172 and M2 173. This DC current does not compete with the AC signal generated by the electrode 174. This DC current will then go to one or another capacitor (175 and 176) and would either charge up the electrode or charge up another capacitor. The concept behind this embodiment is to have a DC current created between M1 and M2 and an AC signal generated at the single electrode. Coupling capacitor 176 is optional.
  • FIG. 18A is an exemplary schematic diagram of a signal-transmission driver circuit. This circuit is based on an 8-pin 555 timer chip. As is shown on FIG. 18A, the pin designations of the 555 timer chip are as follows: pin 1 is the ground; pin 2 is the trigger, pin 3 is the output, pin 4 is reset, pin 5 is the control voltage, pin 6 is the threshold, pin 7 is discharge, and pin 8 is the power supply to the chip Vdd. The output pin and the ground pin are capacitively coupled to two transmission electrodes, respectively. During operation, this circuit transmits a signal at a fixed frequency.
  • FIG. 18B1 to 18B2 is an exemplary schematic diagram of a receiver circuit. Shown on the upper left portion of the diagram is a front-end amplification stage, which receives the signal through a pair of electrodes and performs differential amplification to the signal using an instrumentation amplifier. In the middle portion of the diagram is a cascaded four-stage filter. In one embodiment, the first two stages are high-pass filters with a cut-off frequency higher than 1 KHz, such as a cut-off frequency at approximately 10 KHz. The high-pass filter removes the low-frequency noises and interferences, such as the 60 Hz power-line noise. The last two stages are low-pass filters with a cut-off frequency lower than 500 KHz, such as a cut-off frequency at approximately 200 KHz. The low-pass filters can remove high-frequency noises and interferences. The filtered and amplified signal is fed to an LED, as is shown on the lower left portion of the diagram. When a signal is detected, the LED is lit indicating presence of the signal.
  • The device described above generally includes two circuits: one is a logic circuit that generates the address bit sequence, and one is a driver circuit that drives the transmission electrodes based on the address bit sequence. The power-consumption characteristics of these two circuits are different. Typically, the logic circuit requires a high voltage power supply, e.g., a 1.2 V power supply, to switch the CMOS circuits. However, the current drawn through the logic circuit is relatively small. For example, in one embodiment, the current drawn through the logic circuits is approximately 5 μA.
  • On the other hand, the driver circuit may draw a much larger current, because of the power it requires to transmit a sufficiently detectable signal. Consequently, the voltage of the power supply can be pulled down to a lower level. For example, the driver circuit can draw 100 μA and pull the battery voltage down to 0.5 V.
  • Because the area of the battery electrodes can be limited due to the size constraint of the device, the interference between the two circuits with regard to power supply may be significant. As a result, the driver circuit could pull the battery voltage down to a point that makes the logic circuit inoperable. One embodiment of the present invention uses a split battery configuration to decouple the power supplies for the logic and driver circuits.
  • FIG. 19 shows one exemplary split (i.e., segmented) battery design. Two battery electrodes 193 and 194, which are made from copper iodine, constitute the battery anodes for the logic circuit 191 and driver circuit 192, respectively. Effectively, electrodes 193 and 194 form two separate batteries with a shared common magnesium cathode 195. In this way, the driver circuit 192 can draw sufficient current to drive transmission electrodes 196 without significantly impairing the power supply for the logic circuit 191.
  • During operation, driver circuit 192 draws a current from the battery formed by electrodes 194 and 195, and pushes this current through transmission electrodes 196 into the body. In a further embodiment, the device can avoid the use of separate transmission electrodes by using the battery electrodes for transmission. FIG. 20 shows such a configuration. The driver circuit 206 essentially contains a switch coupled between the anode 204 and the cathode. This switch can be turned on or off by the address signal from the logic circuit 201. When the switch is turned on, the battery for the driver circuit is effectively short-circuited within the chip. Consequently, a current 207 flows through the body from the cathode to anode 204. The resistance of the body tissue can thereby generate a voltage difference, which can be readily detected by, for example, a differential amplifier.
  • In some cases, the size of the cathode could be limited, resulting in coupling between the power supplies for the logic and driver circuits even with split anodes. According to one embodiment, as is shown in FIG. 21, the cathode can also be split to further decouple the two power supplies. Here, two separate magnesium electrodes 211 and 212 serve as separate cathodes for the two batteries respectively serving the logic and driver circuits. The coupling between the two circuits can thus be minimized.
  • In a further embodiment, the battery electrodes for the driver circuit can be detached from the chip and coupled to the driver circuit through two external wires, as is shown in FIG. 22. The battery electrodes for the logic circuit, on the other hand, can still be deposited on the chip to provide high-voltage power supply to the logic circuit. The external wires 221 and 222, which can be approximately 1 cm long each, form a long dipole and can provide attendant signal amplification. As a result, the effectiveness of the transmission is not limited by the size of the chip. In one embodiment, the wires are initially folded within a pill and can unfold when the pill is digested.
  • Methods of Making Compositions
  • A variety of manufacturing protocols may be employed to produce compositions according to the invention. In manufacturing the subject compositions, a signal generation element is stably associated with the pharmaceutical dosage from in some manner. By stably associated is meant that the signal generation element and the dosage form to do separate from each other, at least until administered to the subject in need thereof, e.g., by ingestion. The signal generation element may be stably associated with the pharmaceutical carrier/active agent component of the composition in a number of different ways. In certain embodiments, where the carrier/active agent component is a solid structure, e.g., such as a tablet or pill, the carrier/active agent component is produced in a manner that provides a cavity for the signal generation element. The signal generation element is then placed into the cavity and the cavity sealed, e.g., with a biocompatible material, to produce the final composition. For example, in certain embodiments a tablet is produced with a die that includes a feature which produces a cavity in the resultant compressed tablet. The signal generation element is placed into the cavity and the cavity sealed to produce the final tablet. In a variation of this embodiment, the tablet is compressed with a removable element, e.g., in the shape of a rod or other convenient shape. The removable element is then removed to produce a cavity in the tablet. The signal generation element is placed into the cavity and the cavity sealed to produce the final tablet. In another variation of this embodiment, a tablet without any cavity is first produced and then a cavity is produced in the tablet, e.g., by laser drilling. The signal generation element is placed into the cavity and the cavity sealed to produce the final tablet. In yet other embodiments, a tablet is produced by combining the signal generation element with subparts of the tablet, where the subparts may be pre-made subparts or manufactured sequentially. For example, in certain embodiments tablets are produced by first making a bottom half of the tablet, placing the signal generation element on a location of the bottom half of the tablet, and then placing top portion of the tablet over the bottom half and signal generation element to produce the final desired composition. In certain embodiments, a tablet is produced around a signal generation element such that the signal generation element is located inside of the produced tablet. For example, a signal generation element, which may or may not be encapsulated in a biocompatible compliant material, e.g., gelatin (to protect the signal generation element), is combined with carrier/active agent precursor, e.g., powder, and compressed or molded into a tablet in a manner such that the signal generation element is located at an internal position of the tablet. Instead of molding or compressing, the carrier/active agent component is, in certain embodiments, sprayed onto the signal generation element in a manner that builds up the tablet structure. In yet another embodiment, the active agent/carrier component precursor may be a liquid formulation which is combined with the signal generation element and then solidified to produce the final composition. In yet other embodiments, pre-made tablets may be fitted with the signal generation element by stably attaching the signal generation element to the tablet. Of interest are protocols that do not alter the properties of the tablet, e.g., dissolution etc. For example, a gelatin element that snap fits onto one end of a tablet and has the chip integrated with it is employed in certain embodiments. The gelatin element is colored in certain embodiments to readily identify tablets that have been fitted with the signal generation element. Where the composition has a active agent/carrier composition filled capsule configuration, e.g., such as a gelatin capsule filled configuration, the signal generation element may be integrated with a capsule component, e.g., top or bottom capsule, and the capsule filled with the active agent/carrier composition to produce the final composition. The above reviewed methods of manufacture are merely illustrative of the variety of different ways in which the compositions of the invention may be manufactured.
  • Systems
  • Also provided are systems that include the subject compositions. Systems of the subject invention include, in certain embodiments, one or more active agent containing compositions, e.g., as reviewed above, as well as a signal detection component, e.g., in the form of a receiver. The signal detection component may vary significantly depending on the nature of the signal that is generated by the signal generation element of the composition, e.g., as reviewed above.
  • In certain embodiments, the signal detection component is an implantable component. By implantable component is meant that the signal detection component is designed, i.e., configured, for implantation into a subject, e.g., on a semi-permanent or permanent basis. In these embodiments, the signal detection component is in vivo during use. In yet other embodiments, the signal detection component is ex vivo, by which is meant that the detection component is present outside of the body during use. In certain of these embodiments, as developed in greater detail below, either separate from or integrated with the ex vivo detection component may be a dosage dispenser element, e.g., for dispensing dosages of the compositions based on signal detected from the signal generation element of the detector. Such features may also be present in implantable detection components, e.g., to provide a closed loop administration system that administers a subsequent dosage based on input about ingestion of a previous dosage.
  • As reviewed above, in certain embodiments the signal generation element of the composition is activated upon contact with a target body site. In certain of these embodiments, the signal detection component is activated upon detection of a signal from the signal generation element. In certain of these embodiments, the composition generates an intermittent signal. In certain of these embodiments, the detection element is capable of simultaneously detecting multiple compositions.
  • The signal detection component may include a variety of different types of signal receiver elements, where the nature of the receiver element necessarily varies depending on the nature of the signal produced by the signal generation element. In certain embodiments, the signal detection component may include one or more electrodes for detecting signal emitted by the signal generation element. In certain embodiments, the receiver device will be provided with two electrodes that are dispersed at some distance. This distance allows the electrodes to detect a differential voltage. In certain embodiments, the first electrode is in contact with an electrically conductive body element, e.g., blood, and the second electrode is in contact with an electrically insulative body element relative to said conductive body element, e.g., adipose tissue (fat). In an alternative embodiment, a receiver that utilizes a single electrode is employed. In certain embodiments, the signal detection component may include one or more coils for detecting signal emitted by the signal generation element. In certain embodiments, the signal detection component includes an acoustic detection element for detecting signal emitted by the signal generation element.
  • For those embodiments where the signal generated by the identifier is a near-field conductive signal, e.g., as reviewed above, the receiver of the present systems may also be viewed as “data collectors.” As used herein, a “data collector” is any device equipped with receiving antenna to detect the potential differences created in the body by a transmitter as described above, thus receiving the information transmitted. A data collector may handle received data in various ways. In some embodiments, the collector simply retransmits the data to an external device (e.g., using conventional RF communication). In other embodiments, the data collector processes the received data to determine whether to take some action such as operating an effector that is under its control, activating a visible or audible alarm, transmitting a control signal to an effector located elsewhere in the body, or the like. In still other embodiments, the data collector stores the received data for subsequent retransmission to an external device or for use in processing of subsequent data (e.g., detecting a change in some parameter over time). It is to be understood that data collectors may perform any combination of these and/or other operations using received data.
  • While the receiving antenna is advantageously inside the patient or in contact with the patient's skin, it is not required that data collector be entirely internal to the patient. For instance, a watch or belt worn externally and equipped with suitable receiving electrodes can be used as a data collector in accordance with one embodiment of the present invention. The data collector may provide a further communication path via which collected data can be extracted by a patient or health care practitioner. For instance, an implanted collector may include conventional RF circuitry (operating, e.g., in the 405-MHz medical device band) with which a practitioner can communicate, e.g., using a data retrieval device, such as a wand as is known in the art. Where the data collector includes an external component, that component may have output devices for providing, e.g., audio and/or visual feedback; examples include audible alarms, LEDs, display screens, or the like. The external component may also include an interface port via which the component can be connected to a computer for reading out data stored therein.
  • In some embodiments, the data collector is implanted. For instance, as noted above, pacemaker leads provide a suitably sized receiving antenna. Typical pacemakers include a control unit (referred to as a “can”) that incorporates logic circuits configured to perform various data collection and processing operations. The can is also connected to RF transmitter/receiver circuitry that allows communication between the pacemaker and an external wand operated by a health care practitioner. Thus, where the patient has a pacemaker, leveraging the existing unit as a data collector may be an efficient choice.
  • In certain embodiments, the system further includes an element for storing data, i.e., a data storage element. Typically, the data storage element is a computer readable medium. The term “computer readable medium” as used herein refers to any storage or transmission medium that participates in providing instructions and/or data to a computer for execution and/or processing. Examples of storage media include floppy disks, magnetic tape, CD-ROM, a hard disk drive, a ROM or integrated circuit, a magneto-optical disk, or a computer readable card such as a PCMCIA card and the like, whether or not such devices are internal or external to the computer. A file containing information may be “stored” on computer readable medium, where “storing” means recording information such that it is accessible and retrievable at a later date by a computer. With respect to computer readable media, “permanent memory” refers to memory that is permanent. Permanent memory is not erased by termination of the electrical supply to a computer or processor. Computer hard-drive ROM (i.e. ROM not used as virtual memory), CD-ROM, floppy disk and DVD are all examples of permanent memory. Random Access Memory (RAM) is an example of non-permanent memory. A file in permanent memory may be editable and re-writable.
  • In certain embodiments, the data that is recorded on the data storage element includes at least one of, if not all of, time, date, and an identifier of each composition administered to a patient, where the identifier may be the common name of the composition or a coded version thereof. In certain embodiments, the data of interest includes hemodynamic measurements. In certain embodiments, the data of interest includes cardiac tissue properties. In certain embodiments, the data of interest includes pressure or volume measurements.
  • The invention also provides computer executable instructions (i.e., programming) for performing the above methods. The computer executable instructions are present on a computer readable medium. Accordingly, the invention provides a computer readable medium containing programming for use in detecting and processing a signal generated by a composition of the invention, e.g., as reviewed above.
  • As such, in certain embodiments the systems include one or more of: a data storage element, a data processing element, a data display element, data transmission element, a notification mechanism, and a user interface. These additional elements may be incorporated into the receiver and/or present on an external device, e.g., a device configured for processing data and making decisions, forwarding data to a remote location which provides such activities, etc.
  • In certain embodiments, the signal detection component includes a cardiac monitoring element, such as shown in the system of FIG. 1. FIG. 1 shows a human 10 who has an implanted cardiovascular device “can” 8 and a lead 6, which components are employed to monitor and detect the signal emitted from pill 14. The monitoring device can be positioned in other locations as well, such as subcutaneously, in the heart, or in the waist near the stomach, for example. Positioning may be suggested by a particular application.
  • The inventive monitoring system can also be positioned as an external device. By example, it could be positioned by a harness that is worn outside the body and has one or more electrodes that attach to the skin at different locations. The inventive construct can be linked to a portable device, for example a watch that has one or two electrodes dispersed on the wrist There are many places where such a receiving electrode system could be placed and created such as, hearing aids that beep, necklace, belt, shoes (PZT—powered), or earrings.
  • As indicated above, in certain embodiments the systems include an external device which is distinct from the receiver (which may be implanted or topically applied in certain embodiments), where this external device provides a number of functionalities. Such an apparatus can include the capacity to provide feedback and appropriate clinical regulation to the patient. Such a device can take any of a number of forms. By example, the device can be configured to sit on the bed next to the patient. The device can read out the information described in more detail in other sections of the subject patent application, both from pharmaceutical ingestion reporting and from psychological sensing devices, such as is produced internally by a pacemaker device or a dedicated implant for detection of the pill. The purpose of the external apparatus is to get the data out of the patient and into an external device. One feature of external apparatus is its ability to provide pharmacologic and physiologic information in a form that can be transmitted through a transmission medium, such as a telephone line, to a remote location such as a clinician or to a central monitoring agency.
  • In certain embodiments, the cardiac monitoring element includes a conduction velocity measurement element. In certain embodiments, the cardiac monitoring element includes a pressure sensor. In certain embodiments, the cardiac monitoring element includes a dimension sensor.
  • Additional physiological sensors with various designs have been described in additional applications by some of the present inventors. These sensors can by used jointly with the present inventive systems. In addition, other applications by some of the present inventors describe multiplexing systems with which the present invention can be very usefully employed in an interactive, synergistic manner.
  • This prior work by some of the present inventors describes the use of dimension sensors to determine heart parameters in order to facilitate appropriate therapy intervention, such as resynchronization therapy. Using the present invention to determining the time of blood-stream absorption of cardiac treatment pharmaceutical and correlating this with changes produced in heart function sensed by those devices provides highly valuable information for the clinician in titrating medications and providing synergy between pharmacological and electrophysiological treatment.
  • Embodiments of the present invention can be used in various systems. Such systems may include various types of sensors. Such sensors and systems have been described in various applications by some of the present inventors. These applications also describe multiplexing systems previously developed by some of the present inventors with which the present invention can be employed. These applications include: U.S. patent application Ser. No. 10/734,490 published as 20040193021 titled: “Method And System For Monitoring And Treating Hemodynamic Parameters”; U.S. patent application Ser. No. 11/219,305 published as 20060058588 titled: “Methods And Apparatus For Tissue Activation And Monitoring”; International Application No. PCT/US2005/046815 titled: “Implantable Addressable Segmented Electrodes”; U.S. patent application Ser. No. 11/324,196 titled “Implantable Accelerometer-Based Cardiac Wall Position Detector”; U.S. patent application Ser. No. 10/764,429, entitled “Method and Apparatus for Enhancing Cardiac Pacing,” U.S. patent application Ser. No. 10/764,127, entitled “Methods and Systems for Measuring Cardiac Parameters,” U.S. patent application Ser. No. 10/764,125, entitled “Method and System for Remote Hemodynamic Monitoring”; International Application No. PCT/US2005/046815 titled: “Implantable Hermetically Sealed Structures”; U.S. application Ser. No. 11/368,259 titled: “Fiberoptic Tissue Motion Sensor”; International Application No. PCT/US2004/041430 titled: “Implantable Pressure Sensors,”; U.S. patent application Ser. No. 11/249,152 entitled “Implantable Doppler Tomography System,” and claiming priority to: U.S. Provisional Patent Application No. 60/617,618; International Application Serial No. PCT/US05/39535 titled “Cardiac Motion Characterization by Strain Gauge”. These applications are incorporated in their entirety by reference herein.
  • Some of the present inventors have developed a variety of display and software tools to coordinate multiple sources of sensor information. Examples of these can be seen in PCT application serial no. PCT/US2006/12246 titled: “Automated Optimization of Multi-Electrode Pacing for Cardiac Resynchronization” and filed on Mar. 31, 2006 and claiming priority to U.S. Provisional Patent Applications “Automated Timing Combination Selection” and “Automated Timing Combination Selection Using Electromechanical Delay”, both filed Mar. 31, 2005. These applications are incorporated in their entirety by reference herein.
  • The above described systems are reviewed in terms of communication between an identifier on a pharmaceutical composition and a receiver. However, the systems are not so limited. In a broader sense, the systems are composed of two or more different modules that communicate with each other, e.g., using the transmitter/receiver functionalities as reviewed above, e.g., using the monopole transmitter (e.g., antenna) structures as described above. As such, the above identifier elements may be incorporated into any of a plurality of different devices, e.g., to provide a communications system between two self-powered devices in the body, where the self-powered devices may be sensors, data receivers and storage elements, effectors, etc. In an exemplary system, one of these devices may be a sensor and the other may be a communication hub for communication to the outside world. This inventive embodiment may take a number of forms. There can be many sensors, many senders and one receiver. They can be transceivers so both of these can take turns sending and receiving according to known communication protocols. In certain embodiments, the means of communication between the two or more individual devices is the mono polar system, e.g., as described above. In these embodiments, each of these senders may be configured to take turns sending a high frequency signal into the body using a monopole pulling charge into and out of the body which is a large capacitor and a conductor. The receiver, a monopole receiver is detecting at that frequency the charge going into and out of the body and decoding an encrypted signal such as an amplitude modulated signal or frequency modulated signal. This embodiment of the present invention has broad uses. For example, multiple sensors can be placed and implanted on various parts of the body that measure position or acceleration. Without having wires connecting to a central hub, they can communicate that information through a communication medium.
  • Methods
  • In the methods of the subject invention, an effective amount of a composition of the invention is administered to a subject in need of the active agent present in the composition, where “effective amount” means a dosage sufficient to produce the desired result, e.g. an improvement in a disease condition or the symptoms associated therewith, the accomplishment of a desired physiological change, etc. The amount that is administered may also be viewed as a therapeutically effective amount. A “therapeutically effective amount” means the amount that, when administered to an subject for treating a disease, is sufficient to effect treatment for that disease.
  • The composition may be administered to the subject using any convenient means capable of producing the desired result, where the administration route depends, at least in part, on the particular format of the composition, e.g., as reviewed above. As reviewed above, the compositions can be formatted into a variety of formulations for therapeutic administration, including but not limited to solid, semi solid or liquid, such as tablets, capsules, powders, granules, ointments, solutions, suppositories and injections. As such, administration of the compositions can be achieved in various ways, including, but not limited to: oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intracheal, etc., administration. In pharmaceutical dosage forms, a given composition may be administered alone or in combination with other pharmaceutically active compounds, e.g., which may also be compositions having signal generation elements stably associated therewith.
  • The subject methods find use in the treatment of a variety of different conditions, including disease conditions. The specific disease conditions treatable by with the subject compositions are as varied as the types of active agents that can be present in the subject compositions. Thus, disease conditions include, but are not limited to: cardiovascular diseases, cellular proliferative diseases, such as neoplastic diseases, autoimmune diseases, hormonal abnormality diseases, infectious diseases, pain management, and the like.
  • By treatment is meant at least an amelioration of the symptoms associated with the disease condition afflicting the subject, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. symptom, associated with the pathological condition being treated. As such, treatment also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g. prevented from happening, or stopped, e.g. terminated, such that the subject no longer suffers from the pathological condition, or at least the symptoms that characterize the pathological condition. Accordingly, “treating” or “treatment” of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease). For the purposes of this invention, a “disease” includes pain.
  • A variety of subjects are treatable according to the present methods. Generally such subjects are “mammals” or “mammalian,” where these terms are used broadly to describe organisms which are within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In representative embodiments, the subjects will be humans.
  • In certain embodiments, the subject methods, as described above, are methods of managing a disease condition, e.g., over an extended period of time, such as 1 week or longer, 1 month or longer, 6 months or longer, 1 year or longer, 2 years or longer, 5 years or longer, etc. The subject methods may be employed in conjunction with one or more additional disease management protocols, e.g., electrostimulation based protocols in cardiovascular disease management, such as pacing protocols, cardiac resynchronization protocols, etc; lifestyle, such a diet and/or exercise regimens for a variety of different disease conditions; etc.
  • In certain embodiments, the methods include modulating a therapeutic regimen based data obtained from the compositions. For example, data may be obtained which includes information about patient compliance with a prescribed therapeutic regimen. This data, with or without additional physiological data, e.g., obtained using one or more sensors, such as the sensor devices described above, may be employed, e.g., with appropriate decision tools as desired, to make determinations of whether a given treatment regimen should be maintained or modified in some way, e.g., by modification of a medication regimen and/or implant activity regimen. As such, methods of invention include methods in which a therapeutic regimen is modified based on signals obtained from the composition(s).
  • In certain embodiments, also provided are methods of determining the history of a composition of the invention, where the composition includes an active agent, an identifier element and a pharmaceutically acceptable carrier. In certain embodiments where the identifier emits a signal in response to an interrogation, the identifier is interrogate, e.g., by a wand or other suitable interrogation device, to obtain a signal. The obtained signal is then employed to determine historical information about the composition, e.g., source, chain of custody, etc.
  • In yet other embodiments where the identifier is one that survives digestion, the methods generally include obtaining the signal generation element of the composition, e.g., by retrieving it from a subject that has ingested the composition, and then determining the history of the composition from obtained signal generation element. For example, where the signal generation element includes an engraved identifier, e.g., barcode or other type of identifier, the engraved identifier may be retrieved from a subject that has ingested the composition and then read to identify at least some aspect of the history of the composition, such as last known purchaser, additional purchasers in the chain of custody of the composition, manufacturer, handling history, etc. In certain embodiments, this determining step may include accessing a database or analogous compilation of stored history for the composition.
  • Utility
  • The present invention provides the clinician an important new tool in their therapeutic armamentarium: automatic detection and identification of pharmaceutical agents actually delivered into the body. The applications of this new information device and system are multi-fold. Applications include, but are not limited to: (1) monitoring patient compliance with prescribed therapeutic regimens; (2) tailoring therapeutic regimens based on patient compliance; (3) monitoring patient compliance in clinical trials; (4) monitoring usage of controlled substances; and the like. Each of these different illustrative applications is now reviewed in greater detail below.
  • Monitoring Patient Compliance with Prescribed Therapeutic Regimens
  • As summarized above, one type of application in which the subject compositions and systems find use is in monitoring patient compliance with prescribed therapeutic regimens. By monitoring patient compliance is meant tracking whether a patient is actually taking medication in the manner prescribed to the patient. As such, the present invention provides accurate data of when a pill has been taken and which pill has been taken. This allows the precise determination of which pill was taken at a specific point in time. Such monitoring capability assures patients are taking the prescribed medication correctly. This information avoids the potential for over prescription of medications that are not actually being taken. By example, if pain killers are intended to be administered to a patient, it is possible to verify with the present invention that the patient did in fact take those pain killers in a certain period of time. This knowledge is an important tool in limiting the illicit sale of unconsumed drugs to an unintended party. In the case of cardio vascular pills, the clinician or care giver is able to verify that the amount of the drug was taken has been taken at approximately the right point and time. Thus, the true efficacy of the drug can be accurately evaluated. Proper administration and patient compliance is especially critical in Alzheimer's, psychiatric, and alcohol aversion drugs, and in the treatment of rest home residents. In the case of accidental and other overdoses situations, the intervening clinician will be able to discern how far the ingestion has proceeded, and how many pills are involved.
  • In more complex embodiments of the present invention, correct, timely ingestion of the drugs will automatically trigger a prescription refill signal which is forwarded to a pharmacy data system, and in some cases the refill will be automatically delivered directly to the patient's home, or released by a device in the patient's home some period of time later. This feature is particularly valuable in patients with compromised mental capacity and/or limited physical mobility.
  • The invention is particularly useful in complex administration regimens, such as when multiple pharmaceuticals are being taken, and confusion is more likely to occur. The inventive pills can have multiple external layers, with only correct dosage allowing dissolution and absorption of the pharmaceutical component. Specific indicators, such as electrical conduction velocity in the heart or electrolytic levels in the blood in response to pharmaceutical can also be titrated.
  • In certain embodiments, a patient can be alerted when the patient is in some way non-compliant with a given treatment regimen. For example, by a sound, visual, or computer reminder, if the pharmacological regimen is not being accurately adhered to, a reminder is provided. If that reminder is not accurately responded to, the system can provide an alert to family members, caregivers, or clinicians in order to remedy the gap in treatment or overdose. The device may also automatically modify the dosage and timing of the regimen to compensate for prior non-standard dosing.
  • Tailoring Therapeutic Regimens Based on Patient Compliance
  • As summarized above, one type of application in which the subject compositions and systems find use is in tailoring therapeutic regimens based on patient compliance. In such applications, data obtained about whether a patient has or has not taken a particular dosage is employed to determine future dosages and/or timing of such dosages. In certain embodiments, data concerning patient compliance is combined with additional data, e.g., sensed physiological data, to make customized changes or modifications to a given therapeutic regimen. By example, when data about dosage compliance obtained according to the invention is used in concert with other medical sensing devices, correlation between drug delivery, batch and dosage can be correlated to a physiological response. In this manner, optimal pharma-therapeutic regimens may be formulated by the clinician. By example, cardiac stimulating drugs can be titrated to the most appropriate dosages, minimizing side effects such as cardiac muscle exhaustion and rebound effects among others, and optimizing both dosage and timing for each individual patient.
  • Assessment of a range of alternate medications is made possible by the present invention without resort to awaiting overt clinical sequel of treatment, many of which can be seriously adverse. By example, positive effects would be quickly ascertainable without being obscured by more random factors. Negative responses, such as changes in blood pressure, would become clearly evident as drug related or independent above background physiologic variation.
  • In one clinical arena, the present invention allows, in concert with other sensing devices developed by some of the present inventors, the measurement and assessment of the cardiac response to those medications. These co-employed sensing devices can be those enumerated below, among others. Other sensing technology, e.g., as mentioned above, developed by some of the present inventors allows measurement of heart health and cardiac efficiency. Using these tools in concert with the present inventive device, the clinician will be able to compare the response of the heart and body to the administered pharmaceutical. The data provided by the present invention can optionally be recorded over time. The recording system records synchrony or conduction velocity of a signal going through cardiac tissue and how that is mediated by the presence of a certain medication. This unique data is made possible by the present invention since it can determine electronically exactly when the pill or other medication was being absorbed into the body.
  • In more standard clinical environments, this unique data allows careful selection and titration of drug administration without resort to more overt physical symptoms to ascertain contraindications, efficacy, and optimal dosage levels. The present invention provides a record for emergency room technicians or doctors when a patient is admitted to a hospital so that the patient's status can be accurately ascertained. Dosage events within the last hour or day prior to admission, and the identity of the last medication, will be immediately available. As such, future therapeutic regimens can be made based on accurate records of patient drug medication history.
  • In certain embodiments, the clinician obtains this information through simple interrogation of the implanted or portable device. This device would tell them without any uncertainty what pills have been taken. As the inventive technology becomes more wide spread, this data will become more regularly available. The present inventive microchips are sufficiently inexpensive such that when they are put into standard production, most or all pharmaceuticals will be fitted with them as a matter of course.
  • The patient monitoring capacity of the external reporting apparatus is an importation function which the inventive device can provide. When coordinated with internal or external physiologic sensing data, the device can read out the physiological response of the patient to the ingestion of medication, and then transmit this information back to the clinician. The clinician can then modify therapy to optimal effectiveness, as indicated by the new data in response to the modified therapy, and so forth.
  • In more sophisticated embodiments of the present invention, the dosage adjustment function, within certain parameters, can be performed by an intelligence circuit in the apparatus. By example, for a blood pressure medication, the patient takes their blood pressure pill. 20 minutes later, the internal monitoring circuitry in the implantable device registers a drop in blood pressure. The circuitry quantifies this drop, and transmits it to this bedside apparatus. The apparatus then can adjust the dosage of the pill to optimally treat the patient. Similarly, when the patient is connected to an IV, the dosage can be dispensed directly into the IV fluid. In certain embodiments, the closed-loop system is provided as a fully implantable device.
  • Current clinical practice for drug treatment optimization is considerably more limited than that which is available by use of the present inventive device. Currently, blood pressure medication treatment is set at so many pills per day. Such a blunt dosage regime takes a long time to optimize appropriately because the feedback loop is very slow. By contrast, with the present invention, the feedback loop of physiologic response to pharmaceutical dosage is very rapid and very efficient. Ultimately, the present invention allows tailoring the drug dosages day to day, or even more finely, to account for change in activity, change in physiological conditions in the patient, and other dosage parameter.
  • In more sophisticated embodiments of the present invention, physiological reactions to specific dosages and time intervals would also be continually monitored. In some embodiments, the level of drug in the blood stream is monitored, allowing for individual and time of day variations in drug metabolism.
  • This aspect of the present invention effectively minimizes underdosing or overdosing the controlled substances, in some cases addressing these changes before they produce external symptoms apparent to the patient or clinician. The drug dosage can be automatically titrated so that, by example, the smallest appropriate level to quell anxiety due to pain, other physiologic reactions to pain, or provide steady or gradually diminishing blood levels of the drug would be dispensed. This feature of the present invention provides an automatic, appropriately gradual, weaning off of the drug, lessening the chance of serious addiction or severe, adverse withdrawal reactions.
  • Clinical Trial Applications
  • An important application of the invention is to provide immediate feedback of physiological data response to administration of a pharmaceutical agent in clinical drug trails. A current challenge is that the experimental drug is administered broadly to a population without a comprehensive foreknowledge of which sub-groups within this population are most likely to benefit from the treatment. Another challenge is monitoring patient compliance with the treatment regimen, by determining if the tests subjects are taking the medicine as indicated. The later challenge is addressed in the sections above. Both patient non-compliance levels and actual response to drug ingestion can thus be determined. As such, compliance intervention can then be addressed early in the study.
  • In certain embodiments of the present invention, clinical researchers are provided with immediate access to physiological data. The clinical researchers are able to identify the subset for which the drug is most likely effective from within the original test population of possible participants in the trial. The example above of a patient receiving blood pressure medication and getting feedback immediately demonstrates how effectiveness of a novel medicine can be quickly determined.
  • Upon administration of the first doses of medication to initial test subjects, the clinical researchers are likely to find that some subjects in the population respond to the medication and others do not. This immediate feedback allows the administrator of the trail to exclude those patients who do not respond to the medication and target only that subgroup for which there is clear efficacy. This culling process allows the overall results of the trail to get a much higher effective percentage, because one is able to target the drug to the group for whom it is effective. It also avoids side effect challenges for subjects who would not have a benefit balance to such risks.
  • As such, from this innovative data, the present invention provides the clinician an accurate dose response curve showing the response to that medication and the timing of the digestion of the pill. Such innovative data has many applications. For instance, the clinician now has the ability to determine which patients have no response to the medicine in the pill. In a study situation, such patients can be removed from a study or a test of the clinical utility of a certain medication. This ability provides that only people who have a beneficial response to a certain medication are retained in the trail. This feature will improve the efficacy of medications and to reduce the amount of medications that people take that are not being useful. It may also be used in trials to determine which patients actually consumed the medicine, and which did not.
  • The present invention allows identification of physiological proxies for the efficacy of a drug. By example, for a drug which has a long term administration prior to the development of overt clinical changes, there are typically certain short term physiological factors which appear immediately after ingestion of the drug. By example, cancer medication which requires many months to show an effect, can have shorter term indicia of its efficacy in one or a constellation of physiologic factors. Changes, both local or throughout the whole body, in blood pressure, body temperature, internal chemical enzymes or other factors will serve as proxies for the longer term desired effects. A precise correlation of these factors with the time of the pills ingestion enhances the ability to find meaningful indicia.
  • With the very closely timed correlated response to the ingestion of the pill provided for the first time by the present innovation, demonstrating that a physiologic response is a result of the drug ingestion rather than any of the other possibility confounding factors, is much more likely. This capacity of the present invention can serve as a partial or complete proxy for clinical trials.
  • The invention provides a way to determine very quickly whether a patient should be taking the medication or not, whether it will be effective or not, and allow its appropriate titration. Synergies between medications, both helpful and adverse, will also become more readily apparent.
  • Monitoring Usage of Controlled Substances
  • As reviewed above, in other embodiments of the inventive microchips, the identifiers can be fitted with coils, susceptible of interrogation without being dissolved in the body. This is accomplished by transmitting RF energy into the coil in such a way that the inquirer will be apprised of the presence and identity of a pill before it is ingested.
  • In an additional embodiment of the present invention, a “smart box” is provided that can interrogate each pill and ascertain its address. The box can write a distinctive product number or product code so that every single pill ever made is provided with a unique identifier. Fuses, for example, may be selectively destroyed so the addresses may be detected electrically or optically. Particularly in the case of controlled substances, such as a narcotic, this will be important in limiting the illegal used of previously legitimate medicines. The present invention makes it possible to identify precisely who bought such a pill from the authorized pharmacist. This use of the present invention will rein in the number of illicit uses of controlled substances on the market place.
  • An important application for the external apparatus aspect of the present invention is in monitoring and regulating the use of controlled pharmaceutical substances. A serious risk when patients are prescribed heavy narcotics for pain control is the possibility of addiction. In its simplest analysis, addiction occurs from the ingestion of too much of the controlled medication by inadvertent overdosing, purposeful misuse, or through inexact dosage prescription. Additionally, as described above, individual serial number are provided on such pharmaceuticals to track the legitimate distribution of the drug before the illicit distribution of such drugs.
  • In one application of the present invention, a means for locking and regulating the dosage of a potential addictive drug is provided. An example of this capacity of the present invention is when a patient takes their narcotic pill, in which the ingestion of the medication is registered by the internal device. This information is then automatically transmitted to the external apparatus.
  • The inventive apparatus is so configured that only after the patient has taken the pill and at the appropriate time has elapsed does this accessory apparatus dispense a further pill. In this manner, the addiction rate for the drug is dramatically lowered by limiting legal drug availability by dispensing exactly the prescribed dosage at precisely the appropriate time interval.
  • The external apparatus can also be effectively employed in mandatory medication forensic applications. For example, in the case of a convicted criminal, the criminal can be required to take court ordered medication as a condition of release from jail. Using the present invention, the court or probation officer has access to a real-time record of the administration of this drug as this information is fed back through the accessory apparatus to the appropriate official. There is a current trend towards court mandated psychotropic or chemical sterilization drug maintenance for sex offenders which would be addressed by this aspect of the present invention. This use of the present invention is analogous to house arrests where physical position monitoring bands are worn on the ankle of the offender.
  • Kits
  • Also provided are kits for practicing the subject methods. Kits may include one or more compositions of the invention, as described above. The dosage amount of the one or more pharmacological agents provided in a kit may be sufficient for a single application or for multiple applications. Accordingly, in certain embodiments of the subject kits a single dosage amount of a pharmacological agent is present and in certain other embodiments multiple dosage amounts of a pharmacological agent may be present in a kit. In those embodiments having multiple dosage amounts of pharmacological agent, such may be packaged in a single container, e.g., a single tube, bottle, vial, and the like, or one or more dosage amounts may be individually packaged such that certain kits may have more than one container of a pharmacological agent.
  • Suitable means for delivering one or more pharmacological agents to a subject may also be provided in a subject kit. The particular delivery means provided in a kit is dictated by the particular pharmacological agent employed, as describe above, e.g., the particular form of the agent such as whether the pharmacological agent is formulated into preparations in solid, semi solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols, and the like, and the particular mode of administration of the agent, e.g., whether oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intracheal, etc. Accordingly, certain systems may include a suppository applicator, syringe, I.V. bag and tubing, electrode, etc.
  • In certain embodiments the kits may also include a signal receiving element, as reviewed above. In certain embodiments, the kits may also include an external monitor device, e.g., as described above, which may provide for communication with a remote location, e.g., a doctor's office, a central facility etc., which obtains and processes data obtained about the usage of the composition.
  • The subject kits may also include instructions for how to practice the subject methods using the components of the kit. The instructions may be recorded on a suitable recording medium or substrate. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub-packaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate.
  • Some or all components of the subject kits may be packaged in suitable packaging to maintain sterility. In many embodiments of the subject kits, the components of the kit are packaged in a kit containment element to make a single, easily handled unit, where the kit containment element, e.g., box or analogous structure, may or may not be an airtight container, e.g., to further preserve the sterility of some or all of the components of the kit.
  • The following example is offered by way of illustration and not by way of limitation.
  • EXPERIMENTAL Example 1
  • In the following experiment, a transmitter (Tx) and receiver (Rx), each powered by batteries and encased in a water-tight Rubbermaid™ container, are employed. The Tx and Rx float in a bath of saline, and an LED glows on the Rx when the Tx is placed in the bath. Both Tx and Rx are completely isolated from the outside world.
  • The Tx, representing the compositions of the present application, e.g., a pill composition having an active agent and signal generation element, is an oscillator circuit based on a CMOS timer chip. It produces a square wave at about 80 kHz of 3V amplitude from a Lithium battery. A tightly twisted pair of wires extends from the circuit, out of the container, and into the bath. At the end of the twisted pair, the wires are striped of insulation by about 1 mm and separated to form a dipole antenna. The signal amplitude was found to scale linearly with the separation distance characterizing this dipole. The signal was easily detectable with this setup when the dipole was 5 mm in extent.
  • The Rx is a filtered amplifier circuit with outputs to detect the transmitted signal. A square of copper, 10 cm on a side, was attached to the bottom of the outside of the container and attached to the negative differential input of the circuit; this represents the pacing can. A bipolar pacing lead, about 40 cm long, was attached to the positive differential input of the circuit; the ring electrode was selected for the input. The differential signal was coupled into the inputs of a gain 100 instrumentation amplifier through 0.1 uF series capacitors. The output of the instrumentation amplifier was fed into a 4-pole high-pass filter, with gain of 100 and cutoff frequency 5 kHz. This output was fed into a 2-pole low-pass filter with gain 20 and cutoff frequency 100 kHz. Thus, the overall gain of the circuit is 200,000. This output signal is applied across an LED and resistor in series, which glows when the output signal exceeds a few volts.
  • When not in the bath, the Rx LED was on all the time as it picked up interference and power line noise from the environment. When the pacing lead was shorted to the mock can the LED turned off.
  • When placed in solution, the LED turned off. When the Tx was also placed in solution, the Rx LED turned on and the dependence on position and orientation was investigated. The intensity of the LED was found to depend on the cosine of the angle between the Rx and Tx dipole, with a null for perpendicular orientation and sign inversion as the sense of the dipole was reversed, as observed with an external oscilloscope. The intensity of the LED was found to vary directly with position, with a bright, saturated glow observed for spacing less than 5 cm and a dim, diffuse glow observed for the maximum spacing allowed by the bath, about 50 cm.
  • The key to making the detection robust is differentiating the desired signal from spurious interference. Such was accomplished in this experiment by restricting the frequency band of sensitivity to between 5 and 100 kHz. To the extent this band can be narrowed, the more robust the system will be. The challenge here is to match the frequency of the Tx and Rx circuits, in light of the fact that the Tx frequency may vary by 30% due to manufacturing variation. The Rx circuit can be very narrow through the use of a narrow bandpass or by using demodulation techniques from the radio. The Rx circuit can be swept across a tuning frequency range to detect the presence of the pill. The presence of the pill can be confirmed by encoding an unlikely bit sequence in the digital information transmitted by the pill.
  • Two problems with this approach are that it consumes power from the Rx circuit while it scans frequencies, and that synchronization with multiple pills, which may burst the transmission of their codes, is difficult. If the frequency of the Tx is known ab intio, as is possible with circuit trimming or advanced manufacturing processes, an elegant solution to both these problems is presented. At the input to the Rx circuit, a tuned LC oscillator matched to the Tx frequency will “ring up” when the desired signal is present. This power can be detected by a simple diode circuit, which serves as a trigger to turn the detection circuit on, greatly reducing the time it must draw current. This tuned input also serves to narrow the bandwidth and reject spurious signals.
  • This above experiment demonstrates the ability to transmit and detect signals through a synthetic biological medium. The Tx may be readily powered off a chemical battery, such as a Pt/Mg system. Furthermore, digital information is readily encoded in the signal using a variety of encoding techniques to eliminate errors and improve the overall reliability of the system.
  • Example 2
  • A transmitter according to the subject invention was set up as follows. The circuit was powered off a 9V battery and floated on a bath of saline. The circuit was an oscillator based on the TLC551 chip, a CMOS version of the popular 555 timer. The oscillator was run at ˜7 kHz, with a duty cycle of perhaps 15%. The outputs of the oscillator were each capacitively coupled through 7 uF to a twisted pair, which was terminated in a small “Y” shaped dipole, with the arms separated by ˜1 mm, and ˜2 mm of bare wire exposed to the saline bath.
  • The signal was received through two Cu electrodes, each with ˜1 cm2 exposed to the bath. This was routed to the input of a Stanford pre-amp operated off batteries, set to a gain of 1000 with a pass band between 3 kHz and 30 kHz. The output of the pre-amp was observed on a battery powered oscilloscope.
  • A maximum signal of ˜200 uV referenced to the amplifier input was observed for an Rx electrode separation of ˜20 cm. A dipolar coupling strength was observed, displaying a sinusoidal angular dependence, with a null in received signal for perpendicular orientation; phase inversion was seen between parallel and anti-parallel orientations. The received signal strength was seen to scale linearly with separation of the Rx electrodes.
  • The above demonstrates that the signal is clearly detectable with proper amplification and filtering. Furthermore, a capacitor on the input of the Rx amplifier is not necessary; as the same results were obtained using DC coupling on the input with a high-pass filter later in the signal chain.
  • The above results also verified that the Tx can run off an Mg/Pt potato battery.
  • Example 3
  • A prototype smart pill microchip, which broadcasts a fixed code using frequency shift keying, was first powered by a 1.5V AA battery. The conductive signal was applied to a physiological saline bath with a twisted pair T-shaped dipole, approximately 1 cm across with 1 mm of conductor exposed on each arm of the T. The signal was detected by two copper electrodes, spaced approximately 10 cm apart, which feed into a battery powered, isolated differential pre-amp. The signal was observed on an oscilloscope. An oscillatory signal, clearly representative of the transmitted data, was observed with a frequency of about 300 kHz and an input-referenced amplitude of about 10 mV. Furthermore, a dependence of the received signal strength on the cosine of the angle between the transmit and receive conductors, as is characteristic of a dipolar interaction, was observed.
  • A Mg—CuI water-activated battery, with each electrode having an exposed surface area of ˜1 mm2 was constructed. The Mg electrode was formed by simply potting commercial grade Mg ribbon in epoxy and polishing the end flat with sandpaper. The CuI electrode was produced by first polishing the end of Cu wire potted in epoxy.
  • Approximately 100 μm of Cu was then electroplated on the end of the Cu wire using standard techniques, with the parameters chosen to give a large roughness coefficient, increasing the effective area of the electrode. The surface of this plated Cu was then transformed electrochemically to CuI by applying a potential corresponding to the potential of the Cu+ ion in a solution of I− ions. In approximately 15 min 40 mC of CuI was produced. The battery was demonstrated to have an open cell voltage of ˜1.05V in a pH 2 solution, corresponding to the acidity of a typical stomach.
  • The CuI—Mg battery was connected to the power terminals of the chip, and the output terminals were connected to the dipole conductor described above in a physiological saline bath. The battery was activated by dropping the electrodes in the bath, and a signal of amplitude ˜2 mV at a frequency of 20 kHz was observed for at least a minute.
  • Finally, the output terminals of the chip were shorted together, effectively configuring the chip for the 2-terminal operation described above. An output signal was observed, but its amplitude was much weaker, probably because of the decreased effective transmitter dipole length in this configuration. That is, in the 4-terminal configuration, the effective transmit conductor size is determined by the spacing between the battery and dipolar T, which was several centimeters; in the 2-terminal mode, the effective dipole length is reduced to the separation between the Mg and CuI electrodes, which was less than 1 cm. The observed signal was perhaps a few hundred μV, and could be quantified using averaging to overcome an interfering signal amplified by the broadband receiver. More sophisticated detection schemes will have little problem detecting such a signal reliably.
  • Example 4
  • A pill composition as described above prior to ingestion may be composed of two main components, an address generating logic circuit and a signal transmission circuit. The address generation circuit is powered with low current adequate to the required tasks. However, if the voltage supplied to the address generation circuit changes, the frequency of the oscillator therein will also change. This may produce changes in signal transmission, introduce noise into the transmission, and cause other undesired effects.
  • For design purposes, it is simpler to power the address generation circuit with a constant voltage. However, in certain embodiments a more complex configuration may be desired. By example, when the transmission starts, the transmitter consumes considerable energy. As a result, the voltage will drop because as more energy is consumed, the voltage of the power source drops. The change in voltage will result in a change of frequency in the oscillator within the address generation circuit.
  • An example of this challenge in a different area of engineering is when a remote control device is made from a receiver and servos. By contrast, the receiver works permanently, and consumes low current in proportion to the servo which consumes a very large current. The servos work only when a signal is transmitted to the remote site. In that case, the whole system consumes a relatively large amount of power when the servos start to work. When the servo starts to work, the voltage drops, and produces some noise. As a result, the stability of signal transmission is compromised.
  • In order to avoid this problem, embodiments of the system are powered with two voltage sources. The receivers are powered with one battery, and the servos are powered with another battery. With this configuration, whatever occurs in the servo does not affect the receiver. As such, a more stable remote control results, thereby improving the performance of the complete system.
  • In one embodiment, a common cathode is provided. There are also two positive electrodes, A1 and A2. In this case, with the battery divided into two parts, one part of the battery will power the address generation circuit, and the other will power the transmission circuit. This configuration provides a stable voltage to the address generation circuit. When the transmitter section of the device is turned on, only the voltage on the transmitter will change, but no change of voltage will occur in the address generation section of the device. Hence, the changes will typically cause a change in signal amplitude, but not in the frequency. As a result, the transition will be more stable, and the frequency of RF transmission will be unaffected, or minimally effected.
  • The above phenomena are not of concern if there is a big area of battery electrode, because the voltage of the system as a whole will not change. However, in the case of a small battery electrode, the transmitter can potentially lower the voltage of the battery, and there will be a change in voltage over the entire circuitry. If the battery is divided into two parts, the voltage of one battery can be changed while the other will continue to power the address generation circuit with a constant voltage.
  • A consideration in the design development is how one battery will affect the other. Experiments conducted by some of the present inventors show that a change of load on one battery does not affect the other; i.e., they worked independently. In this experiment, as is shown in FIG. 23, two copper iodine anode electrodes were provided with a magnesium electrode as a common cathode. These were connected to a zero-resistance ammeter, and performance was measured. One copper iodine electrode was connected through a 2.5 KΩ resistor, and the other through a 200 KΩ resistor. All the electrodes are submerged in a pH2 HCl solution at about 37° C. The data derived from this experiment is shown in FIG. 24. The two copper iodine electrodes work independently of each other.
  • An ordinary skilled artesian will easily identify different materials and configurations for the above device. The chemistry of this copper iodine and various manners of preparation will be understood or quickly developed.
  • The surface preparation before the copper iodine is forming is of interest. One approach is to use copper wire embedded in epoxy. This can be plated with electrolytic copper. After the copper is polarized in solution of potassium iodide, copper iodine is formed on the tip of the electrode. Copper iodine can also be formed by chemically deposition. Other means are also available.
  • 10 μm is a typical range for thickness of copper iodide to produce an adequate amount of electricity to accomplish the activity of the device for a 15 minute period. If less thickness is employed, the transmission will last a shorter time. Thus, the thickness of copper iodide is determined by the time required to produce electricity to provide the results needed for a particular application. For several seconds of transmission, less than 1 μm of copper iodide would be adequate. For one microsecond of transmission, a few nanometers of copper iodine thickness, such as in the range of about 10-100 nanometers, more specifically, about 20-50 nanometers is sufficient.
  • It is to be understood that this invention is not limited to particular embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
  • Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
  • Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described.
  • All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
  • It is noted that, as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.
  • As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.
  • Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
  • Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.

Claims (22)

What is claimed is:
1. An apparatus, comprising:
a partial power source comprising a first material and a second material, the partial power source configured to:
generate, upon contact with a conducting medium, a potential difference between the first material and the second material to provide power to a control device; and
generate, using the first material and the second material, a current flow within the conducting medium, the current flow comprising information encoded based on a variable conductance between the first material and the second material.
2. The apparatus of claim 1, further comprising:
a control device, the control device configured to produce the variable conductance between the first material and the second material when the partial power source is in contact with the conducting medium.
3. The apparatus of claim 1, further comprising:
a control device, the control device comprising a switch disposed between the first material and the second material, the switch configured to control the variable conductance between the first material and the second material to encode the information when the partial power source is in contact with the conducting medium.
4. The apparatus of claim 1, further comprising:
a control device, the control device comprising a switch disposed between the first material and the second material, the switch configured to short-circuit the partial power source when the partial power source is in contact with the conducting medium and the switch is closed.
5. The apparatus of claim 1, wherein the first material is an anode and the second material is a cathode.
6. The apparatus of claim 1, wherein the conducting medium is a physiological fluid.
7. The apparatus of claim 1, wherein the information comprises at least one of time information, date information, or identity information associated with a composition coupled to the partial power source.
8. The apparatus of claim 1, further comprising:
a power storage element configured to receive and store power from the partial power source, the power storage element configured to provide the power from the partial power source to the control device.
9. The apparatus of claim 1, wherein the partial power source is ingestible.
10. The apparatus of claim 1, wherein the current flow is detectable by an external device.
11. An apparatus, comprising:
a partial battery comprising a first electrode and a second electrode, the partial battery configured to:
generate, upon contact with a physiological fluid, a potential difference between the first electrode and the second electrode to provide power to a signal generation element; and
generate, using the first electrode and the second electrode, a current within the physiological fluid when in contact with the physiological fluid to conductively transmit a signal.
12. The apparatus of claim 11, wherein the signal encodes at least one of time information, date information, or identity information associated with a composition coupled to the partial battery.
13. The apparatus of claim 11, wherein the first electrode is an anode and the second electrode is a cathode.
14. The apparatus of claim 11, further comprising:
a power storage element configured to receive and store power from the partial battery, the power storage element configured to provide the power from the partial power source to the signal generation element.
15. The apparatus of claim 11, further comprising:
a signal generation element, the signal generation element comprising a switch disposed between the first electrode and the second electrode, the switch configured to control the current within the physiological fluid to encode information in the signal when the partial battery is in contact with the physiological fluid.
16. An apparatus, comprising:
a partial battery comprising a first material and a second material, the partial battery configured to:
generate, upon contact of the first material and the second material with a physiological fluid, a potential difference between the first material and the second material using the physiological fluid as an electrolyte of the partial battery to provide power to a control device; and
modulate a current flow within the physiological fluid being used as the electrolyte and based on a variable conductance within the control device and between the first material and the second material.
17. The apparatus of claim 16, wherein the variable conductance encodes at least one of time information, date information, or identity information associated with a composition coupled to the partial battery.
18. The apparatus of claim 16, further comprising:
a control device, the control device configured to produce the variable conductance between the first material and the second material when the partial battery is in contact with the physiological fluid.
19. The apparatus of claim 16, wherein the first material is an anode and the second material is a cathode.
20. The apparatus of claim 16, further comprising:
a power storage element configured to receive and store power from the partial battery, the power storage element configured to provide the power from the partial battery to the control device.
21. The apparatus of claim 16, further comprising:
a control device, the control device comprises a switch disposed between the first material and the second material, the switch configured to short-circuit the partial battery when the partial battery is in contact with the physiological fluid and the switch is closed.
22. The apparatus of claim 16, further comprising:
a control device, the control device comprises a switch disposed between the first material and the second material, the switch configured to control the variable conductance between the first material and the second material to encode information when the partial power source is in contact with the physiological fluid.
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US13/153,312 Active 2026-05-31 US8816847B2 (en) 2005-04-28 2011-06-03 Communication system with partial power source
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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9107806B2 (en) 2010-11-22 2015-08-18 Proteus Digital Health, Inc. Ingestible device with pharmaceutical product
US9161707B2 (en) 2005-04-28 2015-10-20 Proteus Digital Health, Inc. Communication system incorporated in an ingestible product
US9268909B2 (en) 2012-10-18 2016-02-23 Proteus Digital Health, Inc. Apparatus, system, and method to adaptively optimize power dissipation and broadcast power in a power source for a communication device
US9270025B2 (en) 2007-03-09 2016-02-23 Proteus Digital Health, Inc. In-body device having deployable antenna
US9271897B2 (en) 2012-07-23 2016-03-01 Proteus Digital Health, Inc. Techniques for manufacturing ingestible event markers comprising an ingestible component
US9320455B2 (en) 2009-04-28 2016-04-26 Proteus Digital Health, Inc. Highly reliable ingestible event markers and methods for using the same
US9415010B2 (en) 2008-08-13 2016-08-16 Proteus Digital Health, Inc. Ingestible circuitry
US9439582B2 (en) 2005-04-28 2016-09-13 Proteus Digital Health, Inc. Communication system with remote activation
US9597487B2 (en) 2010-04-07 2017-03-21 Proteus Digital Health, Inc. Miniature ingestible device
US9649066B2 (en) 2005-04-28 2017-05-16 Proteus Digital Health, Inc. Communication system with partial power source
US9756874B2 (en) 2011-07-11 2017-09-12 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
US9796576B2 (en) 2013-08-30 2017-10-24 Proteus Digital Health, Inc. Container with electronically controlled interlock
US20180042538A1 (en) * 2016-08-09 2018-02-15 Verily Life Sciences Llc Wake-up batteries for invasive biosensors
US9962107B2 (en) 2005-04-28 2018-05-08 Proteus Digital Health, Inc. Communication system with enhanced partial power source and method of manufacturing same
US10084880B2 (en) 2013-11-04 2018-09-25 Proteus Digital Health, Inc. Social media networking based on physiologic information
US10175376B2 (en) 2013-03-15 2019-01-08 Proteus Digital Health, Inc. Metal detector apparatus, system, and method
US10187121B2 (en) 2016-07-22 2019-01-22 Proteus Digital Health, Inc. Electromagnetic sensing and detection of ingestible event markers
US10398161B2 (en) 2014-01-21 2019-09-03 Proteus Digital Heal Th, Inc. Masticable ingestible product and communication system therefor
US11051543B2 (en) 2015-07-21 2021-07-06 Otsuka Pharmaceutical Co. Ltd. Alginate on adhesive bilayer laminate film
US11149123B2 (en) 2013-01-29 2021-10-19 Otsuka Pharmaceutical Co., Ltd. Highly-swellable polymeric films and compositions comprising the same
US11529071B2 (en) 2016-10-26 2022-12-20 Otsuka Pharmaceutical Co., Ltd. Methods for manufacturing capsules with ingestible event markers

Families Citing this family (231)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7414534B1 (en) 2004-11-09 2008-08-19 Pacesetter, Inc. Method and apparatus for monitoring ingestion of medications using an implantable medical device
US9198608B2 (en) * 2005-04-28 2015-12-01 Proteus Digital Health, Inc. Communication system incorporated in a container
US8730031B2 (en) 2005-04-28 2014-05-20 Proteus Digital Health, Inc. Communication system using an implantable device
US20120004520A1 (en) * 2005-04-28 2012-01-05 Proteus Biomedical, Inc. Communication System with Multiple Sources of Power
ES2820430T3 (en) 2005-05-09 2021-04-21 Labrador Diagnostics Llc Fluid systems for care centers and their uses
WO2007028035A2 (en) * 2005-09-01 2007-03-08 Proteus Biomedical, Inc. Implantable zero-wire communications system
EP1770603A1 (en) * 2005-10-03 2007-04-04 Assa Abloy Identification Technology Group AB Encapsulated transponder and method for manufacturing the same
US8920343B2 (en) 2006-03-23 2014-12-30 Michael Edward Sabatino Apparatus for acquiring and processing of physiological auditory signals
US8741230B2 (en) 2006-03-24 2014-06-03 Theranos, Inc. Systems and methods of sample processing and fluid control in a fluidic system
US11287421B2 (en) 2006-03-24 2022-03-29 Labrador Diagnostics Llc Systems and methods of sample processing and fluid control in a fluidic system
US8956287B2 (en) 2006-05-02 2015-02-17 Proteus Digital Health, Inc. Patient customized therapeutic regimens
US20080027348A1 (en) 2006-06-23 2008-01-31 Neuro Vista Corporation Minimally Invasive Monitoring Systems for Monitoring a Patient's Propensity for a Neurological Event
EP2037999B1 (en) 2006-07-07 2016-12-28 Proteus Digital Health, Inc. Smart parenteral administration system
US20080020037A1 (en) * 2006-07-11 2008-01-24 Robertson Timothy L Acoustic Pharma-Informatics System
EP2063766B1 (en) 2006-09-06 2017-01-18 Innurvation, Inc. Ingestible low power sensor device and system for communicating with same
US8512241B2 (en) 2006-09-06 2013-08-20 Innurvation, Inc. Methods and systems for acoustic data transmission
RU2009116271A (en) * 2006-09-29 2010-11-10 Конинклейке Филипс Электроникс, Н.В. (Nl) MINIATURE THRESHOLD SENSORS
US8054140B2 (en) 2006-10-17 2011-11-08 Proteus Biomedical, Inc. Low voltage oscillator for medical devices
US9622216B2 (en) * 2006-10-20 2017-04-11 Avago Technologies General Ip (Singapore) Ptd. Ltd Method and system for low rate MAC/PHY for 60 GHz transmission
KR101611240B1 (en) 2006-10-25 2016-04-11 프로테우스 디지털 헬스, 인코포레이티드 Controlled activation ingestible identifier
EP2069004A4 (en) 2006-11-20 2014-07-09 Proteus Digital Health Inc Active signal processing personal health signal receivers
EP3785599B1 (en) 2007-02-01 2022-08-03 Otsuka Pharmaceutical Co., Ltd. Ingestible event marker systems
AU2012247015B2 (en) * 2007-02-01 2015-09-17 Otsuka Pharmaceutical Co., Ltd. Ingestible event marker systems
CA2676280C (en) * 2007-02-14 2018-05-22 Proteus Biomedical, Inc. In-body power source having high surface area electrode
AU2012244231B2 (en) * 2007-02-14 2014-09-18 Otsuka Pharmaceutical Co., Ltd. In-body power source having high surface area electrode
EP2127160A1 (en) * 2007-02-14 2009-12-02 Kaba AG System and portable device for transmitting identification signals
EP2124725A1 (en) * 2007-03-09 2009-12-02 Proteus Biomedical, Inc. In-body device having a multi-directional transmitter
US8540632B2 (en) 2007-05-24 2013-09-24 Proteus Digital Health, Inc. Low profile antenna for in body device
PT2192946T (en) 2007-09-25 2022-11-17 Otsuka Pharma Co Ltd In-body device with virtual dipole signal amplification
US20090088618A1 (en) * 2007-10-01 2009-04-02 Arneson Michael R System and Method for Manufacturing a Swallowable Sensor Device
NZ584963A (en) 2007-10-02 2012-11-30 Theranos Inc Modular Point-of-care devices as addressible assay units with tips of assay units having interior to immobilize reagents by capillary action
EP2211974A4 (en) * 2007-10-25 2013-02-27 Proteus Digital Health Inc Fluid transfer port information system
WO2009067463A1 (en) 2007-11-19 2009-05-28 Proteus Biomedical, Inc. Body-associated fluid transport structure evaluation devices
EP2215726B1 (en) 2007-11-27 2018-01-10 Proteus Digital Health, Inc. Transbody communication systems employing communication channels
EP3827811A1 (en) * 2008-03-05 2021-06-02 Otsuka Pharmaceutical Co., Ltd. Multi-mode communication ingestible event markers and systems
US20100280366A1 (en) * 2008-05-13 2010-11-04 Lawrence Arne Continuous field tomography systems and methods of using the same
EP2310987A4 (en) * 2008-07-03 2011-09-14 Mario W Cardullo Nano rfid method and device
WO2010005953A2 (en) * 2008-07-07 2010-01-14 Cardullo Mario W Dynamically distributable nano rfid device and related method
WO2010005877A2 (en) 2008-07-08 2010-01-14 Proteus Biomedical, Inc. Ingestible event marker data framework
AU2009268338A1 (en) * 2008-07-11 2010-01-14 Mario W. Cardullo Dynamically triggerable nano RFID device and related method
EP3536376A1 (en) 2008-07-30 2019-09-11 Ecole Polytechnique Fédérale de Lausanne Apparatus for optimized stimulation of a neurological target
WO2010018524A1 (en) 2008-08-11 2010-02-18 Nxp B.V. Ingestible devices for measuring physiological parameters
US20100069821A1 (en) * 2008-09-16 2010-03-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Ex vivo modifiable medicament release-sites final dosage form
US20100068275A1 (en) * 2008-09-16 2010-03-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Personalizable dosage form
US20100068153A1 (en) * 2008-09-16 2010-03-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Ex vivo activatable final dosage form
US20100068152A1 (en) * 2008-09-16 2010-03-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Ex vivo modifiable particle or polymeric based final dosage form
US20100068254A1 (en) * 2008-09-16 2010-03-18 Mahalaxmi Gita Bangera Modifying a medicament availability state of a final dosage form
US20100069887A1 (en) * 2008-09-16 2010-03-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Multiple chamber ex vivo adjustable-release final dosage form
US20100068235A1 (en) * 2008-09-16 2010-03-18 Searete LLC, a limited liability corporation of Deleware Individualizable dosage form
US20100068233A1 (en) * 2008-09-16 2010-03-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Modifiable dosage form
US20100068256A1 (en) * 2008-09-16 2010-03-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Ex vivo modifiable medicament release-substance
US8159347B2 (en) * 2008-09-25 2012-04-17 General Electric Company Sensors having gap based sensing devices and methods of making and using the same
CN102246198A (en) * 2008-10-14 2011-11-16 普罗秋斯生物医学公司 Method and system for incorporating physiologic data in a gaming environment
EP2604313B1 (en) 2008-11-12 2014-09-17 Ecole Polytechnique Federale de Lausanne Microfabricated neurostimulation device
KR101192690B1 (en) * 2008-11-13 2012-10-19 프로테우스 디지털 헬스, 인코포레이티드 Ingestible therapy activator system, therapeutic device and method
WO2010068818A2 (en) * 2008-12-11 2010-06-17 Proteus Biomedical, Inc. Evaluation of gastrointestinal function using portable electroviscerography systems and methods of using the same
US9659423B2 (en) 2008-12-15 2017-05-23 Proteus Digital Health, Inc. Personal authentication apparatus system and method
US9439566B2 (en) 2008-12-15 2016-09-13 Proteus Digital Health, Inc. Re-wearable wireless device
TWI503101B (en) 2008-12-15 2015-10-11 Proteus Digital Health Inc Body-associated receiver and method
US8830037B2 (en) * 2008-12-31 2014-09-09 The Regents Of The University Of California In vivo RFID chip
WO2010080764A2 (en) * 2009-01-06 2010-07-15 Proteus Biomedical, Inc. Pharmaceutical dosages delivery system
SG172846A1 (en) 2009-01-06 2011-08-29 Proteus Biomedical Inc Ingestion-related biofeedback and personalized medical therapy method and system
AU2010203738B2 (en) * 2009-01-06 2016-02-25 Otsuka Pharmaceutical Co., Ltd. High-throughput production of ingestible event markers
US8540664B2 (en) 2009-03-25 2013-09-24 Proteus Digital Health, Inc. Probablistic pharmacokinetic and pharmacodynamic modeling
EP2432458A4 (en) 2009-05-12 2014-02-12 Proteus Digital Health Inc Ingestible event markers comprising an ingestible component
US8786049B2 (en) * 2009-07-23 2014-07-22 Proteus Digital Health, Inc. Solid-state thin-film capacitor
EP2467707A4 (en) 2009-08-21 2014-12-17 Proteus Digital Health Inc Apparatus and method for measuring biochemical parameters
TWI517050B (en) 2009-11-04 2016-01-11 普羅托斯數位健康公司 System for supply chain management
CA3026948C (en) 2009-12-01 2022-07-12 Ecole Polytechnique Federale De Lausanne Microfabricated neurostimulation device and methods of making and using the same
UA109424C2 (en) * 2009-12-02 2015-08-25 PHARMACEUTICAL PRODUCT, PHARMACEUTICAL TABLE WITH ELECTRONIC MARKER AND METHOD OF MANUFACTURING PHARMACEUTICAL TABLETS
CN102724907A (en) * 2010-01-27 2012-10-10 奥林巴斯株式会社 Power supply system and medical capsule device mounted with same
SG182825A1 (en) 2010-02-01 2012-09-27 Proteus Biomedical Inc Data gathering system
EP2531096A4 (en) 2010-02-01 2013-09-11 Proteus Digital Health Inc Two-wrist data gathering system
US9061879B2 (en) * 2010-03-29 2015-06-23 Ethimedix Sa Secure liquid drug dispenser and method for delivering liquid medication
AU2011234422B2 (en) 2010-04-01 2015-11-05 Ecole Polytechnique Federale De Lausanne (Epfl) Device for interacting with neurological tissue and methods of making and using the same
SG184839A1 (en) * 2010-04-11 2012-11-29 Proteus Digital Health Inc Apparatus, system and method for detection and delivery of a medicinal dose
TWI557672B (en) 2010-05-19 2016-11-11 波提亞斯數位康健公司 Computer system and computer-implemented method to track medication from manufacturer to a patient, apparatus and method for confirming delivery of medication to a patient, patient interface device
US10342444B2 (en) * 2010-06-08 2019-07-09 Alivecor, Inc. Mobile ECG sensor apparatus
EP2580687A4 (en) * 2010-06-14 2014-04-30 Trutag Technologies Inc System for verifying an item in a package using a database
US10349820B2 (en) 2010-07-12 2019-07-16 Therasyn Sensors, Inc. Device and methods for in vivo monitoring of an individual
JP5734614B2 (en) * 2010-10-08 2015-06-17 オリンパス株式会社 Biological information acquisition device
US9037477B2 (en) 2010-10-08 2015-05-19 Cardiac Science Corporation Computer-implemented system and method for evaluating ambulatory electrocardiographic monitoring of cardiac rhythm disorders
US20120089417A1 (en) 2010-10-08 2012-04-12 Bardy Gust H Computer-Implemented System And Method For Mediating Patient-Initiated Physiological Monitoring
US20120089412A1 (en) 2010-10-08 2012-04-12 Bardy Gust H Computer-Implemented System And Method For Facilitating Patient Advocacy Through Online Healthcare Provisioning
US8285370B2 (en) 2010-10-08 2012-10-09 Cardiac Science Corporation Microcontrolled electrocardiographic monitoring circuit with feedback control
US8239012B2 (en) 2010-10-08 2012-08-07 Cardiac Science Corporation Microcontrolled electrocardiographic monitoring circuit with differential voltage encoding
US20120089000A1 (en) 2010-10-08 2012-04-12 Jon Mikalson Bishay Ambulatory Electrocardiographic Monitor For Providing Ease Of Use In Women And Method Of Use
US8613708B2 (en) 2010-10-08 2013-12-24 Cardiac Science Corporation Ambulatory electrocardiographic monitor with jumpered sensing electrode
US20120089001A1 (en) 2010-10-08 2012-04-12 Jon Mikalson Bishay Ambulatory Electrocardiographic Monitor And Method Of Use
UA109691C2 (en) * 2010-12-29 2015-09-25 WIRELESS ENERGY SOURCES FOR USE IN INTEGRATED CIRCUITS
SG191923A1 (en) * 2011-01-10 2013-08-30 Proteus Digital Health Inc System, method, and article to prompt behavior change
EP2666008B1 (en) 2011-01-21 2021-08-11 Labrador Diagnostics LLC Systems and methods for sample use maximization
JP2014514032A (en) 2011-03-11 2014-06-19 プロテウス デジタル ヘルス, インコーポレイテッド Wearable personal body-related devices with various physical configurations
CN103781474B (en) * 2011-03-24 2018-09-21 宝珍那提公司 Deglutible medicament capsule
WO2012138351A1 (en) 2011-04-08 2012-10-11 Empire Technology Development Llc Gel formed battery
US8722228B2 (en) 2011-04-08 2014-05-13 Empire Technology Development Llc Moisture activated battery
US20120259376A1 (en) * 2011-04-08 2012-10-11 Empire Technology Development Llc Charge Storage System
US8828581B2 (en) 2011-04-08 2014-09-09 Empire Technology Development Llc Liquid battery formed from encapsulated components
US8735001B2 (en) 2011-04-08 2014-05-27 Empire Technology Development Llc Gel formed battery
IN2014MN00183A (en) * 2011-07-21 2015-06-19 Proteus Digital Health Inc
JP2014528780A (en) 2011-08-27 2014-10-30 クラフト,ダニエル,エル. Portable drug dispenser
US9268915B2 (en) 2011-09-25 2016-02-23 Theranos, Inc. Systems and methods for diagnosis or treatment
US8475739B2 (en) 2011-09-25 2013-07-02 Theranos, Inc. Systems and methods for fluid handling
US9632102B2 (en) 2011-09-25 2017-04-25 Theranos, Inc. Systems and methods for multi-purpose analysis
US20140170735A1 (en) 2011-09-25 2014-06-19 Elizabeth A. Holmes Systems and methods for multi-analysis
US8380541B1 (en) 2011-09-25 2013-02-19 Theranos, Inc. Systems and methods for collecting and transmitting assay results
US8840838B2 (en) 2011-09-25 2014-09-23 Theranos, Inc. Centrifuge configurations
US9619627B2 (en) 2011-09-25 2017-04-11 Theranos, Inc. Systems and methods for collecting and transmitting assay results
US9664702B2 (en) 2011-09-25 2017-05-30 Theranos, Inc. Fluid handling apparatus and configurations
US9250229B2 (en) 2011-09-25 2016-02-02 Theranos, Inc. Systems and methods for multi-analysis
US10012664B2 (en) 2011-09-25 2018-07-03 Theranos Ip Company, Llc Systems and methods for fluid and component handling
US9810704B2 (en) 2013-02-18 2017-11-07 Theranos, Inc. Systems and methods for multi-analysis
US9235683B2 (en) 2011-11-09 2016-01-12 Proteus Digital Health, Inc. Apparatus, system, and method for managing adherence to a regimen
US20130129869A1 (en) * 2011-11-23 2013-05-23 Hooman Hafezi Compositions comprising a shelf-life stability component
US20140315170A1 (en) * 2011-11-23 2014-10-23 Proteus Digital Health, Inc. Apparatus, System, and Method to Promote Behavior Change Based on Mindfulness Methodologies
EP2659834A1 (en) * 2012-04-30 2013-11-06 Siemens Aktiengesellschaft Costoptimized Hp capsule
US9985320B2 (en) 2012-04-30 2018-05-29 Carnegie Mellon University Water-activated, ingestible battery
WO2013165964A1 (en) 2012-04-30 2013-11-07 Carnegie Mellon University An ingestible, electrical device for stimulating tissues in a gastrointestinal tract of an organism
US11737896B2 (en) 2012-07-31 2023-08-29 Purdue Research Foundation Wirelessly-powered implantable EMG recording system
US8761717B1 (en) 2012-08-07 2014-06-24 Brian K. Buchheit Safety feature to disable an electronic device when a wireless implantable medical device (IMD) is proximate
WO2014071571A1 (en) * 2012-11-07 2014-05-15 Empire Technology Development Llc Liquid-activated hydrogel battery
WO2014098166A1 (en) 2012-12-19 2014-06-26 大塚製薬株式会社 Medicinal tablet, production method therefor, and production device therefor
US20140324216A1 (en) * 2013-01-24 2014-10-30 Sami A Beg Method, system and apparatus for managing medication delivery
KR101381424B1 (en) 2013-01-31 2014-04-14 계명대학교 산학협력단 Implantable wireless ecg sensor device
SG11201506421PA (en) 2013-02-18 2015-09-29 Theranos Inc Systems and methods for collecting and transmitting assay results
US20140283017A1 (en) 2013-03-13 2014-09-18 Motorola Mobility Llc Communicating via a body-area network
JP2016517317A (en) * 2013-03-15 2016-06-16 プロテウス デジタル ヘルス, インコーポレイテッド Removable wireless device
JP6498177B2 (en) 2013-03-15 2019-04-10 プロテウス デジタル ヘルス, インコーポレイテッド Identity authentication system and method
GB201304738D0 (en) * 2013-03-15 2013-05-01 Mars Inc Sampling Device
US11744481B2 (en) 2013-03-15 2023-09-05 Otsuka Pharmaceutical Co., Ltd. System, apparatus and methods for data collection and assessing outcomes
US20140278468A1 (en) 2013-03-15 2014-09-18 I.D. Therapeutics Llc Apparatus and method for optimizing treatment using medication compliance patterns and glucose sensor
DE202013005125U1 (en) * 2013-06-04 2014-09-05 Hugo Vogelsang Maschinenbau Gmbh Device for electrical disintegration of cell aggregates
RU2736776C2 (en) 2013-09-20 2020-11-20 Протеус Диджитал Хелс, Инк. Methods, devices and systems for receiving and decoding signals in the presence of noise using sections and deformation
US9577864B2 (en) 2013-09-24 2017-02-21 Proteus Digital Health, Inc. Method and apparatus for use with received electromagnetic signal at a frequency not known exactly in advance
US9433380B1 (en) 2013-09-25 2016-09-06 Bardy Diagnostics, Inc. Extended wear electrocardiography patch
US9545204B2 (en) 2013-09-25 2017-01-17 Bardy Diagnostics, Inc. Extended wear electrocardiography patch
US10463269B2 (en) 2013-09-25 2019-11-05 Bardy Diagnostics, Inc. System and method for machine-learning-based atrial fibrillation detection
US9737224B2 (en) 2013-09-25 2017-08-22 Bardy Diagnostics, Inc. Event alerting through actigraphy embedded within electrocardiographic data
US9717433B2 (en) 2013-09-25 2017-08-01 Bardy Diagnostics, Inc. Ambulatory electrocardiography monitoring patch optimized for capturing low amplitude cardiac action potential propagation
US10624551B2 (en) 2013-09-25 2020-04-21 Bardy Diagnostics, Inc. Insertable cardiac monitor for use in performing long term electrocardiographic monitoring
US9408545B2 (en) 2013-09-25 2016-08-09 Bardy Diagnostics, Inc. Method for efficiently encoding and compressing ECG data optimized for use in an ambulatory ECG monitor
US10433748B2 (en) 2013-09-25 2019-10-08 Bardy Diagnostics, Inc. Extended wear electrocardiography and physiological sensor monitor
US10165946B2 (en) 2013-09-25 2019-01-01 Bardy Diagnostics, Inc. Computer-implemented system and method for providing a personal mobile device-triggered medical intervention
US9433367B2 (en) 2013-09-25 2016-09-06 Bardy Diagnostics, Inc. Remote interfacing of extended wear electrocardiography and physiological sensor monitor
US10799137B2 (en) 2013-09-25 2020-10-13 Bardy Diagnostics, Inc. System and method for facilitating a cardiac rhythm disorder diagnosis with the aid of a digital computer
US9345414B1 (en) 2013-09-25 2016-05-24 Bardy Diagnostics, Inc. Method for providing dynamic gain over electrocardiographic data with the aid of a digital computer
US10888239B2 (en) 2013-09-25 2021-01-12 Bardy Diagnostics, Inc. Remote interfacing electrocardiography patch
US10806360B2 (en) 2013-09-25 2020-10-20 Bardy Diagnostics, Inc. Extended wear ambulatory electrocardiography and physiological sensor monitor
US9655538B2 (en) 2013-09-25 2017-05-23 Bardy Diagnostics, Inc. Self-authenticating electrocardiography monitoring circuit
US9775536B2 (en) 2013-09-25 2017-10-03 Bardy Diagnostics, Inc. Method for constructing a stress-pliant physiological electrode assembly
US9619660B1 (en) 2013-09-25 2017-04-11 Bardy Diagnostics, Inc. Computer-implemented system for secure physiological data collection and processing
US11213237B2 (en) 2013-09-25 2022-01-04 Bardy Diagnostics, Inc. System and method for secure cloud-based physiological data processing and delivery
US9700227B2 (en) 2013-09-25 2017-07-11 Bardy Diagnostics, Inc. Ambulatory electrocardiography monitoring patch optimized for capturing low amplitude cardiac action potential propagation
US10433751B2 (en) 2013-09-25 2019-10-08 Bardy Diagnostics, Inc. System and method for facilitating a cardiac rhythm disorder diagnosis based on subcutaneous cardiac monitoring data
US9717432B2 (en) 2013-09-25 2017-08-01 Bardy Diagnostics, Inc. Extended wear electrocardiography patch using interlaced wire electrodes
US11723575B2 (en) 2013-09-25 2023-08-15 Bardy Diagnostics, Inc. Electrocardiography patch
US9615763B2 (en) 2013-09-25 2017-04-11 Bardy Diagnostics, Inc. Ambulatory electrocardiography monitor recorder optimized for capturing low amplitude cardiac action potential propagation
US10251576B2 (en) 2013-09-25 2019-04-09 Bardy Diagnostics, Inc. System and method for ECG data classification for use in facilitating diagnosis of cardiac rhythm disorders with the aid of a digital computer
US10820801B2 (en) 2013-09-25 2020-11-03 Bardy Diagnostics, Inc. Electrocardiography monitor configured for self-optimizing ECG data compression
US10736529B2 (en) 2013-09-25 2020-08-11 Bardy Diagnostics, Inc. Subcutaneous insertable electrocardiography monitor
US9364155B2 (en) 2013-09-25 2016-06-14 Bardy Diagnostics, Inc. Self-contained personal air flow sensing monitor
US9408551B2 (en) 2013-11-14 2016-08-09 Bardy Diagnostics, Inc. System and method for facilitating diagnosis of cardiac rhythm disorders with the aid of a digital computer
US10667711B1 (en) 2013-09-25 2020-06-02 Bardy Diagnostics, Inc. Contact-activated extended wear electrocardiography and physiological sensor monitor recorder
US20190167139A1 (en) 2017-12-05 2019-06-06 Gust H. Bardy Subcutaneous P-Wave Centric Insertable Cardiac Monitor For Long Term Electrocardiographic Monitoring
US9655537B2 (en) 2013-09-25 2017-05-23 Bardy Diagnostics, Inc. Wearable electrocardiography and physiology monitoring ensemble
US10736531B2 (en) 2013-09-25 2020-08-11 Bardy Diagnostics, Inc. Subcutaneous insertable cardiac monitor optimized for long term, low amplitude electrocardiographic data collection
US9504423B1 (en) 2015-10-05 2016-11-29 Bardy Diagnostics, Inc. Method for addressing medical conditions through a wearable health monitor with the aid of a digital computer
WO2015048194A1 (en) 2013-09-25 2015-04-02 Bardy Diagnostics, Inc. Self-contained personal air flow sensing monitor
US10219698B2 (en) * 2013-10-29 2019-03-05 General Electric Company Acquisition sample clock synchronization leveraging a global clocking mechanism in a distributed physiological sensing system
USD793566S1 (en) 2015-09-10 2017-08-01 Bardy Diagnostics, Inc. Extended wear electrode patch
USD744659S1 (en) 2013-11-07 2015-12-01 Bardy Diagnostics, Inc. Extended wear electrode patch
USD892340S1 (en) 2013-11-07 2020-08-04 Bardy Diagnostics, Inc. Extended wear electrode patch
USD717955S1 (en) 2013-11-07 2014-11-18 Bardy Diagnostics, Inc. Electrocardiography monitor
USD831833S1 (en) 2013-11-07 2018-10-23 Bardy Diagnostics, Inc. Extended wear electrode patch
USD801528S1 (en) 2013-11-07 2017-10-31 Bardy Diagnostics, Inc. Electrocardiography monitor
US10758132B2 (en) 2013-11-27 2020-09-01 Harinath Garudadri Ambulatory diagnostic device and method thereof
KR20160094397A (en) 2013-12-04 2016-08-09 오발론 테라퓨틱스 인코퍼레이티드 Systems and methods for locating and/or characterizing intragastric devices
JP6354143B2 (en) * 2013-12-10 2018-07-11 Tdk株式会社 Information providing system, electronic device, method and program
US10521561B1 (en) * 2013-12-17 2019-12-31 Etectrx, Inc. Electronic compliance system and associated methods
US11311718B2 (en) 2014-05-16 2022-04-26 Aleva Neurotherapeutics Sa Device for interacting with neurological tissue and methods of making and using the same
US20150330212A1 (en) * 2014-05-16 2015-11-19 Masdar Institute Of Science And Technology Self-powered microsensors for in-situ spatial and temporal measurements and methods of using same in hydraulic fracturing
EP3476430B1 (en) 2014-05-16 2020-07-01 Aleva Neurotherapeutics SA Device for interacting with neurological tissue
US9403011B2 (en) 2014-08-27 2016-08-02 Aleva Neurotherapeutics Leadless neurostimulator
US9474894B2 (en) 2014-08-27 2016-10-25 Aleva Neurotherapeutics Deep brain stimulation lead
WO2016042301A1 (en) 2014-09-17 2016-03-24 Mars, Incorporated Device
RU2712026C2 (en) 2014-09-17 2020-01-24 Марс, Инкорпорейтед Sampling device, method for obtaining sample of gastrointestinal tract of animal
US9895248B2 (en) 2014-10-09 2018-02-20 Obalon Therapeutics, Inc. Ultrasonic systems and methods for locating and/or characterizing intragastric devices
US20160174842A1 (en) * 2014-12-17 2016-06-23 Elwha Llc Epidermal electronics systems having radio frequency antennas systems and methods
TWI762438B (en) * 2015-02-11 2022-05-01 日商大塚製藥股份有限公司 Systems, devices, and methods for ingestible event sensing and analysis
EP3302266B1 (en) 2015-06-02 2024-03-20 Given Imaging Ltd. Devices, systems and methods for in-vivo immunoassay
EP3342042B1 (en) * 2015-08-24 2022-04-13 The Regents of The University of California Low power magnetic field body area network
USD766447S1 (en) 2015-09-10 2016-09-13 Bardy Diagnostics, Inc. Extended wear electrode patch
JP6742605B2 (en) 2015-12-28 2020-08-19 国立大学法人東北大学 Battery and electronic equipment
WO2017134587A1 (en) 2016-02-02 2017-08-10 Aleva Neurotherapeutics, Sa Treatment of autoimmune diseases with deep brain stimulation
US11241166B1 (en) 2016-02-03 2022-02-08 Verily Life Sciences, LLC Communications between smart contact lens and ingestible smart pill
JP6667181B2 (en) * 2016-03-10 2020-03-18 国立大学法人東北大学 Wireless communication system, wireless communication method, and wireless device
US11488714B2 (en) 2016-03-23 2022-11-01 HealthPals, Inc. Machine learning for collaborative medical data metrics
US10188861B2 (en) * 2016-03-29 2019-01-29 Warsaw Orthopedic, Inc. Bioabsorbable or partially-bioabsorbable bone growth stimulator system and method for manufacturing a bioabsorbable or partially-bioabsorbable bone-regeneration stimulator system
US10350100B2 (en) 2016-04-12 2019-07-16 Obalon Therapeutics, Inc. System for detecting an intragastric balloon
WO2017188260A1 (en) * 2016-04-25 2017-11-02 Otsuka Pharmaceutical Co., Ltd. Compositions of pharmaceutical product with ingestible event marker
US10588529B2 (en) 2016-07-08 2020-03-17 General Electric Company ECG monitoring system and method
US10357171B2 (en) 2016-07-08 2019-07-23 General Electric Company Adjustable ECG sensor and related method
US10677761B2 (en) 2016-12-01 2020-06-09 Avery Dennison Retail Information Services, Llc Systems and methods for monitoring blister pack compliance
US11547355B2 (en) 2016-12-21 2023-01-10 General Electric Company Capacitive leadwire for physiological patient monitoring
US10517488B2 (en) 2016-12-21 2019-12-31 General Electric Company Patient monitoring system and leadset having multiple capacitive patient connectors and a single galvanic patient connector
US10307073B2 (en) 2016-12-21 2019-06-04 General Electric Company ECG sensor with capacitive defibrillation protection
EP3585252A1 (en) * 2017-02-24 2020-01-01 Endotronix, Inc. Wireless sensor reader assembly
US11615257B2 (en) * 2017-02-24 2023-03-28 Endotronix, Inc. Method for communicating with implant devices
CA3061479A1 (en) * 2017-04-25 2018-11-01 Proteus Digital Health, Inc. Lisinopril compositions with an ingestible event marker
TWI780183B (en) * 2017-07-20 2022-10-11 日商大塚製藥股份有限公司 Ingestible electronic medical device
WO2019050933A1 (en) * 2017-09-05 2019-03-14 University Of Florida Research Foundation Wireless power transfer to biomedical implants
US11017892B1 (en) 2017-09-11 2021-05-25 Massachusetts Mutual Life Insurance Company System and method for ingestible drug delivery
US10702692B2 (en) 2018-03-02 2020-07-07 Aleva Neurotherapeutics Neurostimulation device
CA3093815A1 (en) * 2018-03-13 2019-09-19 Progenity, Inc. Ingestible device with relatively large payload volume
US10357174B1 (en) 2018-03-29 2019-07-23 General Electric Company Adjustable leadwire device for patient physiological monitoring and methods for making the same
US11278243B2 (en) 2018-05-16 2022-03-22 General Electric Company Repositionable surface electrodes
US11027140B2 (en) * 2018-06-15 2021-06-08 Wisconsin Alumni Research Foundation Self-powered, auto-responsive implanted vagal nerve stimulator for weight control
WO2020117351A2 (en) 2018-09-18 2020-06-11 Northwestern University Liquid flow induced power generation using nanoscale metal layers
US11250939B2 (en) 2019-01-15 2022-02-15 International Business Machines Corporation Managing personalized substance administration
US10998091B2 (en) * 2019-02-07 2021-05-04 Sandeep Patil Systems for monitoring compliance with a patch dosage regimen and methods of using the same
US11019567B2 (en) 2019-02-26 2021-05-25 Chadra Laboratories Llc Multi-interface transponder device-altering power modes
FR3093419B1 (en) * 2019-03-08 2021-06-18 Univ Grenoble Alpes Composition and associated method for measuring therapeutic compliance
US11696681B2 (en) 2019-07-03 2023-07-11 Bardy Diagnostics Inc. Configurable hardware platform for physiological monitoring of a living body
US11116451B2 (en) 2019-07-03 2021-09-14 Bardy Diagnostics, Inc. Subcutaneous P-wave centric insertable cardiac monitor with energy harvesting capabilities
US11096579B2 (en) 2019-07-03 2021-08-24 Bardy Diagnostics, Inc. System and method for remote ECG data streaming in real-time
KR20220115802A (en) * 2019-12-16 2022-08-18 뉴로스팀 테크놀로지스 엘엘씨 Non-invasive neural activator with boost charge transfer function
US20210252291A1 (en) * 2020-02-13 2021-08-19 Advanced Neuromodulation Systems, Inc. Neuromodulation therapy with a multiple stimulation engine system
US20220409490A1 (en) * 2020-03-02 2022-12-29 Craft Health Pte Ltd Method of manufacturing oral dosage forms for extended drug release
US11369789B2 (en) 2021-04-05 2022-06-28 Ishaan Jain Transdermal drug delivery system
WO2023214260A1 (en) * 2022-05-03 2023-11-09 Fondazione Istituto Italiano Di Tecnologia Degradable device for the passive and monitored release of a substance
CN115156018A (en) * 2022-08-02 2022-10-11 广东云声科技有限公司 Personalized multifunctional ultrasonic array device prepared by 3D printing and preparation method

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3682160A (en) * 1969-10-16 1972-08-08 Matsushita Electric Ind Co Ltd Physiological signal transmitter for use inside the body
US6076016A (en) * 1995-10-19 2000-06-13 Feierbach; Gary F. Galvanic transdermal conduction communication system and method
WO2004068748A1 (en) * 2003-01-25 2004-08-12 Korea Institute Of Science And Technology Method and system for data communication in human body and sensor therefor
US20050131281A1 (en) * 2003-12-15 2005-06-16 Ayer Steven M. Method and apparatus for verification of ingestion
US20050154428A1 (en) * 2003-12-30 2005-07-14 Ian Bruinsma Implanted antenna and radio communications link
US20080044721A1 (en) * 2002-05-02 2008-02-21 Adam Heller Miniature biological fuel cell that is operational under physiological conditions, and associated devices and methods
US20110124983A1 (en) * 2004-11-09 2011-05-26 Pacesetter, Inc. Method and apparatus for monitoring ingestion of medications using an implantable medical device
US7978064B2 (en) * 2005-04-28 2011-07-12 Proteus Biomedical, Inc. Communication system with partial power source
US20130328416A1 (en) * 2010-12-29 2013-12-12 Proteus Digital Health, Inc. Wireless Energy Sources for Integrated Circuits
US8912908B2 (en) * 2005-04-28 2014-12-16 Proteus Digital Health, Inc. Communication system with remote activation
US9258035B2 (en) * 2008-03-05 2016-02-09 Proteus Digital Health, Inc. Multi-mode communication ingestible event markers and systems, and methods of using the same

Family Cites Families (2108)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US500654A (en) 1893-07-04 haberthur
US476925A (en) 1892-06-14 jeffebs
US1548459A (en) 1923-12-14 1925-08-04 Hammer Charles Metal cap
US2587158A (en) 1948-02-27 1952-02-26 Rca Corp Metal detector
US2973555A (en) 1955-09-09 1961-03-07 Agustin Mesa Rotary press for fabrication of buttons and plastic articles
NL112438C (en) 1956-02-08
US3069322A (en) 1958-05-28 1962-12-18 Bergstrom Sune Pge and pgf
US3048526A (en) 1958-08-04 1962-08-07 Wander Company Medicinal tablet
US3096248A (en) 1959-04-06 1963-07-02 Rexall Drug & Chemical Company Method of making an encapsulated tablet
US3079824A (en) 1960-08-09 1963-03-05 Houdaille Industries Inc Punching device having a spring biased stripper
US3176399A (en) 1962-09-20 1965-04-06 Anthony J Marino Tool punch with spring actuated impact means
US3799802A (en) 1966-06-28 1974-03-26 F Schneble Plated through hole printed circuit boards
US3852468A (en) 1967-02-27 1974-12-03 Ici Ltd Alkanolamine derivatives as {62 -adrenergic blocking agents
US4089900A (en) 1967-09-13 1978-05-16 Pfizer Inc. Antimicrobial agents
US3928356A (en) 1967-10-06 1975-12-23 Fujisawa Pharmaceutical Co 10-{8 4-({107 -Hydroxy alkyl)-1-piperazimyl{9 -dibenzo (h,f) oxofins and thiepins and acetyl esters thereof
US3726978A (en) 1967-11-02 1973-04-10 Sandoz Ag Tetrahydropyridazines and pyridazinones as anti-inflammatory agents
US3607788A (en) 1967-11-20 1971-09-21 Robert J Adolph Liquid electrode material
US3832470A (en) 1968-01-29 1974-08-27 H Russek Treatment of angina pectoris with a long-acting vasodilating agent and a beta adrenergic receptor blocking agent
US3668210A (en) 1968-02-07 1972-06-06 Yoshitomi Pharmaceutical 3-chloro dihydrodibenzazepine derivatives
US3993763A (en) 1969-03-18 1976-11-23 Ciba-Geigy Corporation Tertiary aminoacids as anti-inflammatory agents
US3789123A (en) 1968-03-27 1974-01-29 Ciba Geigy Corp Tertiary aminoacids as anti-inflammatory agents
US3951950A (en) 1968-08-21 1976-04-20 E. R. Squibb & Sons, Inc. 4-Azatricyclo[4.3.1.13,8 ]undecane and related compounds
US3898210A (en) 1968-08-21 1975-08-05 Squibb & Sons Inc 4-Azatricyclo {8 4.3.1.1{hu 3,8{b {9 undecane and related compounds
US3589943A (en) 1968-08-29 1971-06-29 Gen Electric Electrochemical battery
US3642008A (en) 1968-09-25 1972-02-15 Medical Plastics Inc Ground electrode and test circuit
US3538104A (en) 1969-02-28 1970-11-03 Geigy Chem Corp Pyridyl-2-imidazolones
US3679480A (en) * 1969-05-08 1972-07-25 Dow Chemical Co Electrical cell assembly
US3624126A (en) 1969-09-02 1971-11-30 Squibb & Sons Inc {66 {11 , {60 -adamantane acetic acid
BE757385A (en) 1969-10-13 1971-04-13 American Cyanamid Co CHLOROPREGNANE ACETONIDE DERIVATIVES FOR USE AS CONTRACEPTIVE SUBSTANCES
US3759921A (en) 1969-10-16 1973-09-18 Lilly Co Eli Method of suppressing immuneresponse with 1 substituted-3-(2 pyrimidyl)ureas
US4000275A (en) 1969-11-24 1976-12-28 Eli Lilly And Company Immunosuppressants
US3719183A (en) * 1970-03-05 1973-03-06 H Schwartz Method for detecting blockage or insufficiency of pancreatic exocrine function
US3694471A (en) 1970-06-08 1972-09-26 Warner Lambert Pharmaceutical 17-valerate ester of 6{60 ,9{60 -difluorohydrocortisone, its compositions and use as an anti-inflammatory agent
US3691214A (en) 1970-06-08 1972-09-12 Warner Lambert Pharmaceutical 17-valerate ester of 6alpha,9alpha-difluoroprednisolone,its compositions and use as an anti-inflammatory agent
US3624216A (en) 1970-06-25 1971-11-30 Abbott Lab 8-substituted theophyllines as anti-inflammatory agents
US3934018A (en) 1970-09-03 1976-01-20 Abbott Laboratories 4,6-Dihydro-1,3-dimethyl-8-phenylpyrazolo[4,3-e] [1,4]diazepin-5-(1H)-one and derivatives as anti-inflammatory agents
US3865748A (en) 1970-09-22 1975-02-11 Us Agriculture Cinnamyl phenol antimicrobial agents
US3936393A (en) 1970-09-22 1976-02-03 The United States Of America As Represented By The Secretary Of Agriculture Antimicrobial agents and use thereof
US3670079A (en) 1970-10-06 1972-06-13 Merck & Co Inc Anabolic agents
US3917476A (en) 1970-10-28 1975-11-04 Gates Rubber Co Diethyl alpha phosphonate as an (antimicrobial agent) algaecide
US3764676A (en) 1970-10-28 1973-10-09 Gates Rubber Co Diethyl cyanomethyl phosphonate as an antimicrobial agent
US3783160A (en) 1970-10-28 1974-01-01 Gates Rubber Co Diethyl allyl phosphonate as an anti-microbial agent
US3980652A (en) 1970-11-11 1976-09-14 A. Christiaens Societe Anonyme 2-(4-Methyl-piperazino)-3 or 5 cyano pyridine
GB1368948A (en) 1970-11-11 1974-10-02 Manuf Prod Pharma Pyridine derivatives
US3998954A (en) 1971-02-05 1976-12-21 Pfizer Inc. 1,3(2H,4H)-Dioxoisoquinoline-4-carboxamides used as anti-inflammatory agents
US4148796A (en) 1971-03-15 1979-04-10 Sumitomo Chemical Company, Limited γ-Piperidinobutyrophenones
US3867383A (en) 1971-03-29 1975-02-18 Ciba Geigy Corp Monoanthranilatoanilino-s-triazines
US3857955A (en) 1971-03-29 1974-12-31 Lilly Co Eli Anti-inflammatory agents
US3886157A (en) 1971-03-29 1975-05-27 Ciba Geigy Corp 5,6,8,8B,9-Pentaazanaphth{8 3,2,1-d,e{9 anthracene derivatives
US3764677A (en) 1971-06-25 1973-10-09 Gates Rubber Co Diethyl betaaminoethylphosphonate as an antimicrobial agent
US3984405A (en) 1971-06-28 1976-10-05 E. R. Squibb & Sons, Inc. Anti-inflammatory agents
JPS4834870A (en) 1971-09-10 1973-05-22
US3821401A (en) 1971-09-13 1974-06-28 Lilly Co Eli Other publications
US4029661A (en) 1971-10-04 1977-06-14 Pcr, Inc. Process for producing 5-fluorouracil and derivatives thereof in acid and/or alcohol solvents
US3897441A (en) 1971-10-27 1975-07-29 Syntex Inc Certain thiazole-carboxamides and acylamino-thiazoles
US3982010A (en) 1971-10-27 1976-09-21 Syntex (U.S.A.) Inc. Thiazole cardiovascular agents
US4001421A (en) 1971-10-27 1977-01-04 Syntex (U.S.A.) Inc. Thiazole cardiovascular agents
US3789121A (en) 1971-11-26 1974-01-29 Warner Lambert Co 17{60 ,21-orthobutyrates of 6{60 , 9{60 -difluoro-hydrocortisone and 6{60 , 9{60 -difluoroprednisolone, compositions containing same and the use thereof as anti-inflammatory agents
US3965257A (en) 1972-01-28 1976-06-22 Richardson-Merrell Inc. Compositions and methods for the treatment of the symptoms of histamine induced allergic reactions
US4180583A (en) 1972-01-28 1979-12-25 Richardson-Merrell Inc. Olefinic 4-substituted piperidino derivatives as therapeutics
US3837339A (en) 1972-02-03 1974-09-24 Whittaker Corp Blood glucose level monitoring-alarm system and method therefor
BE794589A (en) 1972-02-08 1973-05-16 Cerm Cent Europ Rech Mauvernay NEW DERIVATIVES OF 1,1-DIPHENYL-ETHYLENE, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS
US3821377A (en) 1972-02-22 1974-06-28 Squibb & Sons Inc Anti-inflammatory agents
US3954868A (en) 1972-03-02 1976-05-04 Uniroyal, Inc. Bis(diphenylaminomethane) antimicrobial agents
US4044139A (en) 1974-02-08 1977-08-23 Uniroyal, Inc. Bis(diphenylaminomethane) antimicrobial agents
US3933834A (en) 1972-03-06 1976-01-20 Bayer Aktiengesellschaft Unsymmetrical esters of N-substituted 1,4-dihydropyridine 3,5-dicarboxylic acid
DE2210672C3 (en) 1972-03-06 1980-03-20 Bayer Ag, 5090 Leverkusen N-substituted asymmetrical 1 ^ -dihydropyridine-S ^ -dicarboxylic acid esters, process for their preparation and their use as medicaments
US3867548A (en) 1972-05-25 1975-02-18 Us Agriculture Dihydrocinnamyl phenols useful as antimicrobial agents
US3915889A (en) 1972-05-25 1975-10-28 Us Agriculture Dihydrocinnamyl phenol antimicrobial agents
US3968117A (en) 1972-06-10 1976-07-06 Bayer Aktiengesellschaft 1,4-Dihydropyridines
DE2228363A1 (en) 1972-06-10 1974-01-03 Bayer Ag 1,4-DIHYDROPYRIDINE, METHOD FOR MANUFACTURING AND USE AS A MEDICINAL PRODUCT
US3959296A (en) 1972-06-10 1976-05-25 Bayer Aktiengesellschaft 1,4-Dihydropyridines
US3828766A (en) 1972-08-14 1974-08-13 Jet Medical Prod Inc Disposable medical electrode
US3989050A (en) 1972-09-19 1976-11-02 Gilbert Buchalter Process for utilizing certain gel compositions for electrical stimulation
GB1399539A (en) 1972-11-03 1975-07-02 Science Union & Cie Tricyclic ureas processes for preparing them and pharma ceutical compositions containing them
US4117012A (en) 1972-12-06 1978-09-26 Pfizer Inc. 2-aminomethyleneindanone analgesic agents
US4022836A (en) 1972-12-06 1977-05-10 Pfizer Inc. 2-Aminomethyleneindanone analgesic agents
US4164514A (en) 1972-12-06 1979-08-14 Pfizer Inc. 2-Aminomethyleneindanone analgesic agents
DE2303761A1 (en) 1973-01-26 1974-08-01 Henkel & Cie Gmbh NEW N, N'-DISUBSTITUTED THIOUR SUBSTANCES, THEIR PRODUCTION AND USE AS ANTIMICROBIAL SUBSTANCES
GB1391862A (en) 1973-04-04 1975-04-23 Yeda Res & Dev Benzodiazepines
US3873715A (en) 1973-04-06 1975-03-25 Univ Miami Therapeutic agent for improving cardiovascular function
US3849041A (en) 1973-04-30 1974-11-19 Minnesota Mining & Mfg Apparatus for manufacturing environmental seed cells
US3930005A (en) 1973-06-15 1975-12-30 Squibb & Sons Inc Antiinflammatory agents and their use
US4002775A (en) 1973-07-09 1977-01-11 Kabara Jon J Fatty acids and derivatives of antimicrobial agents
US3856962A (en) 1973-07-10 1974-12-24 R Alphin Anti-inflammatory agents
US4190587A (en) 1973-08-06 1980-02-26 Hoffmann-La Roche Inc. 4-(3-Oxo-4-trifluoromethyl-1-octenyl)-2-oxo-2H-cyclopenta[b]furans
US3944064A (en) * 1973-10-26 1976-03-16 Alza Corporation Self-monitored device for releasing agent at functional rate
US3968125A (en) 1973-11-05 1976-07-06 Eli Lilly And Company Dihydroxyhexahydrodibenzo[b,d]pyrans
US4011321A (en) 1973-12-19 1977-03-08 Smith Kline & French Laboratories Limited Pharmaceutical compositions and methods of inhibiting β-adrenergic receptors
US3991212A (en) 1973-12-26 1976-11-09 Eli Lilly And Company Anti-inflammatory agents
US4313896A (en) 1974-01-10 1982-02-02 Eli Lilly And Company Aryloxyphenylpropylamines
US4194009A (en) 1974-01-10 1980-03-18 Eli Lilly And Company Aryloxyphenylpropylamines for obtaining a psychotropic effect
US4018895A (en) 1974-01-10 1977-04-19 Eli Lilly And Company Aryloxyphenylpropylamines in treating depression
US4314081A (en) 1974-01-10 1982-02-02 Eli Lilly And Company Arloxyphenylpropylamines
FR2260331B1 (en) 1974-02-08 1978-01-13 Mauvernay Centre Europ Rech
US3931197A (en) 1974-02-08 1976-01-06 Richardson-Merrell Inc. Substituted piperidine derivatives
US3949082A (en) 1974-07-24 1976-04-06 Merck & Co., Inc. Thiadiazoles as anti-inflammatory agents
US4106348A (en) * 1974-02-20 1978-08-15 U.S. Philips Corporation Device for examination by means of ultrasonic vibrations
US3946022A (en) 1974-03-04 1976-03-23 Richardson-Merrell Inc. Piperidine derivatives
US3896139A (en) 1974-03-14 1975-07-22 Syntex Inc Process for preparing 3-(4-or-5-azidocarbonylthiazol-2-oxy)-propanediol-1,2-acetonides
US3893111A (en) * 1974-03-14 1975-07-01 Albert Albert F System and method for remote monitoring of animal temperature
US3949081A (en) 1974-04-08 1976-04-06 Ciba-Geigy Corporation 4-Carbamoyl-1-benzazepines as antiinflammatory agents
US3991201A (en) 1974-06-27 1976-11-09 Janssen Pharmaceutica N.V. 1-(β-Aryl-β-R-ethyl)imidazoles as antimicrobial agents
US3975543A (en) 1974-07-05 1976-08-17 Eli Lilly And Company Ethyl- and vinylbenzenes as anti-inflammatory agents
US4076834A (en) 1974-07-19 1978-02-28 Hoffmann-La Roche Inc. Therapeutic agents for improving cardiovascular function
US4083968A (en) 1974-07-19 1978-04-11 Hoffmann-La Roche Therapeutic agent for improving cardiovascular function
US4058620A (en) 1974-07-19 1977-11-15 Hoffmann-La Roche Inc. Therapeutic agents for improving cardiovascular function
US4164586A (en) 1974-07-19 1979-08-14 Hoffmann-La Roche Inc. Therapeutic agent for improving cardiovascular function
US3967202A (en) 1974-07-25 1976-06-29 Northern Illinois Gas Company Data transmission system including an RF transponder for generating a broad spectrum of intelligence bearing sidebands
US3940407A (en) 1974-09-16 1976-02-24 Syntex (U.S.A.) Inc. β-Adrenergic blocking agents in the 1,2,3-thiadiazole series
US4077397A (en) 1974-10-07 1978-03-07 Baxter Travenol Laboratories, Inc. Diagnostic electrode assembly
US4090752A (en) 1974-10-07 1978-05-23 Baxter Travenol Laboratories, Inc. Diagnostic electrode assembly
ZA755785B (en) 1974-10-07 1976-08-25 Baxter Laboratories Inc Diagnostic electrode assembly
DE2449030A1 (en) 1974-10-11 1976-05-20 Schering Ag NEW PYRIDINE DERIVATIVES
US4000282A (en) 1974-12-16 1976-12-28 Merck & Co., Inc. 2-(3-tert. butyl or isopropylamino-2-hydroxypropoxy)-3-cyanopyridines
US4062750A (en) * 1974-12-18 1977-12-13 James Francis Butler Thin film electrochemical electrode and cell
US4048058A (en) 1975-08-13 1977-09-13 Standard Oil Company (Indiana) Methods to be used in reforming processes employing multi-metallic catalysts
US4139589A (en) 1975-02-26 1979-02-13 Monique Beringer Process for the manufacture of a multi-zone tablet and tablet manufactured by this process
US3998970A (en) 1975-04-28 1976-12-21 Stauffer Chemical Company N,N-dimethyl-N'-phenylthiocarbamyl formamidine and its use as an anti-inflammatory agent
US3959368A (en) 1975-04-28 1976-05-25 Stauffer Chemical Company N,N-dimethyl-N'-phenylthiocarbamyl formamidine and its use as an anti-inflammatory agent
US4027031A (en) 1975-04-28 1977-05-31 Stauffer Chemical Company 2-Cyclopropanecarboxamido-S-halothiazole as anti-inflammatory agents
US3947475A (en) 1975-04-28 1976-03-30 Stauffer Chemical Company 5-Furoyl-2,2,4-trimethyl-1,4-dihydro-1H-1,5-benzodiazepine as an anti-inflammatory agent
US3968224A (en) 1975-04-28 1976-07-06 Stauffer Chemical Company 3-(4'-Chlorophenyl)-5-methyl-4,5-dihydro-1,2,4-oxadiazole, its use as an anti-inflammatory agent
US3978227A (en) 1975-04-28 1976-08-31 Stauffer Chemical Company 5-furoyl-2,2,4-trimethyl-1,4-dihydro-1h-1,5-benzodiazepine as an anti-inflammatory agent
US3966944A (en) 1975-05-19 1976-06-29 Abbott Laboratories 10 (N-methyl-4-piperidylidene)-10H[1]-benzopyrano[3,2-b]-pyridine as an analgesic, anti-inflammatory and agent against type III hypersensitivity disease
US4024284A (en) 1975-06-09 1977-05-17 Eli Lilly And Company Ethyl- and vinylbenzenes as anti-inflammatory agents
GB1495778A (en) 1975-06-18 1977-12-21 Wyeth John & Brother Ltd Hexahydroazepines
US4055655A (en) 1975-07-21 1977-10-25 National Research Laboratories Complexes of heavy metal ions and polyfunctional organic ligands used as antimicrobial agents
US3978219A (en) 1975-07-25 1976-08-31 Stauffer Chemical Company Nicotinamidoxime as an anti-inflammatory agent
US3978202A (en) 1975-07-25 1976-08-31 Stauffer Chemical Company ο-Chlorobenzamidoxime as an anti-inflammatory agent
US4011326A (en) 1975-07-29 1977-03-08 Merck & Co., Inc. 2-Substituted oxazolo[4,5-b]pyridine anti-inflammatory agents
DE2609486A1 (en) 1975-08-07 1977-05-12 Hoffmann La Roche IMIDAZO SQUARE BRACKETS ON 1.5 ANGLE BRACKETS FOR SQUARE BRACKETS ON 1.4 SQUARE BRACKETS FOR DIAZEPINE CONNECTIONS AND THE PROCESS FOR THEIR PRODUCTION
US4025640A (en) 1975-08-26 1977-05-24 American Hoechst Corporation Oxothienobenzoxepin-acetic acids, precursors and derivatives thereof
US4012527A (en) 1975-09-15 1977-03-15 Stauffer Chemical Company N,N-Dimethyl-N'-phenylthiocarbamyl formamidine hydrochloride and its use as an anti-inflammatory agent
US4049805A (en) 1975-09-30 1977-09-20 Akzona Incorporated Steroidal erythropoietic agents and therapeutic compositions and methods
US4004005A (en) 1975-09-30 1977-01-18 Akzona Incorporated Steroidal erythropoietic agents and therapeutic compositions and methods
US3994898A (en) 1975-10-16 1976-11-30 E. R. Squibb & Sons, Inc. 1,2,4-Triazolo (4,3-b) pyridazin-3-ones
FR2330383A1 (en) 1975-11-06 1977-06-03 Synthelabo NEW PHENOL SUBSTITUTE ETHERS, THEIR SALTS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM
US4082843A (en) 1975-11-26 1978-04-04 Smith Kline & French Laboratories Limited 3-(3-(3-Substituted amino-2-hydroxypropoxy)phenyl)-6-hydrazino pyridazines and their use as vasodilators and β-adrenergic blocking agents
US4049665A (en) 1975-12-24 1977-09-20 Colgate-Palmolive Company Unsymmetrical disulfides as antimicrobial agents
JPS5946205B2 (en) 1976-01-01 1984-11-10 科研製薬株式会社 Anti-inflammatory analgesic with benzoyl derivative as active ingredient
US4145444A (en) 1976-01-01 1979-03-20 Kaken Chemical Co., Ltd. Anti-inflammatory agent of benzoyl derivative
US4012448A (en) 1976-01-15 1977-03-15 Stanford Research Institute Synthesis of adriamycin and 7,9-epiadriamycin
US4275064A (en) 1976-02-06 1981-06-23 Interx Research Corporation Transient pro-drug forms of xanthine derivatives and their use as topical anti-inflammatory agents
US4130664A (en) 1976-02-13 1978-12-19 Uniroyal, Inc. (Bis(diphenylaminomethane) antimicrobial agents
US4017856A (en) 1976-03-10 1977-04-12 Westinghouse Electric Corporation Self-calibrating microwave transponder
US4021553A (en) 1976-03-10 1977-05-03 Eli Lilly And Company 5,6-Diaryl-1,2,4-triazines as topically-active anti-inflammatory agents
US4055178A (en) * 1976-03-10 1977-10-25 Harrigan Roy Major Drug delivery device for preventing contact of undissolved drug with the stomach lining
US4018923A (en) 1976-03-10 1977-04-19 Eli Lilly And Company 5,6-Diaryl-1,2,4-triazines as topically-active anti-inflammatory agents
US4013672A (en) 1976-03-15 1977-03-22 E. R. Squibb & Sons, Inc. 2,5,7,8-Tetrahydro-1,2,4,5,6-pentaazabenzo[6,7]-cyclohepta[1,2,3-cd]-as-indacenes
US4018779A (en) 1976-03-25 1977-04-19 E. R. Squibb & Sons, Inc. Derivatives of 10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]-pyrazolo[4,3-e]pyridine-5(1H)ones
PL101032B1 (en) 1976-04-06 1978-11-30 METHOD OF OBTAINING 1-NITRO-9-DUALKYL-AMINOIZOALKYLAMIROACRIDINES OR THEIR SALTS
US4020072A (en) 1976-05-04 1977-04-26 E. R. Squibb & Sons, Inc. 5-Aminomethyl-1H-pyrazolo[3,4-b]pyridines
US4064258A (en) 1976-07-19 1977-12-20 Syntex (U.S.A.) Inc. Thiazole cardiovascular agents
US4092419A (en) 1976-06-15 1978-05-30 Merck & Co., Inc. Substituted (3-loweralkylamino-2-R1 O-propoxy)pyridines, their preparation and use
US4143770A (en) 1976-06-23 1979-03-13 Hoffmann-La Roche Inc. Method and apparatus for color recognition and defect detection of objects such as capsules
IL52448A (en) 1976-07-06 1981-09-13 Bayer Ag Antimycotic and sporicidal pharmaceutical compositions comprising imidazol-1-yl-(4-phenoxy-phenyl)-(pyridin-2-yl)phenyl methane
US4056673A (en) 1976-07-16 1977-11-01 Hoffmann-La Roche Inc. Phosphonoacetic acid derivatives of nucleosides
US4064257A (en) 1976-07-19 1977-12-20 Syntex (U.S.A.) Inc. Thiazole cardiovascular agents
US4064259A (en) 1976-07-19 1977-12-20 Syntex (U.S.A.) Inc. Thiazole cardiovascular agents
DE2635665A1 (en) 1976-08-07 1978-02-09 Bayer Ag ANTIMICROBIAL AGENTS
DE2644833A1 (en) 1976-10-05 1978-04-20 Boehringer Sohn Ingelheim NEW 1-ARYLOXY-2-HYDROXY-3-ALKYLENE AMINOPROPANES AND METHOD FOR THE PRODUCTION THEREOF
US4069341A (en) 1976-10-18 1978-01-17 The Dow Chemical Company Oxybis(4,1-phenylene(2-oxo-2,1-ethanediyl)) thiocyanate and its use as an antimicrobial agent
US4089977A (en) 1976-11-24 1978-05-16 Kewanee Industries Polymeric anti-microbial agent
US4304910A (en) 1978-05-04 1981-12-08 Kewanee Industries, Inc. Quarnary ammonium polymeric anti-microbial agent
US4124707A (en) 1976-12-22 1978-11-07 Schering Corporation 7α-Halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor
US4062858A (en) 1976-12-22 1977-12-13 E. R. Squibb & Sons, Inc. Derivatives of 5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-ones and 11(1H)-imines
US4129125A (en) 1976-12-27 1978-12-12 Camin Research Corp. Patient monitoring system
GB1594214A (en) 1977-01-21 1981-07-30 Cardio Tech Body electrodes
US4082087A (en) 1977-02-07 1978-04-04 Isis Medical Instruments Body contact electrode structure for deriving electrical signals due to physiological activity
JPS53113032A (en) 1977-03-09 1978-10-03 Mitsubishi Chem Ind Ltd Immune depresants
US4246411A (en) 1977-03-14 1981-01-20 Pcr Incorporated 5,5-Difluorouracil
DE2711106A1 (en) 1977-03-15 1978-09-21 Bayer Ag BIS- (5,5'-DIMETHYL-1,3-OXAZOLIDINE-3-YL) METHANE
US4252815A (en) 1977-04-21 1981-02-24 Mead Johnson & Company Methods of treating cardiovascular diseases with phenyltetrazolyloxy propanolamines
FR2388799A1 (en) 1977-04-28 1978-11-24 Rolland Sa A PYRIDAZINONE DERIVATIVES, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS
DE2720868A1 (en) 1977-05-10 1978-11-23 Bayer Ag ANTIMICROBIAL AGENTS
US4128664A (en) 1977-05-16 1978-12-05 Riker Laboratories, Inc. Substituted benzamides as anti-inflammatory agents
US4133819A (en) 1977-06-17 1979-01-09 Pfizer Inc. Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans as analgesic agents
US4209520A (en) 1977-06-17 1980-06-24 Pfizer Inc. Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans as analgesic agents
US4125612A (en) 1977-06-20 1978-11-14 Schering Corporation N-1-(p-Biphenylalkyl)piperazines and their use as anti-inflammatory agents
US4314943A (en) 1977-07-13 1982-02-09 Mead Johnson & Company Heterocyclic substituted aryloxy 3-indolyl-tertiary butylaminopropanols
US4147798A (en) 1977-08-02 1979-04-03 W. R. Grace & Co. Antineoplastic agent
US4147872A (en) 1977-09-13 1979-04-03 Pfizer Inc. 3-[2-Hydroxy-4-(substituted)-phenyl]azacycloalkanes and derivatives thereof as analgesic agents and intermediates therefor
US4306097A (en) 1977-09-13 1981-12-15 Pfizer Inc. 3-[2-Hydroxy-4-(substituted)phenyl]-cycloalkanol analgesic agents
US4145443A (en) 1977-10-31 1979-03-20 Syntex (U.S.A.) Inc. Bicyclo 3.1.0!hexylethylaminocarbonyl-substituted naphthyloxy cardiovascular agents
US4123550A (en) 1977-10-31 1978-10-31 Syntex (U.S.A.) Inc. Bicyclo[3.1.0]hexylethylaminocarbonyl-substituted heteroaryl cardiovascular agents
US4151297A (en) 1977-10-31 1979-04-24 Syntex (U.S.A.) Inc. Bicyclo [3.1.0] hexyl-substituted ethylamino carbonyl phenoxy cardiovascular agents
US4143054A (en) 1977-11-04 1979-03-06 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane- and 7-oxabicycloheptene compounds
US4220594A (en) 1977-11-04 1980-09-02 E. R. Squibb & Sons, Inc. Hexa- and octahydro-4,7-epoxyisobenzofuran-1-ol and hexa- and octahydro-5,8-epoxy-1H-2-benzopyran-3-ol
US4201778A (en) 1977-11-08 1980-05-06 Schering Corporation 6-Acyloxy-1,4,6-pregnatrienes, their use as anti-inflammatory agents, methods for their manufacture, and 6-oxo-1,4-pregnadiene intermediates
JPS5475284A (en) 1977-11-29 1979-06-15 Asahi Chemical Ind Threeeterminal magnetic reluctance effect element
JPS5483301A (en) * 1977-12-16 1979-07-03 Fujitsu Ltd Units of erecting equipment for communiacation device
DE2757680A1 (en) 1977-12-23 1979-06-28 Troponwerke Gmbh & Co Kg NEW 2-OXO-1-PYRROLIDINESSIC ACID DERIVATIVES, THE PROCESS FOR THEIR PRODUCTION AND THEIR USE AS A MEDICINAL PRODUCT
FR2415099A1 (en) 1978-01-20 1979-08-17 Ile De France NEW DERIVATIVES OF 4-AMINO-5-ALKYLSULFONYL ORTHO-ANISAMIDES, THEIR METHODS OF PREPARATION AND THEIR APPLICATION AS PSYCHOTROPES
US4329289A (en) 1978-02-08 1982-05-11 Hoffmann-La Roche Inc. Adrenergic blocking agents
US4247710A (en) 1978-02-08 1981-01-27 Hoffmann-La Roche Inc. Intermediate in the production of adrenergic blocking agents
JPS54119499A (en) 1978-03-09 1979-09-17 Shionogi & Co Ltd Triazolobenzodiazepin derivative
US4181720A (en) 1978-04-05 1980-01-01 Syntex (U.S.A.) Inc. Corticosteroid antiinflammatory agents
GB1573599A (en) 1978-05-24 1980-08-28 Wyeth John & Brother Ltd 4-aminoquinoline derivatives
US4251798A (en) * 1978-05-31 1981-02-17 Symbol Technologies Portable laser scanning arrangement for and method of evaluating and validating bar code symbols
US4177280A (en) 1978-07-03 1979-12-04 Syntex (U.S.A.) Inc. Bicyclo[3.1.0]hexyl-substituted carbonylaminophenoxy cardiovascular agents
US4214089A (en) 1978-07-18 1980-07-22 American Home Products Corporation Thiazolo[3,2-a]benzimidazoles, imidazo [2,1-b]thiazoles, and related compounds as antineoplastic agents, and enhancers of the immune response
DE2960689D1 (en) 1978-07-28 1981-11-19 Synthelabo Fluorene and fluoranthene derivatives, process for their preparation and their therapeutic application
US4267328A (en) 1978-08-01 1981-05-12 Synthelabo 1-Phenylpiperazines
JPS5538325A (en) 1978-09-11 1980-03-17 Sankyo Co Ltd 4-anilinoquinazoline derivative and its preparation
US4239046A (en) 1978-09-21 1980-12-16 Ong Lincoln T Medical electrode
US4342769A (en) 1978-10-02 1982-08-03 Schering Corporation 2-[(Methylsulfinyl)acetyl]-3-heterocyclicindoles and derivatives thereof as immunosuppressants
DE2965394D1 (en) 1978-11-01 1983-06-16 Sanraku Ocean Co Process for producing antibiotic beta-lactam compounds
US5066493A (en) 1978-11-03 1991-11-19 American Home Products Corporation Rapamycin in treatment of tumors
US4173650A (en) 1978-11-03 1979-11-06 American Cyanamid Company Cis-2-benzoyl-3-hydroxy-2-alkenonitriles as anti-inflammatory agents
US4355034A (en) 1979-02-07 1982-10-19 Merck & Co., Inc. Ethenyl derivatives of mercaptoalkylpyridines as anti-inflammatory agents
FI800381A (en) 1979-02-16 1980-08-17 Sandoz Ag NYA KEFALOSPORINDERIVAT DERAS FRAMSTAELLNING OCH ANVAENDNING SOM ANTIMIKROBIELLA AEMNEN
US4173634A (en) 1979-02-23 1979-11-06 E. R. Squibb & Sons, Inc. Basically-substituted tricyclic pyrazoles useful as antiinflammatory agents
US4234593A (en) 1979-03-20 1980-11-18 Stauffer Chemical Company 3-(N-Alkylcarbamyl)-5-(carboalkoxy)-1,3,4-oxadiazole-2-thiones and their use as anti-inflammatory agents
US4226887A (en) 1979-04-16 1980-10-07 Eli Lilly And Company Anti-inflammatory agents
US4345588A (en) * 1979-04-23 1982-08-24 Northwestern University Method of delivering a therapeutic agent to a target capillary bed
FR2455039A1 (en) 1979-04-26 1980-11-21 Synthelabo PYRIMIDO AND IMIDAZO-PYRIDO-INDOLE-DIONES AND THEIR APPLICATION IN THERAPEUTICS
US4244955A (en) 1979-04-30 1981-01-13 Richardson-Merrell Inc. 2,4a-Ethanobenz[g]isoquinolin-5(1H)-ones and their use as anti-fertility and analgesic agents
US4308283A (en) 1979-06-18 1981-12-29 International Minerals & Chemical Corp. Antimicrobial agents
US4260634A (en) 1979-06-18 1981-04-07 International Minerals & Chemical Corp. Antimicrobial agents
US4269189A (en) 1979-07-09 1981-05-26 Consolidated Medical Equipment Inc. Skin conducting electrode assembly
DE2928477C3 (en) * 1979-07-14 1982-04-15 Battelle-Institut E.V., 6000 Frankfurt Device for the release of substances at defined locations in the digestive tract
DE2931778A1 (en) 1979-08-04 1981-02-19 Bayer Ag ANTIMICROBIAL AGENTS
US4283394A (en) 1979-08-06 1981-08-11 Research Corporation Cytotoxic nucleoside-corticosteroid phosphodiesters
JPS5645460A (en) 1979-09-20 1981-04-25 Sumitomo Chem Co Ltd Novel imidazolyl sulfonate derivative
CA1151651A (en) 1979-08-08 1983-08-09 Takao Kiyohara Antitumor and immunosuppressive 4-carbamoyl imidazolium-5-olate derivatives, pharmaceutical composition and production thereof
US4450159A (en) 1979-08-08 1984-05-22 The Upjohn Company Carbamic acid derivatives as selective immunosuppresive agents
US4261328A (en) 1979-08-10 1981-04-14 Kirk Norbert A Teakettle with attached boiling vessel
US4278608A (en) 1979-09-06 1981-07-14 Hoffmann-La Roche Inc. Adrenergic blocking agents
US4281189A (en) 1979-09-06 1981-07-28 Hoffmann-La Roche Inc. Sulfonamide intermediates for adrenergic blocking agents
US4285873A (en) 1979-09-06 1981-08-25 Hoffmann-La Roche Inc. Adrenergic blocking agents
US4304721A (en) 1979-09-06 1981-12-08 Hoffmann-La Roche Inc. Adrenergic blocking agents
HU185926B (en) 1979-09-27 1985-04-28 Agostne Kahan Process for preparing water soluble derivatives of non-steroid antiinflammatory compositions and pharmaceutical compositins containing such derivatives
US4244963A (en) 1979-09-27 1981-01-13 Merck & Co., Inc. 1-[2-(Alkyl and arylsulfonyl)-2-propenyl and propyl] substituted piperidines useful as antimicrobial and antiinflammatory agents
DE2943776A1 (en) 1979-10-26 1981-05-14 Schering Ag Berlin Und Bergkamen, 1000 Berlin 17 (ALPHA) ALKYLSTEROIDS, THE PREPARATIONS CONTAINING THE SAME, AND METHOD FOR THE PRODUCTION THEREOF
JPS6043064B2 (en) 1979-11-28 1985-09-26 ウェルファイド株式会社 New isoxazole derivative
US4252816A (en) 1979-12-03 1981-02-24 Merck & Co., Inc. Tetrahydro-1H-1,4-diazepino(1,7-a)benzimidazoles useful as analgesic agents
MC1357A1 (en) 1979-12-07 1981-08-10 Hoffmann La Roche 2,3-INDOLEDIONE DERIVATIVES
US4311709A (en) 1979-12-26 1982-01-19 Merck & Co., Inc. Loweralkyl substituted diphenyl polyamine as an antimicrobial agent
US4335141A (en) 1979-12-26 1982-06-15 Merck & Co., Inc. 2-Substituted-aminopropene-and propanenitrile antimicrobial and anti-inflammatory agents
EP0034116A3 (en) 1980-02-11 1981-09-02 Berlex Laboratories, Inc. N-(3-phenoxy-2-hydroxypropyl)benzimidazole-1-alkanamines
JPS56113748A (en) 1980-02-13 1981-09-07 Kowa Co Aminoethanol derivative and its preparation
US4251530A (en) 1980-02-19 1981-02-17 Merck & Co., Inc. 2-{[4-(6-Substituted-2-pyrazinyl)-1-piperazinyl]alkyl}-5-substituted-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one analgesic agents
US4391982A (en) 1980-03-05 1983-07-05 The University Of Rochester Intermediates for the production of picropodophyllin and related compounds and processes for the preparation and use thereof
US4294763A (en) 1980-03-05 1981-10-13 University Of Rochester Intermediates for the production of picropodophyllin and related compounds and processes for the preparation and use thereof
US4399283A (en) 1980-03-11 1983-08-16 Warner Lambert Company Pharmaceutical salts of 4'-(9-acridinylamino)-methanesulfon-m-anisidide
FR2480283A1 (en) 1980-04-10 1981-10-16 Science Union & Cie NOVEL TRICYCLIC DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT
DE3018865A1 (en) 1980-05-16 1981-11-26 Bayer Ag, 5090 Leverkusen ANTIMICROBIAL AGENTS
DE3019322A1 (en) 1980-05-21 1981-12-03 Merck Patent Gmbh, 6100 Darmstadt PSYCHOPHARMACONE AND USE OF ADENOSINE DERIVATIVES
US4331654A (en) * 1980-06-13 1982-05-25 Eli Lilly And Company Magnetically-localizable, biodegradable lipid microspheres
US4996335A (en) 1980-07-10 1991-02-26 Nicholas S. Bodor Soft steroids having anti-inflammatory activity
US4710495A (en) 1980-07-10 1987-12-01 Otsuka Pharmaceutical Co., Ltd. Soft steroids having anti-inflammatory activity
US4361583A (en) 1980-08-19 1982-11-30 Synthelabo Analgesic agent
US4393210A (en) 1980-08-28 1983-07-12 Seiyaku Co., Ltd. 1(2H)-Isoquinolone compounds and acid addition salts thereof
US4391827A (en) 1980-09-08 1983-07-05 Pfizer Inc. 3-(2-Hydroxy-4-(substituted)phenyl)-cycloalkanone and cycloalkanol analgesic agents and intermediates therefor
JPS5767516A (en) 1980-09-24 1982-04-24 Microbial Chem Res Found Novel analgesic agent
US4578061A (en) 1980-10-28 1986-03-25 Lemelson Jerome H Injection catheter and method
US4568679A (en) 1980-12-23 1986-02-04 Merck & Co., Inc. Aralkylaminoethanol heterocyclic compounds
JPS57106617A (en) 1980-12-23 1982-07-02 Sankyo Co Ltd Analgesic and anti-inflammatory agent
ZA8231B (en) 1981-01-09 1982-11-24 Roussel Uclaf New 11 -substituted steroid derivatives, their preparation, their use as medicaments, the compositions containing them and the new intermediates thus obtained
US4599228A (en) 1981-01-19 1986-07-08 Vipont Laboratories, Inc. Antimicrobial agent
US4520026A (en) 1981-02-06 1985-05-28 S. A. Labaz N.V. Indolizine derivatives and use as cardiovascular agents
DE3104380A1 (en) 1981-02-07 1982-08-19 Bayer Ag, 5090 Leverkusen ANTIMICROBIAL AGENTS
US4412995A (en) 1981-02-19 1983-11-01 Sterling Drug Inc. Pentacyclic phenylpyrazole compounds as anti-inflammatory agents
US4370484A (en) 1981-03-12 1983-01-25 The Regents Of The University Of California Sceptrin an antimicrobial agent from Agelas sceptrum
US4443451A (en) 1981-07-15 1984-04-17 Janssen Pharmaceutica N.V. Bicyclic pyrimidin-5-one derivatives
US4440763A (en) 1981-03-18 1984-04-03 Block Drug Company, Inc. Use of 4-aminosalicyclic acid as an anti-inflammatory agent
JPS57169490A (en) 1981-04-10 1982-10-19 Kumiai Chem Ind Co Ltd 2,3-disubstituted-5,6-dihydro-imidazo(2,1-b)thiazole, its salt and their preparation
US4501755A (en) 1981-05-01 1985-02-26 Pennwalt Corporation Isoflavones useful as anti-inflammatory agents
US4440779A (en) 1981-06-30 1984-04-03 Merck & Co., Inc. Tricyclic derivatives of substituted pyrrole acids as analgesic and anti-inflammatory agents
US4568762A (en) 1981-07-01 1986-02-04 Hoffmann-La Roche Inc. 4-Methyl-2-oxo-cyclopentylidene acetic acid and esters thereof
US4548938A (en) 1981-07-15 1985-10-22 Janssen Pharmaceutica N.V. 5-H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one compounds
US4434175A (en) 1981-08-10 1984-02-28 Merck & Co., Inc. Nonsteroidal compounds as anti-inflammatory and analgesic agents
US4418697A (en) * 1981-08-17 1983-12-06 Francine Tama Electrode attachment method
US4490540A (en) 1981-09-14 1984-12-25 Janssen Pharmaceutica N.V. (2-Aryl-4-phenylthioalkyl-1,3-dioxolan-2-ylmethyl)azole derivatives
US4410696A (en) 1981-09-24 1983-10-18 Sumitomo Chemical Company, Limited Antitumor and immunosuppressive 4-carbamoylimidazolium-5-olate derivatives
DE3169269D1 (en) 1981-09-25 1985-04-18 Lacer Sa 1-azaxanthone for use as therapeutic agent, processes for its production and pharmaceutical compositions
US4514415A (en) 1981-10-28 1985-04-30 Ciba Geigy Corporation Benzofuran-2(3H)-ones used as anti-inflammatory agents
US4537981A (en) 1981-11-09 1985-08-27 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane and 7-oxabicycloheptene compounds
US4374139A (en) 1981-11-09 1983-02-15 Hoffmann-La Roche Inc. Levorotatory N-substituted acylmorphinans useful as analgesic agents
US4567201A (en) 1981-11-25 1986-01-28 Takeda Chemical Industries, Ltd. Diphenoxypropane derivatives and compositions of antiasthmatic and antiinflammatory agents thereof
DE3172458D1 (en) 1981-12-08 1985-10-31 Smithkline Beckman Corp Pharmaceutical compositions comprising 7,8-dihydroxy-1(hydroxyphenyl)-2,3,4,5-tetrahydro-1h-3-benzazepine derivatives and a beta-adrenergic blocking compound
US4536503A (en) 1981-12-14 1985-08-20 Syntex (U.S.A.) Inc. Naphthoxyalkylamines and related compounds as antiinflammatory agents
US4578390A (en) 1981-12-14 1986-03-25 Merck & Co., Inc. Hydroxybenzylamino derivatives as anti-inflammatory agents
US4891370A (en) 1981-12-14 1990-01-02 Merck & Co., Inc. Cephalosporin derivatives as anti-inflammatory agents
US4432292A (en) 1982-01-18 1984-02-21 Scott Kenneth G Floating planter
US4383994A (en) 1982-01-19 1983-05-17 Mccully Kilmer S Homocysteine thiolactone salts and use thereof as anti-neoplastic agents
US4494950A (en) * 1982-01-19 1985-01-22 The Johns Hopkins University Plural module medication delivery system
DE3204795A1 (en) 1982-02-11 1983-08-18 Bayer Ag, 5090 Leverkusen AZOLYL-PHENOXY-TETRAHYDROFURAN-2-YLIDEN-METHANE, METHOD FOR THE PRODUCTION THEREOF AND ANTIMICROBIAL AGENTS THAT CONTAIN THESE SUBSTANCES
US4512990A (en) 1982-02-18 1985-04-23 Syntex (U.S.A.), Inc. Benzthiazine analogs as antiinflammatory agents
US4439196A (en) * 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4544501A (en) 1982-04-12 1985-10-01 The Research Foundation Of State University Of New York Bis(2,2-dimethyl-1-aziridinyl)phosphinic amides for use in the treatment of tumors
US4435420A (en) 1982-04-12 1984-03-06 Merrell Dow Pharmaceuticals Anti-inflammatory agents and antiasthmatic agents
US4886790A (en) 1982-04-12 1989-12-12 The Research Foundation Of State University Of New York Novel bis(2,2-dimethyl-1-aziridinyl) phosphinic amides for use in the treatment of tumors
US4529727A (en) 1982-04-21 1985-07-16 Janssen Pharmaceutical, N.V. Pyrimido[2,1-b][1,3]-thiazines
JPS58185562A (en) 1982-04-22 1983-10-29 Taisho Pharmaceut Co Ltd 1,4-dihydropyridine derivative
US4418076A (en) 1982-05-03 1983-11-29 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane hydrazone prostaglandin analogs useful in treating thrombolytic diseases
DE3216895A1 (en) 1982-05-06 1983-11-10 Henkel KGaA, 4000 Düsseldorf 2- (3-IOD-2-PROPINYLOXY) ETHANOL CARBAMATE, THEIR PRODUCTION AND THEIR USE AS ANTIMICROBIAL SUBSTANCES
US4474806A (en) 1982-05-10 1984-10-02 Merck & Co., Inc. Sulfonyl or carbonyl inositol derivatives useful as anti-inflammatory/analgesic agents
US4416896A (en) 1982-05-17 1983-11-22 E. R. Squibb & Sons, Inc. 7-Oxabicyclopheptane substituted amino prostaglandin analogs useful in the treatment of thrombolytic disease
US4614825A (en) 1982-05-17 1986-09-30 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane and 7-oxabicycloheptene compounds
US4537904A (en) 1982-05-17 1985-08-27 E. R. Squibb & Sons, Inc. Compositions of 7-oxabicycloheptane and 7-oxabicycloheptene compounds and a method for their use in inhibiting bronchoconstriction
US4556675A (en) 1982-05-17 1985-12-03 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane and 7-oxabicycloheptene compounds
US4493839A (en) 1982-05-24 1985-01-15 Merck & Co., Inc. 1-Carbapenem-3-carboxylic esters as anti-inflammatory agents
US4495197A (en) 1982-05-24 1985-01-22 Merck & Co., Inc. N-Carboxyl-thienamycin esters and analogs thereof as anti-inflammatory agents
US4465687A (en) 1982-05-24 1984-08-14 Merck & Co., Inc. Thienamycin derivatives as anti-inflammatory agents
US4511724A (en) 1982-06-10 1985-04-16 Merck & Co., Inc. 5-(Pyrrol-2-oyl)-1,2-dihydro-3H-pyrrolo [1,2-a]pyrrole derivatives as anti-inflammatory and analgesic agents
US4427694A (en) 1982-06-11 1984-01-24 The Vinoxen Company, Inc. Sesamin as a psychotropic agent
US4440781A (en) 1982-06-11 1984-04-03 The Vinoxen Company, Inc. Oxyoctadecanoates as psychotropic agents
US4424202A (en) 1982-06-11 1984-01-03 The Vinoxen Company, Inc. Azelaaldehydates as psychotropic agents
US4588530A (en) 1982-07-30 1986-05-13 Florida Agricultural And Mechanical University Anti-inflammatory prednisolone steroids
US4463015A (en) 1982-08-18 1984-07-31 E. R. Squibb & Sons, Inc. Aryl substituted 7-oxabicycloheptane compounds, useful in inhibiting platelet aggregation
ES8404694A1 (en) 1982-08-20 1984-05-01 Nativelle Sa Ets 14-Amino steroid derivatives, a process for the preparation thereof and method of use thereof
US4539326A (en) 1982-08-20 1985-09-03 Takeda Chemical Industries, Ltd. 5-Oxo-5H-(1)benzopyrano(2,3-b)pyridine derivatives, their production and use as anti-inflammatory agents
US4495102A (en) 1982-09-03 1985-01-22 G. D. Searle & Co. Aminoalkyl steroids
US4489098A (en) 1982-09-28 1984-12-18 The Dow Chemical Company 2,2,3-Trihalopropionaldehydes as antimicrobial agents
US4631283A (en) 1982-09-30 1986-12-23 Ortho Pharmaceutical Corporation Ortho substituted dihydroxy-2(1H)quinazolinone-1-alkanoic acids
FR2533928A1 (en) 1982-10-05 1984-04-06 Roussel Uclaf NOVEL DICHLORIC DERIVATIVES OF THE 16A-METHYL PREGNANE SERIES, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS MEDICAMENTS
US4536512A (en) 1982-10-08 1985-08-20 Merck & Co., Inc. 5-(2,3-Dihydro-1H-pyrrolizin-5-oyl)-2,3-dihydro-1H-pyrrolizine-1-alkanoic or carboxylic acids and use thereof as anti-inflammatory and analgesic agents
US4533671A (en) 1982-10-08 1985-08-06 Merck & Co., Inc. 5-(2,3-Dihydro-1H-pyrrolizin-5-oyl)-2-alkanoic or carboxylic acids and analogs as anti-inflammatory and analgesic agents
US4456615A (en) 1982-10-25 1984-06-26 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted amino prostaglandin analogs and their use in inhibiting platelet aggregation and bronchoconstriction
JPS59112984A (en) 1982-12-21 1984-06-29 Shionogi & Co Ltd 1,4-benzodiazepine derivative
JPS5997924U (en) 1982-12-22 1984-07-03 宮崎製陶株式会社 Stacking straightening device for ceramic green molded products
US4456616A (en) 1982-12-27 1984-06-26 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted amino prostaglandin analogs and their use in inhibiting platelet aggregation and bronchoconstriction
US4456617A (en) 1983-01-12 1984-06-26 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted amino prostaglandin analogs and their use in inhibiting platelet aggregation and bronchoconstriction
US4466979A (en) 1983-01-21 1984-08-21 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted carbamate prostaglandin analogs useful in treating platelet aggregation and bronchoconstriction
JPS59139400A (en) 1983-01-31 1984-08-10 Shionogi & Co Ltd Steroid derivative with antialdosteronic activity
EP0119774B1 (en) 1983-03-09 1987-06-24 Beecham Group Plc Anti-inflammatory pyrazolo pyridines
US4582854A (en) 1983-03-14 1986-04-15 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted oxa prostaglandin analgos useful in the treatment of thrombolytic disease
US4474803A (en) 1983-03-14 1984-10-02 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted thio prostaglandin analogs useful in treating platelet aggregation and bronchoconstriction
JPS59186969A (en) 1983-04-08 1984-10-23 Yoshitomi Pharmaceut Ind Ltd Benzofurancarboxamide and benzopyranecarboxamide derivative
US4552871A (en) 1983-04-13 1985-11-12 Ciba Geigy Corporation Steroids of the 20-spiroxane series, processes for the manufacture thereof, pharmaceutical preparations containing such compounds and the use of the latter
FR2544718B1 (en) 1983-04-21 1985-12-20 Hexachimie NIFLUMIC ACID MORPHOLINOETHYL ESTER DINIFLUMATE, PREPARATION, THERAPEUTIC USE AS ANALGESIC AND ANTI-INFLAMMATORY
EP0123734A1 (en) 1983-04-29 1984-11-07 Gist-Brocades N.V. 17-(Isocyano-sulfonylmethylene)-steroids, 17-(formamido-sulfonylmethylene)-steroids and their preparation
US4517188A (en) 1983-05-09 1985-05-14 Mead Johnson & Company 1-Pyrimidinyloxy-3-hetaryl-alkylamino-2-propanols
US4680298A (en) 1983-05-31 1987-07-14 Schering Corporation Tricyclic anti-allergy and use as anti-inflammatory agents
FR2547587B1 (en) 1983-06-14 1985-10-25 Roussel Uclaf RADIOACTIVE STEROIDS, THEIR PREPARATION PROCESS, THEIR APPLICATION TO THE EVIDENCE OF GLUCOCORTICOID RECEPTORS AND TO THE DETERMINATION OF THE NUMBER OF FIXING SITES
DE3324193A1 (en) 1983-07-05 1985-01-17 Troponwerke Gmbh & Co Kg DEPOT ANTIPHLOGISTICS
DE3324192A1 (en) 1983-07-05 1985-01-17 Troponwerke Gmbh & Co Kg DEPOT ANTIPHLOGISTICS
FR2559484B2 (en) 1983-07-06 1986-09-26 Provesan Sa NEW DERIVATIVE 7- (PYRROL-1-YL) OF 1-ETHYL-1,4-DIHYDRO-4-OXO- (1,8-NAPHTYRIDIN) -3-CARBOXYLIC ACID, ITS PREPARATION AND ITS APPLICATION AS A MEDICAMENT
US4550186A (en) 1983-07-11 1985-10-29 Duke University Binuclear copper (II) carboxylates formed from amine-carboxyboranes
US4564363A (en) * 1983-07-13 1986-01-14 Smithkline Beckman Corporation Delayed action assembly
US4512986A (en) 1983-07-26 1985-04-23 Research Triangle Institute Progrestationally active steroids
US4541956A (en) 1983-07-28 1985-09-17 Unique Technologies, Inc. Tin steroids and their use as antineoplastic agents
US4634693A (en) 1983-07-28 1987-01-06 Cardarelli Nathan F Tin steroids and their uses
US5656621A (en) 1983-08-02 1997-08-12 Research Corporation Tech., Inc. Steroids useful as anti-cancer and anti-obesity agents
CA1239934A (en) 1983-08-05 1988-08-02 Lloyl D. Hayward D-isoidide and nitrates thereof
JPS6038323A (en) 1983-08-10 1985-02-27 Sankyo Co Ltd Ophthalmic anti-inflammatory agent
GB8322007D0 (en) 1983-08-16 1983-09-21 Wellcome Found Pharmaceutical delivery system
AU571554B2 (en) 1983-08-24 1988-04-21 Kotobuki Seiyaku Co. Ltd. Azulene sulfonates
US4479953A (en) 1983-08-25 1984-10-30 Merck & Co., Inc. Pyrazine aldimine compounds as antimicrobial agents
CA1252778A (en) 1983-08-25 1989-04-18 Hoffmann-La Roche Limited/Hoffmann-La Roche Limitee Steroids
US4525479A (en) 1983-08-29 1985-06-25 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted thiocarbamate prostaglandin analogs useful as cardiovascular agents
US4645836A (en) 1983-09-12 1987-02-24 Ortho Pharmaceutical Corporation Process for the preparation of 6,7-dihydroxy-4-alkyl-2(1H) quinazolinone-1-propionic acids
US4474804A (en) 1983-09-19 1984-10-02 E. R. Squibb & Sons, Inc. 7-Oxabicyclo substituted prostaglandin phenyl carboxylic acid derivatives useful as cardiovascular agents
US4656267A (en) 1983-09-29 1987-04-07 Ortho Pharmaceutical Corporation Substituted 2(1H)-quinazolinone-1-alkanoic acids and esters
US4555571A (en) 1983-09-29 1985-11-26 Ortho Pharmaceutical Corporation Substituted 2(1H)-quinazolinone-1-alkanoic acids and esters
US4556739A (en) 1983-09-29 1985-12-03 Ortho Pharmaceutical Corporation 3,4-Dialkoxy-2-alkylcarbonyl analino compounds
US4555570A (en) 1983-09-29 1985-11-26 Ortho Pharmaceutical Corporation Substituted 4-alkyl-2-(1H) quinazolinone-1-alkanoic acid derivatives
US4613600A (en) 1983-09-30 1986-09-23 Mead Johnson & Company Antidepressant 1,2,4-triazolone compounds
US4774256A (en) 1983-10-03 1988-09-27 E. R. Squibb & Sons, Inc. Use of enkephalinase inhibitors as analgesic agents
US4749575A (en) 1983-10-03 1988-06-07 Bio-Dar Ltd. Microencapsulated medicament in sweet matrix
US4686235A (en) 1983-10-12 1987-08-11 Merck & Co., Inc. Substituted cinnamyl-2,3-dihydrobenzofuran and analogs useful as anti-inflammatory agents
GB8327256D0 (en) 1983-10-12 1983-11-16 Ici Plc Steroid derivatives
US4778818A (en) 1983-10-12 1988-10-18 Merck & Co., Inc. Substituted 2-(heteroaryl-2-propenyl)phenols useful as anti-inflammatory agents
US4537903A (en) 1983-10-12 1985-08-27 Merck & Co., Inc. Substituted cinnamyl-2,3-dihydrobenzofuran and analogs useful as anti-inflammatory agents
US4522949A (en) 1983-10-20 1985-06-11 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted prostaglandin interphenylene analogs useful as cardiovascular agents
US4492700A (en) 1983-10-24 1985-01-08 Merck & Co., Inc. 3-Halo-2-thiopyrazines as antimicrobial agents
GB8328757D0 (en) 1983-10-27 1983-11-30 Wellcome Found Chemical compounds
US4667039A (en) 1983-11-07 1987-05-19 Hoechst-Roussel Pharmaceuticals Inc. 11-substituted 5H,11H-pyrrolo(2,1-C) (1,4)benzoxazepines as antipsychotic and analgesic agents
US4608374A (en) 1983-11-07 1986-08-26 Hoechst-Roussel Pharmaceuticals Inc. 11-substituted 5H,11H-pyrrolo[2,1-c][1,4]benzoxazepines as antipsychotic and analgesic agents
US4681879A (en) 1983-11-07 1987-07-21 Hoechst-Roussel Pharmaceuticals Inc. 11-substituted 5H,11H-pyrrolo[2,1-c][1,4]benzoxazepines as antipsychotic and analgesic agents
US4560557A (en) 1983-11-10 1985-12-24 University Patents, Inc. Silicon and sulfur steroids as irreversible inhibitors of hormone biosynthesis
US4524151A (en) 1983-11-14 1985-06-18 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane thio ethers useful as cardiovascular agents
US4563476A (en) 1983-11-21 1986-01-07 Merck & Co., Inc. Substituted 5-hydroxy-2,3-dihydrobenzofurans and analogs thereof useful as anti-inflammatory agents
US4559950A (en) 1983-11-25 1985-12-24 Graphic Controls Corporation Disposable biomedical and diagnostic electrode
US4652564A (en) 1983-12-14 1987-03-24 Schering Corporation Substituted spiro pyridine derivatives as anti-allergy and antiinflammatory agents
US4632923A (en) 1984-08-15 1986-12-30 Schering Corporation Substituted hetero spiro pyridine derivatives as anti-allergy and anti-inflammatory agents
US4532327A (en) 1983-12-28 1985-07-30 The United States Of America As Represented By The Secretary Of Agriculture Sesbanimide and the use thereof in treating leukemic tumors
DE3402392A1 (en) 1984-01-25 1985-08-01 Sandoz-Patent-GmbH, 7850 Lörrach NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND THEIR USE
US4533673A (en) 1984-01-26 1985-08-06 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted enaminone prostaglandin analogs and their use in treatment of thrombolytic disease
US4526901A (en) 1984-01-26 1985-07-02 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted oxamide prostaglandin analogs and their use in treating thrombolytic disease
US4526900A (en) 1984-01-26 1985-07-02 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted oxa prostaglandin analogs and their use in the treatment of thrombolytic disease
IN163263B (en) 1984-02-07 1988-08-27 Pfizer
US4721712A (en) 1984-06-12 1988-01-26 Pfizer Inc. 1,3-disubstituted 2-oxindoles as analgesic and anti-inflammatory agents
US4593029A (en) 1984-02-15 1986-06-03 Syntex (U.S.A.) Inc. Novel ω-(N-imidazolyl)alkyl ethers of 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-ones
US4558067A (en) 1984-03-01 1985-12-10 Merck & Co., Inc. Phenylthiomethyl-6-hydroxy-2,3-dihydrobenzo-pyran and analogs thereof useful as anti-inflammatory agents
US5135926A (en) 1984-03-14 1992-08-04 Bodor Nicholas S Soft β-adrenergic blocking agents
US5334601A (en) 1984-03-14 1994-08-02 Bodor Nicholas S Soft β-adrenergic blocking agents
US5202347A (en) 1984-03-14 1993-04-13 Bodor Nicholas S Soft β-adrenergic blocking agents
US4829086A (en) 1984-03-14 1989-05-09 Bodor Nicholas S Soft β-adrenergic blocking agents
US4536513A (en) 1984-03-14 1985-08-20 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted prostaglandin interphenylene analogs useful in the treatment of thrombolytic disease
US4556672A (en) 1984-03-19 1985-12-03 Pfizer Inc. 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents
US5000957A (en) 1984-03-19 1991-03-19 Alza Corporation Dispenser comprising hydrophilic osmopolymer
US4701450A (en) 1984-03-21 1987-10-20 Akzo N.V. Steroids for use as immunomodulators
US4542155A (en) 1984-04-02 1985-09-17 E. R. Squibb & Sons, Inc. Tetrahydrofuranyl substituted prostaglandin analogs
US4536514A (en) 1984-04-06 1985-08-20 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted prostaglandin analogs useful in the treatment of thrombolytic disease
US4579867A (en) 1984-04-09 1986-04-01 American Hospital Supply Corporation Stable pharmaceutical compositions of short-acting β-adrenergic receptor blocking agents
US4550187A (en) 1984-04-12 1985-10-29 The Research Foundation Of State University Of New York Synthesis of platinum (IV) antineoplastic agents
US4542156A (en) 1984-04-26 1985-09-17 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted prostaglandin alcohols and their use in the treatment of thrombolytic disease
US4542157A (en) 1984-04-27 1985-09-17 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted oxa prostaglandin analogs and their use in the treatment of thrombolytic disease
US4550120A (en) 1984-04-30 1985-10-29 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted ethers and their use in treating thrombolytic disease
US4569942A (en) 1984-05-04 1986-02-11 Pfizer Inc. N,3-Disubstituted 2-oxindole-1-carboxamides as analgesic and antiinflammatory agents
US4521539A (en) 1984-05-10 1985-06-04 E. R. Squibb & Sons, Inc. Tetrahydrofuranyl substituted ethers
US4542151A (en) 1984-12-17 1985-09-17 E. R. Squibb & Sons, Inc. Tetrahydrothienyl substituted ethers
DK240184D0 (en) 1984-05-15 1984-05-15 Ferrosan As BETA-CARBOLINE-3-CARBOXYLIC ACID DERIVATIVES AND METHOD OF PREPARING THE SAME
DK240084D0 (en) 1984-05-15 1984-05-15 Ferrosan As NEW BETA-CARBOLINE-3-OXADIAZOLYL DERIVATIVES
JPS60248659A (en) 1984-05-25 1985-12-09 Microbial Chem Res Found 3(n-(mercaptoacyl))amino-4-arylbutyric acid derivative and analgesic containing said derivative as active component
US4579866A (en) 1984-05-29 1986-04-01 Usv Pharmaceutical Corp. Phenylacetamides as anti-allergy, anti-asthma and anti-inflammatory agents
US4560698A (en) 1984-06-04 1985-12-24 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted thio prostaglandin analogs and their use in the treatment in thrombolytic disease
US4555523A (en) 1984-06-04 1985-11-26 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted thio prostaglandin analogs and their use in the treatment of thrombolytic disease
GB8414518D0 (en) 1984-06-07 1984-07-11 Pfizer Ltd Therapeutic agents
US4670551A (en) 1984-06-21 1987-06-02 Ciba-Geigy Corporation Epoxy steroids
US5310731A (en) 1984-06-28 1994-05-10 Whitby Research, Inc. N-6 substituted-5'-(N-substitutedcarboxamido)adenosines as cardiac vasodilators and antihypertensive agents
GB8416724D0 (en) 1984-06-30 1984-08-01 Sorbio Sa Lab Active compounds
US4670541A (en) 1984-07-05 1987-06-02 E. R. Squibb & Sons, Inc. Use of diamino alcohols as analgesic agents
US4552866A (en) 1984-07-05 1985-11-12 E. R. Squibb & Sons, Inc. Use of diamino alcohols as analgesic agents
US4539312A (en) 1984-07-11 1985-09-03 E. R. Squibb & Sons, Inc. Use of diamino ketones as analgesic agents
US4594188A (en) 1984-07-11 1986-06-10 E. R. Squibb & Sons, Inc. Use of diamino ketones as analgesic agents
US4730052A (en) 1984-07-13 1988-03-08 Taisho Pharmaceutical Co., Ltd. Method for preparing unsymmetrical 1,4-dihydropyridine-3,5-dicarboxylic acid diesters
US4542160A (en) 1984-07-30 1985-09-17 E. R. Squibb & Sons, Inc. Method of use of bicycloheptane substituted prostaglandin analogs as cardiovascular agents
US4611066A (en) 1984-08-10 1986-09-09 Arizona State University Bryostatins 4 to 8
US4845242A (en) 1987-04-28 1989-07-04 Georgia Tech Research Corporation Isocoumarins with basic substituents as serine proteases inhibitors, anticoagulants and anti-inflammatory agents
US4954519A (en) 1987-04-28 1990-09-04 Georgia Tech Research Corporation Isocoumarins with basic substituents as serine proteases inhibitors, anticoagulants and anti-inflammatory agents
HU203350B (en) 1984-08-24 1991-07-29 Pfizer Process for producing antiinflammatory tricyclic oxindole derivatives
FR2569408B1 (en) 1984-08-24 1986-10-03 Roussel Uclaf NOVEL STEROIDS SUBSTITUTED IN POSITION 10 BY A RADICAL HAVING A DOUBLE OR TRIPLE LINK, THEIR PREPARATION METHOD, THEIR APPLICATION AS MEDICAMENTS, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US4567000A (en) 1984-08-31 1986-01-28 The Upjohn Company 11-Difluoromethylene steroids
GB8422876D0 (en) 1984-09-11 1984-10-17 Secr Defence Silicon implant devices
US4711856A (en) 1984-09-19 1987-12-08 Mayo Medical Resources Nuclear binding assay for steroid receptor functionality in cancerous cells
US4749792A (en) 1984-09-26 1988-06-07 E. R. Squibb & Sons, Inc. Diamino ketones and alcohols as analgesic agents
JPS6172712U (en) 1984-10-12 1986-05-17
FR2571727B1 (en) 1984-10-16 1987-06-12 Roussel Uclaf NEW STEROID PRODUCTS COMPRISING, IN POSITION 23, A RADICAL DIHYDRO OXAZOLYL, THEIR PREPARATION PROCESS, THEIR APPLICATION TO THE PREPARATION OF PRODUCTS OF THE 20 CETOPREGNANES SERIES AND INTERMEDIATES OF THIS APPLICATION
DE3438351A1 (en) 1984-10-19 1986-04-24 Gödecke AG, 1000 Berlin 4-ALKOXY-PYRIDO (2,3-D) PYRIMIDINE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF
US4644005A (en) 1984-10-31 1987-02-17 Pfizer Inc. Oxindole antiinflammatory agents
US4686224A (en) 1984-10-31 1987-08-11 Pfizer Inc. Oxindole antiinflammatory agents
US4575512A (en) 1984-11-01 1986-03-11 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted oxa prostaglandin analogs and their anti-thrombotic compositions and methods
JPS61112075A (en) 1984-11-05 1986-05-30 Shionogi & Co Ltd Thienylpyrazoloquinoline derivative
US4647585A (en) 1984-11-08 1987-03-03 E. R. Squibb & Sons, Inc. Bicycloheptane substituted ethers
US4650874A (en) 1984-11-26 1987-03-17 G. D. Searle & Co. N-(aralkoxybenzyl)-4(benzhydryl) piperidines
US4661506A (en) 1984-11-30 1987-04-28 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted ox prostaglandin analogs
US4638011A (en) 1984-12-17 1987-01-20 E. R. Squibb & Sons, Inc. Tetrahydrothienyl substituted prostaglandin analogs
US4684747A (en) 1984-12-20 1987-08-04 Yale University N,N'-bis(sulfonyl)hydrazines having antineoplastic activity
US4892887A (en) 1984-12-20 1990-01-09 Yale University N,N'-bis(sulfonyl)hydrazines having antineoplastic activity
EP0188010A1 (en) 1985-01-14 1986-07-23 Gist-Brocades N.V. New process for the preparation of certain steroids, especially intermediates for the preparation of proligestone and related compounds, and new intermediates formed in this process
FR2576025B1 (en) 1985-01-14 1987-01-23 Roussel Uclaf NOVEL SUBSTITUTED STEROIDS IN POSITION 10, THEIR PROCESS AND THE PREPARATION INTERMEDIATES, THEIR APPLICATION AS MEDICAMENTS, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US4588743A (en) 1985-01-22 1986-05-13 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane-substituted oxa prostaglandin analogs and their use in the treatment of thrombolytic disease
US4760051A (en) 1985-01-24 1988-07-26 Pickart Loren R Use of GHL-Cu as a wound-healing and anti-inflammatory agent
US4588742A (en) 1985-02-20 1986-05-13 E. R. Squibb & Sons, Inc. Thiabicycloheptane substituted prostaglandin analogs useful in the treatment of thrombotic disease
US4591603A (en) 1985-02-25 1986-05-27 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted prostaglandin analogs useful in the treatment of thrombotic disease
US4588741A (en) 1985-02-28 1986-05-13 E. R. Squibb & Sons, Inc. Platelet aggregation inhibiting and bronchoconstriction inhibiting thiabicycloheptane substituted amino prostaglandin analog derivatives, compositions, and method of use therefor
US4684653A (en) 1985-03-08 1987-08-04 The Trustees Of Princeton University Pyrido(2,3-d)pyrimidine derivatives
US4927828A (en) 1985-03-08 1990-05-22 The Trustees Of Princeton University Diastereoisomeric tetrahydropyrido-(2,3,d) pyrimidine derivatives
DE3510203A1 (en) 1985-03-21 1986-09-25 Bayer Ag, 5090 Leverkusen NEW IODOPROPARGYL ETHER, A METHOD FOR THE PRODUCTION AND THEIR USE
US4596828A (en) 1985-03-28 1986-06-24 Merck & Co., Inc. [(2-hydroxy-5-alkoxyphenyl)methylthio]phenylmethanol and derivatives thereof useful as anti-inflammatory agents
US4681111A (en) * 1985-04-05 1987-07-21 Siemens-Pacesetter, Inc. Analog and digital telemetry system for an implantable device
US4654165A (en) * 1985-04-16 1987-03-31 Micro Tracers, Inc. Microingredient containing tracer
US4611007A (en) 1985-04-22 1986-09-09 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted prostaglandin analogs useful in the treatment of thrombotic disease
US4607049A (en) 1985-04-22 1986-08-19 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted thio prostaglandin analogs useful in the treatment of thrombolytic disease
US4775679A (en) 1985-04-25 1988-10-04 Merck & Co., Inc. Certain heterocyclic-ethyl-2,3-dihydrobenzofurans useful as anti-inflammatory agents
US4713393A (en) 1985-04-25 1987-12-15 Merck & Co., Inc. Phenylpropyl-2,3-dihydrobenzofurans useful as anti-inflammatory agents
US4608386A (en) 1985-04-26 1986-08-26 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane ethers useful in the treatment of thrombotic diseases
US4782058A (en) 1985-04-26 1988-11-01 Pennwalt Corporation 1,3,4,6,7,11b-Hexahydro-6-phenyl-2H-pyrazino-(2,1-a)isoquinolines, for anti-histamine or anti-depression treatment
US4748153A (en) 1985-04-29 1988-05-31 Merck & Co., Inc. Compounds having somatostatin-like activity useful as local anti-inflammatory agents
US4585755A (en) 1985-04-29 1986-04-29 Merck & Co., Inc. Cyclic and bridged cyclic somatostatin analogs useful as local anti-inflammatory agents
JP2617706B2 (en) 1985-05-01 1997-06-04 富士薬品工業 株式会社 3α, 5-cyclo-22,23-dihydroxy-5α-steroid compound
FR2581382B1 (en) 1985-05-06 1987-06-26 Sanofi Sa N- (QUINOLYL) GLYCINAMIDE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION AS PSYCHOTROPES
US4607048A (en) 1985-05-16 1986-08-19 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted aryl amino prostaglandin analogs and their use in inhibiting platelet aggregation and bronchoconstriction
US4595692A (en) 1985-05-17 1986-06-17 E. R. Squibb & Sons, Inc. 7-thiabicycloheptane substituted ethers
US4611005A (en) 1985-05-21 1986-09-09 E. R. Squibb & Sons, Inc. 5,6-epoxy-7-oxabicycloheptane substituted prostaglandin analogs useful in the treatment of thrombotic disease
FR2599039B1 (en) 1986-05-22 1988-08-05 Rhone Poulenc Sante NEW IMMUNO-SUPPRESSIVE SUBSTANCE, ITS PREPARATION BY CULTURE OF STREPTOMYCES SP. (CBS 162.86) AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING IT
US4767627A (en) 1985-05-29 1988-08-30 Merck & Co., Inc. Drug delivery device which can be retained in the stomach for a controlled period of time
US5202330A (en) 1985-06-03 1993-04-13 E. R. Squibb & Sons, Inc. 2-thio or oxo-4-aryl or heterocyclo-1,5(2H)-pyrimidinedicarboxylic acid diesters and 3-acyl-5-pyrimidinecarboxylic acids and esters
US4628095A (en) 1985-06-05 1986-12-09 G. D. Searle & Co. Substituted N-benzyl-4-(benzhydryl) piperidines
US5026712A (en) 1985-06-05 1991-06-25 Schering Ag Novel imidazo[1,5-a]pyridines, useful as cardiovascular and CNS agents
US4863955A (en) 1985-06-06 1989-09-05 Eli Lilly And Company Scytophycins
US4996229A (en) 1985-06-06 1991-02-26 University Of Hawaii Scytophycins
US4861765A (en) 1985-06-26 1989-08-29 Jouveinal 21-alkyl-, cycloalkyl- or aryl-substituted thio steroids and pharmaceutical compositions containing them
US4609671A (en) 1985-06-27 1986-09-02 E. R. Squibb & Sons, Inc. 5,6-epoxy-7-oxabicycloheptane substituted amino prostaglandin analogs useful in the treatment of thrombotic disease
US4611006A (en) 1985-06-28 1986-09-09 E. R. Squibb & Sons, Inc. 5,6-epoxy-7-oxabicycloheptane substituted ethers useful in the treatment of thrombotic disease
US4737493A (en) 1985-07-01 1988-04-12 Warner-Lambert Company 7-((substituted)amino)-8-((substituted)carbonyl)-methylamino)-1-oxaspiro(4,5)decanes as analgesic agents
US4663336A (en) 1985-07-01 1987-05-05 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted diamide and its congener prostaglandin analogs useful in the treatment of thrombotic disease
US4678802A (en) 1985-07-09 1987-07-07 Pfizer Inc. 1-acylcarbamoyloxindole-3-carboxamides as antiinflammatory agents
US4654335A (en) 1985-07-11 1987-03-31 E. R. Squibb & Sons, Inc. Antihypertensive 1,5-benzothiazepine derivatives, compositions, and method of use therefor
US4704382A (en) 1985-07-29 1987-11-03 G. D. Searle & Co. Phenylpiperazine phosphonates
US4654356A (en) 1985-08-01 1987-03-31 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted diacid diamide prostaglandin analogs
US4654355A (en) 1985-08-01 1987-03-31 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted amide-thioamide prostaglandin analogs
US4647561A (en) 1985-08-05 1987-03-03 E. R. Squibb & Sons, Inc. 1,5-benzodiazepine compounds
US4654357A (en) 1985-08-09 1987-03-31 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted sulfonamide prostaglandin analogs
US4923892A (en) 1985-08-17 1990-05-08 Burroughs Wellcome Co. Tricyclic aromatic compounds
US4626548A (en) 1985-08-19 1986-12-02 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted prostaglandin compounds useful in the treatment of thrombotic disease
US4763659A (en) 1985-08-21 1988-08-16 Spring Creek Institute, Inc. Dry electrode system for detection of biopotentials
US4669479A (en) 1985-08-21 1987-06-02 Spring Creek Institute, Inc. Dry electrode system for detection of biopotentials
GB2191186B (en) 1985-08-26 1989-11-01 Manchak Frank In situ hazardous waste treating apparatus and method of using same
GB8521350D0 (en) 1985-08-28 1985-10-02 Euro Celtique Sa Analgesic composition
US5380840A (en) 1985-09-12 1995-01-10 The Upjohn Company Triazinylpiperazinyl steroids
US4632931A (en) 1985-09-25 1986-12-30 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted amide-sulfonamide prostaglandin analogs useful in the treatment of thrombotic disease
US4686221A (en) 1985-10-01 1987-08-11 Kanebo, Ltd. Quinolinecarboxylic acid compounds and antimicrobial agent containing the same
US4635641A (en) 1985-10-16 1987-01-13 Murray Electronics Associates Limited Multi-element electrode
US5373095A (en) 1985-10-18 1994-12-13 The Upjohn Company Steroid compounds
US4652576A (en) 1985-10-18 1987-03-24 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted amide-carbamate prostaglandin analogs
US4593042A (en) 1985-10-18 1986-06-03 G. D. Searle & Co. Bicyclo-substituted phenylacetonitrile derivatives
CA1306260C (en) 1985-10-18 1992-08-11 Shionogi & Co., Ltd. Condensed imidazopyridine derivatives
US4975537A (en) 1985-10-23 1990-12-04 The Upjohn Company Δ9(11) -angiostatic steroids
US4639461A (en) 1985-10-28 1987-01-27 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted keto-amide prostaglandin analogs useful in the treatment of thrombotic disease
US4638012A (en) 1985-11-05 1987-01-20 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane α-substituted ketone prostaglandin analogs useful in the treatment of thrombotic disease
DE3540653A1 (en) 1985-11-13 1987-05-14 Schering Ag NEW 3-OXADIAZOLE AND 3-CARBONIC ACID SS-CARBOLINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS
US4824955A (en) 1985-11-15 1989-04-25 Nippon Kayaku Kabushiki Kaisha Selenium oxy chloride-pyridine or bipyridine complexes
US4647573A (en) 1985-11-22 1987-03-03 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted thioamide-amide prostaglandin analogs
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5106996A (en) 1985-12-05 1992-04-21 Bristol-Myers Company Process for the preparation of podophyllotoxin
US4656185A (en) 1985-12-05 1987-04-07 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted aminoalkyl amide prostaglandin analogs
US5055290A (en) 1985-12-18 1991-10-08 Boehringer Mannehim Gmbh Ciamexone as a selective immunosuppressant
US4618685A (en) 1985-12-18 1986-10-21 Mccully Kilmer S N-homocysteine thiolactonyl retinamide and use thereof as an antineoplastic agent
US4668787A (en) 1985-12-20 1987-05-26 Ortho Pharmaceutical Corporation 5,6-dialkoxy-4-imino-2(1H)quinazolinone derivatives
US4622326A (en) 1985-12-23 1986-11-11 Hoechst-Roussel Pharmaceuticals Inc. 6H-isoxazolo(5,4-d)pyrazolo(3,4-b)pyridines, and their use as antihypertensive and analgesic agents
GB8600490D0 (en) 1986-01-09 1986-02-12 Erba Farmitalia Aminoglycoside norcholanic acid lactams
GB8600489D0 (en) 1986-01-09 1986-02-12 Erba Farmitalia Aminoglycoside steroids
US4849563A (en) 1986-01-21 1989-07-18 Yale University Novel 1-alkyl-1-arenesulfonyl-2-alkoxycarbonylsulfenylhydrazines having antineoplastic activity
US4962114A (en) 1986-01-21 1990-10-09 Yale University 1-alkyl-1-sulfonyl-2-alkoxycarbonylsulfenylhydrazines having antineoplastic activity
US4904786A (en) 1986-01-27 1990-02-27 American Home Products Corporation Quinoline compounds as antiallergic and antiinflammatory agents
US4772703A (en) 1986-01-27 1988-09-20 American Home Products Corporation 2-(phenoxymethyl)-quinazolines as antiallergic and antiinflammatory agents
US4727072A (en) 1986-02-12 1988-02-23 Mcneilab, Inc. 3-alkoxy-2-aminopropylamines compositions and use as cardiovascular agents
US4780538A (en) 1986-02-12 1988-10-25 Merck & Co., Inc. Process for 1,4-dihydropyridine compounds using a titanamine catalyst
US4745123A (en) 1986-02-18 1988-05-17 Warner-Lambert Company Substituted tetrahydro-3-pyridine-carboxylic acid, ester, and amide cholinergic agents
US4775536A (en) 1986-02-24 1988-10-04 Bristol-Myers Company Enteric coated tablet and process for making
US4652578A (en) 1986-02-24 1987-03-24 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted amide prostaglandin analogs
IL81610A (en) 1986-02-27 1990-12-23 Roussel Uclaf Derivatives of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde oxime,their preparation and pharmaceutical compositions containing them
US4663250A (en) 1986-03-12 1987-05-05 Institute Of Gas Technology Reduction of electrode dissolution
US4784991A (en) 1986-03-14 1988-11-15 Bio-Technology General Corp. Heavy metal salts of hyaluronic acid and their use as antimicrobial agents
US4746504A (en) 1986-03-14 1988-05-24 Bio-Technology General Corp. Heavy metal salts of hyaluronic acid and their use as antimicrobial agents
FR2596395B1 (en) 1986-03-26 1989-05-26 Roussel Uclaf NOVEL STEROIDS COMPRISING A SPIRANIC CYCLE IN POSITION 17, THEIR PREPARATION METHOD, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS CONTAINING THEM
US4663337A (en) 1986-04-18 1987-05-05 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted amides useful in the treatment of thrombotic disease
US4670560A (en) 1986-04-28 1987-06-02 Ortho Pharmaceutical Corporation Thienopyrimidine-2,4-dione derivatives and intermediates thereof
US4703120A (en) 1986-04-28 1987-10-27 Ortho Pharmaceutical Corporation Furo(3,4-d)pyrimidine-2,4-dione derivatives and intermediates thereof
US4707550A (en) 1986-04-28 1987-11-17 Ortho Pharmaceutical Corporation N-(substituted thienyl)-N'-(substituted piperazinyl)-ureas
DE3773746D1 (en) 1986-05-07 1991-11-21 Fisons Plc Pyrazole.
US4670453A (en) 1986-05-08 1987-06-02 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted amido-carbamoyl prostaglandin analogs useful in the treatment of thrombotic disease
US5036088A (en) 1986-06-09 1991-07-30 Pfizer Inc. Antiallergy and antiinflammatory agents, compositions and use
US4835166A (en) 1986-06-09 1989-05-30 Pfizer Inc. Antiallergy and antiinflammatory agents
US4708966A (en) 1986-06-27 1987-11-24 The Procter & Gamble Company Novel anti-inflammatory agents, pharmaceutical compositions and methods for reducing inflammation
US4833145A (en) 1986-06-30 1989-05-23 The Trustees Of Princeton University 4(3H)-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine derivatives
US4650797A (en) 1986-07-18 1987-03-17 E. R. Squibb & Sons, Inc. Substituted 1,5-benzodiazepine compounds
US4725997A (en) 1986-08-22 1988-02-16 Aprex Corporation Contingent dosing device
GB8620880D0 (en) 1986-08-29 1986-10-08 Pfizer Ltd Therapeutic agents
US4861763A (en) 1986-09-17 1989-08-29 Research Triangle Institute 17 α-(substituted-methyl)-17β-hydroxy/esterified hydroxy steroids and their progestational use
US4774236A (en) 1986-09-17 1988-09-27 Research Triangle Institute 17α-(substituted-methyl)-17β-hydroxy/esterified hydroxy steroids and pharmaceutical compositions containing them
US4775757A (en) 1986-09-22 1988-10-04 Ortho Pharmaceutical Corporation Thienopyridines useful as cardiovascular agents
US4784162A (en) 1986-09-23 1988-11-15 Advanced Medical Technologies Portable, multi-channel, physiological data monitoring system
US4734426A (en) 1986-09-24 1988-03-29 E. R. Squibb & Sons, Inc. 5,6-epoxy-7-oxabicycloheptane substituted diamide prostaglandin analogs
US4734424A (en) 1986-09-24 1988-03-29 E. R. Squibb & Sons, Inc. Bicycloheptane substituted diamide and its congener prostaglandin analogs
US4735962A (en) 1986-10-06 1988-04-05 E. R. Squibb & Sons, Inc. 7-thiabicycloheptane substituted diamide and its congener prostaglandin analogs
US5352809A (en) 1986-10-10 1994-10-04 Gist-Brocades N.V. 9-alpha-hydroxy steroids, process for their preparation, process for the preparation of the corresponding 9(11)-dehydro derivatives and pharmaceutical preparations containing such steroids
US4734425A (en) 1986-10-17 1988-03-29 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted hydroxamic acid prostaglandin analogs
US4782071A (en) 1986-11-03 1988-11-01 Warner-Lambert Company Tetrasubstituted urea cholinergic agents
US4847090A (en) 1986-11-07 1989-07-11 Warner-Lambert Company Confection product and method for making same
NO874194L (en) 1986-11-07 1988-05-09 Pfizer Ltd PROCEDURE FOR THE PREPARATION OF DIHYDRO-PYRIDINE DERIVATIVES
US4738978A (en) 1986-11-10 1988-04-19 E. R. Squibb & Sons, Inc. Bisthioamide-7-oxabicycloheptane prostaglandin analogs
US4785085A (en) 1986-11-21 1988-11-15 Bristol-Myers Company Rebeccamycin analogs
US4896261A (en) 1986-11-24 1990-01-23 Motorola Inc. System for scheduling serial message transmission on a bus which is adoptable for rescheduling prioritized messages using a doubly-linked list
FR2607816B1 (en) 1986-12-05 1989-03-31 Roussel Uclaf NEW STEROID PRODUCTS COMPRISING, IN POSITION 23, A SULFINYL RADICAL, THEIR PREPARATION METHOD, THEIR APPLICATION TO THE PREPARATION OF PRODUCTS OF THE 20-CETOPREGNANES SERIES AND INTERMEDIATES OF THIS PREPARATION
US4786648A (en) 1986-12-08 1988-11-22 Warner-Lambert Company O-substituted tetrahydropyridine oxime cholinergic agents
US4710508A (en) 1986-12-08 1987-12-01 Warner-Lambert Company O-substituted tetrahydropyridine oxime cholinergic agents
IT1213555B (en) 1986-12-11 1989-12-20 Boehringer Biochemia Srl 2 METHYLOMETHYL HYDROPYRIDINE, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US5702688A (en) 1986-12-23 1997-12-30 Tristrata Technology, Inc. Amphoteric compositions and polymeric forms of alpha hydroxyacids, and their therapeutic use
US4874760A (en) 1987-01-09 1989-10-17 Toa Eiyo, Ltd. 4,7-dihydroisothiazolo(5,4-b)pyridine derivatives and cardiovascular treating agents containing said derivatives
US4945099A (en) 1987-01-12 1990-07-31 Eli Lilly And Company Anti-inflammatory agents
US5098613A (en) 1987-01-12 1992-03-24 Eli Lilly And Company Anti-inflammatory agents
US4791129A (en) 1987-01-20 1988-12-13 Pfizer Inc. 1,3-dicarboxamidooxindoles as analgesic and antiinflammatory agents
US5272140A (en) 1987-01-23 1993-12-21 Akzo N.V. 11-aryl steroid derivatives
US4888336A (en) 1987-01-28 1989-12-19 Smithkline Beckman Corporation Steroid 5-alpha-reductase inhibitors
US5034548A (en) 1987-01-30 1991-07-23 E. I. Du Pont De Nemours And Company Steroid derivatives useful as hypocholesterolemics
US5041432A (en) 1987-01-30 1991-08-20 E. I. Du Pont De Nemours And Company Steroid derivatives useful as hypocholesterolemics
US5109024A (en) 1987-02-03 1992-04-28 Merrell Dow Pharmaceuticals Inc. Polyamine derivatives as antineoplastic agents
US4767776A (en) 1987-02-20 1988-08-30 Warner-Lambert Company N-1H-tetrazol-5-yl-2-naphthalene carboxamides and their use as antiallergy and antiinflammatory agents
US4764525A (en) 1987-02-25 1988-08-16 Warner-Lambert Company N-1H-tetrazol-5-ylbenzamides having use as antiallergy and antiinflammatory agents
US4749715A (en) 1987-03-02 1988-06-07 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted amino prostaglandin analogs
US5017618A (en) 1987-03-16 1991-05-21 University Of Florida Labile derivatives of ketone analogs of 3-substituted-1-alkylamino-2-propanols and their use as beta-adrenergic blockers
US4798841A (en) 1987-03-31 1989-01-17 Warner-Lambert Company Tetrahydropyridine oxime cholinergic agents and method of treatment
US4753946A (en) 1987-04-08 1988-06-28 E. R. Squibb & Sons, Inc. Pyrimidinecarboxylic acid derivatives
FR2613719B1 (en) 1987-04-10 1991-03-22 Sanofi Sa AROMATIC DERIVATIVES, THEIR PREPARATION AND THEIR USE AS ANTIMICROBIALS
US5002955A (en) 1987-04-23 1991-03-26 Hoechst-Roussel Pharmaceuticals Inc. Fused heteroalkylene quinolinamines and use as cholinergic agents
US5219873A (en) 1987-04-24 1993-06-15 Roussel Uclaf Compounds of 1,2,5,6-tetrahydropyridine which are useful as cholinergic agents
US5324648A (en) 1987-04-28 1994-06-28 Georgia Tech Research Corporation Substituted isocoumarins as serine protease inhibitors and anti-inflammatory agents
US4910226A (en) 1987-04-29 1990-03-20 Smithkline Beckman Corporation Steroid 5-alpha-reductase inhibitors
US5041433A (en) 1987-04-29 1991-08-20 Smithkline Beecham Corporation 11-keto or hydroxy 3,5-diene steroids as inhibitors of steriod 5-α-reductase
US4769371A (en) 1987-05-01 1988-09-06 E. R. Squibb & Sons, Inc. Dihydropyrimidine carboxylic acid esters
US4912248A (en) 1987-05-18 1990-03-27 The Procter & Gamble Company Novel anti-inflammatory agents, pharmaceutical compositions and methods for reducing inflammation
GB8711802D0 (en) 1987-05-19 1987-06-24 Fujisawa Pharmaceutical Co Dithioacetal compounds
US4888434A (en) 1987-05-26 1989-12-19 Dow Corning K.K. Antimicrobial agent
US5019390A (en) 1987-05-29 1991-05-28 Research Corporation Technologies, Inc. Anticancer agent--IMIC
GB8712747D0 (en) 1987-05-30 1987-07-01 Pfizer Ltd Therapeutic agents
US5081147A (en) 1990-03-15 1992-01-14 Allergan, Inc. 4-(1-hydroxy-2-substituted amino)ethyl-5-hydroxy-2(5H)-furanones as anti-inflammatory agents
US5043457A (en) 1990-04-17 1991-08-27 Allergan, Inc. 2(5H)-furanones substituted in the 3 position, as Ca2+ channel antagonists and anti-inflammatory agents
US5298633A (en) 1987-06-08 1994-03-29 Allergan, Inc. Intermediates and processes for preparing 4-substituted 2-5(H)-furanones as anti-inflammatory agents
US5037811A (en) 1990-04-17 1991-08-06 Allergan, Inc. 4-(oxygen, sulfur or nitrogen substituted)-methyl 5-hydroxy-2(5H)-furanones as anti-inflammatory agents
US4889866A (en) 1987-06-11 1989-12-26 Syntex (U.S.A.) Inc. Arylsulfonyl dihydropyridine derivatives
US4752616A (en) 1987-06-29 1988-06-21 E. R. Squibb & Sons, Inc. Arylthioalkylphenyl carboxylic acids, compositions containing same and method of use
US4876093A (en) 1987-07-02 1989-10-24 Alza Corporation Dispenser with dispersing member for delivering beneficial agent
GB8716278D0 (en) 1987-07-10 1987-08-19 Fujisawa Pharmaceutical Co Antimicrobial agent
US5008264A (en) 1987-07-13 1991-04-16 Hoechst-Roussel Pharmaceuticals Inc. N-substituted-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine and related compounds as analgesic and hypotensive agents
US4980365A (en) 1987-07-13 1990-12-25 Hoechst-Roussel Pharmaceuticals Inc. N-substituted-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine and related compounds as analgesic and hypotensive agents
US5030639A (en) 1987-07-13 1991-07-09 Hoechst-Roussel Pharmaceuticals Inc. N-substituted-5,6-dimethoxy-1,2-benzisoxazole-3-propanamine and related compounds as analgesic and hypotensive agents
PL154186B1 (en) 1987-07-15 1991-07-31 Wellcome Found Method for manufacturing arylic derivatives of the hydroxamic acid
DE3723310A1 (en) 1987-07-15 1989-01-26 John Urquhart PHARMACEUTICAL PREPARATION AND METHOD FOR THE PRODUCTION THEREOF
CA1322199C (en) 1987-07-15 1993-09-14 Masami Eigyo N-¬(2-oxopyrrolidin-1-yl) acetyl)| piperazine derivatives and drug for senile dementia
GB8716971D0 (en) 1987-07-17 1987-08-26 Pfizer Ltd Therapeutic agents
US4767756A (en) 1987-07-17 1988-08-30 E. R. Squibb & Sons, Inc. 3-substituted benzazepines
US4794110A (en) 1987-07-20 1988-12-27 Hoechst-Roussel Pharmaceuticals, Inc. 5-Aryl-11-substituted-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepined as analgesic and hypotensive agents
US4771047A (en) 1987-07-27 1988-09-13 E. R. Squibb & Sons, Inc. Benzazepine derivatives
US4847290A (en) 1987-08-17 1989-07-11 Sumner Burstein Delta 1-thc-7-oic acid and analgesic and anti-inflammatory agents
CA1305148C (en) 1987-08-19 1992-07-14 Hiromu Matsumura Carbamoylpyrrolidone derivatives and drugs for senile dementia
US4774239A (en) 1987-08-26 1988-09-27 E. R. Squibb & Sons, Inc. Benzazepine derivatives
US4891223A (en) 1987-09-03 1990-01-02 Air Products And Chemicals, Inc. Controlled release delivery coating formulation for bioactive substances
US4814181A (en) 1987-09-03 1989-03-21 Alza Corporation Dosage form comprising fast agent delivery followed by slow agent delivery
FR2620704B1 (en) 1987-09-17 1991-04-26 Sanofi Sa (BENZYL-4 PIPERIDINO) -1 PROPANOL-2 DERIVATIVES, THEIR PREPARATION, THEIR USE AS ANTIMICROBIALS AND THE PRODUCTS CONTAINING THEM
FR2620707B1 (en) 1987-09-18 1989-12-08 Roussel Uclaf NOVEL STEROIDS COMPRISING A 3, 4 OR 6-CHAIN SPIRANIC CYCLE IN POSITION 17, THEIR PROCESS AND PREPARATION INTERMEDIATES, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US4942236A (en) 1987-09-30 1990-07-17 American Home Products Corporation 2-aryl substituted pyridyl-containing phenyl sulfonamido compounds as antiallergic and antiinflammatory agents
US4826990A (en) 1987-09-30 1989-05-02 American Home Products Corporation 2-aryl substituted heterocyclic compounds as antiallergic and antiinflammatory agents
US4895953A (en) 1987-09-30 1990-01-23 American Home Products Corporation 2-Aryl substituted heterocyclic compounds as antiallergic and antiinflammatory agents
FR2621316B1 (en) 1987-10-02 1991-06-21 Nativelle Sa Ets NOVEL ANDROSTANE 17-CARBOXYLIC ACID ESTERS, PROCESS FOR THEIR PREPARATION, AND MEDICAMENTS CONTAINING THEM
US4927807A (en) 1987-10-06 1990-05-22 Abbott Laboratories Glaucoma treatment
US5346887A (en) 1987-10-06 1994-09-13 Abbott Laboratories Glaucoma treatment
US5654484A (en) 1987-10-08 1997-08-05 Merrell Pharmaceuticals Inc. Polyamine derivatives as antineoplastic agents
US4874855A (en) 1987-11-04 1989-10-17 Dainippon Ink And Chemicals, Inc. Steroid compounds and process of preparing the same
GB8726950D0 (en) 1987-11-18 1987-12-23 Boots Co Plc Chemical process
US5266562A (en) 1987-11-19 1993-11-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Anti-inflammatory agents
US5055466A (en) 1987-11-23 1991-10-08 E. R. Squibb & Sons, Inc. N-morpholino derivatives and their use as anti-hypertensive agents
US4847303A (en) 1987-11-23 1989-07-11 The Procter & Gamble Company Tert-butylphenyl compounds useful as anti-inflammatory agents
US4883872A (en) 1987-11-25 1989-11-28 E. R. Squibb & Sons, Inc. 3-oxo-1,2,4-triazolo(4,3-A) pyrimidine-6-carboxylic acid esters
US4847379A (en) 1987-11-30 1989-07-11 E. R. Squibb & Sons, Inc. 3,6-dihydro-1,5(2H)-pyrimidinecarboxylic acid esters
US4910192A (en) 1987-12-04 1990-03-20 Sri International Topically active steroidal anti-inflammatory agents
KR920000799B1 (en) 1987-12-11 1992-01-23 미쓰이 세끼유 가가꾸 고오교오 가부시끼가이샤 Novel amines and their use
US4870210A (en) 1987-12-18 1989-09-26 American Home Products Corporation Aminoguanidine derivative as anti-inflammatory agents
US4824831A (en) 1987-12-21 1989-04-25 E. R. Squibb & Sons, Inc. 4,5-dihydro-1H-benzazepine-3-carboxylic acid esters which are useful as anti-hypertensive agents
ES2052693T3 (en) 1987-12-23 1994-07-16 Roussel Uclaf MICROBIOLOGICAL PREPARATION OF 9-ALPHA-HYDROXY-17-CETO-STEROIDS.
JPH01294683A (en) 1988-02-04 1989-11-28 Kanebo Ltd Novel platinum complex, antitumor agent containing said complex as active ingredient and intermediate for preparing the same compound
US4889859A (en) 1988-02-05 1989-12-26 The Trustees Of Princeton University Pyrido[2,3-d]pyrimidine derivatives
GB8803259D0 (en) 1988-02-12 1988-03-09 Zambeletti Spa L Compounds
GB8803963D0 (en) 1988-02-19 1988-03-23 Pfizer Ltd Therapeutic agents
GB8804439D0 (en) 1988-02-25 1988-03-23 Pfizer Ltd Dihydropyridines
US5217958A (en) 1988-03-03 1993-06-08 E. R. Squibb & Sons, Inc. 1,2-hydroxy phosphonates and derivatives thereof
GB2216515A (en) 1988-03-04 1989-10-11 Nippon Shinyaku Co Ltd Acylphenol derivatives
US4900748A (en) 1988-03-04 1990-02-13 The United States Of America As Represented By The Department Of Health And Human Services Carbamates related to (-)-physostigmine as cholinergic agents
US4906634A (en) 1988-03-08 1990-03-06 Schering A.G. Novel N-[4-(aminosubstituted)phenyl]methanesulfonamides and their use as cardiovascular agents
US4835157A (en) 1988-03-15 1989-05-30 Ortho Pharmaceutical Corporation Thieno- and furopyrimidine-2,4-dione piperidine derivatives as serotonin antagonists and alpha adrenergic blocking agents
US4900552A (en) 1988-03-30 1990-02-13 Watson Laboratories, Inc. Mucoadhesive buccal dosage forms
US4981843A (en) 1988-04-07 1991-01-01 E. R. Squibb & Sons, Inc. N-heterocyclic alcohol derivatives
EP0336521B1 (en) 1988-04-08 1992-04-01 Roussel-Uclaf 9-alpha-hydroxy-17-methylene steroids, process for their preparation and their use in the preparation of corticosteroids
US5266684A (en) 1988-05-02 1993-11-30 The Reagents Of The University Of California Peptide mixtures
JPH01285247A (en) 1988-05-12 1989-11-16 Olympus Optical Co Ltd Medical capsule
US4868167A (en) 1988-05-20 1989-09-19 University Of Pittsburgh Novel peptidyl amino steroids
US4970318A (en) 1988-05-24 1990-11-13 Pfizer Inc. Aromatic and heterocyclic carboxamide derivatives as antineoplastic agents
US4882334A (en) 1988-05-25 1989-11-21 The Trustees Of Princeton University N-(5,6,7,8-tetrahydropyrido]2,3-d]pyrimidin-6-ylethl-thineyl-and furylcarbonyl)-glutamic acid derivatives
US5208250A (en) 1988-05-25 1993-05-04 Warner-Lambert Company Known and selected novel arylmethylenyl derivatives of thiazolidinones, imidazolidinones and oxazolidinones useful as antiallergy agents and anti-inflammatory agents
US4882333A (en) 1988-05-25 1989-11-21 The Trustess Of Princeton University N-(5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl-alkanoyl)-glutamic acid derivatives
US5306822A (en) 1988-05-25 1994-04-26 Warner-Lambert Company Arylmethylenyl derivatives of oxazolidinone
US4954446A (en) 1988-05-25 1990-09-04 Smithkline Beecham Corporation Aromatic steroid 5-α-reductase inhibitors
US5096892A (en) 1988-05-27 1992-03-17 The Children's Medical Center Corporation Arylsulfatase inhibition and potentiation of angiostatic steroids and heparin
US4871746A (en) 1988-05-31 1989-10-03 The Trustees Of Princeton University N-[N-(tetrahydropyrido[2,3-D]pyrimidinylmethyl)-aminomethylbenzoyl]glutamic acid derivatives as neoplastic growth inhibitors
US5002772A (en) 1988-05-31 1991-03-26 Pfizer Inc. Gastric retention system for controlled drug release
US4857644A (en) 1988-06-09 1989-08-15 American Home Products Corporation Aryl sulfonopiperazines as anti-inflammatory agents
US5273066A (en) 1988-06-10 1993-12-28 Graham Neil B Control valves and method of plant growing using flow control
CA1327838C (en) * 1988-06-13 1994-03-15 Fred Zacouto Implantable device to prevent blood clotting disorders
US4975230A (en) 1988-06-17 1990-12-04 Vapor Technologies Inc. Method of making an open pore structure
US5245332A (en) * 1988-06-22 1993-09-14 Iedsco Oy Programmable memory for an encoding system
US5290772A (en) 1988-06-29 1994-03-01 Merck & Co., Inc. Immunosuppressant agent
US4981792A (en) 1988-06-29 1991-01-01 Merck & Co., Inc. Immunosuppressant compound
JPH0211501A (en) 1988-06-30 1990-01-16 Chisso Corp Antimicrobial composition
ATE124416T1 (en) 1988-07-05 1995-07-15 Kuraray Co STEROID COMPOUNDS.
US5051423A (en) 1988-07-13 1991-09-24 Schering Ag Derivatized alkanolamines as cardiovascular agents
US4888335A (en) 1988-07-25 1989-12-19 Mcneilab, Inc. 3-alkoxy-2-aminopropyl heterocyclic amines and their use as cardiovascular agents
US5665752A (en) 1988-07-26 1997-09-09 Sankyo Company, Limited Use of imidazopyrazole derivatives as analgesics and anti-inflammatory agents
US5232939A (en) 1988-07-26 1993-08-03 Sankyo Company Limited Use of imidazopyrazole derivatives as analgesics and anti-inflammatory agents
US5354768A (en) 1988-07-26 1994-10-11 Sankyo Company, Limited Use of imidazopyrazole derivatives as analgesics and anti-inflammatory agents
US4977144A (en) 1988-08-02 1990-12-11 Ciba-Geigy Corporation Imidazo[4,5-b]pyridine derivatives as cardiovascular agents
US5175160A (en) 1988-08-09 1992-12-29 Daiichi Pharmaceutical Co., Ltd. Antimicrobial agent for animals
US5691346A (en) 1988-08-10 1997-11-25 The Australian National University Castanospermine as an anti-inflammatory and immunosuppressant agent
DE3828588C1 (en) 1988-08-23 1989-12-07 Alcatel Hochvakuumtechnik Gmbh, 6980 Wertheim, De
US4844076A (en) 1988-08-26 1989-07-04 The Johns Hopkins University Ingestible size continuously transmitting temperature monitoring pill
DE3829524A1 (en) 1988-08-31 1990-03-01 Behringwerke Ag USE OF TRANSGLUTAMINASES AS IMMUNE SUPPRESSIVA
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
JPH0635464B2 (en) 1988-09-02 1994-05-11 明治製菓株式会社 Novel cephem compound, its production method and antibacterial agent
US5073570A (en) 1988-09-14 1991-12-17 Lonza Inc. Mono-iodopropargyl esters of dicarboxylic anhydrides and their use as antimicrobial agents
US5185362A (en) 1988-09-14 1993-02-09 Mcneilab, Inc. Diphenylamine cardiovascular agents, compositions and use
EP0436020A4 (en) 1988-09-14 1992-03-25 Yoshitomi Pharmaceutical Industries, Ltd. Immunosuppressant
DE3832303A1 (en) 1988-09-20 1990-04-12 Schering Ag 11SS-PHENYL-14SSH STEROIDS
JPH02111766A (en) 1988-10-20 1990-04-24 Taiho Yakuhin Kogyo Kk Benzothiazepine derivative and salt thereof
US4882322A (en) 1988-10-27 1989-11-21 Merrell Dow Pharmaceuticals Inc. 3β,17β-hydroxy-substituted steroids and related steroidal compounds
US4959383A (en) 1988-10-31 1990-09-25 E. R. Squibb & Sons, Inc. Phenylsulfone alkenoic acids, derivatives thereof, compositions containing same and method of use
US5006542A (en) 1988-10-31 1991-04-09 E. R. Squibb & Sons, Inc. Arylthioalkylphenyl carboxylic acids, derivatives thereof, compositions containing same and method of use
US5371078A (en) 1988-10-31 1994-12-06 Alcon Laboratories, Inc. Angiostatic steroids and methods and compositions for controlling ocular hypertension
US5070099A (en) 1988-10-31 1991-12-03 E. R. Squibb & Sons, Inc. Arylthioalkylphenyl carboxylic acids, derivatives thereof, compositions containing same method of use
US4883811A (en) 1988-11-17 1989-11-28 Misra Raj N 7-Oxabicycloheptane imino interphenylene substituted prostaglandin analogs useful in the treatment of thrombotic disease
US5155122A (en) 1988-11-29 1992-10-13 Warner-Lambert Company 3,5-di-tertiary-butyl-4-hydroxyphenyl-1,3,4-thiadiazoles, and oxadiazoles and 3,5-di-tertiary-butyl-4-hydroxy-phenyl-1,2,4-thiadazoles, oxadiazoles and triazoles as antiinflammatory agents
US5256680A (en) 1988-11-29 1993-10-26 Warner-Lambert Company 3,5-di-tertiary-butyl-4-hydroxyphenyl-1,3,4-thiadiazoles, and oxadiazoles and 3,5-di-tertiary-butyl-4-hydroxy-phenyl-1,2,4-thiadazoles, oxadiazoles and triazoles as antiinflammatory agents
US4897397A (en) 1988-12-16 1990-01-30 Schering Corporation Aryl-alkynoic, alkenoic or alkanoic compounds and compositions useful as antiallergy and anti-inflammatory agents
US4946834A (en) 1988-12-23 1990-08-07 Smithkline Beecham Corporation Phosphonic acid substituted steroids as steroid 5α-reductase inhibitors
US4882319A (en) 1988-12-23 1989-11-21 Smithkline Beckman Corporation Phosphonic acid substituted aromatic steroids as inhibitors of steroid 5-α-reductase
US4937237A (en) 1988-12-23 1990-06-26 Smithkline Beckman Corporation Phosphinic acid substituted aromatic steroids as inhibitors of steroid 5-60 -reductase
US4970205A (en) 1988-12-23 1990-11-13 Smithkline Beecham Corporation Sulfonic acid substituted aromatic steroids as inhibitors of steroid 5-α-reductase
US5026882A (en) 1988-12-23 1991-06-25 Smithkline Beecham Corporation Phosphinic acid substituted steroids as inhibitors of steroid 5α-reductase
JPH02178263A (en) 1988-12-27 1990-07-11 Kaken Pharmaceut Co Ltd Azaazulene derivative, production thereof and anti-allergic and anti-inflammatory containing the derivative as active component
JPH02180265A (en) 1988-12-28 1990-07-13 Nippon Eranko Kk Charging device into capsule
US5013751A (en) 1989-01-10 1991-05-07 Alcon Laboratories, Inc. (+) Suprofen esters and amides as opthalmic anti-inflammatory agents
US4906655A (en) 1989-01-24 1990-03-06 Warner-Lambert Company Novel 1,2-cyclohexylaminoaryl amides useful as analgesic agents
JP2694361B2 (en) 1989-02-09 1997-12-24 アストラ アクチエボラグ Antibacterial agent
US5084281A (en) 1989-02-14 1992-01-28 Dillon Richard S Method and solution for treating tissue wounds
US4954526A (en) 1989-02-28 1990-09-04 The United States Of America As Represented By The Department Of Health And Human Services Stabilized nitric oxide - primary amine complexes useful as cardiovascular agents
US5540931A (en) 1989-03-03 1996-07-30 Charles W. Hewitt Methods for inducing site-specific immunosuppression and compositions of site specific immunosuppressants
US4981870A (en) 1989-03-07 1991-01-01 Pfizer Inc. Use of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine derivatives in the treatment of psychosis, inflammation and as immunosuppressants
SE466684B (en) 1989-03-07 1992-03-23 Draco Ab DEVICE INHALATOR AND PROCEDURE TO REGISTER WITH THE DEVICE INHALATOR MEDICATION
HU203562B (en) 1989-03-09 1991-08-28 Richter Gedeon Vegyeszet Process for producing new steroide diols and pharmaceutical compositions containing them
HU203769B (en) 1989-03-09 1991-09-30 Richter Gedeon Vegyeszet Process for producing new steroide derivatives and pharmaceutical compositions containing them
DE69015393T2 (en) 1989-03-15 1995-06-01 Merck & Co Inc Immunosuppressant.
FR2644789B1 (en) 1989-03-22 1995-02-03 Roussel Uclaf NOVEL 19-NOR, 3-CETO STEROIDS COMPRISING AN AMINOSUBSTITUTED 17-CHAIN, THEIR PREPARATION METHOD AND THE INTERMEDIATES THEREOF, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US4952692A (en) 1989-04-04 1990-08-28 E. R. Squibb & Sons, Inc. Benzazepine derivatives
DE58908945D1 (en) 1989-04-10 1995-03-09 Pacesetter Ab Implantable medical device with means for the telemetric transmission of data.
US5068323A (en) 1989-04-21 1991-11-26 Merck & Co., Inc. Thermally re-arranged FK-506 derivatives having immunosuppressant activity
IT1230145B (en) 1989-05-05 1991-10-14 Boehringer Biochemia Srl RUTHENIUM (III) COMPLEXES AS ANTINEOPLASTIC AGENTS.
CA2016517C (en) 1989-05-11 1999-01-12 Dale R. Shackle Solid state electrochemical cell having microroughened current collector
US4980385A (en) 1989-05-22 1990-12-25 Basf Corporation Polyurethane/polycarbonate compatibility
DE3917274A1 (en) 1989-05-24 1990-11-29 Schering Ag 9 (ALPHA) -HYDROXY-19, 11 (BETA) -BRIDGED STEROIDS, THEIR PRODUCTION AND THEIR PHARMACEUTICAL PREPARATIONS CONTAINING THEM
US4981865A (en) 1989-05-26 1991-01-01 Warner-Lambert Co. N-hydroxyamide, N-hydroxythioamide, hydroxyurea, and N-hydroxythiourea derivatives of selected nsaids as antiinflammatory agents
US5075330A (en) 1989-05-26 1991-12-24 Warner-Lambert Co. N-hydroxyamide, N-hydroxythioamide, N-hydroxyurea, and N-hydroxythiourea derivatives of selected NSAIDS as antiinflammatory agents
US5112846A (en) 1989-05-26 1992-05-12 Warner-Lambert Company N-hydroxyamide, N-hydroxythioamide, hydroxyurea, and N-hydroxythiourea derivatives of selected nsaids as antiinflammatory agents
US5140031A (en) 1989-05-31 1992-08-18 E. R. Squibb & Sons, Inc. Pyranyl cyanoguanidine derivatives
FI902771A0 (en) 1989-06-09 1990-06-04 Warner Lambert Co FOERFARANDE FOER FRAMSTAELLNING AV ANTIINFLAMMATORISKA 1,3,4-TIADIAZOLER OCH 1,3,4-OXADIAZOLER.
US5017578A (en) 1989-06-09 1991-05-21 Hoechst-Roussel Pharmaceuticals Inc. N-heteroaryl-purin-6-amines useful as analgesic and anticonvulsant agents
US5066668A (en) 1989-06-09 1991-11-19 Warner-Lambert Co. Triazole derivatives of fenamates as antiinflammatory agents
US4962119A (en) 1989-06-09 1990-10-09 Warner-Lambert Company Triazole derivatives of fenamates as antiinflammatory agents
US5104656A (en) 1989-06-16 1992-04-14 Seth Pyare L Percutaneous treatment with a high potency non-steroidal anti-inflammatory agent
US4931457B1 (en) 1989-06-28 1993-11-16 Hoechst-Roussel Pharmaceuticals Incorporated Naphthylamino-and naphthyloxy-pyridineamin compounds useful as topical antiinflammatory agents for the treatment of skin disorders
US4939137A (en) 1989-06-28 1990-07-03 Ortho Pharmaceutical Corporation Ring-fused thienopyrimidinedione derivatives
US5116867A (en) 1989-06-30 1992-05-26 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services D-propranolol as a selective adenosine antagonist
US5068247A (en) 1989-07-07 1991-11-26 Yoshitomi Pharmaceutical Industries, Ltd. 2-aminopentanoic acid compounds and their use as immunosuppressants
US5281287A (en) 1989-07-21 1994-01-25 Iomed, Inc. Method of making a hydratable bioelectrode
DE69008454T2 (en) 1989-08-07 1994-08-25 Takeda Chemical Industries Ltd Nitrolsothiol derivatives, their production and use.
US4904674A (en) 1989-08-16 1990-02-27 Hoechst-Roussel Pharmaceuticals Inc. 1-(Benzo[b]thienyl)-2-(thienyl)ethenes and related compounds useful as anti-inflammatory agents
US5032586A (en) 1989-08-24 1991-07-16 Smithkline Beecham Corporation 7-keto or hydroxy 3,5-diene steroids as inhibitors of steroid 5-alpha reductase
US5252745A (en) 1989-08-25 1993-10-12 Rohm And Haas Company Preparation and use of iodopropargyl esters of α-amino acid derivatives as antimicrobial agents
US4988710A (en) 1989-08-25 1991-01-29 Washington University Aryl-cycloalkyl-alkanolamines for treatment of cholinergic neurotoxins
US5077404A (en) 1989-08-29 1991-12-31 Piper James R Cyclized 5,10-dideazaaminopterin compounds
US5214068A (en) 1989-09-06 1993-05-25 Yale University Sulfonylhydrazines and their use as antineoplastic agents and as antitrypanosomal agents
US5101072A (en) 1989-09-06 1992-03-31 Yale University Sulfonylhydrazines and their use as antineoplastic agents and as antitrypanosomal agents
GB8920957D0 (en) 1989-09-15 1989-11-01 Hitech Metal Detectors Ltd Metal detecting apparatus and apparatus for testing metal detecting apparatus
US4966967A (en) 1989-09-15 1990-10-30 Berlex Laboratories, Inc. 3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonines as cardiovascular agents
US4987897A (en) * 1989-09-18 1991-01-29 Medtronic, Inc. Body bus medical device communication system
US4970226A (en) 1989-10-03 1990-11-13 Harbor Branch Oceanographic Institution, Inc. Bis-indole imidazole compounds which are useful antitumor and antimicrobial agents
US5071848A (en) 1989-10-23 1991-12-10 Abbott Laboratories Tricyclic quinoline antineoplastic agents
US5037835A (en) 1989-10-24 1991-08-06 Hoechst-Roussel Pharmaceuticals Inc. Benzocycloalkylaminopyridinamines and related compounds as topical antiinflammatory agents for the treatment of skin disorders
US4992448A (en) 1989-10-24 1991-02-12 Hoechst-Roussel Pharmaceuticals Inc. Benzocycloalkylaminopyridinamines and related compounds as topical antiinflammatory agents for the treatment of skin disorders
US4959378A (en) 1989-10-24 1990-09-25 Hoechst-Roussel Pharmaceuticals Inc. Aminopyridinylaminophenol compounds useful as topical antiinflammatory agents for the treatment of skin disorders
EP0425016B1 (en) 1989-10-27 1995-12-20 The Procter & Gamble Company Antimicrobial method and formulation employing type II endoglycosidase and antimicrobial agent
FR2653767B1 (en) 1989-10-30 1992-02-14 Lafon Labor 1- (AMINOPHENYL) -2-PIPERIDINOPROPANONE DERIVATIVES, PROCESS AND USE IN THERAPEUTICS.
US4988728A (en) 1989-11-03 1991-01-29 Alcon Laboratories, Inc. Suprofen esters and amides as ophthalmic anti-inflammatory agents
US5208228A (en) 1989-11-13 1993-05-04 Merck & Co., Inc. Aminomacrolides and derivatives having immunosuppressive activity
US5064837A (en) 1989-11-13 1991-11-12 Schering Corporation 3-substituted-1-aryl-2(h)-quinolones and their pharmaceutical compositions
US5215972A (en) 1989-11-22 1993-06-01 Hoffmann-La Roche Inc. Steroids
GB8926512D0 (en) 1989-11-23 1990-01-10 Pfizer Ltd Therapeutic agents
GB9024617D0 (en) 1989-12-05 1991-01-02 Ici Plc Heterocyclic compounds
US5028608A (en) 1989-12-11 1991-07-02 The Trustees Of Princeton University N-(6-Amino-(pyrrolo(2,3-d)pyrimidin-3-ylacyl) )-glutamic acid derivatives
US5110441A (en) 1989-12-14 1992-05-05 Monsanto Company Solid state ph sensor
US5491136A (en) 1989-12-20 1996-02-13 Merrell Dow Pharmaceuticals Inc. 2,19-methyleneoxy and 2,19-methylenethio bridged steroids as aromatase, 19-hydroxylaser inhibitors and methods of their use in the treatment of estrogen mediated disorders
US5099037A (en) 1989-12-20 1992-03-24 Merrell Dow Pharmaceuticals Inc. 2,19-methyleneoxy and 2,19-methylenethio bridged steroids as aromatase and 19-hydroxylase inhibitors
US5095037B1 (en) 1989-12-21 1995-12-19 Nissho Kk Combined anti-inflammatory agent
FR2656310B1 (en) 1989-12-22 1992-05-07 Roussel Uclaf NEW STEROUID PRODUCTS COMPRISING IN POSITION 10, A SUBSTITUTED THIOETHYL RADICAL, THEIR PREPARATION METHOD AND THE INTERMEDIATES THEREOF, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2656309B1 (en) 1989-12-22 1992-05-07 Roussel Uclaf NEW STEROUID PRODUCTS COMPRISING IN POSITION 10, A SUBSTITUTED ETHYL RADICAL, THEIR PREPARATION METHOD, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
DE4003410A1 (en) * 1990-02-05 1991-08-08 Anatoli Stobbe PORTABLE FIELD PROGRAMMABLE DETECTOR TAG
GB9003939D0 (en) 1990-02-21 1990-04-18 Imperial College Sulphatase inhibitors
FR2658516B1 (en) 1990-02-22 1992-06-12 Roussel Uclaf NEW STEROUID PRODUCTS COMPRISING A RADICAL SPIRO IN POSITION 17, THEIR PREPARATION METHOD AND THE INTERMEDIATES THEREOF, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US5064835A (en) 1990-03-01 1991-11-12 Merck & Co., Inc. Hydroxymacrolide derivatives having immunosuppressive activity
US5219879A (en) 1990-03-05 1993-06-15 Du Pont Merck Pharmaceutical Company Heterocyclic steroid compounds
US5306718A (en) 1990-03-06 1994-04-26 Warner-Lambert Company Oxime and amine substituted azabicyclo and azocyclo muscarinic agonists and methods of treatment
US5346911A (en) 1990-03-06 1994-09-13 Warner-Lambert Company Azabicyclo and azacyclo oxime and amine cholinergic agents and methods of treatment
AU7473791A (en) 1990-03-13 1991-10-10 Acic (Canada) Inc. Process for producing 2,2'-o-cyclonucleosides, nucleosides, and analogs thereof
US5360811A (en) 1990-03-13 1994-11-01 Hoechst-Roussel Pharmaceuticals Incorporated 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols and related compounds as anti-inflammatory agents
US5091430A (en) 1990-03-13 1992-02-25 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services O6 -substituted guanine compounds and methods for depleting O6 -alkylguanine-DNA alkyltransferase levels
US5079247A (en) 1990-03-14 1992-01-07 American Cyanamid Company N1 -substituted benz(cd)indol-2-imine compounds as cardiovascular agents
US5212172A (en) 1990-03-15 1993-05-18 Allergan, Inc. 4-(1-hydroxy-2-substituted amino)ethyl-5-hydroxy-2(5H)-furanones as anti-inflammatory agents
DE69130216T2 (en) 1990-03-16 1999-03-25 Beth Israel Hospital USE OF SPIPERON AS AN IMMUNE SUPPRESSIVE AND ANTI-INFLAMMATIVE
US5574041A (en) 1990-03-16 1996-11-12 Beth Israel Hospital Association Use of spiperone derivatives as immunosuppressant agents
US5223516A (en) 1990-03-22 1993-06-29 E. R. Squibb & Sons, Inc. 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same
US5081261A (en) 1990-03-23 1992-01-14 Allergan, Inc. 4-(1-hydroxy-2-N-substituted sulfonamido) ethyl-5-hydroxy-2(5H)-furanones and 4-(N-substituted sulfonamido)-2-ethenyl-5-hydroxy-2(5H)-furanones as anti-inflammatory agents
US5234939A (en) 1990-03-27 1993-08-10 Warner-Lambert Company 3,5-di-tertiary-butyl-4-hydroxyphenyl imidazolyl methanones and related compounds as antiinflammatory agents
US5086064A (en) 1990-03-27 1992-02-04 Warner-Lambert Company 3,5-di-tertiary-butyl-4-hydroxyphenyl thiazolyl, oxazolyl, and imidazolyl methanones and related compounds as antiinflammatory agents
US5234937A (en) 1990-03-27 1993-08-10 Warner-Lambert Company 3,5-di-tertiary-butyl-4-hydroxphenyl oxazolyl methanones and related compounds as antiinflammatory agents
US5143928A (en) 1990-03-27 1992-09-01 Warner-Lambert Company 3,5-di-tertiarybutyl-4-hydroxyphenylmethylene derivatives of 2-substituted thiazolidinones, oxazolidinones, and imidazolidinones as antiinflammatory agents
US5013850A (en) 1990-03-30 1991-05-07 Allergan, Inc. 4-ethyl and 4-ethenyl-5-hydroxy-2(5H)-furanones substituted on alpha carbon of the ethyl or ethenyl side chain with a long chain alkyl group and on the beta carbon with a polar group, as anti-inflammatory agents
US5061813A (en) 1990-04-02 1991-10-29 E. R. Squibb & Sons, Inc. Substituted cyanoimino benzopyranes
US5116829A (en) 1990-04-23 1992-05-26 Kao Corporation Steroid compounds
US5198449A (en) 1990-04-27 1993-03-30 A. H. Robins Company Incorporated N-substituted alpha-arylazacycloalkylmethanamines and their use as cardiovascular agents
ATE129013T1 (en) 1990-04-30 1995-10-15 Univ Texas STEROID 5-ALPHA REDUCTASE.
US5018813A (en) 1990-05-01 1991-05-28 Eastman Kodak Company Multichannel integrated optic modulator for laser printer
US5260444A (en) 1990-05-07 1993-11-09 Wakunaga Seiyaku Kabushiki Kaisha Dihydropyridine derivative
JPH0413679A (en) 1990-05-07 1992-01-17 Wakunaga Pharmaceut Co Ltd Novel dihydropyridine derivative
US5213738A (en) 1990-05-15 1993-05-25 L. Perrigo Company Method for making a capsule-shaped tablet
EP0458160A3 (en) 1990-05-25 1992-03-18 Sociedad Espanola De Especialidades Farmaco-Terapeuticas, S.A. Substituted diphenylmethane derivatives as analgesic or anti-inflammatory agents
US6359872B1 (en) 1997-10-28 2002-03-19 Intermec Ip Corp. Wireless personal local area network
US6749122B1 (en) 1990-05-25 2004-06-15 Broadcom Corporation Multi-level hierarchial radio-frequency system communication system
DE4017780A1 (en) 1990-06-01 1991-12-05 Sensoplan Messtechnik Gmbh Electronic metal component sensor device - uses component sensors providing sequential response signals upon component proximity
US5252319A (en) 1990-06-12 1993-10-12 Insite Vision Incorporated Aminosteroids for ophthalmic use
US5209926A (en) 1990-06-12 1993-05-11 Insite Vision Incorporated Aminosteroids for ophthalmic use
US5256408A (en) 1990-06-12 1993-10-26 Insite Vision Incorporated Aminosteroids for ophthalmic use
US5036070A (en) 1990-06-13 1991-07-30 American Home Products Corporation Polycyclic phenalkyl amines as psychotropic agents
DE4019024A1 (en) 1990-06-14 1991-12-19 Bayer Ag USE OF EFOMYCINES A, E AND G AS DEHUMIDIFYING AGENTS
US5189036A (en) 1990-06-20 1993-02-23 Schering Ag Imidazolylbenzoyl substituted heterocycles
US5192773A (en) 1990-07-02 1993-03-09 Vertex Pharmaceuticals, Inc. Immunosuppressive compounds
DE4021433A1 (en) 1990-07-04 1992-01-09 Schering Ag ANTIANDROGEN WITH STEROID (3,2-C) PYRAZOLE STRUCTURE
US5073560A (en) 1990-07-20 1991-12-17 Fisons Corporation Spiro-isoxazolidine derivatives as cholinergic agents
US5211937A (en) 1990-07-30 1993-05-18 Glycomed Incorporated Method of determining a site of inflammation utilizing elam-1 ligands
JPH04364160A (en) 1990-08-03 1992-12-16 Terumo Corp Thiourea derivative, and antibacterial agent and anti-ulcer agent containing the same
US5124455A (en) 1990-08-08 1992-06-23 American Home Products Corporation Oxime-carbamates and oxime-carbonates as bronchodilators and anti-inflammatory agents
US5399553A (en) 1990-08-09 1995-03-21 Wakunaga Seiyaku Kabushiki Kaisha Tricyclic compound or salts thereof, method for producing the same and anti-microbial agent containing the same
KR920004385A (en) 1990-08-09 1992-03-27 와꾸나가 기스께 New tricyclic compounds or salts thereof, preparation method thereof and antimicrobial agent containing same
US5302592A (en) 1990-08-17 1994-04-12 Rohm And Haas Company Use of substituted 3-thioacryloyl compounds as antimicrobial agents
US5308837A (en) 1990-08-22 1994-05-03 Merrell Dow Pharmaceuticals Inc. 5'-amine substituted adenosine analogs as immunosuppressants
US5318965A (en) 1990-08-24 1994-06-07 Abbott Laboratories Quinobenzoxazine, antineoplastic agents
US5059602A (en) 1990-08-27 1991-10-22 Hoechst-Roussel Pharmaceuticals Inc. 4-substituted dihydropyrido(4,3-d)pyrimidines as analgesics and topical antiinflammatory agents for the treatment of skin disorders
US5095019A (en) 1990-08-27 1992-03-10 Hoechst-Roussel Pharmaceuticals Inc. 4-substituted dihydropyrido(4,3-D)pyrimidines as analgesics and topical antiinflammatory agents for the treatment of skin disorders
US5091528A (en) 1990-09-12 1992-02-25 Allergan, Inc. 6- or 7- (2-imino-2-imidazolidine)-1,4-benzoxazines as α adrenergic agents
US5244896A (en) 1990-09-14 1993-09-14 Marion Merrell Dow Inc. Carbocyclic adenosine analogs useful as immunosuppressants
US5470857A (en) 1990-09-14 1995-11-28 Marion Merrell Dow Inc. Carbocyclic nucleoside analogs useful as immunosuppressants
US5514688A (en) 1990-09-14 1996-05-07 Merrell Dow Pharmaceuticals Inc. Carbocyclic adenosine analogs useful as immunosuppressants
US5096700A (en) 1990-09-28 1992-03-17 The Procter & Gamble Company Halogenated aminohexanoates and aminobutyrates antimicrobial agents
US5167626A (en) 1990-10-02 1992-12-01 Glaxo Inc. Medical capsule device actuated by radio-frequency (RF) signal
US5216165A (en) 1990-10-03 1993-06-01 American Home Products Corporation N-substituted aminoquinolines as analgesic agents
JPH0764841B2 (en) 1990-10-03 1995-07-12 ファイザー製薬株式会社 Indole derivative and its use
US5143918A (en) 1990-10-11 1992-09-01 Merck & Co., Inc. Halomacrolides and derivatives having immunosuppressive activity
DE4033415A1 (en) 1990-10-20 1992-04-23 Bayer Ag ANTIMICROBIAL AGENTS AND SUBSTITUTED 2-CYCLOHEXAN-1-YL-AMINE DERIVATIVES AND THE PRODUCTION THEREOF
DE4038128A1 (en) 1990-11-27 1992-06-04 Schering Ag 8-EN-19, 11 (BETA) BRIDGED STEROIDS, THEIR PRODUCTION AND THEIR PHARMACEUTICAL PREPARATIONS CONTAINING THEM
US5166201A (en) 1990-11-30 1992-11-24 Merrell Dow Pharmaceuticals Inc. 2β,19-ethylene bridged steroids as aromatase inhibitors
US5126488A (en) 1990-11-30 1992-06-30 Merrell Dow Pharmaceuticals Inc. 2β,19-methyleneamino bridged steroids as aromatase inhibitors
EP0561948B1 (en) 1990-12-07 1995-04-05 The Upjohn Company Phosphonic acid derivatives useful as antiinflammatory agents
US5209930A (en) 1990-12-10 1993-05-11 Rohm And Haas Company Preparation and use of n-iodopropargyl oxycarbonyl amino acid esters and derivatives as antimicrobial agents
US5883087A (en) 1991-01-07 1999-03-16 Pherin Corporation Androstane steroids as neurochemical initiators of change in human hypothalamic function and related pharmaceutical compositions and methods
JP2528741B2 (en) 1991-01-09 1996-08-28 ファイザー製薬株式会社 Oxazole, thiazole and imidazole compounds
US5319099A (en) 1991-01-21 1994-06-07 Shionogi Seiyaku Kabushiki Kaisha 3-benzylidene-1-carbamoyl-2-pyrrolidone compounds useful as antiinflammatory agents
US5177079A (en) 1991-01-31 1993-01-05 Warner-Lambert Company 2-substituted-4,6-di-tertiarybutyl-5-hydroxy-1,3-pyrimidines useful as antiinflammatory agents
US5356898A (en) 1991-01-31 1994-10-18 Warner-Lambert Company Substituted 4,6-di-tertiary-butyl 5-hydroxy-pyrimidines
US5248682A (en) 1991-01-31 1993-09-28 Warner-Lambert Company 2-substituted-4,6-di-tertiary-butyl-5-hydroxy-1,3-pyrimidines useful as antiinflammatory agents
US5888995A (en) 1991-02-04 1999-03-30 Astra Aktiebolag Steroid esters
SE9100341D0 (en) 1991-02-04 1991-02-04 Astra Ab NOVEL STEROIDS
SE9100342D0 (en) 1991-02-04 1991-02-04 Astra Ab NOVEL STEROID ESTERS
US5679640A (en) 1991-02-12 1997-10-21 Cytel Corporation Immunosuppressant peptides
IT1250410B (en) 1991-02-14 1995-04-07 Simes STEROID COMPOUNDS ACTIVE ON THE CARDIOVASCULAR SYSTEM
EP0530368A4 (en) 1991-02-28 1994-08-24 Fujisawa Pharmaceutical Co Process for producing tricyclic compound or salt thereof
US5856364A (en) 1991-03-01 1999-01-05 Warner Lambert Company Therapeutic antiviral-wound healing compositions and methods for preparing and using same
US5614561A (en) 1991-03-01 1997-03-25 Warner-Lambert Company Antihistamine-wound healing compositions and methods for preparing and using same
US5863938A (en) 1991-03-01 1999-01-26 Warner Lambert Company Antibacterial-wound healing compositions and methods for preparing and using same
US5646190A (en) 1991-03-01 1997-07-08 Warner-Lambert Company Acne treating-wound healing compositions and methods for preparing and using same
US5658957A (en) 1991-03-01 1997-08-19 Warner Lambert Company Immunostimulating wound healing compositions and method for preparing and using same
US5652274A (en) 1991-03-01 1997-07-29 Martin; Alain Therapeutic-wound healing compositions and methods for preparing and using same
US5641814A (en) 1991-03-01 1997-06-24 Warner-Lambert Company Antikeratolytic-wound healing compositions and methods for preparing and using same
US5674912A (en) 1991-03-01 1997-10-07 Warner-Lambert Company Sunscreen-wound healing compositions and methods for preparing and using same
US5663208A (en) 1991-03-01 1997-09-02 Warner-Lambert Company Antifungal wound healing compositions and methods for preparing and using same
US5633285A (en) 1991-03-01 1997-05-27 Warner-Lambert Company Cytoprotective wound healing compositions and methods for preparing and using same
US5874479A (en) 1991-03-01 1999-02-23 Warner-Lambert Company Therapeutic permeation enhanced-wound healing compositions and methods for preparing and using same
US5602183A (en) 1991-03-01 1997-02-11 Warner-Lambert Company Dermatological wound healing compositions and methods for preparing and using same
US5648380A (en) 1991-03-01 1997-07-15 Warner-Lambert Company Anti-inflammatory wound healing compositions and methods for preparing and using same
ATE116546T1 (en) 1991-03-07 1995-01-15 Kanto Ishi Pharma Co Ltd COLOMIC ACID AND PRODUCTS OF PARTIAL HYDROLYSIS OF COLOMIC ACID FOR THE PRODUCTION OF MEDICINAL PRODUCTS FOR THE TREATMENT OF HEPATITIS, NEPHRITIS AND ARTHRITIS.
DE69220397T2 (en) 1991-03-13 1997-10-02 Morinaga Milk Industry Co Ltd Antimicrobial peptide and antimicrobial agent
GB9107043D0 (en) 1991-04-04 1991-05-22 Pfizer Ltd Therapeutic agents
US5147877A (en) 1991-04-18 1992-09-15 Merck & Co. Inc. Semi-synthetic immunosuppressive macrolides
CA2107479C (en) 1991-04-22 1997-12-16 Makoto Inoue Pyrazolo[1,5-a]pyrimidine derivatives and anti-inflammatory agent containing the same
US5091389A (en) 1991-04-23 1992-02-25 Merck & Co., Inc. Lipophilic macrolide useful as an immunosuppressant
US5093338A (en) 1991-04-23 1992-03-03 Merck & Co., Inc. Lipophilic macrolide useful as an immunosuppressant
DK0510912T3 (en) 1991-04-24 1998-02-09 Morinaga Milk Industry Co Ltd Antimicrobial peptide and antimicrobial agent
US5223503A (en) 1991-04-29 1993-06-29 Eli Lilly And Company 6-substituted pyrido[2,3-d]pyrimidines as antineoplastic agents
US5225571A (en) 1991-04-30 1993-07-06 Allergan, Inc. Substituted dihydroxy-bis-[5-hydroxy-2(5H)-furanone-4-yl]-alkanes as anti-inflammatory agents
US5183906A (en) 1991-04-30 1993-02-02 Allergan, Inc. 2- and 5-alkyl and phenyl substituted 4-(1-hydroxy, 1-acyloxy or 1-carbamoyloxy)-5-hydroxy-2 (5h)-furanones as anti-inflammatory agents
US5250700A (en) 1991-05-01 1993-10-05 American Home Products Corporation Phenyl pyrazolidinones as bronchodilators and anti-inflammatory agents
US5191084A (en) 1991-05-01 1993-03-02 American Home Products Corporation Phenyl pyrazolidinones as bronchodilators and anti-inflammatory agents
US5138051A (en) 1991-08-07 1992-08-11 American Home Products Corporation Rapamycin analogs as immunosuppressants and antifungals
US5250552A (en) 1991-05-09 1993-10-05 Warner-Lambert Company 3-[thiazolidinone, oxazolidinone, imidazolidinone]-indoles as antiinflammatory agents
US5143927A (en) 1991-05-09 1992-09-01 Warner-Lambert Company 3-(thiazolidone, oxazolidinone, imidazolidinone)-indoles as antiinflammatory agents
US5114958A (en) 1991-05-09 1992-05-19 Warner-Lambert Company 1,2,4-oxadiazole and 1,2,4-thiadiazole derivatives of fenamates as antiinflammatory agents
US5143929A (en) 1991-05-09 1992-09-01 Warner-Lambert Company 2-substituted thiazolidinone, oxazolidinone, and imidazolidinone derivatives of fenamates as antiinflammatory agents
US5162334A (en) 1991-05-13 1992-11-10 Merck & Co., Inc. Amino O-alkyl, O-alkenyl and O-alkynlmacrolides having immunosuppressive activity
US5250678A (en) 1991-05-13 1993-10-05 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity
US5262533A (en) 1991-05-13 1993-11-16 Merck & Co., Inc. Amino O-aryl macrolides having immunosuppressive activity
US5565560A (en) 1991-05-13 1996-10-15 Merck & Co., Inc. O-Aryl,O-alkyl,O-alkenyl and O-alkynylmacrolides having immunosuppressive activity
IT1259419B (en) 1991-05-24 1996-03-18 Erba Carlo Spa 3-CARBOSE STEROIDS 17B - UNSATURATED SUBSTITUTES USEFUL AS INHIBITORS OF TESTOSTERONE 5 IN REDUCTASE
US5395366A (en) 1991-05-30 1995-03-07 The State University Of New York Sampling capsule and process
US5279607A (en) * 1991-05-30 1994-01-18 The State University Of New York Telemetry capsule and process
WO1992021341A1 (en) 1991-05-31 1992-12-10 Pfizer Inc. Use of rapamycin prodrugs as immunosuppressant agents
AU657554B2 (en) 1991-06-19 1995-03-16 Pharmacia & Upjohn Company Dialkyl (dialkoxyphosphinyl)methyl phosphates as anti-inflammatory agents
JPH057097A (en) 1991-06-27 1993-01-14 Tenryu Technic:Kk Chip comopomnent feeding device for chip mounter
EP0526166A2 (en) 1991-07-29 1993-02-03 Albert L. Dessertine Patient compliance monitoring method and system
US5124347A (en) 1991-07-31 1992-06-23 Warner-Lambert Co. 3-5-ditertiarybutylphenyl-4-hydroxymethylidene derivatives of 1,3-dihydro-2H-indole-2-ones as antiinflammatory agents
US5273979A (en) 1991-08-01 1993-12-28 Merck & Co., Inc. C-31 desmethyl FR-900520 cyclic hemiketal immunosuppressant agent
US5149701A (en) 1991-08-01 1992-09-22 Merck & Co., Inc. C-31 methylated FR-900520 cyclic hemiketal immunosuppressant agents
US5202332A (en) 1991-08-07 1993-04-13 American Home Products Corporation Rapamycin analog as immunosuppressant
US5169851A (en) 1991-08-07 1992-12-08 American Home Products Corporation Rapamycin analog as immunosuppressants and antifungals
US5189042A (en) 1991-08-22 1993-02-23 Merck & Co. Inc. Fluoromacrolides having immunosuppressive activity
GB9118478D0 (en) 1991-08-29 1991-10-16 Imperial College Steroid sulphatase inhibitors
GB9118465D0 (en) 1991-08-29 1991-10-16 Imperial College Steroid sulphatase inhibitors
US5597831A (en) 1991-08-29 1997-01-28 Vufb A.S 6-[X-(2-hydroxyethyl) aminoalkyl]-5,11-dioxo-5,6-dihydro-11-H-indeno[1,2-c]isoquinolines and their use as antineoplastic agents
US5202350A (en) 1991-08-29 1993-04-13 Bristol-Myers Squibb Co. Furanone anti-inflammatory agents
US5169963A (en) 1991-08-30 1992-12-08 Allergan, Inc. Di-(5-hydroxy-2(5H)2-oxo-4-furyl)alkylmethyl-alpha,omega alkanedioates and N,N-bis-(5-hydroxy-2(5H)2-oxo-4-furyl)alkylmethyl-alpha,omega-dialkanoic acid amides as anti-inflammatory agents
US5171864A (en) 1991-08-30 1992-12-15 Allergan, Inc. Di-(5-hydroxy-2(5H)-2-oxo-4-furyl)methyl-alpha,omega alkane-dioates and N,N-bis-(5-hydroxy-2(5H)-2-oxo-4-furyl)methyl-alpha,omega-dialkanoic acid amides as anti-inflammatory agents
US5247076A (en) 1991-09-09 1993-09-21 Merck & Co., Inc. Imidazolidyl macrolides having immunosuppressive activity
US5208241A (en) 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
US5270319A (en) 1991-09-09 1993-12-14 Warner-Lambert Company 5-hydroxy-2-pyrimidinylmethylene derivatives useful as antiinflammatory agents
US5252732A (en) 1991-09-09 1993-10-12 Merck & Co., Inc. D-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity
US5639603A (en) 1991-09-18 1997-06-17 Affymax Technologies N.V. Synthesizing and screening molecular diversity
ATE148889T1 (en) 1991-09-18 1997-02-15 Affymax Tech Nv METHOD FOR SYNTHESIS OF VARIOUS COLLECTIONS OF OLIGOMERS
AU667318B2 (en) 1991-09-26 1996-03-21 United States Of America, Represented By The Secretary, Department Of Health And Human Services, The Carbamate analogs of thiaphysovenine, pharmaceutical compositions, and method for inhibiting cholinesterases
WO1993008191A1 (en) 1991-10-15 1993-04-29 Warner-Lambert Company Azabicyclo oxime and amine cholinergic agents and methods of treatment
US5280045A (en) 1991-10-16 1994-01-18 The Procter & Gamble Company 4(3,5-bis(1,1-dimethylethyl-4-hydroxyphenyl)-4-oxobutanamide compound useful as an anti-inflammatory agent
US5266567A (en) 1991-10-24 1993-11-30 Rohm And Haas Company Halopropargylated cyclic quaternary ammonium compounds as antimicrobial agents
US5151413A (en) 1991-11-06 1992-09-29 American Home Products Corporation Rapamycin acetals as immunosuppressant and antifungal agents
GB9123638D0 (en) 1991-11-07 1992-01-02 Magill Alan R Apparel & fabric & devices suitable for health monitoring applications
US5817672A (en) 1991-12-06 1998-10-06 Hoechst Marion Roussel, Inc. Trans cyclopentanyl purine analogs useful as immunosuppressants
US5723466A (en) 1991-12-06 1998-03-03 Hoechst Marion Roussel, Inc. Trans cyclopentanyl purine analogs useful as immunosuppressants
US5817661A (en) 1991-12-06 1998-10-06 Hoechst Marion Roussel, Inc. Trans cyclopentanyl purine analogs useful as immunosuppressants
US5817660A (en) 1991-12-06 1998-10-06 Hoechst Marion Roussel, Inc. Trans cyclopentanyl purine analogs useful as immunosuppressants
US5472973A (en) 1991-12-12 1995-12-05 Scios Nova Inc. Fluorenyl derivatives as anti-inflammatory agents
US5338837A (en) 1991-12-13 1994-08-16 The Trustees Of Princeton University Glycosylated steroid derivatives for transport across biological membranes and process for making same
ZA929008B (en) 1991-12-13 1993-05-21 Bristol Myers Squibb Co Piperazinyl- and piperidinyl-cyclohexanols.
US5225418A (en) 1991-12-17 1993-07-06 Du Pont Merck Pharmaceutical Company 5H-(1,2)benzisothiazolo[2,3-a]quinoline-5-ones and analogs as antiinflammatory agents
JP3802555B2 (en) 1991-12-17 2006-07-26 フイズ テクノロジーズ リミテッド Ulcer prevention and treatment composition and method
US5212189A (en) 1991-12-17 1993-05-18 Warner-Lambert Company Thiadiazole or oxadiazole analogs of fenamic acids containing substituted hydroxamate side chains as antiinflammatory agents
ZA929315B (en) 1991-12-20 1993-05-24 Akzo Nv 17-spirofuran-3'-ylidene steroids.
US5206415A (en) 1991-12-20 1993-04-27 Washington University Tricyclic steroid analogs
US5438064A (en) 1991-12-23 1995-08-01 American Home Products Corporation Derivatives of 4-anilinoquinoline-3-carboxamide as analgesic agents
US5238689A (en) 1992-01-07 1993-08-24 Procept, Inc. Use of ruthenium red as immunosuppressive agents
US5176626A (en) 1992-01-15 1993-01-05 Wilson-Cook Medical, Inc. Indwelling stent
DK0629347T3 (en) 1992-01-23 1998-02-16 Morinaga Milk Industry Co Ltd Antibacterial agent and treatment of objects therewith
US5378848A (en) 1992-02-12 1995-01-03 Shionogi & Co., Ltd. Condensed imidazopyridine derivatives
JP2746041B2 (en) 1992-02-14 1998-04-28 三菱化学株式会社 New steroid derivatives
US5196431A (en) 1992-02-24 1993-03-23 Warner-Lambert Company 2-substituted amino-4, 6-di-tertiary-buthyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents
US5220025A (en) 1992-02-24 1993-06-15 Warner-Lambert Company 2-substituted amino-4, 6-di-tertiary-butyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents
JPH05228128A (en) 1992-02-25 1993-09-07 Olympus Optical Co Ltd Capsule for medical treatment
FR2688004A1 (en) 1992-02-27 1993-09-03 Roussel Uclaf NOVEL STEROUIDS COMPRISING IN POSITION 17 A RADICAL METHYLENE LACTONE, THEIR PROCESS AND PREPARATION INTERMEDIATES, THEIR APPLICATION AS MEDICAMENTS.
ATE205496T1 (en) 1992-03-02 2001-09-15 Pfizer DESOSAMINO DERIVATIVES OF MACROLIDS AS IMMUNOSUPPRESSIVE AND ANTIFUNGAL AGENTS
US5776427A (en) 1992-03-05 1998-07-07 Board Of Regents, The University Of Texas System Methods for targeting the vasculature of solid tumors
US5965132A (en) 1992-03-05 1999-10-12 Board Of Regents, The University Of Texas System Methods and compositions for targeting the vasculature of solid tumors
US6004554A (en) 1992-03-05 1999-12-21 Board Of Regents, The University Of Texas System Methods for targeting the vasculature of solid tumors
US5157051A (en) 1992-03-05 1992-10-20 The Dow Chemical Company Composition and use of 3-thiocyano-2-halo-2-propenenitriles as antimicrobial agents
US5187175A (en) 1992-03-06 1993-02-16 Warner-Lambert Company 2-carbonyl substituted-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents
US5196424A (en) 1992-03-24 1993-03-23 Eli Lilly And Company N-[2-amino-4-substituted[[(pyrrollo or pyrido)[2,3-d]pyrimidinyl]-alkyl]benzoyl]-L-glutamic acids
US5389675A (en) 1992-03-27 1995-02-14 The United States Of America As Represented By The Department Of Health And Human Services Mixed ligand metal complexes of nitric oxide-nucleophile adducts useful as cardiovascular agents
US5604213A (en) 1992-03-31 1997-02-18 British Technology Group Limited 17-substituted steroids useful in cancer treatment
ATE197761T1 (en) 1992-04-03 2000-12-15 Micromedical Ind Ltd ARRANGEMENT FOR MONITORING PHYSIOLOGICAL PARAMETERS
CA2091194A1 (en) 1992-04-08 1993-10-09 Richard D. Connell 2-oxo-ethyl derivatives as immunosuppressants
WO1993021186A1 (en) 1992-04-13 1993-10-28 Fujisawa Pharmaceutical Co., Ltd. Substituted 3-pyrrolidinylthio-carbapenems as antimicrobial agents
ES2105108T3 (en) 1992-04-20 1997-10-16 Sankyo Co STEROIDS FOR THE TREATMENT OF PROSTATIC HYPERTROPHY, ITS PREPARATION AND ITS USE.
US5698720A (en) 1992-04-20 1997-12-16 Sankyo Company, Limited Steroid derivatives
US5256664A (en) 1992-04-28 1993-10-26 Bristol-Myers Squibb Company Antidepressant 3-halophenylpiperazinylpropyl derivatives of substituted triazolones and triazoldiones
US5541061A (en) 1992-04-29 1996-07-30 Affymax Technologies N.V. Methods for screening factorial chemical libraries
US5552397A (en) 1992-05-18 1996-09-03 E. R. Squibb & Sons, Inc. Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase
US5263481A (en) 1992-05-21 1993-11-23 Jens Axelgaard Electrode system with disposable gel
GB9210880D0 (en) 1992-05-21 1992-07-08 Smithkline Beecham Corp Compounds
US5346913A (en) 1992-05-26 1994-09-13 Rohm And Haas Company N-iodopropargyl hydantoin compounds, compositions, preparation, and use as antimicrobial agents
US5244917A (en) 1992-06-02 1993-09-14 The Dupont Merck Pharmaceutical Company Substituted naphthofurans as anti-inflammatory agents
US5283136A (en) 1992-06-03 1994-02-01 Ramot University Authority For Applied Research And Industrial Development Ltd. Rechargeable batteries
FR2691968B1 (en) 1992-06-04 1994-07-29 Roussel Uclaf NEW PROCESS FOR THE PREPARATION OF A 11-CETO STEROUID DERIVATIVE.
HU212308B (en) 1992-06-09 1996-05-28 Richter Gedeon Vegyeszet Process for producing novel pregnane steroids and pharmaceutical compositions containing the same
US5284877A (en) 1992-06-12 1994-02-08 Merck & Co., Inc. Alkyl and alkenyl macrolides having immunosuppressive activity
US5284840A (en) 1992-06-12 1994-02-08 Merck & Co., Inc. Alkylidene macrolides having immunosuppressive activity
AU675651B2 (en) 1992-06-23 1997-02-13 Zaidan Hojin Biseibutsu Kagaku Kenkyukai Novel antibiotics with immunosuppressive activity, delaminomycins, and production thereof
WO1994000478A1 (en) 1992-06-26 1994-01-06 Pfizer Inc. Steroidal beta-o-cellobioside heptaalkanoate process
US5318557A (en) 1992-07-13 1994-06-07 Elan Medical Technologies Limited Medication administering device
US5338753A (en) 1992-07-14 1994-08-16 Sumner H. Burstein (3R,4R)-Δ6 -tetrahydrocannabinol-7-oic acids useful as antiinflammatory agents and analgesics
US5261402A (en) 1992-07-20 1993-11-16 Graphic Controls Corporation Snapless, tabless, disposable medical electrode with low profile
CA2100514C (en) 1992-07-29 2005-03-29 Johannes A. M. Hamersma 17-spiromethylene steroids
US5338625A (en) 1992-07-29 1994-08-16 Martin Marietta Energy Systems, Inc. Thin film battery and method for making same
WO1994003480A1 (en) 1992-07-31 1994-02-17 Pfizer Inc. Peptidyl 4-amino-2,2-difluoro-3-oxo-1,6-hexanedioic acid derivatives as antiinflammatory agents
US5240929A (en) 1992-08-03 1993-08-31 Warner-Lambert Company 2-heterocyclic-5-hydroxy-1,3-pyrimidines useful as antiinflammatory agents
US7758503B2 (en) 1997-01-27 2010-07-20 Lynn Lawrence A Microprocessor system for the analysis of physiologic and financial datasets
US5288514A (en) 1992-09-14 1994-02-22 The Regents Of The University Of California Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support
WO1994007501A1 (en) 1992-09-23 1994-04-14 The Upjohn Company Arylmethylphosphonates and phosphonic acids useful as anti-inflammatory agents
US5288564A (en) 1992-09-30 1994-02-22 Magnavox Electronic Systems Company Compact, cylindrical, multi-cell seawater battery
US5721099A (en) 1992-10-01 1998-02-24 Trustees Of Columbia University In The City Of New York Complex combinatorial chemical libraries encoded with tags
US5565324A (en) 1992-10-01 1996-10-15 The Trustees Of Columbia University In The City Of New York Complex combinatorial chemical libraries encoded with tags
JP2711202B2 (en) 1992-10-06 1998-02-10 東洋製薬株式会社 Staphylococcal antibacterial agent
PT619730E (en) 1992-10-08 2001-04-30 Supratek Pharma Inc COMPOSITION OF ANTI-NEOPLASTIC AGENTS INCORPORATED IN MICELAS
GB9221220D0 (en) 1992-10-09 1992-11-25 Sandoz Ag Organic componds
DK0627406T3 (en) 1992-10-21 1999-07-12 Taito Co 2-Amino-1,3-propanediol compounds and immunosuppressants
US5843452A (en) 1992-11-09 1998-12-01 Pharmagenesis, Inc. Immunotherapy composition and method
ES2058024B1 (en) 1992-11-10 1995-05-01 Menarini Lab NEW ARILPROPIONIC DERIVATIVE, MANUFACTURING PROCEDURE OF THE SAME AND ITS USE AS AN ANALGESIC.
US5561124A (en) 1992-11-18 1996-10-01 Webb; Robert L. 17-α-acyl steroids which inhibit 5-α-reductase
US5260300A (en) 1992-11-19 1993-11-09 American Home Products Corporation Rapamycin carbonate esters as immuno-suppressant agents
JP2738486B2 (en) 1992-11-20 1998-04-08 ファイザー製薬株式会社 New isoxazolines as anti-inflammatory agents
CA2146549C (en) 1992-12-01 2005-01-04 Karl F. Roenigk Durable antimicrobial agents
DK148292D0 (en) 1992-12-09 1992-12-09 Lundbeck & Co As H RELATIONS
FR2699176B1 (en) 1992-12-11 1995-03-03 Adir New bicyclic pyrimidine compounds, process for their preparation and pharmaceutical compositions containing them.
IL108031A0 (en) 1992-12-22 1994-04-12 Procter & Gamble Difluoro pentapeptide derivatives and pharmaceutical compositions containing them
GB9226830D0 (en) 1992-12-23 1993-02-17 Celltech Ltd Chemical compounds
US5693645A (en) 1992-12-23 1997-12-02 Beth Israel Deaconess Medical Center, Inc. Use of spiperone or spiperone derivatives as immunosuppressant agents
US5506221A (en) 1992-12-24 1996-04-09 University Of British Columbia Contignasterol, and related 3-alpha hydroxy-6-alpha hydroxy-7-beta hydroxy-15-keto-14-beta steroids useful as anti-inflammatory and anti-thrombosis agents
FR2700339B1 (en) 1993-01-14 1995-03-03 Roussel Uclaf New 17,20-epoxide derivatives of pregnane, their preparation, their application to the preparation of cortisonic and intermediate derivatives.
US5298522A (en) 1993-01-22 1994-03-29 Pfizer Inc. 6-chloro-5-fluoro-3-(2-thenoyl)-2-oxindole-1-carboxamide as an analgesic and anti-inflammatory agent while maintaining a normal urine protein/creatinine ratio
DE69317399T2 (en) 1993-01-29 1998-07-02 American Cyanamid Co Aminocycloalkanobenzodioxole as beta-3 selective adrenergic agents
US5424301A (en) 1993-02-01 1995-06-13 Warner-Lambert Company Starch stabilized o-substituted tetrahydropyridine oxime cholinergic agents
US5710144A (en) 1993-02-08 1998-01-20 Akzo Nobel N.V. C-11 substituted steroids for treating menopausal complaints
US5686469A (en) 1993-02-09 1997-11-11 Miles Inc. Aminomethylene derivaties as immunosuppressants
US5385918A (en) 1993-02-09 1995-01-31 Miles Inc. Aminomethylene-peptides as immunosuppressants
DK0610744T3 (en) 1993-02-09 1999-07-19 Bayer Ag Sulfonamidaminomethylene derivatives as immunosuppressants
CA2155664C (en) 1993-02-09 1999-06-15 Ralph P. Robinson Oxindole 1-[n-(alkoxycarbonyl)]carboxamides and 1-(n-carboxamido)carboxamides as antiinflammatory agents
JP3525221B2 (en) 1993-02-17 2004-05-10 味の素株式会社 Immunosuppressants
CA2090171A1 (en) 1993-02-23 1994-08-24 Peter W. Schiller Opioid receptor antagonists, their synthesis and use as analgesic and immunosuppressive compounds
US5463181A (en) 1993-02-23 1995-10-31 Merrell Dow Pharmaceuticals Inc. Farnesyl: protein transferase inhibitors as anticancer agents
WO1994019357A1 (en) 1993-02-23 1994-09-01 Merrell Dow Pharmaceuticals Inc. Farnesyl:protein transferase inhibitors as anticancer agents
US5292736A (en) 1993-02-26 1994-03-08 Sterling Winthrop Inc. Morpholinoalkylindenes as antiglaucoma agents
US5914132A (en) * 1993-02-26 1999-06-22 The Procter & Gamble Company Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery
CA2116621C (en) 1993-03-03 2001-07-24 Rene C. Gaudreault Novel anticancer agents
US5391544A (en) 1993-03-04 1995-02-21 Kagome Kabushiki Kaisha Cyathane derivatives and antimicrobial agents containing same
FR2702214B1 (en) 1993-03-05 1995-04-14 Adir New (aryl (alkyl) carbonyl) -heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing them.
CA2157594A1 (en) 1993-03-10 1994-09-15 Leah L. Frye Steroid derivatives, pharmaceutical compositions containing them, and their use as antibiotics or disinfectants
US5484788A (en) 1993-03-26 1996-01-16 Beth Israel Hospital Association Buspirone as a systemic immunosuppressant
US5757326A (en) 1993-03-29 1998-05-26 Seiko Epson Corporation Slot antenna device and wireless apparatus employing the antenna device
EP0618182B1 (en) 1993-03-31 1996-12-18 Kagome Kabushiki Kaisha Indene derivatives and antimicrobial agents containing them
JPH06298611A (en) 1993-04-16 1994-10-25 Nippon Chemiphar Co Ltd Antibacterial agent
US5459151A (en) 1993-04-30 1995-10-17 American Home Products Corporation N-acyl substituted phenyl piperidines as bronchodilators and antiinflammatory agents
FR2704969B1 (en) 1993-05-06 1995-07-28 Centre Scient Tech Batiment Acoustic attenuation device with active double wall.
US5393771A (en) 1993-05-12 1995-02-28 Brisol-Myers Squibb Company 4-substituted benzopyran and related compounds
US5654294A (en) 1993-05-13 1997-08-05 Bristol-Myers Squibb Spiro lactam dual action inhibitors
US5380738A (en) 1993-05-21 1995-01-10 Monsanto Company 2-substituted oxazoles further substituted by 4-fluorophenyl and 4-methylsulfonylphenyl as antiinflammatory agents
ES2164704T3 (en) 1993-05-24 2002-03-01 Aventis Bulk S P A DERIVATIVES IN POSITION 36 OF RIFAMICINES AND ITS USE AS ANTIMICROBIAL AGENTS.
US5406945A (en) 1993-05-24 1995-04-18 Ndm Acquisition Corp. Biomedical electrode having a secured one-piece conductive terminal
FR2706454B1 (en) 1993-06-17 1995-09-15 Roussel Uclaf New 19-Nor steroids, preparation process and intermediates, application as medicaments and pharmaceutical compositions containing them.
US5440016A (en) 1993-06-18 1995-08-08 Torrey Pines Institute For Molecular Studies Peptides of the formula (KFmoc) ZZZ and their uses
AU676293B2 (en) 1993-06-24 1997-03-06 Wilson Greatbatch Ltd. Electrode covering for electrochemical cells
US5436265A (en) 1993-11-12 1995-07-25 Merck Frosst Canada, Inc. 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents
US5288693A (en) 1993-06-25 1994-02-22 Rohm And Haas Company 2-(3-oxoalk(en)yl)-3-isothiazolones and derivatives as antimicrobial agents
DE4321306A1 (en) 1993-06-26 1995-01-05 Sanol Arznei Schwarz Gmbh disulfide
CA2166289A1 (en) 1993-07-02 1995-01-12 Barrie Walsham Bycroft Immunosuppressant and antiallergic compounds e.g. n-(3-oxohexanoyl) homoserine lactone
US5394882A (en) 1993-07-21 1995-03-07 Respironics, Inc. Physiological monitoring system
US5494895A (en) 1993-07-22 1996-02-27 Merck & Co., Inc. Scorpion peptide margatoxin with immunosuppressant activity
JPH0741484A (en) 1993-07-29 1995-02-10 Katayama Seiyakushiyo:Kk Cephem compound and antimicrobial agent
US5506248A (en) 1993-08-02 1996-04-09 Bristol-Myers Squibb Company Pharmaceutical compositions having good dissolution properties
ES2124905T3 (en) 1993-08-04 1999-02-16 Akzo Nobel Nv ANTIGLUCOCORTICOID STEROIDS INTENDED FOR THE TREATMENT OF ANXIETY DISORDERS.
US5458141A (en) 1993-08-04 1995-10-17 Quinton Instrument Company Abrasive skin electrode
NZ271338A (en) 1993-08-06 1998-06-26 Smithkline Beecham Spa Fused tricyclic octahydro-isoquinoline derivatives and pharmaceutical compositions
JP3193205B2 (en) 1993-08-09 2001-07-30 日本臓器製薬株式会社 Eosinophilia inhibitor
WO1995005830A1 (en) 1993-08-20 1995-03-02 The Regents Of The University Of California Polyanion anti-inflammatory agents
US5443461A (en) 1993-08-31 1995-08-22 Alza Corporation Segmented device for simultaneous delivery of multiple beneficial agents
US5385902A (en) 1993-09-01 1995-01-31 Rohm And Haas Company Iodopropargylated oxalic derivatives as antimicrobial agents
DE4329898A1 (en) 1993-09-04 1995-04-06 Marcus Dr Besson Wireless medical diagnostic and monitoring device
US5512678A (en) 1993-09-14 1996-04-30 Merrell Pharmaceuticals Inc. 5-(1-fluoro-vinyl)-1H-pyrimidine-2,4-dione derivatives useful as antineoplastic agents
US5525633A (en) 1993-09-24 1996-06-11 Merrell Dow Pharmaceuticals Inc. Triaryl-ethylene derivatives
CN1131415A (en) 1993-09-24 1996-09-18 默里尔药物公司 Triaryl-ethylene derivatives for use in therapy
US5470885A (en) 1993-09-29 1995-11-28 The Research Foundation Of The State University Of New York Fluorocarbons as anti-inflammatory agents
US5837702A (en) 1993-10-07 1998-11-17 Bristol-Myers Squibb Co. 4-arylamino-benzopyran and related compounds
US5547966A (en) 1993-10-07 1996-08-20 Bristol-Myers Squibb Company Aryl urea and related compounds
US5401758A (en) 1993-10-07 1995-03-28 Bristol-Myers Squibb Company Pyridinyl cyanoguanidine compounds
US5580892A (en) 1993-10-22 1996-12-03 Allergan Method for using 2-(2-alkylphenylamino)-oxazolines as adrenergic agents
HUT73855A (en) 1993-10-27 1996-09-30 Merrell Pharma Inc Delta16 unsaturated c17 heterocyclic steroids useful as steroid c17-20 lyase inhibitors, pharmaceutical compositions containing them and process for their production
US5541230A (en) 1993-11-05 1996-07-30 Us Health Therapeutic polyamines
US5554373A (en) 1993-11-05 1996-09-10 Seabrook; Samuel G. Compositions containing anti-microbial agents and methods for making and using same
WO1995014694A1 (en) 1993-11-22 1995-06-01 Merck & Co., Inc. Benzodiazepines
CA2176019A1 (en) 1993-11-22 1995-06-01 John J. Baldwin 3-acylaminobenzazepines
CA2176255C (en) 1993-11-26 1999-02-23 Edward F. Kleinman Isoxazoline compounds as antiinflammatory agents
EP0730587B1 (en) 1993-11-26 1999-12-08 Pfizer Inc. 3-phenyl-2-isoxazolines as antiinflammatory agents
US6390088B1 (en) * 1993-12-13 2002-05-21 Boehringer Ingelheim Kg Aerosol inhaler
WO1995016699A1 (en) 1993-12-15 1995-06-22 Taisho Pharmaceutical Co., Ltd. Steroid derivative
US5462950A (en) 1993-12-21 1995-10-31 Eli Lilly And Company Methods of treating menstrual symptoms and compositions therefore
CA2136803A1 (en) 1993-12-22 1995-06-23 Kazumi Ogata Steroid derivatives
US5646136A (en) 1994-01-04 1997-07-08 Duke University Methods of inhibiting angiogenesis and tumor growth, and treating ophthalmologic conditions with angiostatic and therapeutic steroids
US5631283A (en) 1994-02-02 1997-05-20 The United States Of America As Represented By The Secretary Of The Army Use of sialic acid or antibodies to sialidase as anti-infectious agents and anti-inflammatory agents
US5593853A (en) 1994-02-09 1997-01-14 Martek Corporation Generation and screening of synthetic drug libraries
US5444043A (en) 1994-02-18 1995-08-22 The Regents Of The University Of California Cyclic heptapeptide anti-inflammatory agent
US5508417A (en) 1994-02-23 1996-04-16 Rohm And Haas Company Broad-spectrum isothiazole antimicrobial agents
US5659247A (en) 1994-03-10 1997-08-19 Denver Dynamics, Inc. Device for detecting metal objects passing through an opening
US5482925A (en) 1994-03-17 1996-01-09 Comedicus Incorporated Complexes of nitric oxide with cardiovascular amines as dual acting cardiovascular agents
US6231593B1 (en) 1994-03-21 2001-05-15 Dusa Pharmaceuticals, Inc. Patch, controller, and method for the photodynamic therapy of a dermal lesion
EP0673881B1 (en) 1994-03-25 1999-06-16 Kabushiki Kaisha Kaisui Kagaku Kenkyujo Antimicrobial agent
US5551020A (en) 1994-03-28 1996-08-27 Flextech Systems, Inc. System for the compacting and logical linking of data blocks in files to optimize available physical storage
US5451686A (en) 1994-04-15 1995-09-19 Allergan, Inc. 3 and 5 alkyl and phenyl 4-(hydroxy or acyloxy)-alkyl substituted 2(5H)-furanones as anti-inflammatory agents
EP0757985A4 (en) 1994-04-28 1997-09-03 Yamanouchi Pharma Co Ltd N-(3-pyrrolidinyl)benzamide derivative
DE69507139T2 (en) 1994-05-02 1999-09-30 Merrell Pharma Inc METHOD FOR PRODUCING 4-AMINO-DELTA 4-3-KETOSTEROIDS VIA 4-NITRO-DELTA-4-3-KETOSTEROIDS
US5683709A (en) 1994-05-05 1997-11-04 Ciba Vision Corporation Poly(benzalkonium salt) as an anti-microbial agent for aqueous drug compositions
US5688997A (en) 1994-05-06 1997-11-18 Pharmacopeia, Inc. Process for preparing intermediates for a combinatorial dihydrobenzopyran library
JP3179286B2 (en) 1994-05-19 2001-06-25 ファイザー製薬株式会社 N-hydroxyurea anti-inflammatory agent
US5476876A (en) 1994-05-24 1995-12-19 The Procter & Gamble Company Di-tert-butylphenol compounds useful as anti-inflammatory agents
US5880280A (en) 1994-06-15 1999-03-09 Merck & Co., Inc. Aryl, alkyl, alkenyl and alkynylmacrolides having immunosuppressive activity
US5550233A (en) 1994-06-21 1996-08-27 Merck & Co., Inc. Aryl, alkyl, alkenyl and alkynylmacrolides having immunosuppressive activity
US5525735A (en) 1994-06-22 1996-06-11 Affymax Technologies Nv Methods for synthesizing diverse collections of pyrrolidine compounds
US5549974A (en) 1994-06-23 1996-08-27 Affymax Technologies Nv Methods for the solid phase synthesis of thiazolidinones, metathiazanones, and derivatives thereof
FR2721610B1 (en) 1994-06-28 1996-08-23 Adir New (thia) cycloalkyl [b] indole derivatives, process for their preparation and pharmaceutical compositions containing them.
FR2721927B1 (en) 1994-07-01 1996-08-09 Roussel Uclaf NEW PROCESS FOR THE PREPARATION OF 20-OXO 17 ALPHA, 21-DIHYDROXYL STEROID DERIVATIVES AND NEW INTERMEDIARIES
US5786344A (en) 1994-07-05 1998-07-28 Arch Development Corporation Camptothecin drug combinations and methods with reduced side effects
US5656661A (en) 1994-07-27 1997-08-12 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
US5525606A (en) 1994-08-01 1996-06-11 The United States Of America As Represented By The Department Of Health And Human Services Substituted 06-benzylguanines and 6(4)-benzyloxypyrimidines
US5563131A (en) 1994-08-04 1996-10-08 Pherin Corporation Pregnane steroids as neurochemical initiators of change in human hypothalamic function and related pharmaceutical compositions and methods
US5792757A (en) 1994-08-04 1998-08-11 Pherin Pharmaceuticals 19-nor-pregnane steroids as neurochemical initiators of change in human hypothalamic function
JPH0853424A (en) 1994-08-11 1996-02-27 Kureha Chem Ind Co Ltd Benzimidazolesulfonic acid amide derivative
US5600548A (en) 1994-08-11 1997-02-04 Sundstrand Corporation DC content control for an inverter
IE70735B1 (en) * 1994-08-15 1996-12-11 Elan Med Tech Orally administrable delivery device
US5461070A (en) 1994-08-29 1995-10-24 The Regents Of The University Of California Anti-flammatory method using indole alkaloids
DE9414065U1 (en) 1994-08-31 1994-11-03 Roehm Gmbh Thermoplastic plastic for pharmaceutical casings soluble in intestinal juice
US5684002A (en) 1994-09-07 1997-11-04 The Procter & Gamble Company Dihydorbenzofuran and related compounds useful as anti-inflammatory agents
US5463564A (en) 1994-09-16 1995-10-31 3-Dimensional Pharmaceuticals, Inc. System and method of automatically generating chemical compounds with desired properties
US5693648A (en) 1994-09-30 1997-12-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity
US5554645A (en) 1994-10-03 1996-09-10 Mars, Incorporated Antineoplastic cocoa extracts and methods for making and using the same
BR9509183A (en) 1994-10-05 1997-12-30 Helsinn Healthcare Sa Anti-inflammatory agent for external use
JP3121503B2 (en) 1994-10-18 2001-01-09 レンゴー株式会社 Antibacterial agent
US5510361A (en) 1994-10-20 1996-04-23 The Procter & Gamble Company Di-tert-butylphenol compounds with heterocyclic moiety, useful as anti-inflammatory agents
IL111396A (en) 1994-10-25 1997-07-13 Ness Neuromuscular Electrical Stimulation Systems Ltd Electrode system
US5545734A (en) 1994-10-25 1996-08-13 Merck & Co., Inc. Aryl and heteroaryl macrolides having immunosuppressive activity
IL115659A (en) 1994-10-27 2000-06-01 Akzo Nobel Nv Steroids with a 17-spiromethylene lactone or lactol group process for their preparation and pharmaceutical compositions containing them
US5512687A (en) 1994-10-28 1996-04-30 Procept, Inc. Compounds for inhibiting immune response
US5622948A (en) 1994-12-01 1997-04-22 Syntex (U.S.A.) Inc. Pyrrole pyridazine and pyridazinone anti-inflammatory agents
US5688696A (en) 1994-12-12 1997-11-18 Selectide Corporation Combinatorial libraries having a predetermined frequency of each species of test compound
US5718098A (en) 1994-12-30 1998-02-17 Pharmagraphics L.L.C., Midwest Method for producing sample package
US5552422A (en) 1995-01-11 1996-09-03 Merck Frosst Canada, Inc. Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents
US5648376A (en) 1995-01-19 1997-07-15 Pharmagenesis, Inc. Immunosuppressant diterpene compound
EP0754460B1 (en) 1995-02-07 2002-06-05 Shiseido Company Limited Antiinflammatory agents
US5485841A (en) 1995-02-14 1996-01-23 Univ Mcgill Ultrasonic lung tissue assessment
US5506228A (en) 1995-02-23 1996-04-09 Merck & Co., Inc. 2,6-diaryl pyridazinones with immunosuppressant activity
US5670504A (en) 1995-02-23 1997-09-23 Merck & Co. Inc. 2,6-diaryl pyridazinones with immunosuppressant activity
US5778882A (en) * 1995-02-24 1998-07-14 Brigham And Women's Hospital Health monitoring system
US6374670B1 (en) 1995-03-13 2002-04-23 University Of Washington Non-invasive gut motility monitor
US5604262A (en) 1995-03-22 1997-02-18 Research Corporation Technologies, Inc. Topical antimicrobial agents
US5661141A (en) 1995-03-27 1997-08-26 Petrow; Vladimir 19-oxygenated steroids as therapeutic agents
US5845265A (en) 1995-04-26 1998-12-01 Mercexchange, L.L.C. Consignment nodes
BR9608465A (en) 1995-05-08 1998-12-29 Massachusetts Inst Technology Wireless communication system and computer system
IT1282286B1 (en) 1995-05-11 1998-03-16 Sigma Tau Ind Farmaceuti SECO-D STEROIDS ON THE CARDIOVASCULAR SYSTEM, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.
CA2176412C (en) 1995-05-18 2008-10-07 David Henry Wilson Rotary tabletting press
US5618813A (en) 1995-05-26 1997-04-08 Abbott Laboratories Benzo[5.6]pyrano[2.3.4-ij]quinolizine and benzo[5.6]thiopyrano[2.3.4-ij]quinolizine derivatives as antibacterial and antineoplastic agents
US5552411A (en) 1995-05-26 1996-09-03 Warner-Lambert Company Sulfonylquinolines as central nervous system and cardiovascular agents
US5753715A (en) 1995-06-02 1998-05-19 Ortho Pharmaceutical Corporation 2-disubstituted cyclohexenyl and cyclohexyl antimicrobial agents
US5643950A (en) 1995-06-02 1997-07-01 Ortho Pharmaceutical Corporation Triphenylalkyl antimicrobial agents
US5645063A (en) 1995-06-05 1997-07-08 Quinton Instrument Company Skin electrode having multiple conductive center members
US5612370A (en) 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phenylglycine and phenylalaninen amido benzopyran derivatives
CA2222491A1 (en) 1995-06-07 1996-12-19 Merck & Co., Inc. Novel n-(2,4-dioxo-2,3,4,5-tetrahydro-1h-1,5-benzodiazepin-3yl)-3-amides
US5726171A (en) 1995-06-07 1998-03-10 Merck & Co Inc N-(1-alkyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo B! 1,4!diazepin-3yl)-acetamides
US5631251A (en) 1995-06-07 1997-05-20 Merck & Co., Inc. 5-cyclopropyl-1,4 benzodiazepine-2-ones
US5869478A (en) 1995-06-07 1999-02-09 Bristol-Myers Squibb Company Sulfonamido substituted benzopyran derivatives
US5612323A (en) 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phosphinic ester substituted benzopyran derivatives
US5738708A (en) * 1995-06-07 1998-04-14 The Regents Of The University Of California Office Of Technology Transfer Composite metal membrane
US5603363A (en) 1995-06-20 1997-02-18 Exel Nelson Engineering Llc Apparatus for dispensing a carbonated beverage with minimal foaming
JPH11509086A (en) 1995-06-21 1999-08-17 マーテック・バイオサイエンシズ・コーポレイション Combinatorial library of labeled biochemical compounds and its preparation method
US6083248A (en) * 1995-06-23 2000-07-04 Medtronic, Inc. World wide patient location and data telemetry system for implantable medical devices
US5720771A (en) 1995-08-02 1998-02-24 Pacesetter, Inc. Method and apparatus for monitoring physiological data from an implantable medical device
US5686488A (en) 1995-08-25 1997-11-11 Alcon Laboratories, Inc. Polyethoxylated castor oil products as anti-inflammatory agents
US5776946A (en) 1995-08-28 1998-07-07 Mcgeer; Patrick L. Peripheral benzodiazepine receptor ligands as antiinflammatory agents
US5772575A (en) 1995-09-22 1998-06-30 S. George Lesinski Implantable hearing aid
US5802467A (en) 1995-09-28 1998-09-01 Innovative Intelcom Industries Wireless and wired communications, command, control and sensing system for sound and/or data transmission and reception
EP0855064A4 (en) 1995-10-11 2001-07-18 Motorola Inc Remotely powered electronic tag and associated exciter/reader and related method
JPH09110877A (en) 1995-10-17 1997-04-28 Katayama Seiyakushiyo:Kk Cephem compound, its production and antibacterial agent containing the compound
US5763361A (en) 1995-10-23 1998-06-09 Merck & Co., Inc. 17-alkyl-7-substituted-4-aza steroid derivatives as 5-α-reductase inhibitors
US5696156A (en) 1995-10-31 1997-12-09 Merck & Co. Inc. Triterpene derivatives with immunosuppressant activity
US5883119A (en) 1995-10-31 1999-03-16 Merck & Co., Inc. Triterpene derivatives with immunosuppressant activity
US5679705A (en) 1995-10-31 1997-10-21 Merck & Co., Inc. Triterpene derivatives with immunosuppressant activity
US5696117A (en) 1995-11-07 1997-12-09 Ortho Pharmaceutical Corporation Benzoxazine antimicrobial agents
GB9522872D0 (en) 1995-11-08 1996-01-10 Oxford Medical Ltd Improvements relating to physiological monitoring
US5684204A (en) 1995-11-15 1997-11-04 The Procter & Gamble Company Sulfur containing di-tert-butylphenol compounds useful as anti-inflammatory agents
US8092224B2 (en) 1995-11-22 2012-01-10 James A. Jorasch Systems and methods for improved health care compliance
SE9504258D0 (en) 1995-11-28 1995-11-28 Pacesetter Ab Device and method for generating a synthesized ECG
US5707984A (en) 1995-12-08 1998-01-13 G. D. Searle & Co. Steroid nitrite/nitrate ester derivatives useful as anti-inflammatory drugs
US5792758A (en) 1995-12-08 1998-08-11 G. D. Searle & Co. Steroid nitrite ester derivatives useful as anti-inflammatory drugs
DE19547648A1 (en) 1995-12-20 1997-06-26 Hoechst Ag Preparation containing high density lipoproteins and crotonic acid amide derivatives
US5596302A (en) 1996-01-17 1997-01-21 Lucent Technologies Inc. Ring oscillator using even numbers of differential stages with current mirrors
US5707990A (en) 1996-01-30 1998-01-13 Ortho Pharmaceutical Corporation 2-substituted amino and thio alkyl benzoxazine antimicrobial agents
US5821250A (en) 1996-02-01 1998-10-13 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
US5684041A (en) 1996-02-01 1997-11-04 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
US5750543A (en) 1996-02-01 1998-05-12 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
US5618835A (en) 1996-02-01 1997-04-08 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
US5686471A (en) 1996-02-01 1997-11-11 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
US5672620A (en) 1996-02-01 1997-09-30 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
US5684031A (en) 1996-02-01 1997-11-04 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
US5760041A (en) 1996-02-05 1998-06-02 American Cyanamid Company 4-aminoquinazoline EGFR Inhibitors
AU710983B2 (en) 1996-02-15 1999-10-07 Armand P. Neukermans Improved biocompatible transducers
US5868136A (en) 1996-02-20 1999-02-09 Axelgaard Manufacturing Co. Ltd. Medical electrode
US20010044588A1 (en) 1996-02-22 2001-11-22 Mault James R. Monitoring system
US5859027A (en) 1996-02-26 1999-01-12 Chektec Corporation Antimicrobial agent
US5833603A (en) 1996-03-13 1998-11-10 Lipomatrix, Inc. Implantable biosensing transponder
US5731423A (en) 1996-03-21 1998-03-24 Transcell Technologies, Inc. Process for preparing sulfoxides
US6453199B1 (en) 1996-04-01 2002-09-17 Valery Ivanovich Kobozev Electrical gastro-intestinal tract stimulator
GB9608268D0 (en) 1996-04-22 1996-06-26 Robertson James L Blister pack
US5864578A (en) 1996-04-29 1999-01-26 Golden Bridge Technology, Inc. Matched filter-based handoff method and apparatus
JP3740212B2 (en) * 1996-05-01 2006-02-01 株式会社ルネサステクノロジ Nonvolatile semiconductor memory device
US5837698A (en) 1996-05-02 1998-11-17 G. D. Searle & Co. Steroid nitrite and nitrate ester derivatives useful as anti-inflammatory drugs
FR2749012B1 (en) 1996-05-22 1998-08-07 Hoechst Marion Roussel Inc NOVEL 1 OR 6-HYDROXYL STEROIDS, THEIR PREPARATION PROCESS, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US5739169A (en) 1996-05-31 1998-04-14 Procept, Incorporated Aromatic compounds for inhibiting immune response
US5688825A (en) 1996-05-31 1997-11-18 University Of Connecticut Anandamide amidase inhibitors as analgesic agents
US5741798A (en) 1996-06-03 1998-04-21 Boehringer Ingelheim Pharmaceuticals, Inc. 2-benzyl-4-sulfonyl-4H-isoquinolin-1,3-diones and their use as antiinflammatory agents
US5800421A (en) 1996-06-12 1998-09-01 Lemelson; Jerome H. Medical devices using electrosensitive gels
US5773469A (en) 1996-06-18 1998-06-30 Ortho Pharmaceutical Corporation Diaryl antimicrobial agents
JP3636826B2 (en) 1996-07-01 2005-04-06 積水化学工業株式会社 Bioelectrical impedance measuring device
US6535929B1 (en) 1996-07-02 2003-03-18 Sun Microsystems, Inc. Universal communication mechanism for applications running in a multitasking environment
US5677318A (en) 1996-07-11 1997-10-14 Merck Frosst Canada, Inc. Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents
US5877184A (en) 1996-08-06 1999-03-02 Merck & Co., Inc. Macrolides having immunosuppressive activity
JP4215277B2 (en) 1996-08-09 2009-01-28 アルコン ラボラトリーズ,インコーポレイテッド Preservative system for pharmaceutical compositions containing cyclodextrin
US5874476A (en) 1997-07-14 1999-02-23 Rohm And Haas Company Dihaloformaldoxime carbamates as antimicrobial agents
DE19780856D2 (en) 1996-08-16 1999-09-23 Roche Diagnostics Gmbh Control system for monitoring the regular intake of a drug
PL191546B1 (en) 1996-08-29 2006-06-30 Jagotec Ag Tablet featurated by controllable release of alphusozine hydrochloride contained therein
US5792048A (en) * 1996-09-03 1998-08-11 Schaefer; Guenter Indentification pill with integrated microchip: smartpill, smartpill with integrated microchip and microprocessor for medical analyses and a smartpill, smartbox, smartplague, smartbadge or smartplate for luggage control on commercial airliners
US5884031A (en) 1996-10-01 1999-03-16 Pipe Dream, Inc. Method for connecting client systems into a broadcast network
US5963132A (en) 1996-10-11 1999-10-05 Avid Indentification Systems, Inc. Encapsulated implantable transponder
US5763478A (en) 1996-10-16 1998-06-09 Merck & Co., Inc. Triterpene derivatives with immunosuppressant activity
US5874594A (en) 1996-10-16 1999-02-23 Merck & Co., Inc. Triterpene derivatives with immunosuppressant activity
US6364834B1 (en) 1996-11-13 2002-04-02 Criticare Systems, Inc. Method and system for remotely monitoring multiple medical parameters in an integrated medical monitoring system
GB9623634D0 (en) 1996-11-13 1997-01-08 Bpsi Holdings Inc Method and apparatus for the coating of substrates for pharmaceutical use
US5796827A (en) * 1996-11-14 1998-08-18 International Business Machines Corporation System and method for near-field human-body coupling for encrypted communication with identification cards
US8734339B2 (en) 1996-12-16 2014-05-27 Ip Holdings, Inc. Electronic skin patch for real time monitoring of cardiac activity and personal health management
US5928142A (en) 1996-12-17 1999-07-27 Ndm, Inc. Biomedical electrode having a disposable electrode and a reusable leadwire adapter that interfaces with a standard leadwire connector
US5684042A (en) 1997-01-10 1997-11-04 Medlogic Global Corporation Cyanoacrylate compositions comprising an antimicrobial agent
US6122351A (en) 1997-01-21 2000-09-19 Med Graph, Inc. Method and system aiding medical diagnosis and treatment
US5974124A (en) 1997-01-21 1999-10-26 Med Graph Method and system aiding medical diagnosis and treatment
US5763432A (en) 1997-01-29 1998-06-09 Sri International Steriod inhibitors of estrone sulfatase and associated pharmaceutical compositions and methods of use
US6317714B1 (en) 1997-02-04 2001-11-13 Microsoft Corporation Controller and associated mechanical characters operable for continuously performing received control data while engaging in bidirectional communications over a single communications channel
US5703463A (en) 1997-02-18 1997-12-30 National Semiconductor Corporation Methods and apparatus for protecting battery cells from overcharge
EP0969897B1 (en) 1997-03-17 2010-08-18 Adidas AG Physiologic signs feedback system
US5855907A (en) 1997-03-24 1999-01-05 Peyman; Gholam A. Method of treatment of migraine
EP0973437A4 (en) 1997-03-31 2001-03-07 Telecom Medical Inc Patient monitoring apparatus
US5801193A (en) 1997-04-15 1998-09-01 Immune Modulation, Inc. Compositions and methods for immunosuppressing
US5981166A (en) * 1997-04-23 1999-11-09 Pharmaseq, Inc. Screening of soluble chemical compounds for their pharmacological properties utilizing transponders
DE19717023C2 (en) 1997-04-23 2003-02-06 Micronas Gmbh Device for treating malignant, tumorous tissue areas
US5866558A (en) 1997-05-08 1999-02-02 Regents Of The University Of Minnesota 6-alkynyl steroids
US6288629B1 (en) 1997-05-23 2001-09-11 Intermec Ip Corp. Method of using write—ok flag for radio frequency (RF) transponders (RF Tags)
US5921925A (en) 1997-05-30 1999-07-13 Ndm, Inc. Biomedical electrode having a disposable electrode and a reusable leadwire adapter that interfaces with a standard leadwire connector
US6018229A (en) 1997-06-30 2000-01-25 Compaq Computer Corporation Lithium-ion battery pack with integral switching regulator using cutoff transistor
US5880115A (en) 1997-07-18 1999-03-09 Duquesne University Of The Holy Ghost Steroid sulfatase inhibitors and methods for making and using the same
GB2327591A (en) * 1997-07-24 1999-02-03 Nestle Sa Reduced fat chocolate
US5984875A (en) 1997-08-22 1999-11-16 Innotek Pet Products, Inc. Ingestible animal temperature sensor
US5862808A (en) 1997-08-26 1999-01-26 Cigar Savor Enterprises Llc Cigar punch
US6409674B1 (en) 1998-09-24 2002-06-25 Data Sciences International, Inc. Implantable sensor with wireless communication
JPH11195415A (en) 1997-11-05 1999-07-21 Matsushita Electric Ind Co Ltd Nonaqueous electrolyte battery and its manufacture
US6211799B1 (en) * 1997-11-06 2001-04-03 Massachusetts Institute Of Technology Method and apparatus for transbody transmission of power and information
US7035818B1 (en) 1997-11-21 2006-04-25 Symbol Technologies, Inc. System and method for electronic inventory
US5948227A (en) 1997-12-17 1999-09-07 Caliper Technologies Corp. Methods and systems for performing electrophoretic molecular separations
GB9801363D0 (en) 1998-01-22 1998-03-18 Danbiosyst Uk Novel dosage form
US6099259A (en) 1998-01-26 2000-08-08 Bristol Compressors, Inc. Variable capacity compressor
US6097927A (en) 1998-01-27 2000-08-01 Symbix, Incorporated Active symbolic self design method and apparatus
US6038464A (en) 1998-02-09 2000-03-14 Axelgaard Manufacturing Co., Ltd. Medical electrode
US6275476B1 (en) 1998-02-19 2001-08-14 Micron Technology, Inc. Method of addressing messages and communications system
US7542878B2 (en) 1998-03-03 2009-06-02 Card Guard Scientific Survival Ltd. Personal health monitor and a method for health monitoring
US6141592A (en) 1998-03-06 2000-10-31 Intermedics Inc. Data transmission using a varying electric field
US6579231B1 (en) 1998-03-27 2003-06-17 Mci Communications Corporation Personal medical monitoring unit and system
US6091975A (en) 1998-04-01 2000-07-18 Alza Corporation Minimally invasive detecting device
US6949816B2 (en) 2003-04-21 2005-09-27 Motorola, Inc. Semiconductor component having first surface area for electrically coupling to a semiconductor chip and second surface area for electrically coupling to a substrate, and method of manufacturing same
US6175752B1 (en) 1998-04-30 2001-01-16 Therasense, Inc. Analyte monitoring device and methods of use
CA2332112C (en) * 1998-05-13 2004-02-10 Cygnus, Inc. Monitoring of physiological analytes
AU4094599A (en) 1998-05-21 1999-12-06 Telecom Medical, Inc. Patient monitoring apparatus
US6205745B1 (en) 1998-05-27 2001-03-27 Lucent Technologies Inc. High speed flip-chip dispensing
US6477424B1 (en) 1998-06-19 2002-11-05 Medtronic, Inc. Medical management system integrated programming apparatus for communication with an implantable medical device
CN1116044C (en) * 1998-06-24 2003-07-30 凌沛学 Antisticking particle and powder containing sodium hyaluronate and their preparation process
US6704602B2 (en) 1998-07-02 2004-03-09 Medtronic, Inc. Implanted medical device/external medical instrument communication utilizing surface electrodes
US7209787B2 (en) 1998-08-05 2007-04-24 Bioneuronics Corporation Apparatus and method for closed-loop intracranial stimulation for optimal control of neurological disease
US7548787B2 (en) 2005-08-03 2009-06-16 Kamilo Feher Medical diagnostic and communication system
US6703047B2 (en) 2001-02-02 2004-03-09 Incept Llc Dehydrated hydrogel precursor-based, tissue adherent compositions and methods of use
US6558320B1 (en) 2000-01-20 2003-05-06 Medtronic Minimed, Inc. Handheld personal data assistant (PDA) with a medical device and method of using the same
US6333699B1 (en) 1998-08-28 2001-12-25 Marathon Oil Company Method and apparatus for determining position in a pipe
BR9913610A (en) 1998-09-04 2001-10-09 Wolfe Res Pty Ltd Medical implant system
US6204764B1 (en) 1998-09-11 2001-03-20 Key-Trak, Inc. Object tracking system with non-contact object detection and identification
US6344824B1 (en) 1998-09-18 2002-02-05 Hitachi Maxell, Ltd. Noncontact communication semiconductor device
FI116957B (en) 1998-10-29 2006-04-13 Nokia Corp The method of communication between the wireless device and the electronic device and the communication device
US6708060B1 (en) 1998-11-09 2004-03-16 Transpharma Ltd. Handheld apparatus and method for transdermal drug delivery and analyte extraction
US6547994B1 (en) 1998-11-13 2003-04-15 Therics, Inc. Rapid prototyping and manufacturing process
US6526135B1 (en) * 1998-11-18 2003-02-25 Nortel Networks Limited Automated competitive business call distribution (ACBCD) system
AU1832800A (en) 1998-11-25 2000-06-19 Ball Semiconductor Inc. Method of and system for identifying medical products
IT1304779B1 (en) 1998-12-03 2001-03-29 Ima Spa DISC AND PESTEL DISPENSER, INTERMITTENTLY OPERATING, SINGLE-SIDED, PARTICULARLY SUITABLE FOR PACKAGING DOSES
US6217744B1 (en) 1998-12-18 2001-04-17 Peter Crosby Devices for testing fluid
ATE244022T1 (en) 1998-12-21 2003-07-15 Sequella Inc METHODS OF USE AND COMPOSITIONS CONTAINING MONITORING SYSTEM
US6115636A (en) 1998-12-22 2000-09-05 Medtronic, Inc. Telemetry for implantable devices using the body as an antenna
US6269058B1 (en) 1999-01-04 2001-07-31 Texas Instruments Incorporated Wide capture range circuitry
US6358202B1 (en) 1999-01-25 2002-03-19 Sun Microsystems, Inc. Network for implanted computer devices
US8636648B2 (en) 1999-03-01 2014-01-28 West View Research, Llc Endoscopic smart probe
US20050272652A1 (en) 1999-03-29 2005-12-08 Gault Victor A Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity
US6285897B1 (en) 1999-04-07 2001-09-04 Endonetics, Inc. Remote physiological monitoring system
US6494829B1 (en) 1999-04-15 2002-12-17 Nexan Limited Physiological sensor array
US6755783B2 (en) 1999-04-16 2004-06-29 Cardiocom Apparatus and method for two-way communication in a device for monitoring and communicating wellness parameters of ambulatory patients
US6200265B1 (en) 1999-04-16 2001-03-13 Medtronic, Inc. Peripheral memory patch and access method for use with an implantable medical device
US6290646B1 (en) 1999-04-16 2001-09-18 Cardiocom Apparatus and method for monitoring and communicating wellness parameters of ambulatory patients
DE69913743T2 (en) 1999-05-25 2004-10-07 Medicotest As Olstykke SKIN ELECTRODE
WO2000072463A2 (en) 1999-05-26 2000-11-30 Johnson Controls Interiors Technology Corp. Wireless communications system and method
US6366206B1 (en) 1999-06-02 2002-04-02 Ball Semiconductor, Inc. Method and apparatus for attaching tags to medical and non-medical devices
EP1060704A3 (en) 1999-06-18 2002-09-18 Agilent Technologies, Inc. (a Delaware corporation) Multi-parameter capability transmitter for wireless telemetry systems
JP3402267B2 (en) 1999-06-23 2003-05-06 ソニーケミカル株式会社 Electronic element mounting method
DE19929328A1 (en) 1999-06-26 2001-01-04 Daimlerchrysler Aerospace Ag Device for long-term medical monitoring of people
US6287252B1 (en) 1999-06-30 2001-09-11 Monitrak Patient monitor
US6307468B1 (en) 1999-07-20 2001-10-23 Avid Identification Systems, Inc. Impedance matching network and multidimensional electromagnetic field coil for a transponder interrogator
JP2003504415A (en) 1999-07-20 2003-02-04 メルク エンド カムパニー インコーポレーテッド Sustained-release drug dispersant delivery device
HN2000000165A (en) 1999-08-05 2001-07-09 Dimensional Foods Corp EDIBLE HOLOGRAPHIC PRODUCTS, PARTICULARLY PHARMACEUTICALS, AND METHODS AND APPLIANCES FOR PRODUCERS.
US6428809B1 (en) 1999-08-18 2002-08-06 Microdose Technologies, Inc. Metering and packaging of controlled release medication
US6206702B1 (en) 1999-08-24 2001-03-27 Deborah A. Hayden Methods and devices for treating unilateral neglect
US6526034B1 (en) 1999-09-21 2003-02-25 Tantivy Communications, Inc. Dual mode subscriber unit for short range, high rate and long range, lower rate data communications
US6533733B1 (en) 1999-09-24 2003-03-18 Ut-Battelle, Llc Implantable device for in-vivo intracranial and cerebrospinal fluid pressure monitoring
US6990082B1 (en) 1999-11-08 2006-01-24 Intel Corporation Wireless apparatus having a transceiver equipped to support multiple wireless communication protocols
KR100739357B1 (en) 1999-09-30 2007-07-18 소니 가부시끼 가이샤 Recording apparatus, recording method and recording media
CA2386673A1 (en) 1999-10-07 2001-04-12 Anthony R. Montgomery Physiological signal monitoring apparatus and method
US6852084B1 (en) 2000-04-28 2005-02-08 Peter V. Boesen Wireless physiological pressure sensor and transmitter with capability of short range radio frequency transmissions
US6882881B1 (en) 1999-10-19 2005-04-19 The Johns Hopkins University Techniques using heat flow management, stimulation, and signal analysis to treat medical disorders
US6426863B1 (en) 1999-11-25 2002-07-30 Lithium Power Technologies, Inc. Electrochemical capacitor
US6612984B1 (en) 1999-12-03 2003-09-02 Kerr, Ii Robert A. System and method for collecting and transmitting medical data
WO2001045793A1 (en) 1999-12-21 2001-06-28 Medtronic, Inc. System for dynamic remote networking with implantable medical devices
GB9930000D0 (en) 1999-12-21 2000-02-09 Phaeton Research Ltd An ingestible device
EP1205405B1 (en) 1999-12-28 2008-08-20 Matsushita Electric Industrial Co., Ltd. Information recording medium and access device
US6294999B1 (en) 1999-12-29 2001-09-25 Becton, Dickinson And Company Systems and methods for monitoring patient compliance with medication regimens
US8002700B2 (en) 1999-12-30 2011-08-23 Medtronic, Inc. Communications system for an implantable medical device and a delivery device
US6471645B1 (en) 1999-12-30 2002-10-29 Medtronic, Inc. Communications system for an implantable device and a drug dispenser
GB0000566D0 (en) 2000-01-12 2000-03-01 Willett Int Ltd Apparatus and method
EP1119137B1 (en) 2000-01-20 2006-08-16 Lucent Technologies Inc. Interoperability for bluetooth/IEEE 802.11
AR026148A1 (en) * 2000-01-21 2003-01-29 Osmotica Argentina S A OSMOTIC DEVICE WITH PREFORMED PASSAGE THAT INCREASES SIZE
US6567685B2 (en) 2000-01-21 2003-05-20 Kabushiki Kaisha Toshiba Magnetic resonance imaging apparatus
US6368190B1 (en) 2000-01-26 2002-04-09 Agere Systems Guardian Corp. Electrochemical mechanical planarization apparatus and method
US7039453B2 (en) * 2000-02-08 2006-05-02 Tarun Mullick Miniature ingestible capsule
GB0003197D0 (en) 2000-02-11 2000-04-05 Aid Medic Ltd Improvements in and relating to controlling drug delivery
KR20030025222A (en) * 2000-03-08 2003-03-28 기븐 이미징 리미티드 A device and system for in vivo imaging
US6526315B1 (en) 2000-03-17 2003-02-25 Tanita Corporation Portable bioelectrical impedance measuring instrument
DE10014588A1 (en) 2000-03-27 2001-10-04 Basf Ag Sustained-release oral dosage form that floats in gastric fluid includes a blend of polyvinyl acetate and polyvinylpyrrolidone
GB0007617D0 (en) 2000-03-29 2000-05-17 Psion Dacom Plc A short range radio transceiver device
US6622050B2 (en) 2000-03-31 2003-09-16 Medtronic, Inc. Variable encryption scheme for data transfer between medical devices and related data management systems
US6757523B2 (en) 2000-03-31 2004-06-29 Zeus Wireless, Inc. Configuration of transmit/receive switching in a transceiver
US6922592B2 (en) 2000-04-04 2005-07-26 Medtronic, Inc. Implantable medical device controlled by a non-invasive physiological data measurement device
US6654638B1 (en) 2000-04-06 2003-11-25 Cardiac Pacemakers, Inc. Ultrasonically activated electrodes
US6441747B1 (en) 2000-04-18 2002-08-27 Motorola, Inc. Wireless system protocol for telemetry monitoring
US6496705B1 (en) 2000-04-18 2002-12-17 Motorola Inc. Programmable wireless electrode system for medical monitoring
US6561975B1 (en) 2000-04-19 2003-05-13 Medtronic, Inc. Method and apparatus for communicating with medical device systems
GB2361544B (en) 2000-04-20 2004-07-07 Goring Kerr Ltd Metal detector
US6836862B1 (en) 2000-04-24 2004-12-28 3Com Corporation Method of indicating wireless connection integrity
US7231451B2 (en) 2000-05-08 2007-06-12 Microtune (San Diego), Inc. Transmit-only and receive-only Bluetooth apparatus and method
US6432292B1 (en) 2000-05-16 2002-08-13 Metallic Power, Inc. Method of electrodepositing metal on electrically conducting particles
US6988989B2 (en) 2000-05-19 2006-01-24 Welch Allyn Protocol, Inc. Patient monitoring system
US6680923B1 (en) 2000-05-23 2004-01-20 Calypso Wireless, Inc. Communication system and method
EP1284644B1 (en) 2000-05-29 2004-10-20 Medicotest A/S An electrode for establishing electrical contact with the skin
IL163684A0 (en) 2000-05-31 2005-12-18 Given Imaging Ltd Measurement of electrical characteristics of tissue
GB0014854D0 (en) 2000-06-16 2000-08-09 Isis Innovation System and method for acquiring data
US20060122474A1 (en) 2000-06-16 2006-06-08 Bodymedia, Inc. Apparatus for monitoring health, wellness and fitness
US7689437B1 (en) * 2000-06-16 2010-03-30 Bodymedia, Inc. System for monitoring health, wellness and fitness
GB0014855D0 (en) 2000-06-16 2000-08-09 Isis Innovation Combining measurements from different sensors
US6605038B1 (en) 2000-06-16 2003-08-12 Bodymedia, Inc. System for monitoring health, wellness and fitness
US7261690B2 (en) 2000-06-16 2007-08-28 Bodymedia, Inc. Apparatus for monitoring health, wellness and fitness
US7527807B2 (en) * 2000-06-21 2009-05-05 Cubist Pharmaceuticals, Inc. Compositions and methods for increasing the oral absorption of antimicrobials
US7009946B1 (en) 2000-06-22 2006-03-07 Intel Corporation Method and apparatus for multi-access wireless communication
US6607744B1 (en) 2000-06-23 2003-08-19 Segan Industries Ingestibles possessing intrinsic color change
GB0016561D0 (en) 2000-07-05 2000-08-23 Rolls Royce Plc Health monitoring
US6961285B2 (en) 2000-07-07 2005-11-01 Ddms Holdings L.L.C. Drug delivery management system
DE60107685T2 (en) 2000-07-19 2005-10-06 Medicotest A/S SKIN ELECTRODE WITH A BYPASS ELEMENT
JP2004516863A (en) 2000-07-24 2004-06-10 モトローラ・インコーポレイテッド Ingestible electronic capsule
US6564079B1 (en) 2000-07-27 2003-05-13 Ckm Diagnostics, Inc. Electrode array and skin attachment system for noninvasive nerve location and imaging device
JP4428835B2 (en) 2000-08-09 2010-03-10 昭和電工株式会社 Magnetic recording medium and method for manufacturing the same
US8036731B2 (en) 2001-01-22 2011-10-11 Spectrum Dynamics Llc Ingestible pill for diagnosing a gastrointestinal tract
KR20020015907A (en) 2000-08-23 2002-03-02 정병렬 A method and system of a fitness using a game control for a beating of the heart
US20020026111A1 (en) * 2000-08-28 2002-02-28 Neil Ackerman Methods of monitoring glucose levels in a subject and uses thereof
US7685005B2 (en) 2000-08-29 2010-03-23 Medtronic, Inc. Medical device systems implemented network scheme for remote patient management
DE60102331T2 (en) 2000-09-08 2005-03-17 Matsushita Electric Works, Ltd., Kadoma Data transmission system using a human body as a signal transmission path
US6720923B1 (en) 2000-09-14 2004-04-13 Stata Labs, Llc Antenna design utilizing a cavity architecture for global positioning system (GPS) applications
US6572636B1 (en) 2000-09-19 2003-06-03 Robert Sean Hagen Pulse sensing patch and associated methods
AU2001292946A1 (en) 2000-09-26 2002-04-08 Advantage 3D Llc Method and system for generation, storage and distribution of omni-directional object views
WO2002030401A2 (en) * 2000-10-11 2002-04-18 Microchips, Inc. Microchip reservoir devices and facilitated corrosion of electrodes
US7024248B2 (en) 2000-10-16 2006-04-04 Remon Medical Technologies Ltd Systems and methods for communicating with implantable devices
US7857626B2 (en) 2000-10-23 2010-12-28 Toly Christopher C Medical physiological simulator including a conductive elastomer layer
US6738671B2 (en) 2000-10-26 2004-05-18 Medtronic, Inc. Externally worn transceiver for use with an implantable medical device
US6632175B1 (en) 2000-11-08 2003-10-14 Hewlett-Packard Development Company, L.P. Swallowable data recorder capsule medical device
US6929636B1 (en) 2000-11-08 2005-08-16 Hewlett-Packard Development Company, L.P. Internal drug dispenser capsule medical device
ES2177434B1 (en) 2000-12-05 2004-10-16 Gesimpex Comercial, S.L. PROCEDURE AND CAPSULE FOR REMOTE IDENTIFICATION AND MONITORING OF BIRDS.
US20020128934A1 (en) 2000-12-11 2002-09-12 Ari Shaer Interactive event planning and payment method and system
US6689117B2 (en) 2000-12-18 2004-02-10 Cardiac Pacemakers, Inc. Drug delivery system for implantable medical device
US6879810B2 (en) 2000-12-20 2005-04-12 Nokia Corporation Control of short range RF communication
KR100526699B1 (en) 2001-01-17 2005-11-08 이종식 Method and System for Network Games
TW567695B (en) 2001-01-17 2003-12-21 Ibm Digital baseband system
JP2002224053A (en) 2001-02-05 2002-08-13 Next:Kk Remote medical control system
JP3927495B2 (en) 2001-02-08 2007-06-06 ミニ−ミッター カンパニー,インコーポレイテッド Skin patch with built-in temperature sensor
US20050208251A1 (en) 2001-02-15 2005-09-22 Integral Technologies, Inc. Low cost electrically conductive tapes and films manufactured from conductive loaded resin-based materials
JP2002263185A (en) 2001-03-12 2002-09-17 Sanyo Electric Co Ltd Medicine administration system and method and medicine administration device
GB0107045D0 (en) 2001-03-21 2001-05-09 Pace Micro Tech Plc Control system for control of power supply for lnb in broadcast data receiving system
JP2002282219A (en) * 2001-03-22 2002-10-02 Toshio Chiba Intracorporeal capsule
US6342774B1 (en) 2001-03-27 2002-01-29 Motorola, Inc. Battery having user charge capacity control
JP2002290212A (en) 2001-03-27 2002-10-04 Nec Corp Voltage controlled oscillator
EP1383575A4 (en) 2001-03-28 2010-01-20 Televital Inc System and method for real-time monitoring, assessment, analysis, retrieval, and storage of physiological data over a wide area network
JP2002291684A (en) 2001-03-29 2002-10-08 Olympus Optical Co Ltd Endoscope for surgical operation, and outer tube
US6595929B2 (en) 2001-03-30 2003-07-22 Bodymedia, Inc. System for monitoring health, wellness and fitness having a method and apparatus for improved measurement of heat flow
GB0108208D0 (en) 2001-04-02 2001-05-23 Glaxo Group Ltd Medicament dispenser
JP2004527296A (en) 2001-04-02 2004-09-09 エヌ アイ メディカル リミテッド Hemodynamic measurement device
WO2002080762A1 (en) 2001-04-06 2002-10-17 Medic4All Inc. A physiological monitoring system for a computational device of a human subject
US6694161B2 (en) 2001-04-20 2004-02-17 Monsanto Technology Llc Apparatus and method for monitoring rumen pH
US6801137B2 (en) 2001-04-23 2004-10-05 Cardionet, Inc. Bidirectional communication between a sensor unit and a monitor unit in patient monitoring
US6782290B2 (en) 2001-04-27 2004-08-24 Medtronic, Inc. Implantable medical device with rechargeable thin-film microbattery power source
WO2002087696A1 (en) 2001-04-30 2002-11-07 Medtronic,Inc. Transcutaneous monitor and method of use, using therapeutic output from an implanted medical device
MXPA03010059A (en) 2001-05-03 2004-12-06 Telzuit Technologies Llc Wireless medical monitoring apparatus and system.
US7039033B2 (en) 2001-05-07 2006-05-02 Ixi Mobile (Israel) Ltd. System, device and computer readable medium for providing a managed wireless network using short-range radio signals
EP1397660B1 (en) 2001-05-20 2013-05-15 Given Imaging Ltd. A floatable in vivo sensing device
BRPI0209720A2 (en) 2001-05-31 2017-06-13 Microdose Tech Inc dosage and packaging of controlled release medication
GB0113212D0 (en) 2001-05-31 2001-07-25 Oxford Biosignals Ltd Patient condition display
US20020192159A1 (en) 2001-06-01 2002-12-19 Reitberg Donald P. Single-patient drug trials used with accumulated database: flowchart
US20020179921A1 (en) 2001-06-02 2002-12-05 Cohn Michael B. Compliant hermetic package
EP1418833B1 (en) 2001-06-18 2008-08-13 Given Imaging Ltd. Swallowable in vivo sensing capsule with a circuit board having rigid sections and flexible sections
BR0210508A (en) 2001-06-19 2006-04-04 Digital Sports Media physiological monitoring and system
JP2004531399A (en) 2001-06-25 2004-10-14 ファルマシア・コーポレーション Method and apparatus for producing compression-coated tablets
US7160258B2 (en) * 2001-06-26 2007-01-09 Entrack, Inc. Capsule and method for treating or diagnosing the intestinal tract
US6602518B2 (en) 2001-06-28 2003-08-05 Wm. Wrigley Jr. Company Chewable product including active ingredient
US7044911B2 (en) 2001-06-29 2006-05-16 Philometron, Inc. Gateway platform for biological monitoring and delivery of therapeutic compounds
WO2003004975A1 (en) 2001-07-02 2003-01-16 Battelle Memorial Institute Intelligent microsensor module
ES2329452T3 (en) 2001-07-11 2009-11-26 Cns Response, Inc. PROCEDURE TO PREACH THE RESULT OF TREATMENTS.
AU2002317466B2 (en) * 2001-07-12 2008-02-28 Given Imaging Ltd Device and method for examining a body lumen
US20030017826A1 (en) 2001-07-17 2003-01-23 Dan Fishman Short-range wireless architecture
US7368191B2 (en) 2001-07-25 2008-05-06 Biosource, Inc. Electrode array for use in electrochemical cells
FR2827919B1 (en) 2001-07-26 2004-03-05 Thermodyn SEALING FOR COMPRESSOR AND CENTRIFUGAL COMPRESSOR PROVIDED WITH SUCH A SEAL
US7257438B2 (en) 2002-07-23 2007-08-14 Datascope Investment Corp. Patient-worn medical monitoring device
US6951536B2 (en) 2001-07-30 2005-10-04 Olympus Corporation Capsule-type medical device and medical system
US6747556B2 (en) 2001-07-31 2004-06-08 Medtronic Physio-Control Corp. Method and system for locating a portable medical device
JP2003050867A (en) 2001-08-08 2003-02-21 Nippon Signal Co Ltd:The Method for supporting health check of walker or the like and device therefor
US20030065536A1 (en) 2001-08-13 2003-04-03 Hansen Henrik Egesborg Portable device and method of communicating medical data information
WO2003015890A1 (en) * 2001-08-20 2003-02-27 President And Fellows Of Harvard College Fluidic arrays and method of using
JP3962250B2 (en) 2001-08-29 2007-08-22 株式会社レアメタル In vivo information detection system and tag device and relay device used therefor
US6650191B2 (en) 2001-09-07 2003-11-18 Texas Instruments Incorporated Low jitter ring oscillator architecture
KR100543992B1 (en) 2001-09-21 2006-01-20 토크 엔지니어링 가부시키가이샤 Method for detecting metallic foreign matter and system for detecting metallic foreign matter
EP1438028A1 (en) 2001-09-28 2004-07-21 McNEIL-PPC, INC. Modified release dosage forms
US6604650B2 (en) 2001-09-28 2003-08-12 Koninklijke Philips Electronics N.V. Bottle-cap medication reminder and overdose safeguard
US6982094B2 (en) 2001-09-28 2006-01-03 Mcneil-Ppc, Inc. Systems, methods and apparatuses for manufacturing dosage forms
US7122143B2 (en) 2001-09-28 2006-10-17 Mcneil-Ppc, Inc. Methods for manufacturing dosage forms
US6767200B2 (en) 2001-09-28 2004-07-27 Mcneil-Ppc, Inc. Systems, methods and apparatuses for manufacturing dosage forms
US20050137480A1 (en) 2001-10-01 2005-06-23 Eckhard Alt Remote control of implantable device through medical implant communication service band
US20030062551A1 (en) 2001-10-02 2003-04-03 Jds Uniphase Corporation Electrode structure including encapsulated adhesion layer
US6840904B2 (en) 2001-10-11 2005-01-11 Jason Goldberg Medical monitoring device and system
US7357891B2 (en) 2001-10-12 2008-04-15 Monosol Rx, Llc Process for making an ingestible film
US6745082B2 (en) 2001-10-22 2004-06-01 Jens Axelgaard Current-controlling electrode with adjustable contact area
US20030152622A1 (en) 2001-10-25 2003-08-14 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral diuretic
US20030083559A1 (en) 2001-10-31 2003-05-01 Thompson David L. Non-contact monitor
US6643541B2 (en) 2001-12-07 2003-11-04 Motorola, Inc Wireless electromyography sensor and system
AU2002352369A1 (en) 2001-12-10 2003-07-09 Innovision Research And Technology Plc Detectable components and detection apparatus for detecting such components
US20030107487A1 (en) 2001-12-10 2003-06-12 Ronen Korman Method and device for measuring physiological parameters at the wrist
GB0130010D0 (en) 2001-12-14 2002-02-06 Isis Innovation Combining measurements from breathing rate sensors
US7016648B2 (en) 2001-12-18 2006-03-21 Ixi Mobile (Israel) Ltd. Method, system and computer readable medium for downloading a software component to a device in a short distance wireless network
US7729776B2 (en) 2001-12-19 2010-06-01 Cardiac Pacemakers, Inc. Implantable medical device with two or more telemetry systems
US7035877B2 (en) 2001-12-28 2006-04-25 Kimberly-Clark Worldwide, Inc. Quality management and intelligent manufacturing with labels and smart tags in event-based product manufacturing
US7877273B2 (en) 2002-01-08 2011-01-25 Fredric David Abramson System and method for evaluating and providing nutrigenomic data, information and advice
EP1464026A2 (en) 2002-01-11 2004-10-06 Hexalog SA Systems and methods for medication monitoring
JP3957272B2 (en) * 2002-01-22 2007-08-15 オリンパス株式会社 Capsule medical device
US7184820B2 (en) 2002-01-25 2007-02-27 Subqiview, Inc. Tissue monitoring system for intravascular infusion
JP2003212965A (en) 2002-01-28 2003-07-30 Brother Ind Ltd Active-energy-ray-curable composition
US7519416B2 (en) * 2002-02-04 2009-04-14 Heartview, Llc Diagnostic method utilizing standard lead ECG signals
FR2835730B1 (en) 2002-02-11 2004-12-10 C T M Ct De Transfert Des Micr DEVICE FOR DELIVERY OF SUBSTANCES AND INTRACORPOREAL SAMPLING
US6958034B2 (en) * 2002-02-11 2005-10-25 Given Imaging Ltd. Self propelled device
US6935560B2 (en) 2002-02-26 2005-08-30 Safety Syringes, Inc. Systems and methods for tracking pharmaceuticals within a facility
US20030162556A1 (en) 2002-02-28 2003-08-28 Libes Michael A. Method and system for communication between two wireless-enabled devices
US8660645B2 (en) 2002-02-28 2014-02-25 Greatbatch Ltd. Electronic network components utilizing biocompatible conductive adhesives for direct body fluid exposure
US7043305B2 (en) 2002-03-06 2006-05-09 Cardiac Pacemakers, Inc. Method and apparatus for establishing context among events and optimizing implanted medical device performance
US7468032B2 (en) 2002-12-18 2008-12-23 Cardiac Pacemakers, Inc. Advanced patient management for identifying, displaying and assisting with correlating health-related data
US6968153B1 (en) 2002-03-13 2005-11-22 Nokia Corporation Apparatus, method and system for a Bluetooth repeater
US6957107B2 (en) 2002-03-13 2005-10-18 Cardionet, Inc. Method and apparatus for monitoring and communicating with an implanted medical device
US7188767B2 (en) 2002-03-18 2007-03-13 Precision Dynamics Corporation Physical condition or environmental threat detection appliance system
US7022070B2 (en) 2002-03-22 2006-04-04 Mini-Mitter Co., Inc. Method for continuous monitoring of patients to detect the potential onset of sepsis
JP3869291B2 (en) 2002-03-25 2007-01-17 オリンパス株式会社 Capsule medical device
US6850788B2 (en) 2002-03-25 2005-02-01 Masimo Corporation Physiological measurement communications adapter
US7376435B2 (en) 2002-04-01 2008-05-20 Intel Corporation Transferring multiple data units over a wireless communication link
US7797033B2 (en) * 2002-04-08 2010-09-14 Smart Pill Corporation Method of using, and determining location of, an ingestible capsule
US7654901B2 (en) 2002-04-10 2010-02-02 Breving Joel S Video game system using bio-feedback devices
US7645262B2 (en) 2002-04-11 2010-01-12 Second Sight Medical Products, Inc. Biocompatible bonding method and electronics package suitable for implantation
US6942770B2 (en) 2002-04-19 2005-09-13 Nova Biomedical Corporation Disposable sub-microliter volume biosensor with enhanced sample inlet
US7424268B2 (en) 2002-04-22 2008-09-09 Cisco Technology, Inc. System and method for management of a shared frequency band
KR101124876B1 (en) 2002-04-22 2012-03-28 마시오 마크 아우렐리오 마틴스 애브리우 Apparatus and method for measuring biological parameters
AU2003234159A1 (en) 2002-04-22 2003-11-03 Purdue Research Foundation Hydrogels having enhanced elasticity and mechanical strength properties
EP1356762A1 (en) 2002-04-22 2003-10-29 UbiCom Gesellschaft für Telekommunikation mbH Device for remote monitoring of body functions
US7697995B2 (en) * 2002-04-25 2010-04-13 Medtronic, Inc. Surgical lead paddle
US20030216622A1 (en) 2002-04-25 2003-11-20 Gavriel Meron Device and method for orienting a device in vivo
US20040167465A1 (en) 2002-04-30 2004-08-26 Mihai Dan M. System and method for medical device authentication
TW553735B (en) 2002-05-01 2003-09-21 Jin-Shing Luo Common electrode using human body as common electric reservoir and application thereof
US7901939B2 (en) * 2002-05-09 2011-03-08 University Of Chicago Method for performing crystallization and reactions in pressure-driven fluid plugs
US6946156B2 (en) * 2002-05-15 2005-09-20 Mcneil-Ppc, Inc. Process for enrobing a core
JP2003325439A (en) * 2002-05-15 2003-11-18 Olympus Optical Co Ltd Capsule type medical treatment device
JP2004041709A (en) 2002-05-16 2004-02-12 Olympus Corp Capsule medical care device
JP4187463B2 (en) * 2002-05-16 2008-11-26 オリンパス株式会社 Capsule medical device
US20030216729A1 (en) 2002-05-20 2003-11-20 Marchitto Kevin S. Device and method for wound healing and uses therefor
GB0211620D0 (en) 2002-05-21 2002-07-03 Bioprogress Technology Ltd Powder compaction and enrobing
JP3576150B2 (en) 2002-05-31 2004-10-13 株式会社東芝 Relay device and power control method
US6847844B2 (en) * 2002-06-06 2005-01-25 University Of Pittsburgh Of The Commonwealth System Of Higher Education Method of data communication with implanted device and associated apparatus
US8003179B2 (en) * 2002-06-20 2011-08-23 Alcan Packaging Flexible France Films having a desiccant material incorporated therein and methods of use and manufacture
US6864692B1 (en) 2002-06-20 2005-03-08 Xsilogy, Inc. Sensor having improved selectivity
AU2003280415A1 (en) 2002-07-01 2004-01-19 Gmp Wireless Medicine, Inc. Wireless ecg system
US20060129060A1 (en) 2002-07-02 2006-06-15 Healthpia America Management method of fat mass and management device of fat mass using mobile phone
US20040008123A1 (en) * 2002-07-15 2004-01-15 Battelle Memorial Institute System and method for tracking medical devices
AU2003213529B2 (en) 2002-07-19 2005-01-20 Panasonic Healthcare Holdings Co., Ltd. ZrO2-AI2O3 composite ceramic material and production method thereof
FR2842721B1 (en) 2002-07-25 2005-06-24 Assist Publ Hopitaux De Paris METHOD FOR NON-INVASIVE AND AMBULATORY EXPLORATION OF DIGESTIVE TRACTION AND TRANSIT AND CORRESPONDING SYSTEM
US20040019172A1 (en) 2002-07-26 2004-01-29 Tou-Hsiung Yang Biodegradable, water absorbable resin and its preparation method
US7211349B2 (en) 2002-08-06 2007-05-01 Wilson Greatbatch Technologies, Inc. Silver vanadium oxide provided with a metal oxide coating
US20040143182A1 (en) 2002-08-08 2004-07-22 Pavel Kucera System and method for monitoring and stimulating gastro-intestinal motility
US6909878B2 (en) 2002-08-20 2005-06-21 Ixi Mobile (Israel) Ltd. Method, system and computer readable medium for providing an output signal having a theme to a device in a short distance wireless network
US7619819B2 (en) * 2002-08-20 2009-11-17 Illumina, Inc. Method and apparatus for drug product tracking using encoded optical identification elements
US7020508B2 (en) 2002-08-22 2006-03-28 Bodymedia, Inc. Apparatus for detecting human physiological and contextual information
US7294105B1 (en) 2002-09-03 2007-11-13 Cheetah Omni, Llc System and method for a wireless medical communication system
DE60305817T2 (en) 2002-09-04 2007-01-11 Broadcom Corp., Irvine System and method for optimizing power consumption in a mobile environment
US7102508B2 (en) 2002-09-09 2006-09-05 Persephone, Inc. Method and apparatus for locating and tracking persons
US20040049245A1 (en) 2002-09-09 2004-03-11 Volker Gass Autonomous patch for communication with an implantable device, and medical kit for using said patch
GB2393356B (en) 2002-09-18 2006-02-01 E San Ltd Telemedicine system
US7388903B2 (en) 2002-09-18 2008-06-17 Conexant, Inc. Adaptive transmission rate and fragmentation threshold mechanism for local area networks
US7118531B2 (en) 2002-09-24 2006-10-10 The Johns Hopkins University Ingestible medical payload carrying capsule with wireless communication
US6842636B2 (en) 2002-09-27 2005-01-11 Axelgaard Manufacturing Co., Ltd. Medical electrode
US7736309B2 (en) 2002-09-27 2010-06-15 Medtronic Minimed, Inc. Implantable sensor method and system
US7209790B2 (en) 2002-09-30 2007-04-24 Medtronic, Inc. Multi-mode programmer for medical device communication
US7686762B1 (en) 2002-10-03 2010-03-30 Integrated Sensing Systems, Inc. Wireless device and system for monitoring physiologic parameters
MXPA05003688A (en) 2002-10-09 2005-09-30 Bodymedia Inc Method and apparatus for auto journaling of continuous or discrete body states utilizing physiological and/or contextual parameters.
US20040073454A1 (en) 2002-10-10 2004-04-15 John Urquhart System and method of portal-mediated, website-based analysis of medication dosing
US6959217B2 (en) 2002-10-24 2005-10-25 Alfred E. Mann Foundation For Scientific Research Multi-mode crystal oscillator system selectively configurable to minimize power consumption or noise generation
US7027871B2 (en) 2002-10-31 2006-04-11 Medtronic, Inc. Aggregation of data from external data sources within an implantable medical device
US6773360B2 (en) 2002-11-08 2004-08-10 Taylor Made Golf Company, Inc. Golf club head having a removable weight
US20030126593A1 (en) 2002-11-04 2003-07-03 Mault James R. Interactive physiological monitoring system
US7232627B2 (en) 2002-11-08 2007-06-19 Honda Motor Co., Ltd. Electrode for solid polymer fuel cell
US20040092801A1 (en) 2002-11-13 2004-05-13 Budimir Drakulic System for, and method of, acquiring physiological signals of a patient
GB2395613B (en) 2002-11-21 2006-09-06 Hewlett Packard Co Memory tag,read/write device and method of operating a memory tag
AU2003282373A1 (en) 2002-11-29 2004-06-23 Given Imaging Ltd. Methods device and system for in vivo diagnosis
US20040115507A1 (en) 2002-12-05 2004-06-17 Potter Curtis N Monolithic fuel cell and method of manufacture
US8712549B2 (en) 2002-12-11 2014-04-29 Proteus Digital Health, Inc. Method and system for monitoring and treating hemodynamic parameters
JP2006510655A (en) 2002-12-11 2006-03-30 ファイザー・プロダクツ・インク Controlled release of active substances into high fat environments
EP1578260B1 (en) 2002-12-16 2012-10-24 Given Imaging Ltd. Device, system and method for selective activation of in vivo sensors
US20040167226A1 (en) 2002-12-16 2004-08-26 Serafini Tito A. Methods for the treatment of pain and traumatic injury using benzamides and compositions containing the same
US7009511B2 (en) 2002-12-17 2006-03-07 Cardiac Pacemakers, Inc. Repeater device for communications with an implantable medical device
WO2004056418A1 (en) 2002-12-19 2004-07-08 Koninklijke Philips Electronics N.V. An electrode assembly and a system with impedance control
US7127300B2 (en) 2002-12-23 2006-10-24 Cardiac Pacemakers, Inc. Method and apparatus for enabling data communication between an implantable medical device and a patient management system
US7547278B2 (en) 2002-12-27 2009-06-16 Matsushita Electric Industrial Co., Ltd. Tele-care monitoring device
DE10261748B4 (en) 2002-12-30 2011-07-28 Mate Precision Tooling GmbH, 61440 punching tool
US6975174B1 (en) 2002-12-31 2005-12-13 Radioframe Networks, Inc. Clock oscillator
US7505029B2 (en) * 2002-12-31 2009-03-17 Intel Corporation System and method for controlling multiple processing units with a single input device
US20060142648A1 (en) 2003-01-07 2006-06-29 Triage Data Networks Wireless, internet-based, medical diagnostic system
US7396330B2 (en) 2003-01-07 2008-07-08 Triage Data Networks Wireless, internet-based medical-diagnostic system
US7512448B2 (en) 2003-01-10 2009-03-31 Phonak Ag Electrode placement for wireless intrabody communication between components of a hearing system
KR100522132B1 (en) 2003-01-25 2005-10-18 한국과학기술연구원 Data receiving method and apparatus in human body communication system
CN1774239A (en) 2003-01-29 2006-05-17 埃-皮尔制药公司 Active drug delivery in the gastrointestinal tract
US20040267240A1 (en) * 2003-01-29 2004-12-30 Yossi Gross Active drug delivery in the gastrointestinal tract
EP1443780B1 (en) 2003-01-30 2013-05-29 Accenture Global Services Limited Event data acquisition and transmission system
US7002476B2 (en) 2003-01-30 2006-02-21 Leap Of Faith Technologies, Inc. Medication compliance system
US7149581B2 (en) 2003-01-31 2006-12-12 Medtronic, Inc. Patient monitoring device with multi-antenna receiver
US6933026B2 (en) 2003-02-06 2005-08-23 Aradgim Corporation Method to reduce damage caused by irradiation of halogenated polymers
US7392015B1 (en) 2003-02-14 2008-06-24 Calamp Corp. Calibration methods and structures in wireless communications systems
US7215660B2 (en) 2003-02-14 2007-05-08 Rearden Llc Single transceiver architecture for a wireless network
AU2004214420A1 (en) 2003-02-19 2004-09-02 Sicel Technologies Inc. In vivo fluorescence sensors, systems, and related methods operating in conjunction with fluorescent analytes
JP4158097B2 (en) 2003-02-27 2008-10-01 ソニー株式会社 Authentication system
CN101667870A (en) 2003-02-27 2010-03-10 奎法克特股份有限公司 Manufacturing method of electrode used in communication of quasi-electrostatic field
JP4114143B2 (en) * 2003-02-27 2008-07-09 ソニー株式会社 COMMUNICATION SYSTEM, COMMUNICATION METHOD, AND COMMUNICATION DEVICE
US6888337B2 (en) 2003-03-04 2005-05-03 Hewlett-Packard Development Company, L.P. Power system and method
US7653031B2 (en) 2003-03-05 2010-01-26 Timothy Gordon Godfrey Advance notification of transmit opportunities on a shared-communications channel
US7155232B2 (en) 2003-03-05 2006-12-26 Conexant Systems, Inc. Transmit request signaling between transceivers
JP2006520657A (en) 2003-03-21 2006-09-14 ウェルチ・アリン・インコーポレーテッド Personal condition physiological monitoring system and structure, and monitoring method
US7321920B2 (en) 2003-03-21 2008-01-22 Vocel, Inc. Interactive messaging system
DE10313005B4 (en) * 2003-03-24 2007-05-03 Siemens Ag Backup battery and method for its manufacture
US20040193446A1 (en) * 2003-03-27 2004-09-30 Mayer Steven Lloyd System and method for managing a patient treatment program including a prescribed drug regimen
IL161096A (en) * 2003-03-27 2008-08-07 Given Imaging Ltd Device, system and method for measuring a gradient in-vivo
GB0308114D0 (en) 2003-04-08 2003-05-14 Glaxo Group Ltd Novel compounds
JP2006522819A (en) * 2003-04-08 2006-10-05 プロジェニックス ファーマシューティカルズ,インコーポレーテッド Combination therapy of constipation combined with laxatives and peripheral opioid antagonists
JP4593083B2 (en) 2003-04-11 2010-12-08 オリンパス株式会社 Inspection data management method
GB0308467D0 (en) 2003-04-11 2003-05-21 Rolls Royce Plc Method and system for analysing tachometer and vibration data from an apparatus having one or more rotary components
US7972616B2 (en) 2003-04-17 2011-07-05 Nanosys, Inc. Medical device applications of nanostructured surfaces
FI116117B (en) 2003-04-17 2005-09-30 Polar Electro Oy Measuring device and method for measuring heart rate and the method of manufacture of the measuring device
AU2004233670B2 (en) 2003-04-25 2007-11-29 Olympus Corporation Radio-type in-subject information acquisition system and outside-subject device
US20040218683A1 (en) 2003-05-01 2004-11-04 Texas Instruments Incorporated Multi-mode wireless devices having reduced-mode receivers
TWI226761B (en) 2003-05-08 2005-01-11 Ind Tech Res Inst Dual band transceiver architecture for wireless application
US20040225199A1 (en) 2003-05-08 2004-11-11 Evanyk Shane Walter Advanced physiological monitoring systems and methods
US7031745B2 (en) 2003-05-12 2006-04-18 Shen Ein-Yiao Cellular phone combined physiological condition examination and processing device
JP4402655B2 (en) * 2003-05-14 2010-01-20 オリンパス株式会社 Capsule medical device
US7311665B2 (en) 2003-05-19 2007-12-25 Alcohol Monitoring Systems, Inc. Bio-information sensor monitoring system and method
KR100542101B1 (en) 2003-06-02 2006-01-11 삼성전자주식회사 Power control method and bluetooth device using the same
US7188199B2 (en) 2003-06-03 2007-03-06 Silicon Labs Cp, Inc. DMA controller that restricts ADC from memory without interrupting generation of digital words when CPU accesses memory
US20040249257A1 (en) 2003-06-04 2004-12-09 Tupin Joe Paul Article of manufacture for extracting physiological data using ultra-wideband radar and improved signal processing techniques
JP4414682B2 (en) 2003-06-06 2010-02-10 オリンパス株式会社 Ultrasound endoscope device
US7313163B2 (en) 2003-06-17 2007-12-25 Motorola, Inc. Fast synchronization for half duplex digital communications
US20040260154A1 (en) 2003-06-18 2004-12-23 Boris Sidelnik Human physiological and chemical monitoring system
US7252152B2 (en) 2003-06-18 2007-08-07 Weatherford/Lamb, Inc. Methods and apparatus for actuating a downhole tool
EP1637063B1 (en) 2003-06-24 2012-11-28 Olympus Corporation Capsule type medical device communication system
WO2005006968A1 (en) 2003-07-16 2005-01-27 Koninklijke Philips Electronics N.V. A portable electronic device and a health management system arranged for monitoring a physiological condition of an individual
WO2005007223A2 (en) * 2003-07-16 2005-01-27 Sasha John Programmable medical drug delivery systems and methods for delivery of multiple fluids and concentrations
US7554452B2 (en) 2003-07-18 2009-06-30 Cary Cole Ingestible tracking and locating device
US7442164B2 (en) 2003-07-23 2008-10-28 Med-El Elektro-Medizinische Gerate Gesellschaft M.B.H. Totally implantable hearing prosthesis
US7653350B2 (en) 2003-07-24 2010-01-26 Sony Ericsson Mobile Communications Ab Wireless terminals and methods for communicating over cellular and enhanced mode bluetooth communication links
JP4038575B2 (en) * 2003-07-25 2008-01-30 独立行政法人産業技術総合研究所 Biosensor, biosensor device or biosensor storage method
US7243118B2 (en) 2003-07-30 2007-07-10 Broadcom Corporation Method and apparatus for efficient derivation of modulo arithmetic for frequency selection
US7591801B2 (en) 2004-02-26 2009-09-22 Dexcom, Inc. Integrated delivery device for continuous glucose sensor
US20050055014A1 (en) * 2003-08-04 2005-03-10 Coppeta Jonathan R. Methods for accelerated release of material from a reservoir device
EP1670547B1 (en) 2003-08-18 2008-11-12 Cardiac Pacemakers, Inc. Patient monitoring system
WO2005018432A2 (en) * 2003-08-20 2005-03-03 Philometron, Inc. Hydration monitoring
US20050172958A1 (en) 2003-08-20 2005-08-11 The Brigham And Women's Hospital, Inc. Inhalation device and system for the remote monitoring of drug administration
US8346482B2 (en) 2003-08-22 2013-01-01 Fernandez Dennis S Integrated biosensor and simulation system for diagnosis and therapy
JP4398204B2 (en) 2003-08-29 2010-01-13 オリンパス株式会社 In-subject introduction apparatus and wireless in-subject information acquisition system
JP4332152B2 (en) * 2003-09-02 2009-09-16 富士通株式会社 Drug administration status management method and drug
JP3993546B2 (en) 2003-09-08 2007-10-17 オリンパス株式会社 In-subject introduction apparatus and wireless in-subject information acquisition system
US20050062644A1 (en) 2003-09-08 2005-03-24 Leci Jonathan Ilan Capsule device to identify the location of an individual
CA2896407A1 (en) 2003-09-11 2005-03-24 Theranos, Inc. Medical device for analyte monitoring and drug delivery
CA2538710A1 (en) 2003-09-12 2005-03-31 Bodymedia, Inc. Method and apparatus for measuring heart related parameters
US7352998B2 (en) 2003-09-12 2008-04-01 Nokia Corporation Method and system for establishing a wireless communications link
US7499674B2 (en) 2003-09-12 2009-03-03 Nokia Corporation Method and system for repeat request in hybrid ultra wideband-bluetooth radio
JP4153852B2 (en) 2003-09-18 2008-09-24 オリンパス株式会社 Energy supply coil and wireless in-vivo information acquisition system using the same
JP2007521490A (en) 2003-09-22 2007-08-02 ヒョン−ユン,キム Structural health monitor sensor and system
US20090157358A1 (en) 2003-09-22 2009-06-18 Hyeung-Yun Kim System for diagnosing and monitoring structural health conditions
US7218967B2 (en) 2003-09-26 2007-05-15 Medtronic, Inc. System and method for real-time remote monitoring of implantable medical devices
JP2005102959A (en) 2003-09-30 2005-04-21 Seiko Epson Corp Pulse wave detector and pulse wave detecting apparatus using the same
JP4503979B2 (en) 2003-10-22 2010-07-14 オリンパス株式会社 Internal devices and medical devices
US20050075145A1 (en) 2003-10-03 2005-04-07 Dvorak Joseph L. Method and system for coordinating use of objects using wireless communications
ATE327601T1 (en) 2003-10-23 2006-06-15 Sony Ericsson Mobile Comm Ab ADDITIONAL CONTROL OF THE REFERENCE SIGNAL OF THE AUTOMATIC POWER CONTROL IN A MOBILE TERMINAL
US20050096514A1 (en) 2003-11-01 2005-05-05 Medtronic, Inc. Gastric activity notification
ATE482650T1 (en) 2003-11-03 2010-10-15 Microchips Inc MEDICAL DEVICE FOR MEASURING GLUCOSE
US6892590B1 (en) 2003-11-04 2005-05-17 Andermotion Technologies Llc Single-balanced shield electrode configuration for use in capacitive displacement sensing systems and methods
US7101343B2 (en) 2003-11-05 2006-09-05 Temple University Of The Commonwealth System Of Higher Education Implantable telemetric monitoring system, apparatus, and method
US20050101843A1 (en) 2003-11-06 2005-05-12 Welch Allyn, Inc. Wireless disposable physiological sensor
US7415242B1 (en) 2003-11-10 2008-08-19 Sprint Spectrum L.P. Method and system for proximity detection for an in-building wireless repeater
DE102004032812B4 (en) 2003-11-11 2006-07-20 Dräger Safety AG & Co. KGaA Combination sensor for physiological measurements
JP2005158770A (en) 2003-11-20 2005-06-16 Matsushita Electric Ind Co Ltd Laminated substrate and manufacturing method thereof, manufacturing method and apparatus of module using the laminated substrate
WO2005053517A1 (en) 2003-12-01 2005-06-16 Olympus Corporation Endoscope system
US6987691B2 (en) 2003-12-02 2006-01-17 International Business Machines Corporation Easy axis magnetic amplifier
US8306592B2 (en) 2003-12-19 2012-11-06 Olympus Corporation Capsule medical device
JP2005185567A (en) 2003-12-25 2005-07-14 Olympus Corp Medical capsule apparatus
JP4198045B2 (en) 2003-12-25 2008-12-17 オリンパス株式会社 In-subject position detection system
US8185191B1 (en) 2003-12-29 2012-05-22 Michael Evan Shapiro Pulse monitoring and warning system for infants
JP2005192821A (en) 2004-01-07 2005-07-21 Olympus Corp Capsule type medical apparatus
JP2005193535A (en) * 2004-01-07 2005-07-21 Alps Electric Co Ltd Thermal head, method of manufacturing the same, and method of adjusting dot aspect ratio of the thermal head
US7081807B2 (en) 2004-01-14 2006-07-25 Joseph Lai Automatic pill reminder bottles
US7176784B2 (en) 2004-01-21 2007-02-13 Battelle Memorial Institute K1-53 Multi-mode radio frequency device
US7375733B2 (en) 2004-01-28 2008-05-20 Canon Kabushiki Kaisha Method for driving image display apparatus
US7342895B2 (en) 2004-01-30 2008-03-11 Mark Serpa Method and system for peer-to-peer wireless communication over unlicensed communication spectrum
US7647112B2 (en) 2004-02-11 2010-01-12 Ethicon, Inc. System and method for selectively stimulating different body parts
US20060154642A1 (en) 2004-02-20 2006-07-13 Scannell Robert F Jr Medication & health, environmental, and security monitoring, alert, intervention, information and network system with associated and supporting apparatuses
US20050187789A1 (en) 2004-02-25 2005-08-25 Cardiac Pacemakers, Inc. Advanced patient and medication therapy management system and method
ATE473678T1 (en) 2004-02-27 2010-07-15 Koninkl Philips Electronics Nv PORTABLE WIRELESS DEVICE FOR MONITORING, ANALYZING AND COMMUNICATING PHYSIOLOGICAL STATUS
CN1284505C (en) 2004-02-28 2006-11-15 重庆金山科技(集团)有限公司 Radio capsule like endoscope system for medical use
US7406105B2 (en) 2004-03-03 2008-07-29 Alfred E. Mann Foundation For Scientific Research System and method for sharing a common communication channel between multiple systems of implantable medical devices
DE602004024227D1 (en) 2004-03-04 2009-12-31 Olympus Corp MEDICAL SYSTEM OF CAPSULE TYPE
GB0405798D0 (en) 2004-03-15 2004-04-21 E San Ltd Medical data display
EP1734858B1 (en) 2004-03-22 2014-07-09 BodyMedia, Inc. Non-invasive temperature monitoring device
JP4520198B2 (en) 2004-04-07 2010-08-04 オリンパス株式会社 In-subject position display system
US20050234307A1 (en) 2004-04-15 2005-10-20 Nokia Corporation Physiological event handling system and method
US9011329B2 (en) 2004-04-19 2015-04-21 Searete Llc Lumenally-active device
US8512219B2 (en) 2004-04-19 2013-08-20 The Invention Science Fund I, Llc Bioelectromagnetic interface system
JP2005304880A (en) * 2004-04-23 2005-11-04 Hitachi Ltd In-vivo object management system utilizing non-contact ic tag
EP1749246A4 (en) 2004-04-24 2011-11-02 Inrange Systems Inc Integrated, non-sequential, remote medication management and compliance system
US7196495B1 (en) 2004-04-27 2007-03-27 Concord Technologies, Lp Dual battery and monitor arrangement
US20050245794A1 (en) 2004-04-29 2005-11-03 Medtronic, Inc. Communication with implantable monitoring probe
GB0410248D0 (en) 2004-05-07 2004-06-09 Isis Innovation Signal analysis method
US20080051667A1 (en) 2004-05-16 2008-02-28 Rami Goldreich Method And Device For Measuring Physiological Parameters At The Hand
US20050261559A1 (en) 2004-05-18 2005-11-24 Mumford John R Wireless physiological monitoring system
US7575005B2 (en) 2004-05-18 2009-08-18 Excel-Tech Ltd. Mask assembly with integrated sensors
US7125382B2 (en) 2004-05-20 2006-10-24 Digital Angel Corporation Embedded bio-sensor system
JP4459715B2 (en) 2004-05-20 2010-04-28 芝浦メカトロニクス株式会社 Image recognition method, image recognition apparatus, and mounting apparatus
JP2005332328A (en) 2004-05-21 2005-12-02 Toyo Network Systems Co Ltd Tabulation system
US20050259768A1 (en) 2004-05-21 2005-11-24 Oki Techno Centre (Singapore) Pte Ltd Digital receiver and method for processing received signals
KR100592934B1 (en) 2004-05-21 2006-06-23 한국전자통신연구원 Wearable physiological signal detection module and measurement apparatus with the same
US7653542B2 (en) 2004-05-26 2010-01-26 Verizon Business Global Llc Method and system for providing synthesized speech
US20050267556A1 (en) 2004-05-28 2005-12-01 Allan Shuros Drug eluting implants to prevent cardiac apoptosis
EP1766591B1 (en) 2004-05-28 2008-01-16 Jan De Geest Communication unit for a person's skin
JP4666951B2 (en) 2004-06-03 2011-04-06 シーケーディ株式会社 Blister packaging machine and pharmaceutical solid preparation
TWI428271B (en) 2004-06-09 2014-03-01 Smithkline Beecham Corp Apparatus and method for pharmaceutical production
US7289855B2 (en) 2004-06-09 2007-10-30 Medtronic, Inc. Implantable medical device package antenna
WO2006022993A2 (en) 2004-06-10 2006-03-02 Ndi Medical, Llc Implantable generator for muscle and nerve stimulation
US7878064B2 (en) 2004-06-12 2011-02-01 Akubio Limited Analytical apparatus with array of sensors and calibrating element
US7697994B2 (en) 2004-06-18 2010-04-13 Medtronic, Inc. Remote scheduling for management of an implantable medical device
JP2006003307A (en) 2004-06-21 2006-01-05 Mitsutoyo Corp Encoder, and signal regulation method therefor
KR100615431B1 (en) 2004-06-22 2006-08-25 한국전자통신연구원 Physiological signal detection module, a multi-channel connector module and physiological signal detection apparatus with the same
JP2006006377A (en) 2004-06-22 2006-01-12 Elquest Corp Powder paper for packing medicine
US7498940B2 (en) 2004-06-22 2009-03-03 Vubiq, Inc. RFID system utilizing parametric reradiated technology
US20050285746A1 (en) 2004-06-25 2005-12-29 Sengupta Uttam K Radio frequency identification based system to track consumption of medication
US7206630B1 (en) 2004-06-29 2007-04-17 Cleveland Medical Devices, Inc Electrode patch and wireless physiological measurement system and method
US20070027383A1 (en) 2004-07-01 2007-02-01 Peyser Thomas A Patches, systems, and methods for non-invasive glucose measurement
US20060001496A1 (en) 2004-07-02 2006-01-05 Abrosimov Igor A Array oscillator and polyphase clock generator
JP4462614B2 (en) 2004-07-05 2010-05-12 ソニー・エリクソン・モバイルコミュニケーションズ株式会社 Short-range wireless communication system, portable terminal device, and wireless communication device
US7505795B1 (en) 2004-07-07 2009-03-17 Advanced Micro Devices, Inc. Power save management with customized range for user configuration and tuning value based upon recent usage
US7343186B2 (en) 2004-07-07 2008-03-11 Masimo Laboratories, Inc. Multi-wavelength physiological monitor
EP1781162A1 (en) 2004-07-09 2007-05-09 Tadiran Spectralink Ltd. Wearable device, system and method for measuring vital parameters
CN1314134C (en) * 2004-07-15 2007-05-02 上海交通大学 Method for preparing silicon thin film heterojunction solar cell
US20080027679A1 (en) 2004-07-21 2008-01-31 Dror Shklarski Wearable Device, System and Method for Measuring Physiological and/or Environmental Parameters
CN100459614C (en) 2004-07-22 2009-02-04 华为技术有限公司 Mobile phone external device and method
US7537590B2 (en) 2004-07-30 2009-05-26 Microchips, Inc. Multi-reservoir device for transdermal drug delivery and sensing
US7317378B2 (en) 2004-08-17 2008-01-08 Tagent Corporation Product identification tag device and reader
US20060058602A1 (en) 2004-08-17 2006-03-16 Kwiatkowski Krzysztof C Interstitial fluid analyzer
US7253716B2 (en) 2004-08-17 2007-08-07 Tagent Corporation Trackable pills with electronic ID tags
US8518022B2 (en) * 2004-08-27 2013-08-27 Medimetrics Personalized Drug Delivery, Inc. Electronically and remotely controlled pill and system for delivering at least one medicament
JP5032321B2 (en) 2004-08-31 2012-09-26 ライフスキャン・スコットランド・リミテッド Manufacturing method of automatic calibration sensor
WO2006029090A2 (en) 2004-09-02 2006-03-16 Proteus Biomedical, Inc. Methods and apparatus for tissue activation and monitoring
KR100727817B1 (en) * 2004-09-07 2007-06-13 한국전자통신연구원 The communication apparatus using the human body with the medium and method for the same
CA2578078A1 (en) 2004-09-08 2006-03-16 Alertis Medical As Sensor
KR20060023228A (en) 2004-09-09 2006-03-14 이기방 Battery with porous material and fabrication method thereof
GB2418144A (en) 2004-09-17 2006-03-22 Psimedica Ltd Medical device for delivery of beneficial substance
US20060065713A1 (en) 2004-09-24 2006-03-30 John Russell Kingery System and method for monitored administration of medical products to patients
US7618374B2 (en) 2004-09-27 2009-11-17 Siemens Medical Solutions Usa, Inc. Image plane sensing methods and systems for intra-patient probes
US7554464B1 (en) 2004-09-30 2009-06-30 Gear Six, Inc. Method and system for processing data having a pattern of repeating bits
CN101040286B (en) 2004-09-30 2012-10-03 皇家飞利浦电子股份有限公司 System for automatic continuous and reliable patient identification for association of wireless medical devices to patients
US7341560B2 (en) 2004-10-05 2008-03-11 Rader, Fishman & Grauer Pllc Apparatuses and methods for non-invasively monitoring blood parameters
US20060078765A1 (en) 2004-10-12 2006-04-13 Laixia Yang Nano-structured ion-conducting inorganic membranes for fuel cell applications
JP2008011865A (en) 2004-10-27 2008-01-24 Sharp Corp Healthcare apparatus and program for driving the same to function
US7917199B2 (en) 2004-11-02 2011-03-29 Medtronic, Inc. Patient event marking in combination with physiological signals
ATE490724T1 (en) 2004-11-02 2010-12-15 Medtronic Inc DEVICE FOR DATA RETENTION IN AN IMPLANTABLE MEDICAL DEVICE
AU2005229684A1 (en) 2004-11-04 2006-05-18 Given Imaging Ltd Apparatus and method for receiving device selection and combining
KR20060040500A (en) 2004-11-06 2006-05-10 삼성전자주식회사 Method and appratus for measuring bio signal
US7930064B2 (en) 2004-11-19 2011-04-19 Parata Systems, Llc Automated drug discrimination during dispensing
US7214107B2 (en) 2004-11-22 2007-05-08 Cardiodynamics International Corporation Electrical connector apparatus and methods
US8374693B2 (en) 2004-12-03 2013-02-12 Cardiac Pacemakers, Inc. Systems and methods for timing-based communication between implantable medical devices
US7154071B2 (en) 2004-12-07 2006-12-26 Dräger Safety AG & Co. KGaA Device for transmitting an electric signal detected by contact with the skin surface
US7616710B2 (en) * 2004-12-08 2009-11-10 Electronics And Telecommunications Research Institute Frequency offset estimating method and receiver employing the same
CN101073212A (en) * 2004-12-08 2007-11-14 精工电子有限公司 Information transmission through-human-body system and transmitter/receiver
ATE545361T1 (en) 2004-12-13 2012-03-15 Koninkl Philips Electronics Nv MOBILE MONITORING
EP1827388A2 (en) 2004-12-14 2007-09-05 E-Pill Pharma Ltd. Local delivery of drugs or substances using electronic permeability increase
US20060136266A1 (en) 2004-12-20 2006-06-22 E-San Limited Medicinal product order processing system
JP4432766B2 (en) 2004-12-21 2010-03-17 Jfeスチール株式会社 Electrical resistance measurement method and apparatus
US7249212B2 (en) 2004-12-22 2007-07-24 International Business Machines Corporation Bluetooth association based on docking connection
US7146449B2 (en) 2004-12-22 2006-12-05 International Business Machines Corporation Bluetooth association with simple power connection
EP1676522B1 (en) 2004-12-30 2008-07-02 Given Imaging Ltd. System for locating an in-vivo signal source
KR20060077523A (en) 2004-12-30 2006-07-05 충북대학교 산학협력단 Systema and method for monitoring prescription
US20060148254A1 (en) 2005-01-05 2006-07-06 Mclean George Y Activated iridium oxide electrodes and methods for their fabrication
EP1841476B1 (en) 2005-01-17 2011-06-29 Novo Nordisk A/S Fluid delivery device with integrated monitoring of physiological characteristics
WO2006077527A2 (en) * 2005-01-18 2006-07-27 Koninklijke Philips Electronics, N.V. Electronically controlled capsule for releasing radiation
US20080269664A1 (en) * 2005-01-18 2008-10-30 Koninklijke Philips Electronics, N.V. System and Method For Controlling Traversal of an Igested Capsule
WO2006077528A2 (en) * 2005-01-18 2006-07-27 Koninklijke Philips Electronics, N.V. Electronically controlled capsule
WO2006077530A2 (en) * 2005-01-18 2006-07-27 Koninklijke Philips Electronics, N.V. Electronically controlled ingestible capsule for sampling fluids in alimentary tract
US7686839B2 (en) 2005-01-26 2010-03-30 Lumitex, Inc. Phototherapy treatment devices for applying area lighting to a wound
JP4731936B2 (en) * 2005-02-09 2011-07-27 本田技研工業株式会社 Rotary variable resistor
JP4099484B2 (en) 2005-02-09 2008-06-11 株式会社カイザーテクノロジー Communications system.
EP1850747A2 (en) 2005-02-11 2007-11-07 The University Court Of The University Of Glasgow Sensing device, apparatus and system, and method for operating the same
US7850645B2 (en) 2005-02-11 2010-12-14 Boston Scientific Scimed, Inc. Internal medical devices for delivery of therapeutic agent in conjunction with a source of electrical power
DE102005007790B4 (en) 2005-02-19 2007-06-28 Fette Gmbh Method and device for the test extrusion of multilayer tablets or coated tablets
KR20060097523A (en) 2005-03-10 2006-09-14 강성철 Apparatus for automatic peeling and plating of lead wire
US7504954B2 (en) 2005-03-17 2009-03-17 Spaeder Jeffrey A Radio frequency identification pharmaceutical tracking system and method
EP1863559A4 (en) 2005-03-21 2008-07-30 Abbott Diabetes Care Inc Method and system for providing integrated medication infusion and analyte monitoring system
JP5011275B2 (en) 2005-03-22 2012-08-29 コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ Addressing scheme for high performance wireless medical sensor networks
US20060252999A1 (en) 2005-05-03 2006-11-09 Devaul Richard W Method and system for wearable vital signs and physiology, activity, and environmental monitoring
US20060216603A1 (en) 2005-03-26 2006-09-28 Enable Ipc Lithium-ion rechargeable battery based on nanostructures
JP2006278091A (en) 2005-03-29 2006-10-12 Hitachi Maxell Ltd Coin-shaped silver-oxide battery
US20060224326A1 (en) 2005-03-31 2006-10-05 St Ores John W Integrated data collection and analysis for clinical study
GB0506925D0 (en) 2005-04-06 2005-05-11 Zarlink Semiconductor Ab Ultra low power wake-up solution for implantable RF telemetry devices
WO2006107244A1 (en) 2005-04-07 2006-10-12 St. Jude Medical Ab System and method for radio communication between an implantable medical device and an external base unit
US7760104B2 (en) 2005-04-08 2010-07-20 Entegris, Inc. Identification tag for fluid containment drum
WO2006109072A2 (en) 2005-04-14 2006-10-19 Hidalgo Limited Apparatus and system for monitoring
US7270633B1 (en) 2005-04-22 2007-09-18 Cardiac Pacemakers, Inc. Ambulatory repeater for use in automated patient care and method thereof
US8730031B2 (en) 2005-04-28 2014-05-20 Proteus Digital Health, Inc. Communication system using an implantable device
US8836513B2 (en) 2006-04-28 2014-09-16 Proteus Digital Health, Inc. Communication system incorporated in an ingestible product
US20120004520A1 (en) 2005-04-28 2012-01-05 Proteus Biomedical, Inc. Communication System with Multiple Sources of Power
US9198608B2 (en) 2005-04-28 2015-12-01 Proteus Digital Health, Inc. Communication system incorporated in a container
US7414543B2 (en) 2005-04-28 2008-08-19 Honeywell International Inc. Multiple miniature avionic displays
US20120024889A1 (en) * 2005-04-28 2012-02-02 Timothy Robertson Polypharmacy Co-Packaged Medication Dosing Unit Including Communication System Therefor
EP1879649B1 (en) 2005-04-28 2013-05-15 Second Sight Medical Products, Inc. Package for an implantable neural stimulation device
US8802183B2 (en) 2005-04-28 2014-08-12 Proteus Digital Health, Inc. Communication system with enhanced partial power source and method of manufacturing same
US20060247505A1 (en) 2005-04-28 2006-11-02 Siddiqui Waqaas A Wireless sensor system
US7359674B2 (en) 2005-05-10 2008-04-15 Nokia Corporation Content distribution & communication system for enhancing service distribution in short range radio environment
EP2330524A3 (en) 2005-05-10 2012-07-11 CareFusion 303, Inc. Medication safety system featuring a multiplexed RFID interrogator panel
US20060264829A1 (en) 2005-05-10 2006-11-23 Par Technologies, Llc Disposable fluid container with integrated pump motive assembly
US20060262181A1 (en) 2005-05-17 2006-11-23 Robbins Gene A Laser-based image former operable to form dynamically variable images in objects in single shot events
WO2006127355A2 (en) 2005-05-20 2006-11-30 Dow Global Technologies Inc. Oral drug compliance monitoring using radio frequency identification tags
US8082919B2 (en) 2005-05-24 2011-12-27 Shl Group Ab Dose counter device for inhaler
US8285205B2 (en) 2005-05-26 2012-10-09 Broadcom Corporation Method and system for a single chip integrated Bluetooth and FM transceiver and baseband processor
US20060273882A1 (en) 2005-06-01 2006-12-07 Intel Corporation RFID tag with separate transmit and receive clocks and related method
US20060276702A1 (en) 2005-06-03 2006-12-07 Mcginnis William Neurophysiological wireless bio-sensor
US7387607B2 (en) 2005-06-06 2008-06-17 Intel Corporation Wireless medical sensor system
KR100695152B1 (en) 2005-06-07 2007-03-14 삼성전자주식회사 electrode for measuring electrocardiogram and device for measuring electrocardiogram comprising the same
US8588914B2 (en) 2005-06-09 2013-11-19 Medtronic, Inc. Implantable medical device with electrodes on multiple housing surfaces
US20060282001A1 (en) 2005-06-09 2006-12-14 Michel Noel Physiologic sensor apparatus
WO2006130988A1 (en) 2005-06-10 2006-12-14 Telecommunications Research Laboratories Wireless communication system
ITTO20050407A1 (en) 2005-06-13 2006-12-14 Ist Superiore Mario Boella REMOTE MONITORING SYSTEM FOR PHYSIOLOGICAL PARAMETERS OF AN INDIVIDUAL, PROCEDURE AND IT PRODUCT
JP2006346000A (en) 2005-06-14 2006-12-28 Aruze Corp Game machine and server
US7616111B2 (en) 2005-06-20 2009-11-10 Carestream Health, Inc. System to monitor the ingestion of medicines
US7782189B2 (en) 2005-06-20 2010-08-24 Carestream Health, Inc. System to monitor the ingestion of medicines
US7299034B2 (en) 2005-06-21 2007-11-20 Lawrence Kates System and method for wearable electronics
WO2007002697A2 (en) 2005-06-28 2007-01-04 Mayo Foundation For Medical Education And Research System for monitoring a physical parameter of a subject
FI20055366A0 (en) 2005-06-30 2005-06-30 Gen Electric An electrode for obtaining a biopotential signal
JP4120969B2 (en) 2005-07-04 2008-07-16 独立行政法人 宇宙航空研究開発機構 Ultrasonic test method and ultrasonic test apparatus using the same
WO2007008494A2 (en) 2005-07-06 2007-01-18 Liebert Corporation Maximized battery run-time in a parallel ups system
US20070016089A1 (en) 2005-07-15 2007-01-18 Fischell David R Implantable device for vital signs monitoring
CA2616010C (en) 2005-07-20 2013-11-05 Neil R. Euliano Medication compliance system and associated methods
US20100135907A1 (en) 2005-07-22 2010-06-03 Cranley Paul E Oral Drug Compliance Monitoring Using Sound Detection
CN100471445C (en) 2005-08-01 2009-03-25 周常安 Paster style physiological monitoring device, system and network
US20070029195A1 (en) 2005-08-03 2007-02-08 Changming Li Polymer/nanoparticle composites, film and molecular detection device
WO2007021813A2 (en) * 2005-08-11 2007-02-22 Eksigent Technologies, Llc Microfluidic system and methods
WO2007021496A2 (en) 2005-08-18 2007-02-22 Walker Digital, Llc Systems and methods for improved health care compliance
US20090124871A1 (en) 2005-08-22 2009-05-14 Khalil Arshak Tracking system
US8116809B2 (en) 2005-08-29 2012-02-14 Intel Corporation Method and apparatus of multiple entity wireless communication adapter
US8827904B2 (en) 2005-08-31 2014-09-09 Medtronic, Inc. Automatic parameter status on an implantable medical device system
WO2007028035A2 (en) * 2005-09-01 2007-03-08 Proteus Biomedical, Inc. Implantable zero-wire communications system
JP2007068622A (en) * 2005-09-05 2007-03-22 Olympus Corp Acquisition system for biological information of subject
JP2009507617A (en) 2005-09-14 2009-02-26 ネオガイド システムズ, インコーポレイテッド Method and apparatus for performing transluminal and other operations
US20070196456A1 (en) 2005-09-15 2007-08-23 Visible Assets, Inc. Smart patch
US7673679B2 (en) 2005-09-19 2010-03-09 Schlumberger Technology Corporation Protective barriers for small devices
US20080058614A1 (en) 2005-09-20 2008-03-06 Triage Wireless, Inc. Wireless, internet-based system for measuring vital signs from a plurality of patients in a hospital or medical clinic
GB0519837D0 (en) 2005-09-29 2005-11-09 Smartlife Technology Ltd Knitting techniques
GB0519836D0 (en) 2005-09-29 2005-11-09 Smartlife Technology Ltd Contact sensors
GB0519945D0 (en) 2005-09-30 2005-11-09 Cambridge Silicon Radio Ltd Communication in dual protocol environments
US20070078324A1 (en) 2005-09-30 2007-04-05 Textronics, Inc. Physiological Monitoring Wearable Having Three Electrodes
CN100466966C (en) 2005-10-08 2009-03-11 周常安 Physiological signal extracting and monitoring device and system
US7733224B2 (en) 2006-06-30 2010-06-08 Bao Tran Mesh network personal emergency response appliance
US9154616B2 (en) 2005-10-18 2015-10-06 Oia Intellectuals, Inc. Wearable capture and communication
US7720036B2 (en) 2005-10-26 2010-05-18 Intel Corporation Communication within a wireless network using multiple frequency bands
US7499739B2 (en) 2005-10-27 2009-03-03 Smiths Medical Pm, Inc. Single use pulse oximeter
US8515348B2 (en) 2005-10-28 2013-08-20 Electro Industries/Gauge Tech Bluetooth-enable intelligent electronic device
EP3488866A1 (en) 2005-11-04 2019-05-29 Wyeth LLC Antineoplastic combinations with mtor inhibitor, herceptin, and/or hki-272
US9067047B2 (en) 2005-11-09 2015-06-30 The Invention Science Fund I, Llc Injectable controlled release fluid delivery system
US8155016B2 (en) * 2005-11-12 2012-04-10 Rockstar Bidco, LP System and method for unbalanced relay-based wireless communications
GB0523447D0 (en) 2005-11-17 2005-12-28 E San Ltd System and method for communicating environmentally-based medical support advice
US7456329B2 (en) 2005-11-30 2008-11-25 Exxonmobil Chemical Patents Inc. Polyolefins from non-conventional feeds
WO2007063436A1 (en) 2005-11-30 2007-06-07 Koninklijke Philips Electronics N.V. Electro-mechanical connector for thin medical monitoring patch
TWI400800B (en) 2005-12-02 2013-07-01 Semiconductor Energy Lab Semiconductor device
US8016776B2 (en) 2005-12-02 2011-09-13 Medtronic, Inc. Wearable ambulatory data recorder
US8295932B2 (en) * 2005-12-05 2012-10-23 Metacure Limited Ingestible capsule for appetite regulation
NL1030608C2 (en) 2005-12-06 2007-06-07 Patrick Antonius Hendri Meeren Blister package, assembly of a blister package and a holder, and method for packaging objects.
US20070135691A1 (en) 2005-12-12 2007-06-14 General Electric Company Medicament compliance monitoring system, method, and medicament container
CN1985752A (en) 2005-12-19 2007-06-27 周常安 Distributed physiological signal monitor
CA2634059C (en) 2005-12-22 2015-11-24 Otsuka Pharmaceutical Co., Ltd. Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol
US7678043B2 (en) 2005-12-29 2010-03-16 Given Imaging, Ltd. Device, system and method for in-vivo sensing of a body lumen
BRPI0620863A8 (en) * 2005-12-29 2018-01-16 Osmotica Kereskedelmi Es Szolgaltato Kft triple-release combination tablet
US20070156016A1 (en) 2005-12-29 2007-07-05 Ido Betesh Method and system for communication with an ingestible imaging device
TWI306023B (en) 2005-12-30 2009-02-11 Ind Tech Res Inst Monitoring apparatus for physical movements of a body organ and method for acouiring the same
US7492128B2 (en) 2005-12-30 2009-02-17 Flexmedia Electronics Corp. Dynamic distribution device for battery power loop
US20070162089A1 (en) 2006-01-09 2007-07-12 Transoma Medical, Inc. Cross-band communications in an implantable device
US8301254B2 (en) 2006-01-09 2012-10-30 Greatbatch Ltd. Cross-band communications in an implantable device
US8078278B2 (en) 2006-01-10 2011-12-13 Remon Medical Technologies Ltd. Body attachable unit in wireless communication with implantable devices
CN100571239C (en) 2006-01-16 2009-12-16 华为技术有限公司 Synchronizing pilot sequence generation system and method in the communication system
ES2559678T3 (en) 2006-01-18 2016-02-15 Intec Pharma Ltd. Method for forming delivery devices for the oral route of an agent
US20100228113A1 (en) 2006-01-23 2010-09-09 Koninklijke Philips Electronics N.V. Improved biomedical electrode for extended patient wear featuring a tap, or snap, which is isolated from the retentional seal
JP2007200739A (en) 2006-01-27 2007-08-09 Keio Gijuku Living body swallow-type power generating cell
US20070185393A1 (en) 2006-02-03 2007-08-09 Triage Wireless, Inc. System for measuring vital signs using an optical module featuring a green light source
US7809399B2 (en) 2006-02-10 2010-10-05 Syntek International Holding Ltd. Method and device for providing multiple communication protocols with a single transceiver
CN101389265B (en) 2006-02-24 2011-01-26 皇家飞利浦电子股份有限公司 Wireless body sensor network
WO2007101141A2 (en) 2006-02-24 2007-09-07 Hmicro, Inc. A medical signal processing system with distributed wireless sensors
EP2001354B1 (en) 2006-03-03 2016-01-13 Physiowave Inc. Physiologic monitoring systems and methods
US8200320B2 (en) 2006-03-03 2012-06-12 PhysioWave, Inc. Integrated physiologic monitoring systems and methods
JP2007241928A (en) 2006-03-13 2007-09-20 Asahi Seiko Kk Coin residual quantity detecting device of coin hopper
US8457798B2 (en) 2006-03-14 2013-06-04 Jamie Hackett Long-range radio frequency receiver-controller module and wireless control system comprising same
US8131376B1 (en) 2007-09-11 2012-03-06 Second Sight Medical Products, Inc. Method of inspection of materials for defects
US8920343B2 (en) 2006-03-23 2014-12-30 Michael Edward Sabatino Apparatus for acquiring and processing of physiological auditory signals
MX2008012587A (en) 2006-03-29 2009-01-14 Electronic Dietary Foods Inc Ingestible implement for weight control.
WO2007115087A1 (en) 2006-03-30 2007-10-11 Dow Global Technologies Inc. Method and system for monitoring and analyzing compliance with internal dosing regimen
TW200738212A (en) 2006-04-12 2007-10-16 Guo Terry Bo Jau Miniature wireless apparatus for collecting physiological signals of animals
DE102006017196B4 (en) 2006-04-12 2008-09-11 Fette Gmbh Method of controlling the amount of active ingredient of tablets during production in a rotary tablet press
JP2009535103A (en) 2006-04-25 2009-10-01 ダウ グローバル テクノロジーズ インコーポレイティド Compliance monitoring of oral drugs using magnetic field sensors
US7912537B2 (en) 2006-04-27 2011-03-22 Medtronic, Inc. Telemetry-synchronized physiological monitoring and therapy delivery systems
US7942844B2 (en) 2006-04-28 2011-05-17 Medtronic Minimed, Inc. Remote monitoring for networked fluid infusion systems
MY187399A (en) 2006-04-28 2021-09-22 Qualcomm Inc Method and apparatus for enhanced paging
US8956287B2 (en) 2006-05-02 2015-02-17 Proteus Digital Health, Inc. Patient customized therapeutic regimens
GB0608829D0 (en) 2006-05-04 2006-06-14 Husheer Shamus L G In-situ measurement of physical parameters
WO2007128165A1 (en) 2006-05-09 2007-11-15 Fangen Xiong A short-range wireless networks system and erection method which allot time slots with multi-channel rf transceiver
KR101289601B1 (en) 2006-05-10 2013-08-07 인터디지탈 테크날러지 코포레이션 Method and apparatus for battery management in a converged wireless transmit/receive unit
US20080051647A1 (en) 2006-05-11 2008-02-28 Changwang Wu Non-invasive acquisition of large nerve action potentials (NAPs) with closely spaced surface electrodes and reduced stimulus artifacts
US7558622B2 (en) 2006-05-24 2009-07-07 Bao Tran Mesh network stroke monitoring appliance
KR101095589B1 (en) 2006-05-15 2011-12-19 노키아 코포레이션 Contactless programming and testing of memory elements
US7539533B2 (en) 2006-05-16 2009-05-26 Bao Tran Mesh network monitoring appliance
US20080077015A1 (en) 2006-05-17 2008-03-27 Olga Boric-Lubecke Determining presence and/or physiological motion of one or more subjects with multiple receiver Doppler radar systems
CN101073494B (en) 2006-05-18 2010-09-08 周常安 Non-invasive life evidence monitor, monitor system and method
JP2009537281A (en) 2006-05-19 2009-10-29 シーブイレクス インコーポレイテッド Characterization and regulation of physiological responses combined with baroreflex activation and drug treatment
US20070279217A1 (en) 2006-06-01 2007-12-06 H-Micro, Inc. Integrated mobile healthcare system for cardiac care
CA2654095C (en) 2006-06-01 2015-12-22 Biancamed Ltd. Apparatus, system, and method for monitoring physiological signs
FI120482B (en) 2006-06-08 2009-11-13 Suunto Oy Anturointijärjestely
US7346380B2 (en) 2006-06-16 2008-03-18 Axelgaard Manufacturing Co., Ltd. Medical electrode
US20100081895A1 (en) 2006-06-21 2010-04-01 Jason Matthew Zand Wireless medical telemetry system and methods using radio frequency energized biosensors
WO2007149545A2 (en) 2006-06-21 2007-12-27 Proteus Biomedical, Inc. Metal binary and ternary compounds produced by cathodic arc deposition
JP2009541018A (en) 2006-06-23 2009-11-26 コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ Drug administration system
US20080046038A1 (en) 2006-06-26 2008-02-21 Hill Gerard J Local communications network for distributed sensing and therapy in biomedical applications
US7949404B2 (en) 2006-06-26 2011-05-24 Medtronic, Inc. Communications network for distributed sensing and therapy in biomedical applications
US8165896B2 (en) 2006-06-29 2012-04-24 The Invention Science Fund I, Llc Compliance data for health-related procedures
US20080000804A1 (en) 2006-06-29 2008-01-03 Carey David A Carrier tape with integrated cover tape
EP1872765B1 (en) 2006-06-29 2009-04-29 Edwin Kohl Personalized blister pack and method for automated packaging of an individually determined composition
IL176712A0 (en) 2006-07-05 2007-10-31 Michael Cohen Alloro Medication dispenser
EP2037999B1 (en) 2006-07-07 2016-12-28 Proteus Digital Health, Inc. Smart parenteral administration system
US20080020037A1 (en) * 2006-07-11 2008-01-24 Robertson Timothy L Acoustic Pharma-Informatics System
US20080015494A1 (en) 2006-07-11 2008-01-17 Microchips, Inc. Multi-reservoir pump device for dialysis, biosensing, or delivery of substances
US7962174B2 (en) 2006-07-12 2011-06-14 Andrew Llc Transceiver architecture and method for wireless base-stations
US20080021521A1 (en) 2006-07-18 2008-01-24 Cardiac Pacemakers, Inc. Implantable Medical Device Communication System
DE102007020583B4 (en) 2006-07-19 2012-10-11 Erbe Elektromedizin Gmbh Electrode device with an impedance measuring device and method for producing such an electrode device
EP2051615A4 (en) 2006-08-10 2011-03-23 Given Imaging Ltd System and method for in vivo imaging
EP2422841B1 (en) 2006-08-18 2013-10-09 Second Sight Medical Products, Inc. Package for an implantable neural stimulation device
US8172762B2 (en) * 2006-09-01 2012-05-08 Proteus Biomedical, Inc. Simultaneous blood flow and hematocrit sensor
TW200832140A (en) 2006-09-01 2008-08-01 Fairchild Semiconductor Low power serdes architecture using serial I/O burst gating
US20080097549A1 (en) 2006-09-01 2008-04-24 Colbaugh Michael E Electrode Assembly and Method of Using Same
US7756573B2 (en) 2006-09-05 2010-07-13 Cardiac Pacemakers, Inc. Implantable medical device diagnostic data acquisition and storage
EP2063766B1 (en) * 2006-09-06 2017-01-18 Innurvation, Inc. Ingestible low power sensor device and system for communicating with same
US8512241B2 (en) 2006-09-06 2013-08-20 Innurvation, Inc. Methods and systems for acoustic data transmission
WO2008036518A1 (en) 2006-09-18 2008-03-27 Koninklijke Philips Electronics, N.V. Ip based monitoring and alarming
US20080077028A1 (en) 2006-09-27 2008-03-27 Biotronic Crm Patent Personal health monitoring and care system
US20080077184A1 (en) 2006-09-27 2008-03-27 Stephen Denker Intravascular Stimulation System With Wireless Power Supply
RU2009116271A (en) 2006-09-29 2010-11-10 Конинклейке Филипс Электроникс, Н.В. (Nl) MINIATURE THRESHOLD SENSORS
US20080091114A1 (en) 2006-10-11 2008-04-17 Pacesetter, Inc. Techniques for Correlating Thoracic Impedance with Physiological Status
US20080091089A1 (en) * 2006-10-12 2008-04-17 Kenneth Shane Guillory Single use, self-contained surface physiological monitor
US8054140B2 (en) 2006-10-17 2011-11-08 Proteus Biomedical, Inc. Low voltage oscillator for medical devices
US8054047B2 (en) 2006-10-18 2011-11-08 Hewlett-Packard Development Company, L.P. Battery pack charging system and method
US20080097917A1 (en) 2006-10-24 2008-04-24 Kent Dicks Systems and methods for wireless processing and medical device monitoring via remote command execution
KR101611240B1 (en) 2006-10-25 2016-04-11 프로테우스 디지털 헬스, 인코포레이티드 Controlled activation ingestible identifier
US8214007B2 (en) 2006-11-01 2012-07-03 Welch Allyn, Inc. Body worn physiological sensor device having a disposable electrode module
NZ706217A (en) 2006-11-14 2016-01-29 Cfph Llc Gaming system and method of use
US20080119705A1 (en) 2006-11-17 2008-05-22 Medtronic Minimed, Inc. Systems and Methods for Diabetes Management Using Consumer Electronic Devices
EP2069004A4 (en) 2006-11-20 2014-07-09 Proteus Digital Health Inc Active signal processing personal health signal receivers
EP2094158B1 (en) 2006-11-21 2018-05-02 STOCO 10 GmbH Ingestible electronic capsule and in vivo drug delivery or diagnostic system
GB0624085D0 (en) 2006-12-01 2007-01-10 Oxford Biosignals Ltd Biomedical signal analysis method
GB0624081D0 (en) 2006-12-01 2007-01-10 Oxford Biosignals Ltd Biomedical signal analysis method
US8180425B2 (en) 2006-12-05 2012-05-15 Tyco Healthcare Group Lp ECG lead wire organizer and dispenser
US20080137566A1 (en) 2006-12-06 2008-06-12 Bojko Marholev Method and System for Shared High-Power Transmit Path for a Multi-Protocol Transceiver
US8315687B2 (en) 2006-12-07 2012-11-20 Koninklijke Philips Electronics N.V. Handheld, repositionable ECG detector
US20080146889A1 (en) 2006-12-13 2008-06-19 National Yang-Ming University Method of monitoring human physiological parameters and safty conditions universally
US8157730B2 (en) 2006-12-19 2012-04-17 Valencell, Inc. Physiological and environmental monitoring systems and methods
TWI334747B (en) * 2006-12-22 2010-12-11 Unimicron Technology Corp Circuit board structure having embedded electronic components
US7782991B2 (en) 2007-01-09 2010-08-24 Freescale Semiconductor, Inc. Fractionally related multirate signal processor and method
JP2010516179A (en) 2007-01-10 2010-05-13 リコルディ,カミロ Portable emergency alert system and method
CN101663014A (en) 2007-01-16 2010-03-03 陶氏环球技术公司 Oral drug capsule component incorporating a communication device
WO2008091838A2 (en) * 2007-01-22 2008-07-31 Intelliject, Inc. Medical injector with compliance tracking and monitoring
WO2008091683A2 (en) 2007-01-25 2008-07-31 Senior Vitals, Inc. System and method for physiological data readings, transmission and presentation
US20080183245A1 (en) 2007-01-31 2008-07-31 Van Oort Geeske Telemetry of external physiological sensor data and implantable medical device data to a central processing system
EP3785599B1 (en) 2007-02-01 2022-08-03 Otsuka Pharmaceutical Co., Ltd. Ingestible event marker systems
US20080214985A1 (en) 2007-02-02 2008-09-04 Activatek, Inc. Active transdermal medicament patch
WO2008097652A2 (en) 2007-02-08 2008-08-14 Senior Vitals, Inc. Body patch for none-invasive physiological data readings
CA2676280C (en) 2007-02-14 2018-05-22 Proteus Biomedical, Inc. In-body power source having high surface area electrode
EP2124725A1 (en) 2007-03-09 2009-12-02 Proteus Biomedical, Inc. In-body device having a multi-directional transmitter
WO2008112578A1 (en) 2007-03-09 2008-09-18 Proteus Biomedical, Inc. In-body device having a deployable antenna
US8091790B2 (en) 2007-03-16 2012-01-10 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Security for blister packs
US20080303638A1 (en) 2007-03-24 2008-12-11 Hap Nguyen Portable patient devices, systems, and methods for providing patient aid and preventing medical errors, for monitoring patient use of ingestible medications, and for preventing distribution of counterfeit drugs
WO2008120128A2 (en) 2007-03-30 2008-10-09 Koninklijke Philips Electronics N.V. System and method for pill communication and control
JP4920478B2 (en) 2007-04-05 2012-04-18 株式会社東芝 MRI equipment
US7998110B2 (en) 2007-04-25 2011-08-16 Hong Kong Polytechnic University Medical device for delivering drug and/or performing physical therapy
KR100895297B1 (en) 2007-04-30 2009-05-07 한국전자통신연구원 A multi channel electrode sensor apparatus for measuring a plurality of physiological signals
WO2008131557A1 (en) 2007-05-01 2008-11-06 Urodynamix Technologies Ltd. Apparatus and methods for evaluating physiological conditions of tissue
GB0709248D0 (en) 2007-05-14 2007-06-20 T & Medical Ltd System for monitoring chemotherapy associated adverse drug reactions
US8412293B2 (en) 2007-07-16 2013-04-02 Optiscan Biomedical Corporation Systems and methods for determining physiological parameters using measured analyte values
US8540632B2 (en) * 2007-05-24 2013-09-24 Proteus Digital Health, Inc. Low profile antenna for in body device
US7946101B1 (en) 2007-05-30 2011-05-24 Walgreen Co. Method and system for verification of contents of a multi-cell, multi-product blister pack
US20080300572A1 (en) 2007-06-01 2008-12-04 Medtronic Minimed, Inc. Wireless monitor for a personal medical device system
US20080311852A1 (en) 2007-06-15 2008-12-18 Broadcom Corporation Multiple communication link coordination for shared data transmissions
US8060175B2 (en) 2007-06-15 2011-11-15 General Electric Company System and apparatus for collecting physiological signals from a plurality of electrodes
EP2008584A1 (en) 2007-06-26 2008-12-31 Julius-Maximilians-Universität Würzburg In vivo device, system and usage thereof
GB2450517A (en) 2007-06-27 2008-12-31 Smartlife Technology Ltd Electrical resistance of yarn or fabric changes with temperature
CN201076456Y (en) 2007-06-29 2008-06-25 洪金叶 Clamp style wireless transmission pulse detection device
US8404275B2 (en) 2007-07-01 2013-03-26 Vitalis Llc Combination tablet with chewable outer layer
US20090009332A1 (en) 2007-07-03 2009-01-08 Endotronix, Inc. System and method for monitoring ingested medication via rf wireless telemetry
JP5065780B2 (en) 2007-07-03 2012-11-07 株式会社日立製作所 RFID tag mounting board
JP4520491B2 (en) 2007-07-09 2010-08-04 オリンパス株式会社 Capsule medical system
US8340750B2 (en) 2007-07-19 2012-12-25 Medtronic, Inc. Mechanical function marker channel for cardiac monitoring and therapy control
EP2977080B1 (en) 2007-07-27 2024-02-14 Cortigent, Inc. Implantable device for the brain
GB0714807D0 (en) 2007-07-30 2007-09-12 Oxford Biosignals Ltd Method and apparatus for measuring breathing rate
KR101080423B1 (en) 2007-08-03 2011-11-04 삼성전자주식회사 Multi module combination type portable electronic device
KR100863064B1 (en) 2007-08-03 2008-10-13 한국전자통신연구원 Garment for measuring physiological signals and method of fabricating the same
US9179864B2 (en) 2007-08-15 2015-11-10 Integrity Tracking, Llc Wearable health monitoring device and methods for fall detection
US20090048498A1 (en) 2007-08-17 2009-02-19 Frank Riskey System and method of monitoring an animal
US8926509B2 (en) 2007-08-24 2015-01-06 Hmicro, Inc. Wireless physiological sensor patches and systems
US20090062670A1 (en) 2007-08-30 2009-03-05 Gary James Sterling Heart monitoring body patch and system
US20090062728A1 (en) 2007-09-01 2009-03-05 Sang Hoon Woo Control of Body Fluid Condition Using Diuretics, Based on Weight Measurement
WO2009031150A2 (en) 2007-09-05 2009-03-12 Sensible Medical Innovations Ltd. Method and system for monitoring thoracic tissue fluid
JP2009061236A (en) 2007-09-07 2009-03-26 Arimasa Nishida Small terminal with functions of reading and inputting multi-data on personal medical information, of data management, analysis, and display, and of entertainment, game, and communication to facilitate self-management for health, having strong bio-feedback effect on life-style related disease, which allows unified management of measured personal data at first when developing medical information database at medical institute, or local/national government
CN101827555B (en) 2007-09-07 2012-11-21 英戈·弗洛尔 Diagnostic sensor unit
US20090069642A1 (en) 2007-09-11 2009-03-12 Aid Networks, Llc Wearable Wireless Electronic Patient Data Communications and Physiological Monitoring Device
WO2009036260A1 (en) 2007-09-14 2009-03-19 Corventis, Inc. Data collection in a multi-sensor patient monitor
US8460189B2 (en) 2007-09-14 2013-06-11 Corventis, Inc. Adherent cardiac monitor with advanced sensing capabilities
WO2009036319A1 (en) 2007-09-14 2009-03-19 Corventis, Inc. Adherent emergency patient monitor
US8591430B2 (en) 2007-09-14 2013-11-26 Corventis, Inc. Adherent device for respiratory monitoring
WO2009036334A1 (en) 2007-09-14 2009-03-19 Corventis, Inc. Adherent multi-sensor device with empathic monitoring
US8116841B2 (en) 2007-09-14 2012-02-14 Corventis, Inc. Adherent device with multiple physiological sensors
WO2009036333A1 (en) 2007-09-14 2009-03-19 Corventis, Inc. Dynamic pairing of patients to data collection gateways
PT2192946T (en) * 2007-09-25 2022-11-17 Otsuka Pharma Co Ltd In-body device with virtual dipole signal amplification
US20090087483A1 (en) * 2007-09-27 2009-04-02 Sison Raymundo A Oral dosage combination pharmaceutical packaging
US20090088618A1 (en) 2007-10-01 2009-04-02 Arneson Michael R System and Method for Manufacturing a Swallowable Sensor Device
CL2008003007A1 (en) 2007-10-12 2009-10-02 Bigtec Private Ltd A microchip with layers of low temperature firing ceramics (ltcc) forming a reaction chamber, conductive rings that surround the reaction chamber and a heater that supplies heat to the rings, the microchip manufacturing method and a micro polymerase chain reaction (pcr) device.
WO2009051965A1 (en) 2007-10-14 2009-04-23 Board Of Regents, The University Of Texas System A wireless neural recording and stimulating system for pain management
US20090105561A1 (en) 2007-10-17 2009-04-23 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Medical or veterinary digestive tract utilization systems and methods
US20090105567A1 (en) 2007-10-19 2009-04-23 Smiths Medical Pm, Inc. Wireless telecommunications network adaptable for patient monitoring
US8134459B2 (en) 2007-10-19 2012-03-13 Smiths Medical Asd, Inc. Wireless telecommunications system adaptable for patient monitoring
US8139225B2 (en) 2007-10-24 2012-03-20 Siemens Medical Solutions Usa, Inc. System for processing patient monitoring power and data signals
GB0721117D0 (en) 2007-10-26 2007-12-05 T & Medical Ltd system for assisting in drug dose optimisaion
US20090112626A1 (en) 2007-10-30 2009-04-30 Cary Talbot Remote wireless monitoring, processing, and communication of patient data
WO2009063377A1 (en) 2007-11-13 2009-05-22 Koninklijke Philips Electronics N.V. Ingestible electronic capsule
EP2215726B1 (en) * 2007-11-27 2018-01-10 Proteus Digital Health, Inc. Transbody communication systems employing communication channels
EP2217138A4 (en) 2007-11-29 2013-05-01 Integrated Sensing Systems Inc Sensor unit and procedure for monitoring intracranial physiological properties
US20090149839A1 (en) 2007-12-11 2009-06-11 Hyde Roderick A Treatment techniques using ingestible device
US20090157113A1 (en) 2007-12-18 2009-06-18 Ethicon Endo-Surgery, Inc. Wearable elements for implantable restriction systems
US20090287109A1 (en) 2008-05-14 2009-11-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Circulatory monitoring systems and methods
US20100036269A1 (en) 2008-08-07 2010-02-11 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Circulatory monitoring systems and methods
JP5149610B2 (en) 2007-12-19 2013-02-20 株式会社日立ハイテクノロジーズ Plasma processing equipment
EP2241032B1 (en) 2007-12-20 2018-02-28 Koninklijke Philips N.V. Capacitive sensing and communicating
US8177611B2 (en) 2007-12-21 2012-05-15 Sony Computer Entertainment America Llc Scheme for inserting a mimicked performance into a scene and providing an evaluation of same
JP5091657B2 (en) 2007-12-21 2012-12-05 株式会社東芝 Wireless communication apparatus and wireless communication method
US9259591B2 (en) 2007-12-28 2016-02-16 Cyberonics, Inc. Housing for an implantable medical device
US20090171180A1 (en) 2007-12-28 2009-07-02 Trevor Pering Method and apparatus for configuring wearable sensors
US8401659B2 (en) 2008-01-15 2013-03-19 Cardiac Pacemakers, Inc. Implantable medical device with wireless communications
EP2230993B1 (en) 2008-01-15 2018-08-15 Cardiac Pacemakers, Inc. Implantable medical device with antenna
US20090182207A1 (en) * 2008-01-16 2009-07-16 Tenxsys Inc. Ingestible animal health sensor
GB2456567B (en) 2008-01-18 2010-05-05 Oxford Biosignals Ltd Novelty detection
JP5132335B2 (en) 2008-01-29 2013-01-30 富士フイルム株式会社 Capsule endoscope and capsule endoscope system
JP5233298B2 (en) 2008-02-01 2013-07-10 宇部興産株式会社 Polyimide film and method for producing polyimide film
US20090194747A1 (en) 2008-02-04 2009-08-06 Vale Inco Limited Method for improving environmental stability of cathode materials for lithium batteries
JP5156427B2 (en) * 2008-02-13 2013-03-06 富士フイルム株式会社 Capsule endoscope system
WO2009111142A2 (en) 2008-03-06 2009-09-11 Stryker Corporation Foldable, implantable electrode array assembly and tool for implanting same
EP2262419B1 (en) 2008-03-10 2019-06-26 Koninklijke Philips N.V. Wireless outpatient ecg monitoring system
WO2009112977A1 (en) 2008-03-10 2009-09-17 Koninklijke Philips Electronics N.V. Ecg monitoring system with configurable alarm limits
US7983189B2 (en) 2008-03-12 2011-07-19 Embarq Holdings Company, Llc System and method for tracking performance and service level agreement compliance for multipoint packet services
US20090243833A1 (en) 2008-03-31 2009-10-01 Ching Ching Huang Monitoring system and method for patient care
WO2009146082A2 (en) 2008-04-01 2009-12-03 The Research Foundation Of The State University Of New York Rfid monitoring of drug regimen compliance
AU2009231586A1 (en) 2008-04-03 2009-10-08 Kai Medical, Inc. Non-contact physiologic motion sensors and methods for use
US20090253960A1 (en) * 2008-04-03 2009-10-08 Olympus Medical Systems Corp. Antenna unit and receiving apparatus for capsule medical apparatus
DE102009002450A1 (en) 2008-04-18 2009-10-22 Korsch Ag Method and device for inserting inserts (cores) in dies of a rotary tablet press
KR20100139144A (en) 2008-04-21 2010-12-31 카를 프레데릭 에드만 Metabolic energy monitoring system
US8185646B2 (en) 2008-11-03 2012-05-22 Veritrix, Inc. User authentication for social networks
US8170515B2 (en) * 2008-05-21 2012-05-01 Medtronic, Inc. Method and apparatus for the phased detection of a signal including a frequency deviation detection phase
US20090292194A1 (en) 2008-05-23 2009-11-26 Corventis, Inc. Chiropractic Care Management Systems and Methods
US8989837B2 (en) 2009-12-01 2015-03-24 Kyma Medical Technologies Ltd. Methods and systems for determining fluid content of tissue
US9538937B2 (en) 2008-06-18 2017-01-10 Covidien Lp System and method of evaluating a subject with an ingestible capsule
US20090318303A1 (en) * 2008-06-20 2009-12-24 International Business Machines Corporation Microfluidic selection of library elements
US9014778B2 (en) 2008-06-24 2015-04-21 Biosense Webster, Inc. Disposable patch and reusable sensor assembly for use in medical device localization and mapping systems
CH699071A2 (en) 2008-07-02 2010-01-15 Flakes S A A braking and / or mechanical locking.
WO2010005953A2 (en) 2008-07-07 2010-01-14 Cardullo Mario W Dynamically distributable nano rfid device and related method
WO2010005877A2 (en) 2008-07-08 2010-01-14 Proteus Biomedical, Inc. Ingestible event marker data framework
US8152020B2 (en) 2008-07-09 2012-04-10 Flowers Mary E Dosage dispensing and tracking container
WO2010011833A1 (en) 2008-07-23 2010-01-28 Alexander Stuck Secure tracking of tablets
JP5715564B2 (en) 2008-08-13 2015-05-07 プロテウス デジタル ヘルス, インコーポレイテッド Ingestible device and method of producing the same
KR101028584B1 (en) 2008-08-27 2011-04-12 주식회사 바이오프로테크 Tab electrode and wire leading to the same
US20100056878A1 (en) 2008-08-28 2010-03-04 Partin Dale L Indirectly coupled personal monitor for obtaining at least one physiological parameter of a subject
GB2463054A (en) 2008-08-30 2010-03-03 Adavanced Telecare Solutions L Device for monitoring the removal of items placed in compartments of a blister package using ambient light
US9943644B2 (en) 2008-08-31 2018-04-17 Abbott Diabetes Care Inc. Closed loop control with reference measurement and methods thereof
US20100063841A1 (en) 2008-09-05 2010-03-11 Vital Data Technology, Llc System and method of notifying designated entities of access to personal medical records
US8224596B2 (en) 2008-09-09 2012-07-17 International Business Machines Corporation Portable device battery optimization routing system
US20100069002A1 (en) 2008-09-16 2010-03-18 Vcan Sports, Inc. Method and apparatus for a wireless communication device utilizing bluetooth technology
KR101192690B1 (en) 2008-11-13 2012-10-19 프로테우스 디지털 헬스, 인코포레이티드 Ingestible therapy activator system, therapeutic device and method
WO2010068818A2 (en) 2008-12-11 2010-06-17 Proteus Biomedical, Inc. Evaluation of gastrointestinal function using portable electroviscerography systems and methods of using the same
TWI503101B (en) 2008-12-15 2015-10-11 Proteus Digital Health Inc Body-associated receiver and method
US20100160742A1 (en) 2008-12-18 2010-06-24 General Electric Company Telemetry system and method
WO2010080764A2 (en) 2009-01-06 2010-07-15 Proteus Biomedical, Inc. Pharmaceutical dosages delivery system
SG172846A1 (en) 2009-01-06 2011-08-29 Proteus Biomedical Inc Ingestion-related biofeedback and personalized medical therapy method and system
AU2010203738B2 (en) 2009-01-06 2016-02-25 Otsuka Pharmaceutical Co., Ltd. High-throughput production of ingestible event markers
EP2208458A1 (en) 2009-01-14 2010-07-21 Roche Diagnostics GmbH Medical monitoring network
JP4576462B2 (en) 2009-01-30 2010-11-10 株式会社バッファロー Router device
FR2941817B1 (en) 2009-01-30 2011-04-01 Centre Nat Rech Scient PROCESS FOR THE PREPARATION OF AN ELECTRODE COMPOSITION
US8224667B1 (en) 2009-02-06 2012-07-17 Sprint Communications Company L.P. Therapy adherence methods and architecture
US8395521B2 (en) 2009-02-06 2013-03-12 University Of Dayton Smart aerospace structures
US8073401B2 (en) 2009-02-17 2011-12-06 Rfaxis, Inc. Multi mode radio frequency transceiver front end circuit with inter-stage matching circuit
WO2010099268A1 (en) 2009-02-25 2010-09-02 Xanthia Global Limited Wireless physiology monitor
US8452366B2 (en) 2009-03-16 2013-05-28 Covidien Lp Medical monitoring device with flexible circuitry
US8004900B2 (en) 2009-03-17 2011-08-23 Sandisk Technologies Inc. Controlling select gate voltage during erase to improve endurance in non-volatile memory
US8540664B2 (en) 2009-03-25 2013-09-24 Proteus Digital Health, Inc. Probablistic pharmacokinetic and pharmacodynamic modeling
WO2010111489A2 (en) 2009-03-27 2010-09-30 LifeWatch Corp. Methods and apparatus for processing physiological data acquired from an ambulatory physiological monitoring unit
US8805528B2 (en) 2009-03-31 2014-08-12 Medtronic, Inc. Channel assessment and selection for wireless communication between medical devices
US8253586B1 (en) 2009-04-24 2012-08-28 Mayfonk Art, Inc. Athletic-wear having integral measuring sensors
WO2010129288A2 (en) 2009-04-28 2010-11-11 Proteus Biomedical, Inc. Highly reliable ingestible event markers and methods for using the same
EP2432458A4 (en) 2009-05-12 2014-02-12 Proteus Digital Health Inc Ingestible event markers comprising an ingestible component
US20100299155A1 (en) 2009-05-19 2010-11-25 Myca Health, Inc. System and method for providing a multi-dimensional contextual platform for managing a medical practice
US8200321B2 (en) 2009-05-20 2012-06-12 Sotera Wireless, Inc. Method for measuring patient posture and vital signs
US8698006B2 (en) 2009-06-04 2014-04-15 Morgan Advanced Ceramics, Inc. Co-fired metal and ceramic composite feedthrough assemblies for use at least in implantable medical devices and methods for making the same
US8468115B2 (en) 2009-06-25 2013-06-18 George Mason Intellectual Properties, Inc. Cyclical behavior modification
RU2417884C2 (en) 2009-08-03 2011-05-10 Фирдаус Усманович Замалеев Device to apply thermoplastic coat on metal pipe inner surface
EP2465323B1 (en) 2009-08-14 2015-10-07 Telefonaktiebolaget LM Ericsson (publ) Connection set-up between two terminals
EP2467707A4 (en) 2009-08-21 2014-12-17 Proteus Digital Health Inc Apparatus and method for measuring biochemical parameters
BR112012003745A2 (en) 2009-08-21 2019-09-24 3M Innovantive Properties Company fabric lighting methods and products
US9024766B2 (en) 2009-08-28 2015-05-05 The Invention Science Fund, Llc Beverage containers with detection capability
US20110230732A1 (en) 2009-09-14 2011-09-22 Philometron, Inc. System utilizing physiological monitoring and electronic media for health improvement
US20110077719A1 (en) 2009-09-30 2011-03-31 Broadcom Corporation Electromagnetic power bio-medical unit
US8207731B2 (en) 2009-09-30 2012-06-26 Thermofisher Scientific Apparatus and method for automatic product effect compensation in radio frequency metal detectors
US8838217B2 (en) 2009-11-10 2014-09-16 Makor Issues And Rights Ltd. System and apparatus for providing diagnosis and personalized abnormalities alerts and for providing adaptive responses in clinical trials
US20110270135A1 (en) 2009-11-30 2011-11-03 Christopher John Dooley Augmented reality for testing and training of human performance
UA109424C2 (en) 2009-12-02 2015-08-25 PHARMACEUTICAL PRODUCT, PHARMACEUTICAL TABLE WITH ELECTRONIC MARKER AND METHOD OF MANUFACTURING PHARMACEUTICAL TABLETS
US8917798B2 (en) 2009-12-03 2014-12-23 Qualcomm Incorporated Method and apparatus for distributed processing for wireless sensors
US9451897B2 (en) 2009-12-14 2016-09-27 Medtronic Monitoring, Inc. Body adherent patch with electronics for physiologic monitoring
WO2011076884A2 (en) 2009-12-23 2011-06-30 Delta, Dansk Elektronik, Lys Og Akustik A monitoring system
US8560040B2 (en) 2010-01-04 2013-10-15 Koninklijke Philips N.V. Shielded biomedical electrode patch
NL2004210C2 (en) 2010-02-08 2011-08-09 Ipn Ip Bv A refillable liquid product container system.
KR101034998B1 (en) 2010-02-18 2011-05-17 대한메디칼시스템(주) Connecting structure for snap electrode and electric wire
WO2011112972A2 (en) 2010-03-11 2011-09-15 Philometron, Inc. Physiological monitor system for determining medication delivery and outcome
CA2795746C (en) 2010-04-07 2019-10-01 Timothy Robertson Miniature ingestible device
SG184839A1 (en) 2010-04-11 2012-11-29 Proteus Digital Health Inc Apparatus, system and method for detection and delivery of a medicinal dose
US9872637B2 (en) 2010-04-21 2018-01-23 The Rehabilitation Institute Of Chicago Medical evaluation system and method using sensors in mobile devices
WO2011143490A2 (en) 2010-05-12 2011-11-17 Irhythm Technologies, Inc. Device features and design elements for long-term adhesion
EP3492001A1 (en) 2010-05-21 2019-06-05 Medicomp, INC. Method of determining an optimum electrode vector length with a retractable muti-use cardiac monitor
US20110301439A1 (en) 2010-06-08 2011-12-08 AliveUSA LLC Wireless, ultrasonic personal health monitoring system
US8301232B2 (en) 2010-06-08 2012-10-30 Alivecor, Inc. Wireless, ultrasonic personal health monitoring system
EP2580687A4 (en) 2010-06-14 2014-04-30 Trutag Technologies Inc System for verifying an item in a package using a database
SG186282A1 (en) 2010-06-14 2013-01-30 Trutag Technologies Inc System for verifying an item in a package
KR20130057451A (en) 2010-06-14 2013-05-31 트루테그 테크놀로지스, 인코포레이티드 System for producing a packaged item with an identifier
EP2580688A4 (en) 2010-06-14 2017-05-10 Trutag Technologies, Inc. Labeling and verifying an item with an identifier
US20130196012A1 (en) 2010-11-30 2013-08-01 Wellesley Pharmaceuticals, Llc Extended-release formulation for reducing the frequency of urination and method of use thereof
US20120016231A1 (en) 2010-07-18 2012-01-19 Medical Scan Technologies, Inc. System and method for three dimensional cosmetology imaging with structured light
ES2664383T3 (en) 2010-07-22 2018-04-19 K-Fee System Gmbh Capsule in portions with identifier
US9585620B2 (en) 2010-07-27 2017-03-07 Carefusion 303, Inc. Vital-signs patch having a flexible attachment to electrodes
WO2012015756A2 (en) 2010-07-29 2012-02-02 Proteus Biomedical, Inc. Hybrid housing for implantable medical device
US20120032816A1 (en) 2010-08-06 2012-02-09 Cho Jeffrey C System And Method For Controlling Sport Event Transducers
DE102010039416A1 (en) 2010-08-17 2012-02-23 Varta Micro Innovation Gmbh Flexible battery electrodes and their manufacture
US8697057B2 (en) 2010-08-19 2014-04-15 Allergan, Inc. Compositions and soft tissue replacement methods
CN103180801B (en) 2010-09-13 2016-08-03 诺基亚技术有限公司 Haptics communications
WO2012040401A2 (en) 2010-09-21 2012-03-29 Somaxis Incorporated Systems for assessing and optimizing muscular performance
US9167991B2 (en) * 2010-09-30 2015-10-27 Fitbit, Inc. Portable monitoring devices and methods of operating same
EP2642983A4 (en) 2010-11-22 2014-03-12 Proteus Digital Health Inc Ingestible device with pharmaceutical product
US20120316413A1 (en) 2011-01-18 2012-12-13 Beijing Choice Electronic Technology Co., Ltd. Measurement apparatus
US8647358B2 (en) 2011-01-21 2014-02-11 Obalon Therapeutics Inc. Intragastric device
US20120197144A1 (en) 2011-01-27 2012-08-02 Koninklijke Philips Electronics N.V. Exchangeable electrode and ecg cable snap connector
GB2487758A (en) 2011-02-03 2012-08-08 Isansys Lifecare Ltd Health monitoring electrode assembly
WO2012112561A1 (en) 2011-02-18 2012-08-23 Proteus Biomedical, Inc. Wearable personal communicator apparatus, system, and method
AU2011360138B2 (en) 2011-02-25 2015-01-22 Tna Australia Pty Limited A metal detector
JP2014514032A (en) 2011-03-11 2014-06-19 プロテウス デジタル ヘルス, インコーポレイテッド Wearable personal body-related devices with various physical configurations
AU2012231004A1 (en) 2011-03-21 2013-05-02 Purafil, Inc. Systems and methods for detecting and identifying contaminants in a gaseous environment
US9189941B2 (en) 2011-04-14 2015-11-17 Koninklijke Philips N.V. Stepped alarm method for patient monitors
US10853819B2 (en) 2011-04-14 2020-12-01 Elwha Llc Cost-effective resource apportionment technologies suitable for facilitating therapies
WO2015112603A1 (en) 2014-01-21 2015-07-30 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
US9756874B2 (en) 2011-07-11 2017-09-12 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
US9158890B2 (en) 2011-07-27 2015-10-13 At&T Mobility Ii Llc Mobile applications and methods for conveying performance information of a cardiac pacemaker
US8785569B2 (en) 2011-11-22 2014-07-22 Original Biomedicals Co., Ltd. Drug carrier with chelating complex micelles and the application thereof
US20130129869A1 (en) 2011-11-23 2013-05-23 Hooman Hafezi Compositions comprising a shelf-life stability component
US9968284B2 (en) 2011-12-02 2018-05-15 Clinitech, Llc Anti-interferent barrier layers for non-invasive transdermal sampling and analysis device
FR2985382B1 (en) 2012-01-03 2015-03-13 Air Liquide FUEL CELL
US20130171596A1 (en) 2012-01-04 2013-07-04 Barry J. French Augmented reality neurological evaluation method
WO2013102908A1 (en) 2012-01-08 2013-07-11 Powermat Technologies Ltd System and method for providing and controlling inductive power charging
US20130185228A1 (en) 2012-01-18 2013-07-18 Steven Dresner System and Method of Data Collection, Analysis and Distribution
WO2013138169A2 (en) 2012-03-14 2013-09-19 E. I. Du Pont De Nemours And Company Mcm-48 templated carbon compositions, electrodes, cells, methods for making and methods for using
US20130275296A1 (en) 2012-03-16 2013-10-17 esdatanetworks INC Proximal Customer Transaction Incented By Donation of Auto-Boarded Merchant
US8908943B2 (en) 2012-05-22 2014-12-09 Orca Health, Inc. Personalized anatomical diagnostics and simulations
US9277864B2 (en) 2012-05-24 2016-03-08 Vital Connect, Inc. Modular wearable sensor device
MY182541A (en) 2012-07-23 2021-01-25 Proteus Digital Health Inc Techniques for manufacturing ingestible event markers comprising an ingestible component
KR101571688B1 (en) 2012-09-21 2015-11-25 프로테우스 디지털 헬스, 인코포레이티드 Wireless wearable apparatus, system, and method
CA2888871C (en) 2012-10-18 2016-08-09 Proteus Digital Health, Inc. Apparatus, system, and method to adaptively optimize power dissipation and broadcast power in a power source for a communication device
JP2016508529A (en) 2013-01-29 2016-03-22 プロテウス デジタル ヘルス, インコーポレイテッド Highly expandable polymer film and composition containing the same
US9741975B2 (en) 2013-03-13 2017-08-22 Brigham And Women's Hospital, Inc. Safely ingestible batteries
US20140280125A1 (en) 2013-03-14 2014-09-18 Ebay Inc. Method and system to build a time-sensitive profile
JP5941240B2 (en) 2013-03-15 2016-06-29 プロテウス デジタル ヘルス, インコーポレイテッド Metal detector device, system and method
US20140308930A1 (en) 2013-04-12 2014-10-16 Bao Tran Timely, glanceable information on a wearable device
US9529385B2 (en) 2013-05-23 2016-12-27 Medibotics Llc Smart watch and human-to-computer interface for monitoring food consumption
US10545132B2 (en) 2013-06-25 2020-01-28 Lifescan Ip Holdings, Llc Physiological monitoring system communicating with at least a social network
US9086490B2 (en) 2013-08-27 2015-07-21 Franklin H. Cocks Red boron solid state detector
JP5936584B2 (en) 2013-08-29 2016-06-22 富士フイルム株式会社 Radiation image detection apparatus and manufacturing method
JP2015045773A (en) 2013-08-29 2015-03-12 富士フイルム株式会社 Scanning optical system, optical scanning device, and radiation image reading apparatus
US9796576B2 (en) 2013-08-30 2017-10-24 Proteus Digital Health, Inc. Container with electronically controlled interlock
US9517012B2 (en) 2013-09-13 2016-12-13 Welch Allyn, Inc. Continuous patient monitoring
US10084880B2 (en) 2013-11-04 2018-09-25 Proteus Digital Health, Inc. Social media networking based on physiologic information
US20150127738A1 (en) 2013-11-05 2015-05-07 Proteus Digital Health, Inc. Bio-language based communication system
US20150149375A1 (en) 2013-11-22 2015-05-28 Proteus Digital Health, Inc. Crowd endorsement system
WO2015112604A1 (en) 2014-01-22 2015-07-30 Proteus Digital Health, Inc. Edible adhesives and ingestible compositions including the same
US20160345906A1 (en) 2014-02-04 2016-12-01 Proteus Digital Health, Inc. Enhanced ingestible event indicators and methods for making and using the same
US20170020162A1 (en) 2014-04-02 2017-01-26 Am Nutrition As Nutritive product with animal ensilage and method for making the nutritive product
US9226663B2 (en) 2014-04-07 2016-01-05 Physical Enterprises, Inc. Systems and methods for optical isolation in measuring physiological parameters
US9537010B2 (en) 2015-02-04 2017-01-03 Taiwan Semiconductor Manufacturing Co., Ltd. Semiconductor device structure and method for forming the same
US20160380708A1 (en) 2015-06-26 2016-12-29 Proteus Digital Health, Inc. Systems and methods for resolving ingestible event marker (iem) contention
US11051543B2 (en) 2015-07-21 2021-07-06 Otsuka Pharmaceutical Co. Ltd. Alginate on adhesive bilayer laminate film
EP3487393A4 (en) 2016-07-22 2020-01-15 Proteus Digital Health, Inc. Electromagnetic sensing and detection of ingestible event markers
CN109963499B (en) 2016-10-26 2022-02-25 大冢制药株式会社 Method for manufacturing capsules with ingestible event markers

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3682160A (en) * 1969-10-16 1972-08-08 Matsushita Electric Ind Co Ltd Physiological signal transmitter for use inside the body
US6076016A (en) * 1995-10-19 2000-06-13 Feierbach; Gary F. Galvanic transdermal conduction communication system and method
US20080044721A1 (en) * 2002-05-02 2008-02-21 Adam Heller Miniature biological fuel cell that is operational under physiological conditions, and associated devices and methods
US20060243288A1 (en) * 2003-01-25 2006-11-02 Tae-Song Kim Method and system for data communication in human body and sensor therefor
WO2004068748A1 (en) * 2003-01-25 2004-08-12 Korea Institute Of Science And Technology Method and system for data communication in human body and sensor therefor
US20050131281A1 (en) * 2003-12-15 2005-06-16 Ayer Steven M. Method and apparatus for verification of ingestion
US20050154428A1 (en) * 2003-12-30 2005-07-14 Ian Bruinsma Implanted antenna and radio communications link
US20110124983A1 (en) * 2004-11-09 2011-05-26 Pacesetter, Inc. Method and apparatus for monitoring ingestion of medications using an implantable medical device
US7978064B2 (en) * 2005-04-28 2011-07-12 Proteus Biomedical, Inc. Communication system with partial power source
US8816847B2 (en) * 2005-04-28 2014-08-26 Proteus Digital Health, Inc. Communication system with partial power source
US8912908B2 (en) * 2005-04-28 2014-12-16 Proteus Digital Health, Inc. Communication system with remote activation
US20150223751A1 (en) * 2005-04-28 2015-08-13 Proteus Digital Health, Inc. Pharma-informatics system
US9258035B2 (en) * 2008-03-05 2016-02-09 Proteus Digital Health, Inc. Multi-mode communication ingestible event markers and systems, and methods of using the same
US20130328416A1 (en) * 2010-12-29 2013-12-12 Proteus Digital Health, Inc. Wireless Energy Sources for Integrated Circuits

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9649066B2 (en) 2005-04-28 2017-05-16 Proteus Digital Health, Inc. Communication system with partial power source
US9161707B2 (en) 2005-04-28 2015-10-20 Proteus Digital Health, Inc. Communication system incorporated in an ingestible product
US11476952B2 (en) 2005-04-28 2022-10-18 Otsuka Pharmaceutical Co., Ltd. Pharma-informatics system
US9962107B2 (en) 2005-04-28 2018-05-08 Proteus Digital Health, Inc. Communication system with enhanced partial power source and method of manufacturing same
US10610128B2 (en) 2005-04-28 2020-04-07 Proteus Digital Health, Inc. Pharma-informatics system
US10517507B2 (en) 2005-04-28 2019-12-31 Proteus Digital Health, Inc. Communication system with enhanced partial power source and method of manufacturing same
US10542909B2 (en) 2005-04-28 2020-01-28 Proteus Digital Health, Inc. Communication system with partial power source
US9439582B2 (en) 2005-04-28 2016-09-13 Proteus Digital Health, Inc. Communication system with remote activation
US9681842B2 (en) 2005-04-28 2017-06-20 Proteus Digital Health, Inc. Pharma-informatics system
US9270025B2 (en) 2007-03-09 2016-02-23 Proteus Digital Health, Inc. In-body device having deployable antenna
US9415010B2 (en) 2008-08-13 2016-08-16 Proteus Digital Health, Inc. Ingestible circuitry
US10588544B2 (en) 2009-04-28 2020-03-17 Proteus Digital Health, Inc. Highly reliable ingestible event markers and methods for using the same
US9320455B2 (en) 2009-04-28 2016-04-26 Proteus Digital Health, Inc. Highly reliable ingestible event markers and methods for using the same
US10207093B2 (en) 2010-04-07 2019-02-19 Proteus Digital Health, Inc. Miniature ingestible device
US11173290B2 (en) 2010-04-07 2021-11-16 Otsuka Pharmaceutical Co., Ltd. Miniature ingestible device
US9597487B2 (en) 2010-04-07 2017-03-21 Proteus Digital Health, Inc. Miniature ingestible device
US9107806B2 (en) 2010-11-22 2015-08-18 Proteus Digital Health, Inc. Ingestible device with pharmaceutical product
US11504511B2 (en) 2010-11-22 2022-11-22 Otsuka Pharmaceutical Co., Ltd. Ingestible device with pharmaceutical product
US11229378B2 (en) 2011-07-11 2022-01-25 Otsuka Pharmaceutical Co., Ltd. Communication system with enhanced partial power source and method of manufacturing same
US9756874B2 (en) 2011-07-11 2017-09-12 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
US9271897B2 (en) 2012-07-23 2016-03-01 Proteus Digital Health, Inc. Techniques for manufacturing ingestible event markers comprising an ingestible component
US9268909B2 (en) 2012-10-18 2016-02-23 Proteus Digital Health, Inc. Apparatus, system, and method to adaptively optimize power dissipation and broadcast power in a power source for a communication device
US11149123B2 (en) 2013-01-29 2021-10-19 Otsuka Pharmaceutical Co., Ltd. Highly-swellable polymeric films and compositions comprising the same
US10175376B2 (en) 2013-03-15 2019-01-08 Proteus Digital Health, Inc. Metal detector apparatus, system, and method
US10421658B2 (en) 2013-08-30 2019-09-24 Proteus Digital Health, Inc. Container with electronically controlled interlock
US9796576B2 (en) 2013-08-30 2017-10-24 Proteus Digital Health, Inc. Container with electronically controlled interlock
US10084880B2 (en) 2013-11-04 2018-09-25 Proteus Digital Health, Inc. Social media networking based on physiologic information
US10398161B2 (en) 2014-01-21 2019-09-03 Proteus Digital Heal Th, Inc. Masticable ingestible product and communication system therefor
US11051543B2 (en) 2015-07-21 2021-07-06 Otsuka Pharmaceutical Co. Ltd. Alginate on adhesive bilayer laminate film
US10797758B2 (en) 2016-07-22 2020-10-06 Proteus Digital Health, Inc. Electromagnetic sensing and detection of ingestible event markers
US10187121B2 (en) 2016-07-22 2019-01-22 Proteus Digital Health, Inc. Electromagnetic sensing and detection of ingestible event markers
US11026609B2 (en) * 2016-08-09 2021-06-08 Verily Life Sciences Llc Wake-up batteries for invasive biosensors
US20210369156A1 (en) * 2016-08-09 2021-12-02 Verily Life Sciences Llc Wake-up batteries for invasive biosensors
US20180042538A1 (en) * 2016-08-09 2018-02-15 Verily Life Sciences Llc Wake-up batteries for invasive biosensors
TWI775765B (en) * 2016-08-09 2022-09-01 美商維爾利生命科學有限公司 Biosensor devices having wake-up batteries and uses thereof
CN109561861A (en) * 2016-08-09 2019-04-02 威里利生命科学有限责任公司 Wake-up battery for invasive biosensor
US11529071B2 (en) 2016-10-26 2022-12-20 Otsuka Pharmaceutical Co., Ltd. Methods for manufacturing capsules with ingestible event markers
US11793419B2 (en) 2016-10-26 2023-10-24 Otsuka Pharmaceutical Co., Ltd. Methods for manufacturing capsules with ingestible event markers

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