WO2000035357A1 - Methods and apparatus for enhancement of transdermal transport - Google Patents
Methods and apparatus for enhancement of transdermal transport Download PDFInfo
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- WO2000035357A1 WO2000035357A1 PCT/US1999/030065 US9930065W WO0035357A1 WO 2000035357 A1 WO2000035357 A1 WO 2000035357A1 US 9930065 W US9930065 W US 9930065W WO 0035357 A1 WO0035357 A1 WO 0035357A1
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- skin
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- ultrasound
- fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
Definitions
- This invention relates to transdermal molecular transportation. More specifically, this invention relates to methods and apparatus for the regulation of skin permeabilization and analysis of analytes in extracted body fluid.
- Drugs are routinely administered either orally or by injection. The effectiveness of most drugs relies on achieving a certain concentration in the bloodstream. Although some drugs have inherent side effects which cannot be eliminated in any dosage form, many drugs exhibit undesirable behaviors that are specifically related to a particular route of administration. For example, drugs may be degraded in the GI tract by the low gastric pH, local enzymes or interaction with food or drink within the stomach. The drug or disease itself may forestall or compromise drug absorption because of vomiting or diarrhea. If a drug entity survives its trip through the GI tract, it may face rapid metabolism to pharmacologically inactive forms by the liver, the first-pass effect. Sometimes the drug itself has inherent undesirable attributes such as a short half-life or a narrow therapeutic blood level range.
- Transdermal delivery of the drugs Topical application has been used for a very long time, mostly in the treatment of localized skin diseases. Local treatments, however, only require that the drug permeate the outer layers of the skin to treat the diseased state, with little or no systemic accumulation.
- Transdermal delivery systems are designed for, inter alia, obtaining systemic blood levels, and topical drug application.
- the word "transdermal” is used as a generic term to describe the passage of substances into, out of, to, and through the skin.
- TDD offers several advantages over traditional delivery methods, including injections and oral delivery
- TDD avoids gastrointestinal drug metabolism, reduces first-pass effects, and provides sustained release of drugs for up to seven days, as reported by Elias in Percutaneous Absorption Mechanisms-Methodology-Drug Delivery, Bronaugh, R L Maibach, H I (Ed), pp 1-12, Marcel Dekker, New York, 1989
- the transport of drugs to, into, out of, and through the skin is complex since many factors influence their permeation
- these include the skin structure and its properties, the penetrating molecule and its physical-chemical relationship to the skin and the delivery matrix, and the combination of the skin, the penetrant, and the delivery system as a whole
- the skin is a complex structure
- the nonviable epidermis stratum corneum, SC
- the viable epidermis the viable der is
- the subcutaneous connective tissue Located within these layers are the skin's circulatory system, the arterial plexus, and appendages, including hair follicles, sebaceous glands, and sweat glands
- the circulatory system lies in the dermis and tissues below the dermis.
- the capillaries do not actually enter the epidermal tissue but come within 150 to 200 microns ofthe outer surface ofthe skin
- TDD can reduce or eliminate the associated pain and the possibility of infection
- the transdermal route of drug administration could be advantageous in the delivery of many therapeutic drugs, including proteins, because many drugs, including proteins, are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake Proteins, such as interferon, are cleared rapidly from the blood and need to be delivered at a sustained rate in order to maintain their blood concentration at a high value
- Transdermal devices are also easier to use than injections
- U S Patent No 4,309,989 discloses the use of ultrasound for enhancing and controlling transdermal permeation of a molecule, including drugs, antigens, vitamins, inorganic and organic compounds, and various combinations of these substances, through the skin and into the circulatory system
- Ultrasound having a frequency of about 20 kHz and having an intensity between about 0 and 3 W/cm 2 is used essentially to drive molecules through the skin and into the circulatory system
- U S Patent No 5,421 ,816 to Lipkovker describes ultrasonic energy that releases a stored drug and forcibly moves the drug through the skin of an organism and to the blood stream
- a housing includes a cavity defined by an assembly of ultrasonic transducers and separated from the skin by a polymeric membrane that stores the drug to be delivered
- the ultrasonic transducer assembly includes a flat, circular ultrasonic transducer that defines the top of a truncated cone and a polarity of transducer segments that define the walls ofthe cone
- the resonant frequency of the planar transducer is lower than the resonant frequency of the transducer segments
- the planar, flat, circular transducer generates a fixed frequency in the 5 kHz to 1 MHz range, and ultrasonic stimuli impulses for a predetermined period of time, such as 10-20 seconds
- the transducer segments receive variable frequency ultrasonic pumping pulses
- the variable frequency ultrasonic pumping pulses lie in the 50 MHz to 300 MHz range
- the variable frequency ultrasonic pumping pulses are applied to opposing transducer segments
- the transducer segments create beams that impinge on the skin at an oblique angle to create a pulsating wave
- the variable frequency ultrasonic pumping pulses are applied to opposing transducer segments in a rotating manner to create pulsating waves in the skin in a variety of directions
- the stimuli pulses cause the planar transducer to produce an ultrasonic wave that excites the local nerves in a way that trauma, such as heat and force, excites local nerves
- the variable frequency ultrasonic pumping pulses cause the transducer segments to produce ultrasonic waves in both the polymeric membrane and the skin
- the ultrasonic waves pump the drug to the polymeric membrane and, then, through skin openings into the underlying blood vessels
- ultrasound energy may serve to enhance the flux of active
- interstitial fluid occurs in the body in a gel like form with little free fluid and, in fact, is even under negative pressure that limits the amount of free interstitial fluid that can be obtained.
- a method for enhancing transdermal transport includes the steps of increasing a permeability of an area of a membrane with a permeabilizing device Next, the permeability of the area of membrane is monitored A substance is transported into and through the area ofthe membrane
- a method for enhancing permeability of an area of skin comprises applying ultrasound to the area of skin While the ultrasound is being applied, electricity (e g , an ac current source or an ac voltage source) is applied to the area of skin While the electricity is being applied to the area of skin, a first electrical parameter of the area of skin is measured Based on the measured first electrical parameter, the ultrasound is controlled
- the present invention comprises an apparatus for enhancing the permeability of an area of skin
- the apparatus includes an ultrasound-producing device configured to apply ultrasound to the area of skin, an electrical source operable to apply electricity to the area of skin, a circuit to measure a first electrical parameter of the area of skin, and a controller responsive to the circuit and operable to control the ultrasound-producing device
- the present invention comprises a method for enhancing the permeability of an area of skin
- the method begins by creating a volume of fluid adjacent the area of skin
- the fluid has an initial concentration of a first substance
- Ultrasound is then applied to the area of skin While the ultrasound is being applied, changes in the concentration of the first substance are monitored
- the method controls the ultrasound based on the changes in the concentration ofthe substance
- the present invention comprises a method for enhancing the permeability of an area of skin
- the method begins by creating a volume of fluid adjacent the area of skin whose permeability is to be enhanced
- a reference value for an electrical parameter of the volume of fluid is then determined
- the method then applies ultrasound to the area of skin and monitors changes in the electrical parameter of the volume of fluid
- the ultrasound is controlled based on the changes in the electrical parameter of the volume of fluid
- a method for regulating skin permeabilization comprises coupling a first electrode in electrical contact with a first area of skin A second electrode is placed in electrical contact with a second area of skin The initial conductivity between these sites is measured, and then a skin permeabilizing method, such as ultrasound, is applied to the first area of skin The conductivity between the first area and second area is measured again Mathematical analysis or signal processing is performed on the conductivity information Next, parameters describing the kinetics of skin conductance are calculated Next, once the desired value of the parameters are reached, the skin permeabilizing step is terminated
- the present invention comprises an apparatus for enhancing permeability of an area of skin
- the apparatus includes a first electrode for coupling in electrical contact with a first area of skin, and a second electrode for placement in electrical contact with a second area of skin
- a skin permeabilizing device such as an ultrasound-producing device, is provided to apply a skin permeabilizing treatment to the skin at the first area
- a means for measuring the conductivity between the first area and second area are provided
- a controller for performing mathematical analysis or signal processing on the conductivity information, and for calculating the kinetics of skin conductance is provided The controller also controls the skin permeabilizing device
- a method for extraction and analysis of at least one analyte in a body fluid is disclosed according to this method, first the permeability level of an area of skin is increased Next, a body fluid is extracted from the area of skin Then, the body fluid is collected Next, a determination is made as to the presence of at least one analyte in the body fluid
- the body fluid may be extracted by physical forces, chemical forces, biological forces, vacuum pressure, electrical forces, osmotic forces, diffusion forces, electro-magnetic forces, ultrasound forces, cavitation forces, mechanical forces, thermal forces, capillary forces, fluid circulation across the skin, electro- acoustic forces, magnetic forces, magneto-hydrodynamic forces, acoustic forces, convective dispersion, photo acoustic forces, by rinsing body fluid off skin, and any combination thereof
- the body fluid may be collected by a collection method including absorption, adsorption, phase separation, mechanical, electrical, chemically induced, and a combination thereof
- the presence of an analyte may be sensed by a sensing method including electrochemical, optical, acoustical, biological, enzymatic technology, and combinations thereof
- a system for extraction and analysis of at least one analyte in a body fluid comprises a transducer for increasing the permeability of an area of skin, an extraction device for extracting interstitial fluid from the area of skin, a collection device for collecting the extracted interstitial fluid, and a sensing device for sensing the presence of at least one analyte in the extracted interstitial fluid
- a method for blood glucose determination includes first increasing a permeability of an area of skin Next, interstitial fluid, or components thereof, is extracted from the area of skin In another embodiment, the interstitial fluid, or components thereof, diffuse through the skin, and are collected Next, the interstitial fluid is collected in a gel
- the gel may contain at least one glucose sensitive reagent that changes at least one characteristic of the gel, such as color, when glucose is present Finally, the change in the characteristic ofthe gel is monitored
- a system for blood glucose determination comprises a transducer for increasing the permeability of the skin, an extraction device for extracting interstitial fluid from the skin, a collection device for collecting the extracted interstitial fluid, a gel having at least one glucose sensitive reagent that changes a characteristic of the gel when glucose is present; and a monitoring device for monitoring a change in the characteristic of said gel
- a drug delivery patch apparatus includes an ultrasound transducer for applying ultrasound to a membrane
- the membrane may include biological membranes, synthetic membranes, or a cell culture
- a biological membrane may include skin, mucosal and buccal membranes
- the apparatus further includes a power source coupled to the transducer
- the apparatus further includes drug molecules between the transducer and the membrane, and an attaching device that attaches the apparatus to the membrane
- the apparatus further includes drive electronics coupled to the transducer such that the drive electronics enables the transducer to apply ultrasound
- the apparatus further includes an interface coupled to the drive electronics
- the drug delivery patch apparatus may include the interface, drive electronics, power source, transducer, drug molecules, and attaching device contained within the patch for transdermal delivery through the membrane Alternatively, the transducer and the drug molecules as well as the attaching device may be contained in the patch
- the power source and interface may be connected to the patch with a connecting wire, or without a wire
- the drug delivery patch may include the power source, the trans
- a method for transdermal vaccination by sonophoresis comprises the steps of enhancing the permeability of the skin by the application of ultrasound, providing a vaccine to the permeabilized skin, and delivering the vaccine to the skin cells, for example, Langerhans cells, dendric cells, and keratinocytes
- ultrasound is used to enhance the permeability of the skin
- the steps of increasing the permeability of the skin and providing a vaccine to the permeabilized skin occur simultaneously
- ultrasound is used to irritate or inflame an area of skin
- a vaccine is provided to the irritated or inflamed skin This is more effective in inducing the immune response ofthe body BRIEF DESCRIPTION OF THE DRAWINGS
- Fig. 1 depicts a schematic of an electrical model for skin
- Fig. 2 depicts a flow chart of a method for controlled enhancement of transdermal delivery according to one embodiment ofthe present invention
- Fig. 3 depicts a diagram of a circuit that enhances skin permeability and monitors enhancement of skin permeability according to one embodiment of the present invention
- Fig. 4 depicts a permeability monitoring circuit according to another embodiment ofthe present invention
- Fig. 5 depicts a permeability monitoring circuit according to one embodiment ofthe present invention
- Fig. 6 depicts a flow chart of a method for controlled enhancement of transdermal delivery according to one embodiment ofthe present invention
- Fig. 7 depicts a flow chart of a method for controlled enhancement of transdermal delivery according to one embodiment ofthe present invention
- Fig. 8 depicts a flow chart of a method for controlled enhancement of transdermal delivery according to one embodiment ofthe present invention
- Fig. 9 depicts the time variation of the skin conductance while being exposed to ultrasound according to an example
- Fig. 10 shows a relationship between the inflection time and the time to pain on various volunteers according to an example
- Fig. 11 depicts a flowchart of a method of determining when to terminate the application of ultrasound
- Fig. 12 depicts example graphs ofthe method of Fig. 11 .
- Fig. 13 depicts a flowchart of a method for extraction and analysis of at least one analyte in a body fluid according to one embodiment of the present invention
- Fig. 14 depicts a drawing of a tensioner according to one embodiment ofthe present invention
- Fig. 15 depicts a flowchart of a method of determination of blood glucose according to one embodiment ofthe present invention
- Fig. 16 illustrates a drug delivery patch apparatus in accordance with one embodiment ofthe present invention
- Fig. 17 illustrates a cross-sectional view of a transducer in accordance with one embodiment ofthe present invention
- Fig. 18 illustrates a drug delivery patch apparatus having a feedback mechanism in accordance with one embodiment ofthe present invention
- Fig. 19 depicts a flowchart ofthe method for transdermal vaccination by sonophoresis according to one embodiment ofthe present invention.
- the terms skin permeabilizing method or device includes the application of ultrasound, chemicals, electroporation, mechanical, disrupting devices, tape stripping, and laser, and devices for the application of the same.
- skin includes membranes, such as biologic and synthetic skin.
- Ultrasound is generally defined as sound at a frequency of greater than about 20 kHz.
- Therapeutic ultrasound is typically between 20 kHz and 5 MHz.
- Sonophoresis is defined as the application of ultrasound to the skin resulting in enhanced transdermal transport of molecules.
- Low frequency sonophoresis or ultrasound is defined as sonophoresis or ultrasound at a frequency that is less than 2.5 MHz, more typically less than 1 MHz, more preferably in the range of 20 to 100 kHz.
- Near ultrasound is typically about 10 kHz to 20 kHz. It should be understood that in addition to ultrasound, near ultrasound may also be used in the embodiments ofthe present invention. 1. Enhancement and Regulation of Skin Permeability
- ultrasound was initially used as a driving force that essentially pushed drugs through the skin and into the circulatory system.
- Ultrasound is also used to increase the permeability of the skin.
- ultrasound having a particular frequency will disorganize the lipid bilayer in the skin and thus increase the permeability of the skin
- either drugs can be delivered through the skin to the body or analyte or analytes can be extracted through the skin from the body
- a driving force of some type is still required, but the required intensity ofthe driving force is decreased
- a concentration gradient is generally sufficient driving force for transdermal transport through skin whose permeability has been enhanced using ultrasound
- the ultrasound still needs to be controlled That is, overexposure to ultrasound may cause skin damage from increased heat, increased pressure and other factors Therefore according to various embodiments of the present invention, a method and an apparatus for controlled enhancement of skin permeability are disclosed
- the method and apparatus, according to the present invention focus on the use of electrical parameters of the skin as a proxy for skin permeability
- the skin can be modeled using an R-C circuit similar to that shown in Fig. 1.
- the "skin circuit,” shown in Fig. 1, consists of a resistor Ri in parallel with a capacitor C, both of which are in series with a resistor R 2 .
- the value for Ri is about 100 k ⁇
- the value for C is about 13 ⁇ F
- the value for R 2 is about 2k ⁇
- these values will vary from person to person depending on skin type and condition
- the behavior (i e , the frequency response) of the "skin circuit" changes in response to excitations having different frequencies
- the impedance of this circuit will decline sharply as frequency increases, for example, from 10 Hz to 1 kHz That is, at low frequencies, the capacitive component to the impedance of the parallel combination of Ri and C is significant and therefore the overall impedance of the circuit is high
- the capacitive component to the impedance of the parallel combination decreases and, therefore, the overall impedance of the "skin circuit" declines
- Various electrical parameters of the skin have values that correlate with skin permeability
- the value of Ri significantly decreases as the skin becomes permeable
- Ri may drop to a value around 5 k ⁇ for a skin area of about 1 7 cm Therefore, the frequency response of the overall skin circuit becomes much flatter as frequency increases That is, the difference between the impedance of the circuit at 10 Hz and 1 kHz would not be nearly as significant as at 10 Hz alone
- the methods and apparatus of the present invention measure one or more electrical parameters of an area of skin that is being exposed to ultrasound and then adjust the source of ultrasound based on the measured parameters
- a method for controlled enhancement of skin permeability is disclosed, and will be explained in conjunction with Fig. 2
- a skin permeabilizing device such as an ultrasonic device
- the skin permeabilizing device is applied to a small patch of skin
- a baseline measurement for some electrical parameter is determined for the patch of skin to which the skin permeabilizing will be applied to determine baseline parameters
- a baseline impedance is measured for the patch of skin to which the skin permeabilization device is to be applied
- a baseline conductance, a baseline capacitance, a baseline inductance, or a baseline capacitance may be measured The baseline measurement may be made by using two or more electrodes As is shown in greater detail in Fig.
- an electrode such as source electrode 310
- Source electrode 310 does not have to make direct contact with the skin Rather, it may be electrically coupled to the skin through the medium that is being used to transmit ultrasound
- a second or counter electrode such as conductive band 312
- the ultrasonic transducer and horn that apply the ultrasound double as the source electrode through which electrical parameters of the patch of skin may be measured, and is coupled to the skin through a conductive solution, such as saline, used as an ultrasound medium
- a separate electrode may be affixed to the area of skin that ultrasound will be applied to and is used as the source electrode
- the housing of the device used to apply ultrasound to the area of skin may be used as the source electrode The electrode can be
- the counter electrode should make sufficient contact with the skin This can be achieved in a number of ways
- the counter electrode is applied directly to the epidermis of the skin That is, the counter electrode is applied to an area of skin from which the stratum corneum has been removed
- the stratum corneum may be removed in a number of ways
- the stratum corneum is removed by tape stripping
- sufficient electrical contact between the skin and the counter electrode is created by using a counter electrode having a large surface area More specifically, a conductive polymeric path or metallic foil patch having an area much larger than the skin area exposed to ultrasound is used The large area of the counter electrode in this embodiment decreases its impedance and allows accurate measurements of the electrical parameter of the area of skin exposed to ultrasound
- a conductive band is wrapped around the subject's arm and used as the counter electrode
- the counter electrode may be placed in a handle ofthe skin permeabilizing device, to which a subject grasps during operation
- the counter electrode surrounds the skin permeabilizing device
- the baseline measurement may be made by applying an electrical signal to the patch of skin through the electrodes
- the electrical signal supplied preferably has a sufficient intensity so that the electrical parameter of the skin can be measured, but a suitably low intensity so that the electrical signal does not cause damage to the skin or any significant electrophoresis effect for the substance being delivered
- a 10 Hz AC source may be used to create a voltage differential between the source electrode and the counter electrode
- the voltage supplied does not exceed 500 mV, and, preferably, does not exceed 100 mV
- an AC current source is used The current source may also be similarly limited
- the baseline measurement is made after the source has been applied using appropriate circuitry
- a resistive sensor is used to measure the impedance of the patch of skin at 10 Hz
- a 1 kHz source is used Sources of other frequencies are also possible Experiments were performed on human volunteers to ensure that the above described electrode placement would provide accurate measurements
- a second small chamber ( ⁇ 1 5 cm ) was placed on the subject's arm in order to measure skin conductivity This is referred to as the reference chamber
- the skin under the reference chamber was tape-stripped using scotch tape to remove the stratum corneum This process involved placing a piece of scotch tape (1 5 cm wide and 3 cm long) on the subject's arm and removing it This procedure is repeated -25 times in order to remove the stratum corneum from the designated area
- An electrode was then placed on the skin under the chamber
- Another electrode is placed on the subject's arm This electrode consisted of a large piece of aluminum foil placed on intact skin Ultrasound (27 kHz, ⁇ 10 ⁇ m tip displacement, pulsed 5 sec on/ 5 sec off) was applied to the first chamber The conductance of the skin exposed to ultrasound was measured with both counter electrodes (tape stripped and intact) The measured conductances were similar thus proving that a large counter electrode placed over intact skin can be successfully used to measure skin conductance during sonophoresis Referring again to Fig. 2, in step 204, the skin permeabilizing device, such as an ultrasound providing device, is applied to the patch of skin.
- the skin permeabilizing device such as an ultrasound providing device
- ultrasound having a frequency of about 20 kHz, and an intensity of about 10 W/cm 2 may be used to enhance the permeability of the patch of skin to be used for transdermal transport.
- the permeability of the patch of skin is monitored. More specifically, and as discussed above, electrical parameters of the patch of skin are used as a proxy for skin permeability. That is, what is actually being monitored is the electrical parameter for which a baseline measurement was made in step 202. The monitoring measurements are made using the same electrode set up that was used to make the baseline measurement.
- the skin permeabilizing device is controlled based on the monitoring measurements made in step 206. In one embodiment, the monitoring measurements are fed back to a microcontroller that is used to control the skin permeabilizing device.
- the permeability enhancement obtained by supplying ultrasound is limited.
- the ultrasound-producing device when the parameter being monitored reaches is predetermined value, the ultrasound-producing device is turned off. If the parameter being monitored has not reached the predetermined value, the measurement is repeated until the predetermined value is reached.
- the predetermined value may depend upon a number of factors including, inter alia, the skin characteristics of the individual, the drug to be delivered or the analyte or analytes to be extracted (because of varying molecule sizes), and the frequency of the excitation source. As is apparent to one of ordinary skill in the art, a specific correlation between the electrical parameter being used and skin permeability may be determined by conducting experiments and using experimental data The predetermined value may then be determined on a subject- by-subject basis, taking into account all appropriate factors and the empirical data
- the intensity of the skin permeabilizing device may be gradually scaled back as the point of maximum permeability enhancement is approached
- either the intensity or the duty cycle may be reduced by a predetermined amount, such as 50% This is done so that the predetermined value is not "overshot," thereby increasing the risk of skin damage
- a predetermined amount such as 50% This is done so that the predetermined value is not "overshot," thereby increasing the risk of skin damage
- the intensity may be scaled back when the parameter being monitored reaches 25%, 50% and 75% ofthe predetermined value
- permeability enhancement control may be accomplished using two electrical sources having different frequencies This method relies on the observation, discussed above, that as the skin becomes more permeable, the frequency response of the skin becomes flatter
- the initial step 202 of measuring a baseline for the parameter is unnecessary because the ultrasound control is based on a differential between the parameter value at two different frequencies of excitation Nevertheless, a baseline measurement may still be desirable in order to determine the range of values to expect
- the electrode arrangement may be the same as that described above
- step 204 of beginning ultrasound application is also the same as recited above Thus, the details of these steps will not be reiterated
- step 206 skin permeability is monitored
- skin permeability is also monitored using an electrical parameter measured from the skin as a proxy
- the electrical parameter is measured at two frequencies
- the impedance of the skin is measured at frequencies of 10 Hz and 1 kHz
- the parameter measurement at a first frequency is compared with the parameter measurement at a second frequency to determine whether the two measurements are within a predetermined differential If the two values are within a predetermined differential, it provides an indication that the frequency response of the skin has flattened and, therefore, is an indication that the skin has reached an enhanced level of permeability
- the skin permeabilizing device is turned off
- an impedance of the skin is measured at 10 Hz and at 1 kHz And, if the two impedance measurements are within 20% of each other, the skin permeabilizing device may be turned off
- the rate of change in the parameter measurements may also be used to determine a point at which the skin permeabilizing device is scaled back or discontinued
- the rate of change of one, or both, or the parameters may be used
- the rate of change of the difference between the two parameters may also be used
- the intensity of the skin permeabilizing device may be gradually scaled back or discontinued, in a manner similar to that discussed above
- the predetermined differential value may depend upon a number of factors, including, inter alia, the skin characteristics of the individual, the drug to be delivered or the analyte to be extracted (because of varying molecule sizes), and the frequencies of the exciting sources Therefore, the predetermined differential is determined on a subject-by-subject basis taking into account all appropriate factors Empirical data may be used to determine a precise value for the predetermined differential.
- the intensity of the skin permeabilizing device may be gradually scaled back as the point of maximum permeability enhancement is approached
- either the intensity or the duty cycle may be reduced by a predetermined amount, such as 50% Additional controls are possible
- the intensity is scaled back when the differential between the two parameters being monitored reaches 25%, 50% and 75% of the predetermined differential value
- Apparatus 300 uses an ultrasound-producing device as the skin permeabilizing device, it should be noted that other devices for increasing the skin permeability may be used in place of the ultrasound-producing device
- the permeability of the skin may be increased through the application of electric fields, chemicals, mechanical forces, needles, and magnetic forces
- Apparatus 300 includes ultrasound transducer/horn combination 302, source 304, bandpass filter 306, permeability monitoring circuit 308, source electrode 310, return electrode 312, and microcontroller 314
- Permeability monitoring circuit 308 comprises current sensor 315, amplifier 316, A/D converter 318, and resistor 320
- Ultrasound transducer/horn combination 302 is used to apply ultrasound to the area of skin 322
- Transducer 302 may be any known ultrasound transducer, such as a piezoelectric transducer, a ceramic transducer, or polymer block transducer
- the horn can have any known configuration In one embodiment the horn
- Source 304 and bandpass filter 306 are provided to drive the electrical control circuitry That is, in order to obtain the electrical parameter measurements used for controlling source 304, a small signal is passed through the area of skin
- source 304 provides a 10 Hz AC square wave voltage that is used to monitor the permeability ofthe area of skin in apparatus 300
- Bandpass filter 306 is provided to convert the square wave into a sinusoid
- Source electrode 310 and return electrode 312 provide an electrical path through which electrical parameters of the area of skin 322 can be measured
- Source electrode 310 may be incorporated into transducer/horn combination 302, and is preferably formed of any suitable conductive material
- the ultrasound horn is metal and is used as the source electrode
- Return electrode 312 is a conductive band
- Permeability monitoring circuit 308 comprises circuitry designed to measure an electrical parameter of the skin as a proxy for the permeability of the skin More specifically, according to one embodiment of the present invention, permeability monitoring circuit 308 comprises circuitry designed to measure the current flow through the area of skin 322 and to convert that measurement in to a form suitable for use by microcontroller 314
- Permeability monitoring circuit 308 comprises current sensor 315 that is operable to measure the impedance of area of skin 322
- Current sensor 315 may be any sensor that may be used to measure current, and, in one embodiment, current sensor 315 is a 1 k ⁇ current sense resistor where the output voltage generated is 1000 times the current flowing through the skin
- the output of current sensor 315 is an analog signal that should be digitized before it may be used by microcontroller 315
- Amplifier 316 and resistor 320 serve to amplify the output voltage of current sensor 315 so that it may be digitized by A/D converter 318
- A/D converter 318 may be any suitable A/
- Fluids controller 330 controls the pumps and fluids for the system Pump 332 may be provided to provide a seal between transducer 302 and the surface of skin 322 Pump 334, in conjunction with valve 336, may be used to fill and evacuate the chamber of transducer 302
- the coupling fluid used in transducer 302 may be provided in cartridge 338 Other devices and methods for providing coupling fluid may also be used
- a user interface may also be provided User interface 340 includes low battery sensor 342, which may include a comparator Switch 344 may be provided to turn on or off the ultrasound-producing device Input 346 may be provided to allow a user to adjust the ultrasound intensity
- the ultrasound level may be provided in display 350
- the permeability level of the skin may be provided in display 352
- Indicators 354 and 356 may be provided to alert the user of the operation of the ultrasound, as well as a when there is a low battery
- Additional controls and displays may be provided, as required, to prevent a user from applying ultrasound of a harmful intensity or duration, or to prevent ultrasound from being applied before the system is ready (i_e_, before coupling fluid is provided for transducer 302, etc )
- the circuitry described above may be replaced with other elements if the electrical parameter measurements are accomplished in a different way More specifically, the circuitry shown in Figs.
- FIG. 4 schematically depicts one embodiment of a circuit useful for implementing dual frequency control of skin permeability
- the circuit comprises sources F t and F 2 that supply two distinct AC signals to the area of skin to which ultrasound is being applied
- sources F] and F comprise a 10 Hz and a 1kHz current source respectively
- microcontroller 314 would control the switch so that sources Fi and F 2 alternately excite the skin
- the impedance of the skin is measured by measuring the voltage Vi That is, Vj is transmitted to a microprocessor (e g , microcontroller 314 in Fig. 3) through gain circuit 402, diode 404, capacitor Ci, and output resistors Roi and R 02
- the combination of diode 404 and capacitor Ci comprises an AC to DC converter suitable for input to an A/D converter to transform the analog signal from gain circuit 402 to a digital signal suitable for use by a microprocessor
- Output resistors Roi and R 02 provide impedance matching and filtering for the microprocessor, respectively
- the circuit of Fig. 4 in conjunction with a suitably programmed microcontroller alternately applies a 10 Hz and a 1kHz AC source to the skin
- the circuit in conjunction with the microprocessor, measures the impedance of the skin at both frequencies
- the microcontroller makes suitable adjustments to the ultrasound-producing device based on the differential between the impedance ofthe skin at 10 Hz and the impedance of the skin at 1 kHz
- Fig. 5 schematically depicts yet another embodiment of permeability monitoring circuit for use with multiple frequency excitation
- sources Fi and F 2 are applied simultaneously through adder circuit 502 to the area of skin to which ultrasound is being applied
- the output signal from the skin is then fed to two bandpass filters 504 and 506 Elements C], C 2 and Ri of bandpass filter 504 are preferably chosen to create a pass band centered around the frequency of source Fi Elements
- C 3 , C 4 and R of bandpass filter 506 are preferably chosen to create a pass band centered around the frequency of source F 2
- the output signals from bandpass filters 504 and 506 are then subtracted in comparator circuit 508 to create a differential signal for the microprocessor
- a suitably configured microprocessor then uses this differential signal to make suitable adjustments to the ultrasound-producing device
- a method for controlled enhancement of skin permeability by coupling fluid monitoring is disclosed
- a skin permeabilizing device such as an ultrasound-producing device
- some coupling fluid which may be a liquid, gel, or solid
- the method according to this embodiment takes advantage of the enhanced skin permeability that is the desired end point of this invention in order to control the skin permeabilizing device This method will be explained in conjunction with the flow chart of Fig.
- step 602 an initial concentration of a known substance is determined for the coupling medium
- the coupling medium may have a known initial concentration of a known substance That is, step 602 will not require any additional measuring
- the known substance can be any substance (molecular or ionic) as long as its concentration in the coupling medium is known If, however, the substance is going to be passed into the body, the substance should be one that is not harmful to the body
- the term benign is used herein to describe such a substance
- Glucose and calcium are examples of substances that may be used in this embodiment
- the skin permeabilizing device is applied to the patch of skin
- an ultrasound-producing device is used as the skin permeabilizing device
- ultrasound having a frequency of about 20 kHz, and an intensity of about 10 W/cm 2 is used to enhance the permeability ofthe patch of skin to be used for transdermal transport
- permeability monitoring is accomplished by monitoring changes in the concentration of the known substance in the coupling medium That is, as the area of skin is subjected to the skin permeabilizing device it will become permeable As the area of skin becomes permeable, molecules and ions begin to pass into the coupling medium from inside the body and from the coupling medium into the body depending on the concentration gradient of the substance between the body and the coupling medium
- This concentration monitoring may be done in real time using an on-line sensor specifically programmed to detect and measure the concentration of the known substance
- glucose is used as the known substance
- the concentration of glucose is usually greater inside the body than in the coupling medium unless the concentration in the coupling medium is artificially increased
- changes in the concentration of glucose in the coupling medium are monitored to determine when the skin becomes permeable
- mannitol is used as the known substance
- Mannitol is a benign substance as that term is used in the context of this application
- the concentration of mannitol in the coupling medium is adjusted so that it is greater than the concentration of mannitol in the body
- mannitol molecules with begin to pass from the coupling medium into the body decreasing the concentration of mannitol in the coupling medium
- step 606 the decrease in the concentration of mannitol in the coupling medium is monitored to determine when the skin becomes permeable
- step 608 the skin permeabilizing device is controlled based on the concentration measurements made in step 606
- the concentration measurements from the chemical analyzer are fed back to a microcontroller that is used to control the skin permeabilizing device
- the skin permeabilizing device is turned off If the concentration of the substance being monitored has not reached the predetermined value, the measurement is repeated until the predetermined value is reached
- the predetermined value depends upon a number of factors including, inter alia, the skin characteristics of the individual, the known substance, and the frequency of the excitation source As is apparent to one of ordinary skill in the art, a specific correlation between the change in concentration of the known substance being used and skin permeability can be determined by conducting experiments and using experimental data The predetermined value is then determined on a subject-by- subject basis taking into account all appropriate factors as well as any empirical data
- the intensity of the skin permeabilizing device may be gradually scaled back as the point of maximum permeability enhancement is approached
- either the intensity or the duty cycle of the ultrasound may be reduced by a predetermined amount, such as 50% This is done so that the predetermined value is not "overshot” thereby increasing the risk of skin damage
- the intensity may be scaled back when the concentration of the substance being monitored reaches 25%, 50% and 75% ofthe predetermined value
- the rate of change in the concentration of the substance may also be used to determine a point at which the skin permeabilizing device is scaled back or discontinued As the rate of change in the concentration reaches a predetermined value, the intensity of the skin permeabilizing device may be gradually scaled back or discontinued, in a manner similar to that discussed above
- skin permeability can be monitored by detecting an electrical parameter of the coupling fluid More specifically, as skin permeability increases, ions may pass into and out of the coupling medium As ion concentration in the coupling medium increases or decreases, the electrical characteristics of the coupling medium change Therefore, the electrical characteristics of the coupling medium can be used to monitor skin permeability using a methodology that is a hybrid of that shown in Figs. 2 and 6, and is set forth in Fig. 7
- a reference value for an electrical parameter is determined for the coupling medium.
- the coupling medium has a known ionic composition, its electrical parameters should be known
- the coupling fluid has a known concentration of calcium ions Thus, this step should not require an actual measurement
- the electrical parameter determined is conductivity, and in step 702, the conductivity of the coupling medium is determined
- step 704 the skin permeabilizing device is turned on
- step 706 skin permeability is determined by monitoring changes in the electrical parameter of the coupling medium This monitoring may be accomplished using a simple meter
- the coupling medium has a known concentration of calcium ions that is lower than the concentration of calcium ions in the body Therefore, as the skin becomes more permeable, calcium ions begin to pass from the body into the coupling medium
- the skin permeabilizing device is controlled based on the monitoring measurements
- the monitoring measurements are fed back to a microcontroller that is used to control the skin permeabilizing device
- the skin permeabilizing device is turned off If the parameter being monitored has not reached the predetermined value, the measurement is repeated until the predetermined value is reached
- the rate of change in the parameter being monitored may also be used to determine a point at which the skin permeabilizing device is scaled back or discontinued. As the rate of change reaches a predetermined value, the intensity of the skin permeabilizing device may be gradually scaled back or discontinued, in a manner similar to that discussed above.
- the predetermined value depends upon a number of factors including, inter alia, the composition of the coupling medium, the surface area ofthe patch of skin to which the skin permeabilizing device is applied, and the concentration of the particular ion being used in the body.
- the predetermined value is determined on a subject-by- subject basis taking into account all appropriate factors and the empirical data.
- the intensity of the skin permeabilizing device may be gradually scaled back as the point of maximum permeability enhancement is approached. In one embodiment, where ultrasound is used, as the parameter being monitored reaches 50% of the predetermined value, either the intensity or the duty cycle is reduced by a predetermined amount, such as 50%. This is done so that the predetermined value is not "overshot” thereby increasing the risk of skin damage. Additional controls are possible.
- the intensity may be scaled back when the parameter being monitored reaches 25%, 50% and 75% ofthe predetermined value.
- an apparatus and method for regulating the degree of skin permeabilization through a feedback system is provided.
- This apparatus and method may be similar to what has been described above, with the addition of further regulation of the degree of skin permeabilization.
- the application of the skin permeabilizing device is terminated when desired values of parameters describing skin conductance are achieved.
- a first, or source, electrode is coupled in electrical contact with a first area of skin where permeabilization is required.
- the source electrode does not have to make direct contact with the skin. Rather, it may be electrically coupled to the skin through the medium that is being used to transmit ultrasound.
- the ultrasonic transducer and horn that will be used to apply the ultrasound doubles as the source electrode through which electrical parameters of the first area of skin may be measured and is coupled to the skin through a saline solution used as an ultrasound medium
- a separate electrode is affixed to the first area of skin and is used as the source electrode
- the housing of the device used to apply ultrasound to the first area of skin is used as the source electrode
- the source electrode can be made of any suitable conducting material including, for example, metals and conducting polymers
- a second, or counter, electrode is coupled in electrical contact with a second area of skin at another chosen location
- This second area of skin can be adjacent to the first area of skin, or it can be distant from the first area of skin
- the counter electrode can be made of any suitable conducting material including, for example, metals and conducting polymers
- the counter electrode should make sufficient contact with the skin This can be achieved in a number of ways
- the counter electrode is applied directly to the epidermis of the skin That is, the counter electrode is applied to an area of skin from which the stratum corneum has been removed
- the stratum corneum may be removed in a number of ways
- the stratum corneum is removed by tape stripping
- sufficient electrical contact between the skin and the counter electrode is created by using a counter electrode having a large surface area.
- a conductive polymeric path or metallic foil patch having an area much larger than the skin area exposed to the skin permeabilizing device is used.
- the large area of the counter electrode in this embodiment decreases its impedances and allows accurate measurements of the electrical parameter of the area of skin exposed to the skin permeabilizing device
- a conductive band is wrapped around the subject's arm and used as the counter electrode
- the counter electrode may be placed in a handle ofthe skin permeabilizing device, to which a subject grasps during operation
- the counter electrode surrounds the skin permeabilizing device
- an initial conductivity between the two electrodes is measured This may be accomplished by applying an electrical signal to the patch of skin through the electrodes
- the electrical signal supplied may have sufficient intensity so that the electrical parameter of the skin can be measured, but have a suitably low intensity so that the electrical signal does not cause permanent damage to the skin, or any significant electrophoresis effect for the substance being delivered
- a 10 Hz AC source is used to create a voltage differential between the source electrode and the counter electrode The voltage supplied should not exceed 500 mV, and preferably not exceed 100 mV, or there will be a risk of damaging the skin
- an AC current source is used The current source may also be suitably limited
- the initial conductivity measurement is made after the source has been applied using appropriate circuitry
- a resistive sensor is used to measure the impedance of the patch of skin at 10 Hz.
- a 1 kHz source is used Sources of other frequencies are also possible.
- a skin permeabilizing device is applied to the skin at the first site Any suitable device that increases the permeability of the skin may be used.
- ultrasound is applied to the skin at the first site
- ultrasound having a frequency of 20 kHz and an intensity of about 10 W/cm 2 is used to enhance the permeability ofthe patch of skin to be used for transdermal transport
- the conductivity between the two sites is measured The conductivity may be measured periodically, or it may be measured continuously The monitoring measurements are made using the same electrode set up that was used to make the initial conductivity measurement
- step 812 mathematical analysis and/or signal processing may be performed on the time-variance of skin conductance data.
- ultrasound used as the method of permeabilization Ultrasound was applied until the subjects reported pain Skin conductivity was measured once every second during ultrasound exposure After plotting the conductance data, the graph resembled a sigmoidal curve The conductance data was in a general sigmoidal curve equation
- C/ is the final current
- S is a sensitivity constant
- t is the exposure time required to achieve an inflection point
- t is the time of exposure
- Fig. 9 shows the time variation of the skin conductance while being exposed to ultrasound
- the curve is a sigmoidal curve and can be fitted to the above equation
- the line shown in Fig. 9 corresponds to a fit to the above equation
- the values of fitted parameters were obtained and are plotted
- the value of t* corresponds to an exposure time required to achieve an inflection point (a point where the slope of the curve shown changes sign)
- the inflection time approximately indicates the time required to achieve half the total exposure Fig.
- step 1 102 A/D conversion is performed on the conductivity data This results in a graph similar to the one in Fig. 12a
- step 1 104 filtering is performed on the digital data As shown in Fig. 12b, the filtered data has a smoother curve than the unfiltered data of Fig.
- step 1 106 the slope of the curve is calculated
- step 1 108 the maximum value for the slope is saved If the current value for the slope is greater than the maximum value that is saved, the maximum value is replaced with the current value
- step 1 1 10 if the slope is not less than or equal to the maximum value, the process returns to step 1 102 to wait for a peak If the slope is less than or equal to the maximum value, in step 1 1 12 the process detects a peak, or point of inflection, shown in Fig. 12c, then, in step 1 1 14, terminates the application of ultrasound to the skin
- the detection of the peak may be validated This may be provided to ensure that the "peak" detected, in step 1 1 12, was not noise, but was actually a peak
- ultrasound may be applied even after the inflection point is reached.
- ultrasound is applied for a predetermined time This predetermined time may be based on a percentage of the time to reach the inflection point For example, once the inflection point is reached, ultrasound continues to be applied for an additional 50% of the time it took to reach the inflection point Thus, if it took 14 seconds to reach the inflection point, ultrasound is applied for an additional 7 seconds Other percentages may be used, and this percentage may be based on factors including pain threshold and skin characteristics
- ultrasound is applied until the slope decreases to a certain value Referring again to Fig. 11, after the inflection point is reached, the slope decreases as ultrasound is applied
- ultrasound may be applied until the slope decreases by a percentage, such as 50%, or to a predetermined value As above, this determination is flexible and may vary from individual to individual
- the current at the inflection point is measured, and then a percentage of this current is still applied For example, if the inflection point is reached at 40 ⁇ amps, an additional 10% of this, for a total of 44 ⁇ amps, may be reached Again, this determination is flexible and may vary from person to person O 00/35357
- step 814 the parameters describing the kinetics of skin conductance changes are calculated These parameters include, inter alia, skin impedance, the variation of skin impedance with time, final skin impedance, skin impedance at inflection time, final current, exposure time to achieve the inflection time, etc.
- step 816 the skin permeabilizing device applied in step 808 is terminated when desired values of the parameters describing skin conductance are achieved
- ultrasound may be used to extract body fluids through or out of skin that has its permeability increased
- a flowchart depicting a method for extraction and analysis of at least one analyte in a body fluid according to one embodiment of the present invention is disclosed
- the permeability of the skin is increased This may be accomplished by any suitable method for increasing the permeability of the skin, such as iontophoresis
- the permeability ofthe skin may be increased through the application of ultrasound
- the term "interstitial fluid" may include lymph, interstitial fluid, and serum that may be extracted from the body. It is also used to describe components of interstitial fluid.
- interstitial fluid is extracted transdermally from the surface of the skin Extraction can be performed after sonication or other permeation methods using a wide variety of different forces
- forces may include physical forces, chemical forces, biological forces, vacuum pressure, electrical, osmotic, diffusion, electro-magnetic, ultrasound, cavitation, mechanical, thermal, capillary forces, fluid circulation across the skin, electro-acoustic, magnetic, magneto-hydrodynamic, acoustic, convective dispersion, photo acoustic, by rinsing body fluid off skin, or by any combination of these forces.
- Spatial and/or temporal positive and/or negative pressure modulation may be used.
- spatial modulation positive pressure is applied to an area of the skin, while a vacuum is applied to another area, assisting in the extraction of body fluid.
- temporal modulation vacuum and positive pressure alternate at about the same area of skin, assisting in the extraction of body fluid.
- the application of either spatial or temporal modulation may be continuous or discontinuous, and they may be applied separately or in combination.
- vacuum pressure may be applied to extract body fluid.
- Vacuum pressure may be applied continuously, or it may be applied discontinuously. When applied discontinuously, the vacuum may be applied in a pulsed fashion.
- a material that maintains the surface configuration of the skin e.g., flat, convex, or concave
- mesh, membrane, perforated metal, or other porous material may be applied between the vacuum pressure and the skin while the vacuum pressure is applied.
- the vacuum can act through these structures and can be generated mechanically, electro-mechanically, chemically, or electro-chemically.
- the vacuum can be applied in such a manner so as to maintain the skin surface configuration with the vacuum alone.
- a chamber that is applied to skin can have a design (configuration and material properties) to localize high pressure gradient across skin and/or other tissues
- electrical forces may be applied Electrical forces may be iontophoretic, electro-osmotic, or may be electroporation A gel with an electric charge also may be applied, in order to encourage the absorption and evacuation of body fluid and components thereof
- osmotic forces may be used.
- a gel or solution may be applied to the skin surface in order to encourage osmosis
- ultrasound may be used to pump body fluid and fluid components, to levitate, to activate gas bodies, to produce cyclic impulse mechanical stress to the skin, to create microstreaming, to increase temperature, or to set up standing waves
- Single or multiple sources of ultrasound may be used in combination with various characteristics of ultrasound, ejL . , different frequencies, intensities, or coupling media, in order to encourage the extraction of body fluid.
- mechanical forces may be used to extract body fluid
- forces may be achieved by, inter alia, a roller, a squeezer, a stretcher, iris compressor/tensioner device, etc. to increase the volume ofthe body fluid that is extracted.
- a tensioner is used to extract body fluid
- tensioner 1402 consists of a convex geometry held against the skin 1404. By pressing tensioner 1402 against skin 1404, body fluid may be collected within cavity 1406 of tensioner 1402. In another embodiment, thermal forces may be used to extract body fluid.
- the skin temperature may be increased using electricity, chemical, ultrasonic, or optical energy sources or methods and/or utilize temperature sensitive polymers to swell or contract a gel, membrane, and/or solid to encourage the absorption and evacuation of body fluid and components thereof
- Temperature sensitive polymers may be used to move a piston or membrane to push or suck fluid Examples of such polymers include, inter alia, poloxymers
- chemical forces are used Chemical substances may be used to augment convective and/or diffusive forces as a means to extract additional body fluid, and/or to enhance transpo ⁇ and/or accumulation of body fluids at specific body sites
- a hydrogel with an incorporated, trapped, or immobilized bioactive molecules such as enzyme would allow for extraction by osmosis into a sensing scaffold
- pH/ionic forces may be used These forces may be used to change the material properties and characteristics, e ⁇ _. hydrophilic material to a hydrophobic material
- a pH/ionic sensitive membrane and/or gel may be swollen and contracted in order to encourage the absorption and evacuation of body fluid and components thereof
- capillary forces may be used These forces may be used to assist in fluid transport across skin pores
- the body fluid and components thereof are collected This collection may be accomplished by abso ⁇ tion, adsorption, phase separation, mechanical forces, electrical forces, chemically induced forces, or a combination thereof.
- a humid environment is created and maintained in order to control evaporation of analytes during extraction
- the collected volume of body fluid may be the same as the volume extracted, or it may be a fixed constant volume
- absorption or adsorption may be used
- the body fluid may be collected into a gel, which contains a captive enzyme.
- a polymeric, metallic, or ceramic screen, scaffold, mesh, or membrane, or a combination may be used to do this These materials may also be a component of a sensor.
- phase separation may be used.
- Body fluid may be isolated by combining the fluid with an appropriate density immiscible fluid
- the body fluid may be collected into a conical chamber.
- phase separation is achieved by first applying a hydrophobic coating on the skin prior to the extraction step. After the extraction, body fluid is present in the form of droplets on the hydrophobic coating.
- mechanical forces may be used to collect body fluids This includes forces such as vacuum, pressure, and acoustic forces Dispersed body fluid may be collected over a greater area to a smaller area using a microfluidic channel against the skin
- a means to evacuate the fluidic path may include the introduction of a liquid and/or gas This means to evacuate may be applied to all collection processes, and not just mechanical collection
- electrical collection may be used
- solid, liquid droplets, or gas are charged and transported (moved) from skin to a sensor or to a collecting compartment using electrical forces
- chemical collection may be used
- a hydrophilic gel may be used to collect body fluids The material properties and characteristics may be changed, e_g_, hydrophilic material to a hydrophobic material, in order to encourage the absorption and evacuation of body fluid and components thereof
- capillary collection may be used Body fluid may be collected into a capillary or capillaries This allows for quantitative volume or a method to move fluid to a sensor
- the capillary or capillaries may be filled with multiple fibers to increase the surface area on which a liquid's adhesive forces can act This method may be used in conjunction with a chemical substance and/or other driving forces
- step 1308 the concentration of analytes in body fluid is sensed
- Sensing the concentration of an analyte present in body fluid may be accomplished by employing electrochemical, optical, acoustical, biological, and enzymatic technology in combination or alone
- a sensor or sensors can be disposable, replenishable, discrete, or continuous
- a sensing device may have a sensor or sensors capable of detecting more than one analyte If one or more, or a combination of several analytes exists in stable and/or predictable physiologic concentrations, the ratio of one analyte to the other would allow for concentration detection and self-calibration Neither the volume of the body fluid or the dilute volume needs be known A sensing device presented with a known volume of body fluid (undiluted) and a known volume of diluent would not require frequent calibration
- body fluid is extracted and optical analysis is performed on the body fluid
- body fluid is extracted and electrochemical analysis is performed on the body fluid
- the body fluid is extracted and the acoustical emission of an analyte undergoing a chemical reaction is detected and analyzed
- the body fluid is extracted, and living cells may be used to sense a concentration of an analyte in body fluid
- the body fluid is extracted, and thermal analysis is performed on the body fluid
- a user interface may provide features for both daytime and nighttime monitoring In one embodiment, this may include alarms for high/low analyte concentrations, may provide access to trends and history, and may enable a prediction of future concentration values
- the user interface may provide the ability to download history
- Other convenience features, such as a low battery indicator, may be included in the user interface
- the battery may be solar, nickel cadmium, standard alkaline, or lithium ion
- the presence of the analyte may be sensed without extraction Infrared light, for example, may be used to sense the presence of an analyte, with less interference from H 2 0
- at least one analyte is permitted to passively diffuse through the skin
- the analyte may be collected in a gel used as a collecting device, and a sensing device, attached to the gel, may be used to sense the presence ofthe analyte
- additional methods for generating cavitation and convectional flow may be applied with, before, after, or instead of the ultrasound application for skin permeabilization and/or extraction and/or collection steps
- These methods include the use of a propeller, fly wheel, transverse needle, and local shear induced permeabilization
- the non-invasive method disclosed herein may be used to determine the level of blood glucose Referring to Fig. 15, in step 1502, the permeability of the skin is increased This may be achieved by any suitable method Preferably, ultrasound is applied as discussed above
- the interstitial fluid is extracted from the skin This may be accomplished by any suitable method, including those discussed above Preferably, a vacuum is applied to extract the interstitial fluid from the skin In step 1506, the interstitial fluid is collected This may be accomplished by any suitable method, including those discussed above Preferably, the interstitial fluid is collected into a gel containing glucose sensitive reagents The gel may change color when it comes in contact with glucose
- step 1508 the color change of the gel is monitored to determine the glucose concentration in the interstitial fluid.
- ultrasound may be used for detection (evaluation, follow up treatments) of skin and/or other subcutaneous abnormalities presented by pathological concentrations of specific analytes, or detection of specific components administered to the site and detection of their elimination or conversion (psoriasis, skin malignancies, etc )
- This approach may be used, for example, in extracting analytes or reagents from skin-affected sites (lesion plaques), tumors, etc
- the delivery and/or removal of endogenous and non-endogenous components from the skin by the application by a force is disclosed Forces, such as ultrasound, electrical, magnetic, capillary, mechanical, chemical, electromagnetic, osmotic, concentration gradient, or combinations thereof may be used in applications such as, inter alia, removal of residual surfactant, cavitation enhancers, tattoo bleach, and botox (remove from forehead, and neck lines, reduce sweating)
- sensing components may be delivered into the skin to analyze interstitial fluid components in situ
- the sensing components may also be delivered into the skin to measure emitted products or reagents of any sensing reaction (chemical or enzymatic) 3 Sonophoretic Drug Delivery
- a drug is defined as a therapeutic, prophylactic, or diagnostic molecule or agent, that may be in a form dissolved or suspended in a liquid, solid, or encapsulated and/or distributed in or within micro or nanoparticles, emulsion, liposomes, or lipid vesicles
- Drug delivery is defined as the delivery of a drug into blood, lymph, interstitial fluid, cells, tissues, and/or organs, or any combination thereof Referring to Fig.
- Drug delivery apparatus 1602 includes patch 1604
- Patch 1604 includes adhesive 1610
- Patch 1604 is an active patch
- Adhesive 1610 acts as an attaching device Alternatively, the attaching device may be a vacuum, band, or strap
- transducer 1614 oscillates, the permeability of skin 1600 is increased in accordance with the present invention and drug molecules 1612 are delivered to and/or through skin 1600, or/and after skin 1600 is permeabilized, drug molecules 1612 are transported through skin 1600 to the capillaries and blood vessels below skin 1600
- a limiting step membrane 1613 may be located between skin 1600 and drug molecules 1612
- Transducer 1614 preferably operates at a frequency in the range of between 20 kHz to 2 5 MHz, using appropriate electrical signal generators and amplifiers Transducer 1614, more preferably, is operating at a frequency in the range of between 20 and 200 kHz
- Other ultrasound parameters include, but are not limited to, amplitude, duty cycle, distance from the skin, coupling agent composition, and application time and may be varied to achieve sufficient enhancement of transdermal transport The intensity preferably varies from 0 to 20 W/cm 2
- transducer 1614 may be configured as a cylinder, a hollow cylinder, a hemispherical configuration, conical configuration, planer configuration or rectangle configuration
- Transducer 1614 may also consist of an array of acoustic elements that are swept in time
- Transducer 1614 may be comprised of quartz, PVDF, ceramic including PZT and screen printed ceramic, magnetostrictive, or composite material including molded ceramic and benders Transducer 1614 may be used alone, or in conjunction with other forces, or contributor
- Transducer 1614 administers ultrasound preferably at frequencies of less than or equal to about 2 5 MHz, preferably at a frequency that is less than 1 MHz, and more typically in the range of about 20 to 100 kHz Exposures to ultrasounds from transducer 1614 are typically between about 5 seconds and about 10 minutes continuously, but may be shorter and/or pulsed, for example, at 100 to 500 msec pulses every seconds for a time sufficient to permeabilize the skin
- the ultrasound intensity is of a level that preferably does not raise skin 1600's temperature more than about 1 to 2 degrees Centigrade and does not cause permanent damage to the skin
- the intensity typically is less than 20 W/cm , preferably less than 10 W/cm 2 Intensity in time of application is inversely proportional to exposure time, so that high intensities are applied for shorter period of times in order to avoid skin damage It should be noted that although normal low range ultrasound is 20 kHz, comparable results are achieved by varying the frequency to less than 20 kHz, or into the sound region
- the time needed for permeabilization is dependant upon the frequency and intensity of the ultrasound from transducer 1614 and the condition of skin 1600. At 20 kHz, for example, an intensity of 10 W/cm 2 , with a duty cycle of 50 percent, skin 1600 is permeabilized sufficiently in about 5 minutes if skin 1600 is on a human forearm
- Permeabilizing ultrasound may be applied for a predetermined amount of time or may be applied only until permeabilization is attained Because skin 1600 characteristics or properties may change over time, based on aging, diet, stress, and other factors, it may be preferable to measure permeability as ultrasound is applied to minimize the risk of skin 1600 damage Several methods may be used to determine when sufficient permeabilization has been reached One method measures relative skin conductivity at the permeabilization site versus a reference point These measurements are performed by applying a small AC or DC electric potential across two electrically isolated electrodes in contact with skin 1600 Electric current flowing through these electrodes is measured using an ammeter and skin 1600 resistance is measured using the values ofthe potential and current Drug delivery patch apparatus 1602 may serve as one of the electrically isolated electrodes in contact with skin 1600 Preferably, drug delivery patch apparatus 1602 permeabilizes skin 1600 prior to the conductivity tests Another way to determine when sufficient permeabilization has been reached is to measure conductivity Fully permeabilized skin has a resistance of no more than about 5 k ⁇ measured across approximately 1 7 cm 2 Another method is to detect
- Drug delivery patch apparatus 1602 also may be applied to pretreated skin 1600 In other words, permeabilization of skin 1600 is already achieved Drug delivery patch apparatus 1602 is placed over pretreated skin 1600 to deliver drug molecules 1612
- Any known device may be used to pre-treat skin 1600, including, but not limited to, physical forces, chemical forces, biological forces, vacuum pressure, electrical forces, osmotic forces, diffusion forces, electromagnetic forces, ultrasound forces, cavitation forces, mechanical forces, thermal forces, capillary forces, fluid circulation across the skin, electro-acoustic forces, magnetic forces, magneto-hydrodynamic forces, acoustic forces, convective dispersion, photo- acoustic forces, by rinsing body fluid off skin, and any combination thereof
- Drug molecules 1612 include a variety of bio-active agents, including protein and peptides Other materials include nucleic acid molecules such as vaccines including therapeutic proteins, synthetic organic and inorganic molecules including anti-inflammatories, anti-virals, anti-fungal, anti-biotics, and local ane
- Drug delivery patch apparatus 1602 also includes a battery 1616 Battery 1616 acts as a power source for transducer 1614 Battery 1616 provides a relatively high energy burst Drug delivery patch apparatus 1602 also includes electronic coupling 1618 that serves as the drive electronics for drug delivery patch apparatus 1602 Drug delivery patch apparatus 1602 also includes user interface 1620
- patch 1604 includes transducer 1614, drug molecules 1610, and adhesive 1610 In another embodiment, patch 1604 includes transducer 1614, drug molecules 1612, adhesive 1610, battery 1616, electronic coupling 1618, and user interface 1620 In another embodiment, patch 1604 includes transducer 1614, drug molecules 1612, adhesive 1610, and battery 1616. In another embodiment, adhesive 1610 is to the side of transducer 1614 and drug molecules 1612.
- Battery 1616, electronic coupling 1618, and user interface 1620 may be located elsewhere on a user and in communication with patch 1604 via hard wire or telemetry
- user interface 1620 may be located elsewhere on the user and is in communication with patch 1604 via hard wire, telemetry, infrared, or fiber optic means
- the elements of drug delivery apparatus 1602 may be detachable and portable from each other
- any ofthe components of drug delivery apparatus 1602 may be disposable or reusable
- patch 1604, which includes transducer 1614, drug molecules 1612 and adhesive 1610 may be disposed after detachment from skin 1600
- battery 1616, electronic coupling 1618, and user interface 1620 may be re-usable with further patches 1604
- transducer 1614 operates alone to push drug molecules 1612 through and to skin 1600
- drug delivery patch apparatus 1602 and transducer 1614 may operate in conjunction with a driving force that further facilitates the transdermal transport of drug molecules 1612
- forces include, but are not limited to physical forces, chemical forces, biological forces, vacuum pressure, electrical forces, osmotic forces, diffusion forces, electromagnetic forces, ultrasound forces, cavitation forces, mechanical forces, thermal forces, capillary forces, fluid circulation across the skin, electro-acoustic forces, magnetic forces, magneto-hydrodynamic forces, acoustic forces, convective dispersion, photo-acoustic forces, by rinsing body fluid off skin, and any combination thereof
- Transducer 1614 may be an array of acoustic elements that are swept in time as ultrasound is applied to drug molecules 1612, and through adhesive 1610 to skin 1600
- Acoustic elements 1700 comprise transducer 1614
- Elements 1700 are depicted as squares within a larger square Elements 1700 are not limited to this configuration and may be configured as a cylinder, a hollow cylinder, hemispherical, conical, planer, rectangular
- Each acoustic element of elements of 1700 may be swept individually or within a group as transducer 1614 is activated
- element A activates, followed by elements B and E, then followed by elements C, F, and I, and so on Element P may be activated last as transducer 1614 is swept
- acoustic elements 1700 may comprise fingers Referring to Fig.
- a finger may be depicted as elements A, E, I, and M Each finger may be activated or swept in time Acoustic elements 1700 may be configured to channel the ultrasound energy from transducer 1614 to a specified area in 100 smaller than the area of transducer 1614
- feedback mechanism 1802 may be detachable from user interface 1620 Alternatively, feedback mechanism 1802 may be contained within user interface 1620 Thus, feedback mechanism 1802 may be contained within drug delivery patch apparatus 1602 Feedback mechanism 1802 provides for programming of drug delivery rates or pre-set doses of drug molecules 1612 Feedback mechanism 1802 also may provide memory to record or display historical delivery data to user interface 1620 Feedback mechanism 1802 communicates the on time of transducer 1614 to user interface 1620 for display to the user Feedback mechanism 1802 also may provide alarms for low drug molecules 1612 and/or low power in battery 1616 Thus, feedback mechanism 1802 alerts a user via a user interface 1620 that drug molecules 1612 and patch 1604 needs to be replenished or that drug delivery patch apparatus 1602 is low on power
- Feedback mechanism 1802 also may monitor the amount of drug molecules 1612 delivered via transdermal transport Feedback mechanism 1802 also may monitor the amount of ultrasonic energy, or other driving forces listed above, applied to skin 1600 by transducer 1614 Limits may be set in feedback mechanism 1802 to limit the ultrasound energy from transducer 1614 so as to no irritate or damage skin 1600 Feedback mechanism 1802 also may monitor the concentration of drug molecules 1612 remaining in patch 1604 Feedback mechanism 1802 also may monitor the concentration of drug molecules or analytes in the interstitial fluid, blood, and other body fluids Feedback mechanism 1802 also may monitor the amount of cavitation produced by the application of ultrasound energy Feedback mechanism 1802 also may monitor the degree of physiological effects such as blood pressure, EMG, EEG, and ECT feedback in order to measure delivery of drug molecules 1612 Feedback mechanism 1820 also may provide connections with additional patches or testing devices in order to perform conductivity tests 4 Transdermal Vaccination by Sonophoresis
- vaccines are administered for the prevention, amelioration or treatment of infectious diseases
- Vaccines are commonly used to provide immunity from diseases such as influenza, poliomyelitis, varicella zoster (chicken pox), measles, as well as several other diseases
- a vaccine is generally made from an antigen isolated or produced from the disease-causing microorganism
- An antigen is defined as "anything that can be bound by an antibody " This can be an enormous range of substances from simple chemicals, sugars, small peptides to complex protein complexes, such as viruses
- the small antigens are not, however, immunogenic in themselves, and need to be coupled to a carrier to elicit an immune response
- the vaccine is delivered to the bloodstream by an invasive method, such as an injection
- the B cells in the blood stream respond to the antigen by producing antibodies
- These antibodies bind to the antigen to "neutralize,” or inactivate it
- Memory cells are also produced, and remain ready to mount a quick protective immune response against subsequent infection by the same disease-
- Immunization is the process of causing immunity by injecting antibodies or provoking the body to make its own antibodies against a certain microorganism Immunization may be a result of a vaccination
- ultrasound was initially a driving force that essentially pushed drugs through the skin and into the circulatory system
- Ultrasound also increases the permeability of the skin
- drugs may be delivered to the body through the skin, or an analyte may be extracted from the body through the skin
- a driving force is still required for transdermal transport, but the required intensity of the driving force is decreased
- a concentration gradient is generally a sufficient driving force for transdermal transport through skin whose permeability has been enhanced using ultrasound
- the permeability enhancement that results from the application of ultrasound
- step 1902 depicts a method for transdermal vaccination by sonophoresis according to one embodiment of the present invention.
- the permeability of the skin is increased. This may be achieved by several methods, including those discussed above.
- ultrasound may be applied at about 10 W/cm 2 , with a duty cycle of about 50%.
- Ultrasound may be applied at a distance from the skin of about 0.5 mm to 1 cm, and for an application time of from about 30 seconds to about 5 minutes.
- a coupling medium may be used between the transducer and the skin, and may contain aqueous or non-aqueous chemicals including, but not limited to, water, saline, alcohol, including ethanol and isopropanol (1 -100% mixtures with saline), surfactants, fatty acids such as linoleic acid (0.1-2% mixtures in ethanol- water (50:50) mixture), azone (0.1-10% mixtures in ethanol-water (50:50) mixture), 01.-50% polyethylene glycol in saline, 1 -100 mM EDTA, EGTA, or 1% SLS and silica particles.
- the coupling media provide effective transfer of ultrasound energy from transducer to the skin. Appropriate mixtures of these coupling media may also enhance cavitation activity inside, on the surface, or near the skin, thus inducing more effective transport of molecules across the skin.
- step 1904 after the permeability of the skin is increased, sonication is terminated, and a vaccine is provided on the permeated skin.
- the vaccine may be incorporated into a transdermal patch.
- Other forms ofthe vaccine, such as gels and liquids, may also be used.
- the vaccine may comprise as the active ingredient a peptide, protein, allergen, or other antigen, or DNA encoding any of the foregoing and may also include other adjuvants normally employed. These vaccines may be used as cancer vaccines, tetanus vaccines, etc.
- the vaccine is delivered to the skin cells.
- the vaccine is delivered to skin cells, including Langerhans cells, dendritic cells, and keratinocytes. In one embodiment, the vaccine is delivered to the Langerhans cells.
- the Langerhans cells are the cells responsible for capturing a vaccine and presenting it to the Lymphatic system, and eliciting an immune response
- the vaccine may be delivered to other cells to illicit an immune response
- the vaccine may diffuse to the skin cells, including Langerhans cells, dendric cells, and keratinocytes Once the vaccine is received by the skin cells, the vaccine is transported to the lymph nodes efficiently, increasing the efficiency of vaccination
- the vaccine is transported transdermally through, in, or into the skin and into the bloodstream, wherein it acts as if it were injected in a conventional manner
- the vaccine is provided simultaneously with the application of ultrasound
- the ultrasound in this embodiment is used both to permeabilize the skin, as well as and to deliver the vaccine transdermally to the Langerhans cells
- the ultrasound acts as a driving force Examples of using ultrasound to transport drugs from a patch are discussed above
- ultrasound is applied to the skin to increase the permeability of the skin.
- additional driving forces are provided to deliver the vaccine to the body
- driving forces include, inter alia, physical forces, chemical forces, biological forces, vacuum, electrical forces, osmotic forces, diffusion forces, electro-magnetic forces, ultrasound forces, cavitation forces, mechanical forces, thermal forces, capillary forces, fluid circulation across the skin, electro-acoustic forces, magnetic forces, magneto-hydrodynamic forces, acoustic forces, convective dispersion, photo acoustic forces, and any combination thereof
- ultrasound can be used to induce irritation and inflammation of the skin Inducing irritation and inflammation may make the vaccine placed on the skin more effective in inducing an immune response.
- chemical enhancers may be used to increase the permeability ofthe skin
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000587679A JP2002532130A (en) | 1998-12-18 | 1999-12-17 | Method and apparatus for improving transdermal transport |
EP99966358A EP1139886A4 (en) | 1998-12-18 | 1999-12-17 | Methods and apparatus for enhancement of transdermal transport |
AU21919/00A AU2191900A (en) | 1998-12-18 | 1999-12-17 | Methods and apparatus for enhancement of transdermal transport |
CA002355184A CA2355184A1 (en) | 1998-12-18 | 1999-12-17 | Methods and apparatus for enhancement of transdermal transport |
US09/979,096 US7066884B2 (en) | 1998-01-08 | 2001-03-16 | System, method, and device for non-invasive body fluid sampling and analysis |
US11/065,278 US20060015058A1 (en) | 1998-01-08 | 2005-02-25 | Agents and methods for enhancement of transdermal transport |
US13/614,032 US8870810B2 (en) | 1998-12-18 | 2012-09-13 | Method and apparatus for enhancement of transdermal transport |
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11295398P | 1998-12-18 | 1998-12-18 | |
US60/112,953 | 1998-12-18 | ||
US14297599P | 1999-07-12 | 1999-07-12 | |
US14295199P | 1999-07-12 | 1999-07-12 | |
US14294199P | 1999-07-12 | 1999-07-12 | |
US14295099P | 1999-07-12 | 1999-07-12 | |
US60/142,941 | 1999-07-12 | ||
US60/142,951 | 1999-07-12 | ||
US60/142,950 | 1999-07-12 | ||
US60/142,975 | 1999-07-12 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/227,623 Continuation-In-Part US6190315B1 (en) | 1998-01-08 | 1999-01-08 | Sonophoretic enhanced transdermal transport |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09868442 A-371-Of-International | 1999-12-17 | ||
US10/792,862 Division US8287483B2 (en) | 1998-01-08 | 2004-03-05 | Method and apparatus for enhancement of transdermal transport |
US10/792,886 Division US20040171980A1 (en) | 1998-12-18 | 2004-03-05 | Method and apparatus for enhancement of transdermal transport |
US11/065,278 Continuation-In-Part US20060015058A1 (en) | 1998-01-08 | 2005-02-25 | Agents and methods for enhancement of transdermal transport |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000035357A1 true WO2000035357A1 (en) | 2000-06-22 |
Family
ID=27537341
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/030065 WO2000035357A1 (en) | 1998-01-08 | 1999-12-17 | Methods and apparatus for enhancement of transdermal transport |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1139886A4 (en) |
JP (1) | JP2002532130A (en) |
AU (1) | AU2191900A (en) |
CA (1) | CA2355184A1 (en) |
WO (1) | WO2000035357A1 (en) |
Cited By (20)
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US6492180B2 (en) | 1998-06-24 | 2002-12-10 | Transderm Technologies Llc | Non-invasive transdermal detection of analytes |
EP1496831A2 (en) * | 2002-04-17 | 2005-01-19 | Sontra Medical, Inc. | Preparation for transmission and reception of electrical signals |
JP2005504002A (en) * | 2001-02-13 | 2005-02-10 | ガバメント オブ ザ ユナイテッド ステイツ、 アズ リプリゼンティッド バイ ザ セクレタリィ オブ ジ アーミイ | Vaccine for transcutaneous immunization |
EP1505906A1 (en) * | 2002-05-20 | 2005-02-16 | Richard J. Davies | System for detecting precancerous and cancerous tissue |
US7630759B2 (en) | 2002-05-20 | 2009-12-08 | Epi-Sci, Llc | Method and system for detecting electrophysiological changes in pre-cancerous and cancerous breast tissue and epithelium |
US7853319B2 (en) | 2005-04-21 | 2010-12-14 | Epi-Sci, Llc | Method and system for detecting electrophysiological changes in pre-cancerous and cancerous tissue and epithelium |
US8262575B2 (en) | 2002-05-20 | 2012-09-11 | Epi-Sci, Llc | Method and system for detecting electrophysiological changes in pre-cancerous and cancerous tissue |
US8561795B2 (en) | 2010-07-16 | 2013-10-22 | Seventh Sense Biosystems, Inc. | Low-pressure packaging for fluid devices |
US8808202B2 (en) | 2010-11-09 | 2014-08-19 | Seventh Sense Biosystems, Inc. | Systems and interfaces for blood sampling |
US8821412B2 (en) | 2009-03-02 | 2014-09-02 | Seventh Sense Biosystems, Inc. | Delivering and/or receiving fluids |
US8870810B2 (en) | 1998-12-18 | 2014-10-28 | Echo Therapeutics, Inc. | Method and apparatus for enhancement of transdermal transport |
US9033898B2 (en) | 2010-06-23 | 2015-05-19 | Seventh Sense Biosystems, Inc. | Sampling devices and methods involving relatively little pain |
US9041541B2 (en) | 2010-01-28 | 2015-05-26 | Seventh Sense Biosystems, Inc. | Monitoring or feedback systems and methods |
US9113836B2 (en) | 2009-03-02 | 2015-08-25 | Seventh Sense Biosystems, Inc. | Devices and techniques associated with diagnostics, therapies, and other applications, including skin-associated applications |
US9119578B2 (en) | 2011-04-29 | 2015-09-01 | Seventh Sense Biosystems, Inc. | Plasma or serum production and removal of fluids under reduced pressure |
US9295417B2 (en) | 2011-04-29 | 2016-03-29 | Seventh Sense Biosystems, Inc. | Systems and methods for collecting fluid from a subject |
US9572527B2 (en) | 2007-04-27 | 2017-02-21 | Echo Therapeutics, Inc. | Skin permeation device for analyte sensing or transdermal drug delivery |
US10543310B2 (en) | 2011-12-19 | 2020-01-28 | Seventh Sense Biosystems, Inc. | Delivering and/or receiving material with respect to a subject surface |
US10780267B2 (en) | 2014-09-03 | 2020-09-22 | University Of Strathclyde | Apparatus for topical application of material |
US11177029B2 (en) | 2010-08-13 | 2021-11-16 | Yourbio Health, Inc. | Systems and techniques for monitoring subjects |
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JP4961137B2 (en) * | 2005-12-14 | 2012-06-27 | 久光製薬株式会社 | Device for iontophoresis |
CN109077724B (en) * | 2018-07-26 | 2021-12-07 | 北京机械设备研究所 | Conductive medium conveying system and method for electroencephalogram acquisition |
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- 1999-12-17 JP JP2000587679A patent/JP2002532130A/en active Pending
- 1999-12-17 CA CA002355184A patent/CA2355184A1/en not_active Abandoned
- 1999-12-17 EP EP99966358A patent/EP1139886A4/en not_active Withdrawn
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Cited By (34)
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US6492180B2 (en) | 1998-06-24 | 2002-12-10 | Transderm Technologies Llc | Non-invasive transdermal detection of analytes |
US8870810B2 (en) | 1998-12-18 | 2014-10-28 | Echo Therapeutics, Inc. | Method and apparatus for enhancement of transdermal transport |
JP2005504002A (en) * | 2001-02-13 | 2005-02-10 | ガバメント オブ ザ ユナイテッド ステイツ、 アズ リプリゼンティッド バイ ザ セクレタリィ オブ ジ アーミイ | Vaccine for transcutaneous immunization |
EP1496831A2 (en) * | 2002-04-17 | 2005-01-19 | Sontra Medical, Inc. | Preparation for transmission and reception of electrical signals |
EP1496831A4 (en) * | 2002-04-17 | 2007-04-18 | Sontra Medical Inc | Preparation for transmission and reception of electrical signals |
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Also Published As
Publication number | Publication date |
---|---|
EP1139886A4 (en) | 2005-01-26 |
CA2355184A1 (en) | 2000-06-22 |
EP1139886A1 (en) | 2001-10-10 |
AU2191900A (en) | 2000-07-03 |
JP2002532130A (en) | 2002-10-02 |
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