CA2411277C - Neurotoxin implant - Google Patents

Neurotoxin implant Download PDF

Info

Publication number
CA2411277C
CA2411277C CA002411277A CA2411277A CA2411277C CA 2411277 C CA2411277 C CA 2411277C CA 002411277 A CA002411277 A CA 002411277A CA 2411277 A CA2411277 A CA 2411277A CA 2411277 C CA2411277 C CA 2411277C
Authority
CA
Canada
Prior art keywords
botulinum toxin
neurotoxin
controlled release
polymer
implant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CA002411277A
Other languages
French (fr)
Other versions
CA2411277A1 (en
Inventor
Stephen Donovan
Daniel G. Brady
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Inc
Original Assignee
Allergan Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=24349017&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2411277(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Allergan Inc filed Critical Allergan Inc
Publication of CA2411277A1 publication Critical patent/CA2411277A1/en
Application granted granted Critical
Publication of CA2411277C publication Critical patent/CA2411277C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
    • A61K38/48Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886Metalloendopeptidases (3.4.24), e.g. collagenase
    • A61K38/4893Botulinum neurotoxin (3.4.24.69)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02Muscle relaxants, e.g. for tetanus or cramps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Abstract

A biocompatible implant for continuous in vivo release of a neurotoxin over a treatment period extending from one month to five years. The implant can be made of casting a solution of a polymer, such as an ethyl vinyl acetate copolymer and the neurotoxin. The neurotoxin can be a botulinum toxin.</SDOA B>

Description

NEUROTOXIN IMPLANT
by s Stephen Donovan and Daniel G. Brady BACKGROUND
The present invention relates to a controlled release drug delivery system.
In particular, the present invention relates to a controlled release neurotoxin delivery system.
is A controlled release system can deliver a drug in vivo at a predetermined rate over a specific time period. Generally, release rates are determined by the design of the system, and can be largely independent of environmental conditions such as pH. Controlled release systems which can deliver a drug over a period of several years are known. Contrarily, sustained release 2o systems typically deliver drug in 24 hours or less and environmental factors can influence the release rate. Thus, the release rate of a drug from an implanted controlled release system (an "implant") is a function of the physiochemical properties of the carrier implant material and of the drug itself.
Typically, the implant is made of an inert material which elicits little or no host 2s response.
A controlled release system can be comprised of a drug with a biological activity incorporated into a carrier. The carrier can be a polymer or a bioceramic material. The controlled release system can be injected, inserted 30 or implanted into a selected location of a patient's body and reside therein for a prolonged period during which the drug is released by the implant in a manner and at a concentration which provides a desired therapeutic efficacy.

Polymeric materials can release drugs due to diffusion, chemical reaction or solvent activation, as well as upon influence by magnetic, ultrasound or temperature change factors. Diffusion can be from a reservoir or matrix.
Chemical control can be due to polymer degradation or cleavage of the drug s from the polymer. Solvent activation can involve swelling of the polymer or an osmotic effect. See e.g. Science 249;1527-1533:1990.
A membrane or reservoir implant depends upon the diffusion of a bioactive agent across a polymer membrane. A matrix implant is comprised of a io polymeric matrix in which the bioactive agent is uniformly distributed.
Swelling-controlled release systems are usually based on hydrophilic, glassy polymers which undergo swelling in the presence of biological fluids or in the presence of certain environmental stimuli.
is Preferably, the implant material used is substantially non-toxic, non-carcinogenic, and non-immunogenic. Suitable implant materials include polymers, such as poly(2-hydroxy ethyl methacrylate) (p-HEMA), poly(N-vinyl pyrrolidone) (p-NVP)~-, polyvinyl alcohol) (PVA), poly(acrylic acid) (PAA), polydimethyl siloxanes (PDMS), ethylene-vinyl acetate (EVAc) copolymers, 2o polyvinylpyrrolidone/methylacrylate copolymers, polymethylmethacrylate (PMMA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyanhydrides, poly(ortho esters), collagen and cellulosic derivatives and bioceramics, such as hydroxyapatite (HPA), tricalcium phosphate (TCP), and aliminocalcium phosphate (ALCAP). Lactic acid, glycolic acid and collagen can be used to 2s make biodegradable implants.
Controlled release systems comprising a polymer for prolonged delivery of a therapeutic drug are known. For example, a subdermal reservoir implant comprised of a nonbiodegradable polymer can be used to release a 3o contraceptive steroid, such as progestin, in amounts of 25-30 mg/day for up
2 to sixty months (i.e. the Norplant~ implant). Additionally, Dextran (molecular weight about 2 million) has been released from implant polymers.
An implant material can be biodegradable or bioerodible. An advantage of s a bioerodible implant is that is does not need to be removed from the patient.
A bioerodible implant can be based upon either a membrane or matrix release of the bioactive substance. Biodegradable microspheres prepared from PLA-PGA are known for subcutaneous or intramuscular administration.
io A degradable implant preferably retains its structural integrity throughout its duration of controlled release so that it can be removed if removal is desired or warranted. After the incorporated drug falls below a therapeutic level, a biodegradable implant can degrade completely without retaining any drug which can be released at low levels over a further period. Subdermal is implants and injectable microspheres made of degradable materials, such as lactic acid-glycolic acid copolymers, polycaprolactones and cholesterol, for steroid delivery, are known.
Protein Implants 2o Controlled release systems for large macromolecules, such as proteins are known. Thus, biocompatible, polymeric pellets which incorporate a high molecular weight protein have been implanted and shown to exhibit continuous release of the protein for periods exceeding 100 days. Various labile, high molecular weight enzymes (such as alkaline phosphatase, 2s molecular weight 88 kD and catalase, molecular weight 250 kD) have been incorporated into biocompatible, polymeric implants with long term, continuous release characteristics. Generally an increase in the polymer concentration in the casting solution decreases the initial rate at which protein is released from the implant. Nature 263; 797-800:1976.
3 Additionally, albumin can be released from an EVAc implant and polylysine can be released from collagen based microspheres. Mallapragada S.K. et al, at page 431 of chapter 27 in Von Recum, A. F. Handbook of Biomaterials Evaluation, second edition, Taylor & Francis (1999).
s Additionally, the release of tetanus toxoid from microspheres has been studied. Ibid at 432. Sintered EVAc copolymer inserted subcutaneously has been shown to release insulin over a period of 100 days. Ibid at 433.
Furthermore, it is known to encapsulate a protein, such as human growth io hormone (hGH) (molecular weight about 26 kD), within a polymeric matrix which when implanted permits the human growth hormone to be released in vivo over a period of about a week. U.S. patent no. 5,667,808.
A controlled release system (i.e. an "implant") can exhibit a high initial burst of protein release, followed by minimal release thereafter.
is Unfortunately, due to the high concentration of protein within a controlled release matrix, the protein molecules tend to aggregate and form denatured, immunogenic concentrations of protein.
Pulsatile Release Implants 2o Hydrogels have been used to construct single pulse and multiple pulse drug delivery implants. A single pulse implant can be osmotically controlled or melting controlled. Doelker E., Cellulose Derivatives, Adv Polym Sci 107;
199-265:1993. It is known that multiple pulses of certain substances from an implant can be achieved in response to an environmental change in a as parameter such as temperature (Mater Res Soc Symp Proc, 331;211-216:1994; J. Contr Rel 15;141-152:1991 ), pH (Mater Res Soc Symp Proc, 331;199-204:1994), ionic strength (ReactPolym, 25;127-137:1995), magnetic fields (J. Biomed Mater Res, 21;1367-1373:1987) or ultrasound.
4 Unfortunately, a subcutaneous implantable drug pellet made of a nonbiodegradable polymer has the drawback of requiring both surgical implantation and removal. Use of a biocompatible, bioerodible implant can overcome the evident deficiencies of nonbiodegradable implants. A
s biodegradable implant can release a drug over a long period of time with simultaneous or subsequent degradation of the polymer within the tissue into constituents, thereby avoiding any need to remove the implant. See e.g.
Drug Development and Industrial Pharmacy 24(12);1129-1138:1998.
io A degradable polymer can be a surtace eroding polymer, as opposed to a polymer which displays bulk or homogenous. A surface eroding polymer degrades only from its exterior-surface, and drug release is therefore proportional to the polymer erosion rate. A suitable such polymer can be a polyanhydride.
is Botulinum Toxin The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. The spores of 2o Clostridium botulinum are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a Clostridium botulinum culture or spores. The botulinum toxin can apparently pass unattenuated 2s through the lining of the gut and attack peripheral motor neurons. Symptoms of botulinum toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botulinum toxin type A is the most lethal natural biological agent known to so man. About 50 picograms of a commercially available botulinum toxin type A

(purified neurotoxin complex)' is a LDSO in mice (i.e. 1 unit). One unit of BOTOX~ contains about 50 picograms (about 56 attomoles) of botulinum toxin type A complex. Interestingly, on a molar basis, botulinum toxin type A
is about 1.8 billion times more lethal than diphtheria, about 600 million times s more lethal than sodium cyanide, about 30 million times more lethal than cobra toxin and about 12 million times more lethal than cholera. Singh, Critical Aspects of Bacterial Protein Toxins, pages 63-84 (chapter 4) of Natural Toxins II, edited by B.R. Singh et al., Plenum Press, New York (1996) (where the stated LDSo of botulinum toxin type A of 0.3 ng equals 1 U is io corrected for the fact that about 0.05 ng of BOTOX~ equals 1 unit). One unit (U) of botulinum toxin is defined as the LDSO upon intraperitoneal injection into female Swiss Webster mice weighing 18 to 20 grams each.
Seven immunologically distinct botulinum neurotoxins have been is characterized, these being respectively botulinum neurotoxin serotypes A, B, C,, D, E, F and G each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that botulinum 2o toxin type A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is botulinum toxin type B. Additionally, botulinum toxin type B has been determined to be non-toxic in primates at a dose of 480 Uikg which is about 12 times the primate LDSO for botulinum toxin type A.
Botulinum toxin apparently binds with high affinity to cholinergic motor 2s neurons, is translocated into the neuron and blocks the release of acetylcholine.
Regardless of serotype, the molecular mechanism of toxin intoxication appears to be similar and to involve at least three steps or stages. In the first 'Available from Allergan, Inc., of Irvine, California under the tradename BO'DX° in 100 unit vials step of the process, the toxin binds to the presynaptic membrane of the target neuron through a specific interaction between the heavy chain, H chain, and a cell surface receptor; the receptor is thought to be different for each type of botulinum toxin and for tetanus toxin. The carboxyl end segment of the H
s chain, H~, appears to be important for targeting of the toxin to the cell surtace.
In the second step, the toxin crosses the plasma membrane of the poisoned cell. The toxin is first engulfed by the cell through receptor-mediated endocytosis, and an endosome containing the toxin is formed. The toxin then io escapes the endosome into the cytoplasm of the cell. This step is thought to be mediated by the amino end segment of the H chain, HN, which triggers a conformational change of the toxin in response to a pH of about 5.5 or lower.
Endosomes are known to possess a proton pump which decreases intra-endosomal pH. The conformational shift exposes hydrophobic residues in the is toxin, which permits the toxin to embed itself in the endosomal membrane.
The toxin (or at a minimum the light chain) then translocates through the endosomal membrane into the cytoplasm.
The last step of the mechanism of botulinum toxin activity appears to 2o involve reduction of the disulfide bond joining the heavy chain, H chain, and the light chain, L chain. The entire toxic activity of botulinum and tetanus toxins is contained in the L chain of the holotoxin; the L chain is a zinc (Zn++) endopeptidase which selectively cleaves proteins essential for recognition and docking of neurotransmitter-containing vesicles with the cytoplasmic as surtace of the plasma membrane, and fusion of the vesicles with the plasma membrane. Tetanus neurotoxin, and botulinum toxins B, D, F, and G cause degradation of synaptobrevin (also called vesicle-associated membrane protein (VAMP)), a synaptosomal membrane protein. Most of the VAMP
present at the cytoplasmic surtace of the synaptic vesicle is removed as a 3o result of any one of these cleavage events. Serotype A and E cleave SNAP-25. Serotype C, was originally thought to cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Each toxin specifically cleaves a different bond (except tetanus and type B which cleave the same bond).
s Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles.
Botulinum toxin type A was approved by the U.S. Food and Drug Administration in 1989 for the treatment of blepharospasm, strabismus and hemifacial spasm. Non-type A botulinum toxin serotypes apparently have a io lower potency and/or a shorter duration of activity as compared to botulinum toxin type A. Clinical effects of peripheral intramuscular botulinum toxin type A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of botulinum toxin type A averages about three months.
is Although all the botulinum toxins serotypes apparently inhibit release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory proteins and/or cleaving these proteins at different sites. For example, botulinum types A and E both cleave the 25 2o kiloDalton (kD) synaptosomal associated protein (SNAP-25), but they target different amino acid sequences within this protein. Botulinum toxin types B, D, F and G act on vesicle-associated protein (VAMP, also called synaptobrevin), with each serotype cleaving the protein at a different site.
Finally, botulinum toxin type C, has been shown to cleave both syntaxin and 2s SNAP-25. These differences in mechanism of action may affect the relative potency and/or duration of action of the various botulinum toxin serotypes.
Apparently, a substrate for a botulinum toxin can be found in a variety of different cell types. See e.g. Biochem ,J 1;339 (pt 1):159-65:1999, and Mov Disord, 10(3): 376:1995 (pancreatic islet B cells contain at least SNAP-25 so and synaptobrevin).

The molecular weight of the botulinum toxin protein molecule, for all seven of the known botulinum toxin serotypes, is about 150 kD. Interestingly, the botulinum toxins are released by Clostridia) bacterium as complexes comprising the 150 kD botulinum toxin protein molecule along with associated s non-toxin proteins. Thus, the botulinum toxin type A complex can be produced by Clostridia) bacterium as 900 kD, 500 kD and 300 kD forms.
Botulinum toxin types B and C, is apparently produced as only a 700 kD or 500 kD complex. Botulinum toxin type D is produced as both 300 kD and 500 kD complexes. Finally, botulinum toxin types E and F are produced as only io approximately 300 kD complexes. The complexes (i.e. molecular weight greater than about 150 kD) are believed to contain a non-toxin hemaglutinin protein and a non-toxin and non-toxic nonhemaglutinin protein. These two non-toxin proteins (which along with the botulinum toxin molecule comprise the relevant neurotoxin complex) may act to provide stability against is denaturation to the botulinum toxin molecule and protection against digestive acids when toxin is ingested. Additionally, it is possible that the larger (greater than about 150 kD molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.
In vitro studies have indicated that botulinum toxin inhibits potassium cation induced release of both acetylcholine and norepinephrine from primary cell cultures of brainstem tissue. Additionally, it has been reported that botulinum toxin inhibits the evoked release of both glycine and glutamate in 2s primary cultures of spinal cord neurons and that in brain synaptosome preparations botulinum toxin inhibits the release of each of the neurotransmitters acetylcholine, dopamine, norepinephrine (Habermann E., et al., Tetanus Toxin and Botulinum A and C Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain, J Neurochem 51 (2);522-527:1988) 3o CGRP, substance P and glutamate (Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks Glutamate Exocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J. Biochem 165;675-681:1987. Thus, when adequate concentrations are used, stimulus-evoked release of most neurotransmitters is blocked by botulinum toxin. See e.g. Pearce, L.B., Pharmacologic s Characterization of Botulinum Toxin For Basic Science and Medicine, Toxicon 35(9);1373-1412 at 1393 (1997); Bigalke H., et al., Botulinum A Neurotoxin Inhibits Non-Cholinergic Synaptic Transmission in Mouse Spinal Cord Neurons in Culture, Brain Research 360;318-324:1985; Habermann E., Inhibition by Tetanus and Botulinum A Toxin of the Release of to ~HjNoradrenaline and (~HjGABA From Rat Brain Homogenate, Experientia 44;224-226:1988, Bigalke H., et al., Tetanus Toxin and Botulinum A Toxin Inhibit Release and Uptake of Various Transmitters, as Studied with Particulate Preparations From Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's Arch Pharmacol 316;244-251:1981, and; .Jankovic J. et al., is Therapy hVith Botulinum Toxin, Marcel Dekker, Inc., (1994), page 5.
Botulinum toxin type A can be obtained by establishing and growing cultures of Clostridium botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known procedures. All the 2o botulinum toxin serotypes are initially synthesized as inactive single chain proteins which must be cleaved or nicked by proteases to become neuroactive. The bacterial strains that make botulinum toxin serotypes A and G possess endogenous proteases and serotypes A and G can therefore be recovered from bacterial cultures in predominantly their active form. In 2s contrast, botulinum toxin serotypes C,, D and E are synthesized by nonproteolytic strains and are therefore typically unactivated when recovered from culture. Serotypes B and F are produced by both proteolytic and nonproteolytic strains and therefore can be recovered in either the active or inactive form. However, even the proteolytic strains that produce, for so example, the botulinum toxin type B serotype only cleave a portion of the io toxin produced. The exact proportion of nicked to unnicked molecules depends on the length of incubation and the temperature of the culture.
Therefore, a certain percentage of any preparation of, for example, the botulinum toxin type B toxin is likely to be inactive, possibly accounting for the s known significantly lower potency of botulinum toxin type B as compared to botulinum toxin type A. The presence of inactive botulinum toxin molecules in a clinical preparation will contribute to the overall protein load of the preparation, which has been linked to increased antigenicity, without contributing to its clinical efficacy. Additionally, it is known that botulinum io toxin type B has, upon intramuscular injection, a shorter duration of activity and is also less potent than botulinum toxin type A at the same dose level.
High quality crystalline botulinum toxin type A can be produced from the Hall A strain of Clostridium botulinum with characteristics of >_3 X 10' U/mg, is an AZSOlA2,$ of less than 0.60 and a distinct pattern of banding on gel electrophoresis. The known Shantz process can be used to obtain crystalline botulinum toxin type A, as set forth in Shantz, E.J., et al, Properties and Use of Botulinum Toxin and Other Microbial Neurotoxins in Medicine, Microbiol Rev. 56;80-99:1992. Generally, the botulinum toxin type A complex can be 2o isolated and purified from an anaerobic fermentation by cultivating Clostridium botulinum type A in a suitable medium. The known process can also be used, upon separation out of the non-toxin proteins, to obtain pure botulinum toxins, such as for example: purified botulinum toxin type A with an approximately 150 kD molecular weight with a specific potency of 1-2 X 10$
2s LDSO Ulmg or greater; purified botuiinum toxin type B with an approximately 156 kD molecular weight with a specific potency of 1-2 X 10$ LDSO U/mg or greater, and; purified botulinum toxin type F with an approximately 155 kD
molecular weight with a specific potency of 1-2 X 10' LDSO U/mg or greater.
a Botulinum toxins and/or botulinum toxin complexes can be obtained from List Biological Laboratories, Inc., Campbell, California; the Centre for Applied Microbiology and Research, Porton Down, U.K.; Wako (Osaka, Japan), Metabiologics (Madison, Wisconsin) as well as from Sigma Chemicals of St.
s Louis, Missouri.
Pure botulinum toxin is so labile that it is generally not used to prepare a pharmaceutical composition. Furthermore, the botulinum toxin complexes, such as the toxin type A complex are also extremely susceptible to io denaturation due to surtace denaturation, heat, and alkaline conditions.
Inactivated toxin forms toxoid proteins which may be immunogenic. The resulting antibodies can render a patient refractory to toxin injection.
As with enzymes generally, the biological activities of the botulinum toxins is (which are intracellular peptidases) are dependent, at least in part, upon their three dimensional conformation. Thus, botulinum toxin type A is detoxified by heat, various chemicals surface stretching and surface drying. Additionally, it is known that dilution of the toxin complex obtained by the known culturing, fermentation and purification to the much, much lower toxin concentrations 2o used for pharmaceutical composition formulation results in rapid detoxification of the toxin unless a suitable stabilizing agent is present. Dilution of the toxin from milligram quantities to a solution containing nanograms per milliliter presents significant difficulties because of the rapid loss of specific toxicity upon such great dilution. Additionally, the toxin may be used months or years as after the toxin containing pharmaceutical composition is formulated.
Significantly, it is known that the toxin can be stabilized during the manufacture and compounding processes as well as during storage by use of a stabilizing agent such as albumin and gelatin.

A commercially available botulinum toxin containing pharmaceutical composition is sold under the trademark BOTOX° (available from Allergan, Inc., of Irvine, California). BOTOX~ consists of a purified botulinum toxin type A complex, albumin and sodium chloride packaged in sterile, vacuum-dried s form. The botulinum toxin type A is made from a culture of the Hali strain of Clostridium botulinum grown in a medium containing N-Z amine and yeast extract. The botulinum toxin type A complex is purified from the culture solution by a series of acid precipitations to a crystalline complex consisting of the active high molecular weight toxin protein and an associated to hemagglutinin protein. The crystalline complex is re-dissolved in a solution containing saline and albumin and sterile filtered (0.2 microns) prior to vacuum-drying. The vacuum-dried product is stored in a freezer at or below -
5°C. BOTOX~ can be reconstituted with sterile, non-preserved saline prior to intramuscular injection. Each vial of BOTOX~ contains about 100 units (U) of is Clostridium botulinum toxin type A purified neurotoxin complex, 0.5 milligrams of human serum albumin and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried form without a preservative.
To reconstitute vacuum-dried BOTOX°, sterile normal saline without a 2o preservative (0.9% Sodium Chloride Injection) is used by drawing up the proper amount of diluent in the appropriate size syringe. Since BOTOX°
may be denatured by bubbling or similar violent agitation, the diluent is gently injected into the vial. For sterility reasons BOTOX~ is preferably administered within four hours after the vial is removed from the freezer and reconstituted.
2s During these four hours, reconstituted BOTOX~ can be stored in a refrigerator at about 2° C. to about 8°C. Reconstituted, refrigerated BOTOX~
retains its potency for at least two weeks. Neurology, 48:249-53:1997.
It has been reported that botulinum toxin type A has been used in clinical 3o settings as follows:

(1) about 75-125 units of BOTOX~ per intramuscular injection (multiple muscles) to treat cervical dystonia;
(2) 5-10 units of BOTOX~ per intramuscular injection to treat glabellar lines (brow furrows) (5 units injected intramuscularly into the procerus muscle s and 10 units injected intramuscularly into each corrugator supercilii muscle);
(3) about 30-80 units of BOTOX° to treat constipation by intrasphincter injection of the puborectalis muscle;
(4) about 1-5 units per muscle of intramuscularly injected BOTOX~ to treat blepharospasm by injecting the lateral pre-tarsal orbicularis oculi muscle of to the upper lid and the lateral pre-tarsal orbicularis oculi of the lower lid.
(5) to treat strabismus, extraocular muscles have been injected intramuscularly with between about 1-5 units of BOTOX~, the amount injected varying based upon both the size of the muscle to be injected and the extent of muscle paralysis desired (i.e. amount of diopter correction desired).
is (6) to treat upper limb spasticity following stroke by intramuscular injections of BOTOX~ into five different upper limb flexor muscles, as follows:
(a) flexor digitorum profundus: 7.5 U to 30 U
(b) flexor digitorum sublimus: 7.5 U to 30 U
(c) flexor carpi ulnaris: 10 U to 40 U
20 (d) flexor carpi radialis: 15 U to 60 U
(e) biceps brachii: 50 U to 200 U. Each of the five indicated muscles has been injected at the same treatment session, so that the patient receives from 90 U to 360 U of upper limb flexor muscle BOTOX~ by intramuscular injection at each treatment session.
2s~ (7) to treat migraine, pericranial injected (injected symmetrically into glabellar, frontalis and temporalis muscles) injection of 25 U of BOTOX~ has showed significant benefit as a prophylactic treatment of migraine compared to vehicle as measured by decreased measures of migraine frequency, maximal severity, associated vomiting and acute medication use over the so three month period following the 25 U injection.

It is known that botulinum toxin type A can have an efficacy for up to 12 months (European J. Neurology 6 (Supp 4): S111-S1150:1999), and in some circumstances for as long as 27 months, (The Laryngoscope 109: 1344-s 1346:1999). However, the usual duration of an intramuscular injection of Botox~ is typically about 3 to 4 months.
The success of botulinum toxin type A to treat a variety of clinical conditions has led to interest in other botulinum toxin serotypes. A study of io two commercially available botulinum type A preparations (BOTOX~.and Dysport~) and preparations of botulinum toxins type B and F (both obtained from Wako Chemicals, Japan) has been carried out to determine local muscle weakening efficacy, safety and antigenic, potential. Botulinum toxin preparations were injected into the head of the right gastrocnemius muscle is (0.5 to 200.0 units/kg) and muscle weakness was assessed using the mouse digit abduction scoring assay (DAS). EDSO values were calculated from dose response curves. Additional mice were given intramuscular injections to determine LDSOdoses. The therapeutic index was calculated as LDso/EDSO-Separate groups of mice received hind limb injections of BOTOX~ (5.0 to 10.0 2o units/kg) or botulinum toxin type B (50.0 to 400.0 units/kg), and were tested for muscle weakness and increased water consumption, the later being a putative model for dry mouth. Antigenic potential was assessed by monthly intramuscular injections in rabbits (1.5 or 6.5 ng/kg for botulinum toxin type B
or 0.15 ng/kg for BOTOX~). Peak muscle weakness and duration were dose 2s related for all serotypes. DAS EDSO values (units/kg) were as follows:
BOTOX~: 6.7, Dysport~: 24.7, botulinum toxin type B: 27.0 to 244.0, botulinum toxin type F: 4.3. BOTOX~ had a longer duration of action than botulinum toxin type B or botulinum toxin type F. Therapeutic index values were as follows: BOTOX~: 10.5, Dysport~: 6.3, botulinum toxin type B: 3.2.
3o Water consumption was greater in mice injected with botulinum toxin type B
is than with BOTOX~, although botulinum toxin type B was less effective at weakening muscles. After four months of injections 2 of 4 (where treated with 1.5 ng/kg) and 4 of 4 (where treated with 6.5 ng/kg) rabbits developed antibodies against botulinum toxin type B. In a separate study, 0 of 9 s BOTOX° treated rabbits demonstrated antibodies against botulinum toxin type A. DAS results indicate relative peak potencies of botulinum toxin type A
being equal to botulinum toxin type F, and botulinum toxin type F being greater than botulinum toxin type B. With regard to duration of effect, botulinum toxin type A was greater than botulinum toxin type B, and to botulinum toxin type B duration of effect was greater than botulinum toxin type F. As shown by the therapeutic index values, the two commercial preparations of botulinum toxin type A (BOTOX° and Dysport°) are different.
The increased water consumption behavior observed following hind limb injection of botulinum toxin type B indicates that clinically significant amounts is of this serotype entered the murine systemic circulation. The results also indicate that in order to achieve efficacy comparable to botulinum toxin type A, it is necessary to increase doses of the other serotypes examined.
Increased dosage can comprise safety. Furthermore, in rabbits, type B was more antigenic than was BOTOX~, possibly because of the higher protein ao load injected to achieve an effective dose of botuiinum toxin type B. Eur J
Neurol 7999 Nov; 6(Suppl 4): S3-S10.
In addition to having pharmacologic actions at a peripheral location, a botulinum toxin can also exhibit a denervation effect in the central nervous 2s system. Wiegand et al, Naunyn-Schmiedeberg's Arch. Pharmacol. 1976;
292, 161-165, and Habermann, Naunyn-Schmiedeberg's Areh. PharmacoG
1974; 281, 47-56 reported that botulinum toxin is able to ascend to the spinal area by retrograde transport. As such, a botulinum toxin injected at a peripheral location, for example intramuscularly, can potentially be retrograde 3o transported to the spinal cord.

U.S. Patent No. 5,989,545 discloses that a modified clostridia( neurotoxin or fragment thereof, preferably a botulinum toxin, chemically conjugated or recombinantly fused to a particular targeting moiety can be used to treat pain s by administration of the agent to the spinal cord.
Acetylcholine Typically only a single type of small molecule neurotransmitter is released by each type of neuron in the mammalian nervous system. The to neurotransmitter acetylcholine is secreted by neurons in many areas of the brain, but specifically by the large pyramidal cells of the motor cortex, by several different neurons in the basal ganglia, by the motor neurons that innervate the skeletal muscles, by the preganglionic neurons of the autonomic nervous system (both sympathetic and parasympathetic), by the is postganglionic neurons of the parasympathetic nervous system, and by some of the postganglionic neurons of the sympathetic nervous system.
Essentially, only the postganglionic sympathetic nerve fibers to the sweat glands, the piloerector muscles and a few blood vessels are cholinergic as most of the postganglionic neurons of the sympathetic nervous system secret 2o the neurotransmitter norepinephine. 1n most instances acetylcholine has an excitatory effect. However, acetylcholine is known to have inhibitory effects at some of the peripheral parasympathetic nerve endings, such as inhibition of heart rate by the vagal nerve.
Zs The efferent signals of the autonomic nervous system are transmitted to the body through either the sympathetic nervous system or the parasympathetic nervous system. The preganglionic neurons of the sympathetic nervous system extend from preganglionic sympathetic neuron cell bodies located in the intermediolateral horn of the spinal cord. The 3o preganglionic sympathetic nerve fibers, extending from the cell body, synapse m with postganglionic neurons located in either a paravertebral sympathetic ganglion or in a prevertebral ganglion. Since the preganglionic neurons of both the sympathetic and parasympathetic nervous system are cholinergic, application of acetylcholine to the ganglia will excite both sympathetic and s parasympathetic postganglionic neurons.
Acetylcholine activates two types of receptors, muscarinic and nicotinic receptors. The muscarinic receptors are found in all effector cells stimulated by the postganglionic, neurons of the parasympathetic nervous system as io well as in those stimulated by the postganglionic cholinergic neurons of the sympathetic nervous system. The nicotinic receptors are found in the adrenal medulla, as well as within the autonomic ganglia, that is on the cell surface of the postganglionic neuron at the synapse between the preganglionic and postganglionic neurons of both the sympathetic and parasympathetic is systems. Nicotinic receptors are also found in many nonautonomic nerve endings, for example in the membranes of skeletal muscle fibers at the neuromuscular junction.
Acetylcholine is released from cholinergic neurons when small, clear, 2o intracellular vesicles fuse with the presynaptic neuronal cell membrane. A
wide variety of non-neuronal secretory cells, such as, adrenal medulla (as well as the PC12 cell line) and pancreatic islet cells release catecholamines and parathyroid hormone, respectively, from large dense-core vesicles. The PC12 cell line is a clone of rat pheochromocytoma cells extensively used as a as tissue culture model for studies of sympathoadrenal development. Botulinum toxin inhibits the release of both types of compounds from both types of cells in vitro, permeabilized (as by electroporation) or by direct injection of the toxin into the denervated cell. Botulinum toxin is also known to block release of the neurotransmitter glutamate from cortical synaptosomes cell cultures.

A neuromuscular junction is formed in skeletal muscle by the proximity of axons to muscle cells. A signal transmitted through the nervous system results in an action potential at the terminal axon, with activation of ion channels and resulting release of the neurotransmitter acetylcholine from s intraneuronal synaptic vesicles, for example at the motor endplate of the neuromuscular junction. The acetylcholine crosses the extracellular space to bind with acetylcholine receptor proteins on the surface of the muscle end plate. Once sufficient binding has occurred, an action potential of the muscle cell causes specific membrane ion channel changes, resulting in muscle cell to contraction. The acetylcholine is then released from the muscle cells and metabolized by cholinesterases in the extracellular space. The metabolites are recycled back into the terminal axon for reprocessing into further acetylcholine.
is Therefore, a need exists for a biocompatible, nonimmunogenic, nonbiodegradable implant which permits long term continuous release of a therapeutically effective neurotoxin in a human patient.
SUMMARY
The present invention meets this need and provides a biocompatible, nonimmunogenic, nonbiodegradable implant which permits long term, continuous release of a neurotoxin in a human patient.
2s Our invention provides a neurotoxin implant which overcomes the known problems, difficulties and deficiencies associated with repetitive bolus or subcutaneous injection of a neurotoxin, such as a botulinum toxin, to treat an affliction such as a movement disorder, including a muscle spasm.

A controlled release system within the scope of our invention comprises a polymeric matrix, and a quantity of neurotoxin located within the polymeric matrix, wherein fractional amounts of the neurotoxin can be released from the polymeric matrix over a prolonged period of time.
s The neurotoxin can be released from the polymeric matrix in a substantially continuous or monophasic manner and the prolonged period of time during which neurotoxin is released from the polymeric matrix can be from 10 days to about 6 years.
io The polymeric matrix can be made of a substance which is substantially non-biodegradable and the neurotoxin can be a polypeptide. Additionally, the neurotoxin can be a presynaptic neurotoxin, such as a Clostridial neurotoxin.
Further, the neurotoxin can be a botulinum toxin, such as a botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C,, D, E, F
and G. Preferably, the neurotoxin is a botulinum toxin type A.
The polymer which comprises the polymeric matrix is selected from the group consisting of methacrylate, vinyl pyrrolidone, vinyl alcohol, acrylic acid, 2o siloxane, vinyl acetate, lactic acid, glycolic acid, collagen, and bioceramic polymers and copolymers thereof.
The quantity of the neurotoxin held by the implant is between about 1 unit and about 100,000 units of a botulinum toxin and preferably, from about 1 to 2s about 50,000 units of a botulinum toxin. Thus, the quantity of the neurotoxin can be between about 10 units and about 2,000 units of a botulinum toxin type A and the quantity of the neurotoxin can be between about 100 units and about 30,000 units of a botulinum toxin type B.

The neurotoxin can be a botulinum toxin which is released from the implant in an amount effective to cause flaccid muscular paralysis of a muscle or muscle group at or in the vicinity of the implanted system.
A detailed embodiment of the present invention can be a controlled release system comprising a polymeric matrix, and between about 10 units and about 20,000 units of a botulinum toxin within the polymeric matrix, wherein fractional amounts of the botulinum toxin can be released from the polymeric matrix over a prolonged period of time extending from about 2 to months to about 5 years.
A method for making a controlled release system within the scope of our invention can have the steps of (a) dissolving a polymer in a solvent to form a polymer solution; (b) mixing or dispersing a neurotoxin in the polymer solution is to form a polymer-neurotoxin mixture, and; (c) allowing the polymer-neurotoxin mixture to set, thereby making a controlled release system. There can also be the step after the mixing step of evaporating solvent.
Additionally, a method for using a continuous release system within the 2o scope of our invention can comprise injection or implantation of a controlled release system which includes a polymeric matrix, thereby treating a movement disorder or a disorder influenced by cholinergic innervation.
Finally, a method for forming a metal cation-complexed neurotoxin 2s comprising the steps of (a) forming a solution containing a neurotoxin; (b) dispersing a multivalent metal cation component with the neurotoxin solution under pH conditions suitable for complexing the multivalent metal cation with the neurotoxin, thereby forming a metal cation-complexed neurotoxin suspension wherein the molar ratio of metal cation component to neurotoxin is between about 4:1 to about 100:1; and; (c) drying said suspension to form the metal cation-complexed neurotoxin.
The amount of a'neurotoxin administered by a continuous release system s within the scope of the present invention during a given period can be between about 10-3 U/kg and about 35 U/kg for a botulinum toxin type A and up to about 200 U/kg for other botulinum toxins, such as a botulinum toxin type B. 35 U/kg or 200 U/kg is an upper limit because it approaches a lethal dose of certain neurotoxins, such as botulinum toxin type A and botulinum io toxin type B, respectively. Preferably, the amount of the neurotoxin administered by a continuous release system during a given period is between about 10'Z U/kg and about 25 U/kg. More preferably, the neurotoxin is administered in an amount of between about 10-' U/kg and about 15 U/kg.
Most preferably, the neurotoxin is administered in an amount of between is about 1 U/kg, and about 10 U/kg. In many instances, an administration of from about 1 units to about 500 units of a neurotoxin, such as a botulinum toxin type A, provides effective and long lasting therapeutic relief. More preferably, from about 5 units to about 300 units of a neurotoxin, such as a botulinum toxin type A, can be used and most preferably, from about 10 units 2o to about 200 units of a neurotoxin, such as a botulinum toxin type A, can be locally administered into a target tissue with efficacious results. In a particularly preferred embodiment of the present invention from about 1 units to about 100 units of a botulinum toxin, such as botulinum toxin type A, can be locally administered into a target tissue with therapeutically effective 2s results.
The neurotoxin can be made by a Clostridial bacterium, such as by a Clostridium botulinum, Clostridium butyricum, Clostridium beratti or Clostridium tetani bacterium. Additionally, the neurotoxin can be a modified 3o neurotoxin, that is a neurotoxin that has at least one of its amino acids deleted, modified or replaced, as compared to the native or wild type neurotoxin. Furthermore, the neurotoxin can be a recombinant produced neurotoxin or a derivative or fragment thereof.
s The neurotoxin can be a botulinum toxin, such as one of the botulinum toxin serotypes A, B, C,, D, E, F or G. Preferably, the neurotoxin is botulinum toxin type A.
Significantly, the botulinum toxin can be is administered to by subdermal io implantation to the patient by placement of a botulinum toxin implant. The botulinum toxin can administered to a muscle of a patient in an amount of between about 1 unit and about 10,000 units. When the botulinum toxin is botulinum toxin type A and the botulinum toxin can be administered to a muscle of the patient in an amount of between about 1 unit and about 100 is units.
Notably, it has been reported that glandular tissue treated by a botulinum toxin can show a reduced secretory activity for as long as 27 months post injection of the toxin. Laryngoscope 1999; 109:1344-1346, Laryngoscope 20 1998;108:381-384.
Our invention relates to an implant for the controlled release of a .
neurotoxin and to methods for making and using such implants. The implant can comprise a polymer matrix containing a neurotoxin. The implant is 2s designed to administer effective levels of neurotoxin over a prolonged period of time when administered, for example, intramuscularly, epidurally or subcutaneously for the treatment of various diseases conditions.
This invention further relates to a composition, and methods of making and 3o using the composition, for the controlled of biologically active, stabilized neurotoxin. The controlled release composition of this invention can comprise a polymeric matrix of a biocompatible polymer and biologically active, stabilized neurotoxin dispersed within the biocompatible polymer.
s Definitions The following definitions apply herein.
"Biocompatible" means that there is an insignificant inflammatory response at the site of implantation from use of the implant.
io "Biologically active compound" means a compound which can effect a beneficial change in the subject to which it is administered. For example, "biologically active compounds" include neurotoxins.
is "Effective amount" as applied to the biologically active compound means that amount of the compound which is generally sufficient to effect a desired change in the subject. For example, where the desired effect is a flaccid muscle paralysis, an effective amount of the compound is that amount which causes at least a substantial paralysis of the desired muscles without causing 2o a substantial paralysis of adjacent muscle of which paralysis is not desired, and without resulting in a significant systemic toxicity reaction.
"Effective amount" as applied to a non-active ingredient constituent of an implant (such as a polymer used for forming a matrix or a coating composition) refers to that amount of the non-active ingredient constituent 2s which is sufficient to positively influence the release of a biologically active agent at a desired rate for a desired period of time. For example, where the desired effect is muscle paralysis by using a single implant, the "effective amount" is the amount that can facilitate extending the release over a period of between about 60 days and 6 years. This "effective amount" can be determined based on the teaching in this specification and the general knowledge in the art.
"EfFective amount" as applied to the amount of surface area of an implant is that amount of implant surface area which is sufficient to effect a flux of s biologically active compound so as to achieve a desired effect, such as a muscle paralysis. The area necessary may be determined and adjusted directly by measuring the release obtained for the particular active compound.
The surface area of the implant or of a coating of an implant is that amount of membrane necessary to completely encapsulate the biologically active io compound. The surface area depends on the geometry of the implant.
Preferably, the surface area is minimized where possible, to reduce the size of the implant.
"Implant" means a controlled release drug delivery system. The implant is is comprised of a biocompatible polymer or ceramic material which contains or which can act as a carrier for a molecule with a biological activity. The implant can be, injected, inserted or implanted into a human body.
"Local administration" means direct administration of a biologically active 2o compound, such as a therapeutic drug to a tissue by a non-systemic route.
Local administration therefore includes, ubcutaneous, intramuscular, intraspinal (i.e. intrathecal and epidural), intracranial, and intraglandular administration. Local administration excludes a systemic route of administration such as oral or intravenous administration.
"Neurotoxin" means an agent which can interrupt nerve impulse transmission across a neuromuscular or neuroglandular junction, block or reduce neuronal exocytosis of a neurotransmitter or alter the action potential at a sodium channel voltage gate of a neuron. Examples of neurotoxins include botulinum toxins, tetanus toxins, saxitoxins, and tetrodotoxin.
"Treatment" means any treatment of a disease in a mammal, and includes:
s (i) preventing the disease from occurring or; (ii) inhibiting the disease, i.e., arresting its development; (iii) relieving the disease, i.e., reducing the incidence of symptoms of or causing regression of the disease.
A method for making an implant within the scope of the present invention for controlled release of a neurotoxin, can include dissolving a biocompatible io polymer in a polymer solvent to form a polymer solution, dispersing particles of biologically active, stabilized neurotoxin in the polymer solution, and then solidifying the polymer to form a polymeric matrix containing a dispersion of the neurotoxin particles.
A method of using an implant within the scope of the present invention is forming for controlled release of a neurotoxin can comprise providing a therapeutically effective level of biologically active, neurotoxin in a patient for a prolonged period of time by implanting in the patient the implant.
DESCRIPTION
The present invention is based upon the discovery that a continuous release, implant comprising a biocompatible, non-biodegradable or biodegradable polymer can exhibit prolonged in vivo release of therapeutic amounts of a neurotoxin.
2s An implant within the scope of our invention can be surgically inserted by incision at the site of desired effect (i.e. for reduction of a muscle spasm) or the implant can be administered subcutaneously or intramuscularly using a hollow needle implanting gun, for example of the type disclosed in U.S. patent number 4,474,572. The diameter of the needle may be adjusted to correspond to the size of the implant used. Further, an implant within the s scope of the present invention can be implanted intracranially so as to provide long term delivery of a therapeutic amount of a neurotoxin to a target brain tissue. Removal of a non-biodegradable implant within the scope of the present invention is not necessary once the implant has been spent, since the implant is comprised of a biocompatible, nonimmunogenic material.
io To stabilize a neurotoxin, both in a format which renders the neurotoxin useful for mixing with a suitable polymer which can form the implant matrix (i.e. a powdered neurotoxin which has been freeze dried or lyophilized) as well as while the neurotoxin is present or incorporated into the matrix of the selected polymer, various pharmaceutical excipients can be used. Suitable is excipients can include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride and dried skim milk.
The thickness of the implant can be used to control the absorption of water by, and thus the rate of release of a neurotoxin from, a composition of the 2o invention, thicker implants releasing the polypeptide more slowly than thinner ones.
The implant can rapidly release a suboptimal amount of neurotoxin during a first phase, the burst period. The burst period typically lasts less than 24 hours and frequently extends over only about an hour or so after implantation.
2s Thereafter the amount of neurotoxin released by the implant rapidly declines and stabilizes at a much reduced and, significantly, relatively constant (i.e.
zero order kinetics) level of released neurotoxin. This second, prolonged phase. of neurotoxin release can extend over a period of from about one year to about five or six years. An initial portion of the second phase can be termed the make up period.
The additive amount of neurotoxin released during the burst phase and the s make up period is preferably equal to an optimal amount of neurotoxin so as to treat a particular disorder or affliction. The temporal extent of the make up period is somewhat less than the period of time upon the expiry of which an optimal administration of the neurotoxin shows significantly reduced efficacy.
For example; to treat upper limb spasticity the optimal amount of io intramuscular botulinum toxin type A can be about 90 units injected into the biceps brachii muscle. Typically, the flaccid paralysis so induced within 1-7 days of a bolus injection substantially wears off after about 3 months. A
subdermal neurotoxin implant within the scope of our invention can be configured to release about 60 units of botulinum toxin type essentially is immediately upon implantation (i.e. during the burst period). This suboptimal amount of neurotoxin provides rapid and substantial relief. During phase 2 the implant continuously releases about O.A. unit/day of a neurotoxin, such as a botulinum toxin type A, so that after about 75 days the optimal amount of 90 units has been released by the implant into the target tissue. .
The pre-synaptic neuronal receptor for which botulinum toxin exhibits a high and specific affinity has not been identified. Nor has a generally accepted mechanism to account for the long intraneuronal half life of botulinum toxin been elucidated. Nevertheless it is known that a dynamic 2s process, which may be either unblocking, reappearance, resynthesis and/or reactivation of the botulinum toxin receptor or the appearance of new neural sprouts, or both, transpires and accounts for the gradual wearing off of the paralytic effect which results from an administration of a botulinum toxin.
Thus, while in the example above it can take 75 days for an optimal amount (total of 90 units) of botulinum toxin to be released by the implant, due to the dynamic nature of the attenuation of the effect of the botulinum toxin, subsequent release of toxin (i.e. beyond 75 days) by the implant does not result in unwanted or excess areas of paralysis. Thus, it can be expected, in this example, that toxin released by the implant on day 76 binds to the new s receptors and/or neural sprouts formed in response to the denervation caused by the toxin released by the implant on or about day one. The rolling nature of the denervation process means that, rather than resulting in excess toxin which can diffuse systemically or cause unwanted paralysis, the continuous release of toxin after the end of the make up period simply again to denervates within the same desired muscle location. Thus, assuming a spherical pattern of denervation and holding other factors constant, the burst release denervates a sphere of tissue with a diameter about 2/3 the optimal size of the tissue mass for which denervation is desired. Later release of neurotoxin during the make up period and subsequent provides the optimal or is desired extent of tissue denenration and amounts of neurotoxin to renew denenration at recently renervated sites within the target tissue.
It is known that blepharospasm can be treated by intramuscular injection of about 5 units (repeated at 2-4 month intervals) of botulinum toxin type A
2o into the lateral pre-tarsal orbicularis oculi muscle. Significantly, a single implant within the scope of our invention can be used for the treatment of blepharospasm over, for example, a one-year period. With this affliction and a one year period chosen for treatment by implant release of neurotoxin, and a 15°J° burst characteristic polymer used, the total neurotoxin loading into the 2s implant can be 20 units. During the burst period about 3 units of the toxin is released (within 24 hours after implantation) followed by a continuous release of about 0.0467 units per day (i.e. about 2.3 picograms of BOTOX~ released ' per day). Thus, by day 42 about 5 units total of the neurotoxin has been released. The release rate in this example (15% burst, remaining 85% over so 364 days) is 0.234%/day. In this example, on day 1 the patient receives a unit implant and one year later the patient has the spent implant removed and another 20 unit implant inserted. Thus 25 units are administered over 365 days, with effect of second implant on day 365 included.
s Since one mole (M) of the botulinum toxin type A complex contains about 9 X 105 grams, therefore one picogram (pg) of the botulinum toxin type A
complex is about 1.1 X 10-'$ M. Hence, a desired release of 0.234%/day of total incorporated neurotoxin equals a release of about 2.53 X 10-'$ M/day.
With one year treatment period, 20% burst, followed by 80% over 364 days to results in a controlled release of about 0.22%lday or 0.044 units/day or 2.2 picograms/day or about 2.42 X 10-'$ M/day. A 20% burst from a 20 unit implant provides 4 units of the neurotoxin in about the first 24 hours after implantation. Generally, surface area of the implant is equal to x units of toxin released/day for each y cm2 of implant surface area.
Different conditions are treated with botulinum toxin injection ranging from about 5 units to about 100 units per injection. A typical implant to treat, over a one year period, a condition for which 25 units of type A is the optimal bolus dose can be loaded with 100 units of a botulinum toxin type A complex.
2o The burst can be 20%, followed by 80% over 364 days, which is equal to 0.22°l°/day or 0.22 units/day or 11 picograms/day or about 1.21 X 10-" M/day For a five year treatment period, that is 20 bolus injections of 25 units, the first injection is at time zero, and the 20'" injection is at month 57, for a 2s unit total series of injections. Contrarily, with our invention, a 5 year implant to treat a condition responsive to 25 units of a botulinum toxin, such as a botulinum toxin type A, can be made with a 500 toxin unit loaded implant with the characteristics of a 20 unit burst (4% burst), followed by about 480 units released over about 1736 days, which is equal to 0.267 unitJday or 5.56 X 10-30 4°l°/day or 13.35 picograms/day released by the implant.

A matrix implant can be made, by dissolving a selected polymer in an appropriate solvent. Into this casting solution the desired amount of lyophilized or freeze dried, powered neurotoxin (i.e. the total desired amount s of the neurotoxin, such as non-reconstituted BOTOX°, to be released over the therapeutic period) is mixed. This method can be used to make coated implant pellets, with the modification that the coating used in an embodiment of the present invention is a bioerodible polymer which is impermeable to the neurotoxin. Thus, the neurotoxin does not diffuse out of the matrix into the to surrounding tissue until the coating has degraded.
The pH of the casting or other solution in which the botulinum toxin is to be mixed is maintained at pH 4.2-6.8, because at pH above 7 the stabilizing nontoxin proteins dissociate from the botulinum toxin resulting in gradual loss is of toxicity. Preferably, the pH is between about 5-6. Furthermore the temperature of the mixture/solution should not exceed about 35 degrees Celsius, because the toxin is readily detoxified when in a solution/mixture heated above about 40 degrees Celsius.
2o Suitable implants within the scope of the present invention for the controlled in vivo release of a neurotoxin, such as a botulinum toxin, can be prepared so that the implant releases the neurotoxin in either a continuous or in a pulsatile fashion. "Continuous release" means release of toxin in a substantially monophasic manner, after the initial burst phase. A continuous 2s release can have a point of inflection, but not a plateau phase. Continuous release does not require a release from the implant of a similar amount of a neurotoxin per unit if time. A pulsatile release implant can release a neurotoxin is a biphasic or multiphase manner. Thus, a pulsatile release implant can have a relatively short initial induction (burst) period,.followed by 3o periods during which little or no neurotoxin is released.

A controlled release of biologically active neurotoxin is a release which results in therapeutically effective, with negligible serum levels, of biologically active, neurotoxin over a period longer than that obtained following direct s administration of aqueous neurotoxin. It is preferred that a controlled release be a release of neurotoxin for a period of about six months or more, and more preferably for a period of about one year or more.
Suitable implants within the scope of the present invention for the to controlled in vivo release of a neurotoxin, such as a botulinum toxin, can exhibit a continuous release or a pulsatile release of the neurotoxin.
Additionally, the implant can comprise a non-biodegradable or a biodegradable polymeric material. Significantly, our invention encompasses:
(1) continuous release, nonbiodegradable neurotoxin implants; (2) continuous is release, biodegradable neurotoxin implants; (3) pulsatile release, nonbiodegradable neurotoxin implants, and; (4) pulsatile release, biodegradable implants, and each of these four types of encompasses implant can be formulated into a variety of conformations, suitable for sub-dermal injection or implantation such as pellets, discs, microspheres, films, 2o rods and tubes, each of which can have, for example, one or more coatings over a reservoir or matrix structure.
An implant within the scope of our invention can also be formulated as a suspension for injection. Such suspensions may be manufactured by general techniques well known in the pharmaceutical. art, for example by milling the 2s polylactide/polypeptide mixture in an ultracentrifuge mill fitted with a suitable mesh screen, for example a 120 mesh, and suspending the milled, screened particles in a solvent for injection, for example propylene glycol, water optionally with a conventional viscosity increasing or suspending agent, oils or other known, suitable liquid vehicles for injection.

Denaturation of the encapsulated neurotoxin in the body at 37 degrees C.
for a prolonged period of time can be reduced by stabilizing the neurotoxin by lyophilizing it with albumin, lyophilizing from an acidic solution, lyophilizing s from a low moisture content solution (these three criteria can be met with regard to a botulinum toxin type A by use of non-reconstituted Botox°) and using a specific polymer matrix composition.
Preferably, the release of biologically active neurotoxin in vivo does not to result in a significant immune system response during the release period of the neurotoxin.
Matrix Stabilized Neurotoxin is We have discovered that a stabilized neurotoxin can comprise biologically active, non-aggregated neurotoxin complexed with at least one type of multivalent metal ration which has a valiancy of +2 or more.
Suitable multivalent metal rations include metal rations contained in 2o biocompatible metal ration components. A metal ration component is biocompatible if the ration component is non-toxic to the recipient, in the quantities used, and also presents no significant deleterious or untoward effects on the recipient's body, such as an immunological reaction at the injection site.
Preferably, the molar ratio of metal ration component to neurotoxin, for the metal ration stabilizing the neurotoxin, is between about 4:1 to about 100:1 and more typically about 4:1 to about 10:1.

A preferred metal cation used to stabilize neurotoxin is Zn++. Divalent zinc cations are preferred because botulinum toxin is known to be a divalent zinc endopeptidase. In a more preferred embodiment, the molar ratio of metal cation component, containing Zn++ cations, to neurotoxin is about 6:1.
s The suitability of a metal cation for stabilizing neurotoxin can be determined by one of ordinary skill in the art by performing a variety of stability indicating techniques such as polyacrylamide gel electrophoresis, isoelectric focusing, reverse phase chromatography, HPLC and potency tests 1o on neurotoxin lyophilized particles containing metal cations to determine the potency of the neurotoxin after lyophilization and for the duration of release from microparticles. In stabilized neurotoxin, the tendency of neurotoxin to aggregate within a microparticle during hydration in vivo and/or to lose biological activity or potency due to hydration or due to the process of forming is a controlled release composition, or due to the chemical characteristics of a controlled release composition, is reduced by complexing at least one type of metal cation with neurotoxin prior to contacting the neurotoxin with a polymer solution.
2o By our invention, stabilized neurotoxin is stabilized against significant aggregation in vivo over the controlled release period. Significant aggregation is defined as an amount of aggregation resulting in aggregation of about 15% or more of the polymer encapsulated or polymer matrix incorporated neurotoxin. Preferably, aggregation is maintained below about 2s 5% of the neurotoxin. More preferably, aggregation is maintained below about 2% of the neurotoxin present in the polymer.
The neurotoxin in a neurotoxin controlled release composition can also be mixed with other excipients, such as bulking agents or additional stabilizing 3o agents, such as buffers to stabilize the neurotoxin during lyophilization.

Bulking agents typically comprise inert materials. Suitable bulking agents are known to those skilled in the art.
s A polymer, or polymeric matrix, suitable for the controlled release composition of the present invention, must be biocompatible. A polymer is biocompatible if the polymer, and any degradation products of the polymer, are non-toxic to the recipient and also present no significant deleterious or untoward effects on the recipient's body, such as an immunological reaction io at the injection site.
The polymer of the neurotoxin controlled release composition can be made of a biodegradable material. Biodegradable, as defined herein, means the composition will degrade or erode in vivo to form smaller chemical is species. Degradation can result, for example, by enzymatic, chemical and physical processes.
Suitable biocompatible, biodegradable polymers include, for example, poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acids, zo poly(glycolic acids, poly(lactic acid-co-glycolic acids, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, polyp-dioxanone), poly(alkylene oxalates), biodegradable polyurethanes, blends and copolymers thereof.
zs Further, the terminal functionalities of the polymer can be modified. For example, polyesters can be blocked, unblocked or a blend of blocked and unblocked polymers. A blocked polymer is as classically defined in the art, specifically having blocked carboxyl end groups. Generally, the blocking group is derived from the initiator of the polymerization and is typically an 3o alkyl group. An unblocked polymer generally has free carboxyl end groups.

Acceptable molecular weights for a biodegradable polymer used in this invention can be determined by a person of ordinary skill in the art taking into consideration factors such as the desired polymer degradation rate, physical s properties such as mechanical strength, and rate of dissolution of polymer in solvent. Typically, an acceptable range of molecular weights is of about 2,000 Daltons to about 2,000,000 Daltons. In a preferred embodiment, the polymer is a biodegradable polymer or copolymer. In a more preferred embodiment, the polymer is a poly(lactide-co-glycolide) (hereinafter "PLGA") io with a lactide:glycolide ratio of about 1:1 and a molecular weight of about 5,000 Daltons to about 70,000 Daltons. In an even more preferred embodiment, the molecular weight of the PLGA used in the present invention has a molecular weight of about 6,000 to about 31,000 Daltons. ' is The amount of neurotoxin, which is contained in a dose of controlled release microparticles, or in an alternate controlled release system, containing biologically active, stabilized neurotoxin particles is a therapeutically or prophylactically effective amount, which can be determined by a person of ordinary skill in the art taking into consideration factors such as 2o body weight, condition to be treated, type of polymer used, and release rate from the polymer.
In one embodiment, a neurotoxin controlled release composition contains from about 10~% (w/w) to about 1 % (w/w) of biologically active, stabilized 2s neurotoxin. The amount of such neurotoxin particles used will vary depending upon the desired effect of the neurotoxin, the planned release levels, the times at which neurotoxin should be released, and the time span over which the neurotoxin will be released. A preferred range of neurotoxin particle loading is between about 10'~°!° (w/w) to about 0.1%
(wlw) neurotoxin 3o particles. A more preferred range of neurotoxin loading is between about 10-3% (w/w) to about 1 % (w/w) neurotoxin. The most preferred loading of the biologically active, stabilized neurotoxin particles is about 10'2% (w/w).
In another embodiment, a neurotoxin controlled release composition also s contains a second metal ration component, which is not contained in the stabilized neurotoxin particles, and which is dispersed within the polymer.
The second metal ration component preferably contains the same species of metal ration, as is contained in the stabilized neurotoxin. Alternately, the second metal ration component can contain one or more different species of io metal ration.
The second metal ration component acts to modulate the release of the neurotoxin from the polymeric matrix of the controlled release composition, such as by acting as a reservoir of metal rations to further lengthen the period is of time over which the neurotoxin is stabilized by a metal ration to enhance the stability of neurotoxin in the composition.
A metal ration component used in modulating release typically contains at least one type of multivalent metal ration. Examples of second metal ration 2o components suitable to modulate neurotoxin release, include, or contain, for instance, Mg(OH)~, MgC03 (such as 4MgC03Mg(OH)Z5H20), ZnC03(such as 3Zn(OH)22ZnC03), CaC03, Zn3 (C6H507) Z, Mg(OAc) z, MgSO~, Zn(OAc)Z, ZnS04, ZnCl2, MgCh and Mg3 (CsH50,)2. A suitable ratio of second metal ration component-to-polymer is between about 1:99 to about 1:2 by weight.
2s The optimum ratio depends upon the polymer and the second metal ration component utilized.
The neurotoxin controlled release composition of this invention can be formed into many shapes such as a film, a pellet, a cylinder, a disc or a 3o microparticle. A microparticle, as defined herein, comprises a polymeric component having a diameter of less than about one millimeter and having stabilized neurotoxin particles dispersed therein. A microparticle can have a spherical, non-spherical or irregular shape. It is preferred that a microparticle be a microsphere. Typically, the microparticle will be of a size suitable for s injection. A preferred size range for microparticles is from about 1 to about 180 microns in diameter.
In the method of this invention for forming a composition for the controlled release of biologically active, non-aggregated neurotoxin, a suitable amount io of particles of biologically active, stabilized neurotoxin are dispersed in a polymer solution.
A suitable polymer solution contains between about 1 % (w/w) and about 30% (w/w) of a suitable biocompatible polymer, wherein the biocompatible is polymer is typically dissolved in a suitable polymer solvent. Preferably, a polymer solution contains about 2% (w/v) to about 20% (w/v) polymer. A
polymer solution containing 5% to about 10% (w/w) polymer is most preferred.
2o A suitable polymer solvent, as defined herein, is solvent in which the polymer is soluble but in which the stabilized neurotoxin particles are substantially insoluble and non-reactive. Examples of suitable polymer solvents include polar organic liquids, such as methylene chloride, chloroform, ethyl acetate and acetone.
To prepare biologically active, stabilized neurotoxin, neurotoxin is mixed in a suitable aqueous solvent with at least one suitable metal cation component under pH conditions suitable for forming a complex of metal cation and neurotoxin. Typically, the complexed neurotoxin will be in the form of a 3o cloudy precipitate, which is suspended in the solvent. However, the complexed neurotoxin can also be in solution. In an even more preferred embodiment, neurotoxin is complexed with Zn++, Suitable pH conditions to form a complex of neurotoxin typically include pH
s values between about 5.0 and about 6.9. Suitable pH conditions are typically achieved through use of an aqueous buffer, such as sodium bicarbonate, as the solvent.
Suitable solvents are those in which the neurotoxin and the metal cation Io component are each at least slightly soluble, such as in an aqueous sodium bicarbonate buffer. For aqueous solvents, it is preferred that water used be either deionized water or water-for-injection (WFI).
The neurotoxin can be in a solid or a dissolved state, prior to being is contacted with the metal cation component. Additionally, the metal cation component can be in a solid or a dissolved state, prior to being contacted with the neurotoxin. In a preferred embodiment, a buffered aqueous solution of neurotoxin is mixed with an aqueous solution of the metal cation component.
2o Typically, the complexed neurotoxin will be in the form of a cloudy precipitate, which is suspended in the solvent. However, the complexed neurotoxin can also be in solution. In a preferred embodiment, the neurotoxin is complexed with Zn++
2s The Zn~+complexed neurotoxin can then be dried, such as by lyophilization, to form particulates of stabilized neurotoxin. The Zn++
complexed neurotoxin, which is suspended or in solution, can be bulk lyophilized or can be divided into smaller volumes which are then lyophilized.
In a preferred embodiment, the Zn++complexed neurotoxin suspension is 3o micronized, such as by use of an ultrasonic nozzle, and then lyophilized to form stabilized neurotoxin particles. Acceptable means to lyophilize the Zn++
complexed neurotoxin mixture include those known in the art.
Preferably, particles of stabilized neurotoxin are between about 1 to about s 6 micrometers in diameter. The neurotoxin particles can be fragmented separately, Alternately, the neurotoxin particles can be fragmented after being added to a polymer solution, such as by means of an ultrasonic probe or ultrasonic nozzle.
io In another embodiment, a second metal cation component, which is not contained in the stabilized neurotoxin particles, is also dispersed within the polymer solution.
It is understood that a second metal cation component and stabilized is neurotoxin can be dispersed into a polymer solution sequentially, in reverse order, intermittently, separately or through concurrent additions.
Alternately, a polymer, a second metal cation component and stabilized neurotoxin and can be mixed into a polymer solvent sequentially, in reverse order, intermittently, separately or through concurrent additions.
In this method, the polymer solvent is then solidified to form a polymeric matrix containing a dispersion of stabilized neurotoxin particles.
A suitable method for forming an neurotoxin controlled release 2s composition from a polymer solution is the solvent evaporation method is described in U.S. patents numbers 3,737,337; 3,523,906; 3,691,090, and;
4,389,330. Solvent evaporation can be used as a method to form neurotoxin controlled release microparticles.

In the solvent evaporation method, a polymer solution containing a stabilized neurotoxin particle dispersion, is mixed in or agitated with a continuous phase, in which the polymer solvent is partially miscible, to form an emulsion. The continuous phase is usually an aqueous solvent.
s Emulsifiers are often included in the continuous phase to stabilize the emulsion. The polymer solvent is then evaporated over a period of several hours or more, thereby solidifying the polymer to form a polymeric matrix having a dispersion of stabilized neurotoxin particles contained therein.
to A preferred method for forming neurotoxin controlled release microparticles from a polymer solution is described in U.S. patent number 5,019,400. This method of microsphere formation, as compared to other methods, such as phase separation, additionally reduces the amount of neurotoxin required to produce a controlled release composition with a is specific neurotoxin content.
In this method, the polymer solution, containing the stabilized neurotoxin particle dispersion, is processed to create droplets, wherein at least a significant portion of the droplets contain polymer solution and the stabilized 2o neurotoxin particles. These droplets are then frozen by means suitable to form microparticles. Examples of means for processing the polymer solution dispersion to form droplets include directing the dispersion through an ultrasonic nozzle, pressure nozzle, Rayleigh jet, or by other known means for creating droplets from a solution.
2s Means suitable for freezing droplets to form microparticles include directing the droplets into or near a liquefied gas, such as liquid argon and liquid nitrogen to form frozen microdroplets which are then separated from the liquid gas. The frozen microdroplets are then exposed to a liquid non-solvent, so such as ethanol, or ethanol mixed with hexane or pentane.

The solvent in the frozen microdroplets is extracted as a solid andlor liquid into the non-solvent to form stabilized neurotoxin containing microparticles.
Mixing ethanol with other non-solvents, such as hexane or pentane, can s increase the rate of solvent extraction, above that achieved by ethanol alone, from certain polymers, such as poly(lactide-co-glycolide) polymers.
A wide range of sizes of neurotoxin controlled release microparticles can be made by varying the droplet size, for example, by changing the ultrasonic io nozzle diameter. If very large microparticles are desired, the microparticles can be extruded through a syringe directly into the cold liquid. Increasing the viscosity of the polymer solution can also increase microparticle size. The size of the microparticles can be produced by this process, for example microparticles ranging from greater than about 1000 to about 1 micrometers is in diameter.
Yet another method of forming a neurotoxin controlled release composition, from a polymer solution, includes film casting, such as in a mold, to form a film or a shape. For instance, after putting the polymer solution 2o containing a dispersion of stabilized neurotoxin particles into a mold, the polymer solvent is then removed by means known in the art, or the temperature of the polymer solution is reduced, until a film or shape, with a consistent dry weight, is obtained.
2s In the case of a biodegradable polymer implant, release of neurotoxin due to degradation of the polymer. The rate of degradation can be controlled by changing polymer properties that influence the rate of hydration of the polymer. These properties include, for instance, the ratio of different monomers, such as lactide and glycolide, comprising a polymer; the use of 3o the L-isomer of a monomer instead of a racemic mixture; and the molecular weight of the polymer. These properties can affect hydrophilicity and crystallinity, which control the rate of hydration of the polymer. Hydrophilic excipients such as salts, carbohydrates and surfactants can also be incorporated to increase hydration and which can alter the rate of erosion of s the polymer.
By altering the properties of a biodegradable polymer, the contributions of diffusion and/or polymer degradation to neurotoxin release can be controlled.
For example, increasing the glycolide content of a poly(lactide-co-glycolide) io polymer and decreasing the molecular weight of the polymer can enhance the hydrolysis of the polymer and thus, provides an increased neurotoxin release from polymer erosion. In addition, the rate of polymer hydrolysis is increased in non-neutral pH's. Therefore, an acidic or a basic excipient can be added to the polymer solution, used to form the microsphere, to alter the polymer is erosion rate.
The composition of our invention can be administered to a human, or other animal, by any non-system means of administration, such as by implantation (e.g. subcutaneously, intramuscularly, intracranially, intravaginally and ao intradermally), to provide the desired dosage of neurotoxin based on the known parameters for treatment with neurotoxin of various medical conditions.
The specific dosage by implant appropriate for administration is readily as determined by one of ordinary skill in the art according to the factor discussed above. The dosage can also depend upon the size of the tissue mass to be treated or denervated, and the commercial preparation of the toxin.
Additionally, the estimates for appropriate dosages in humans can be extrapolated from determinations of the amounts of botulinum required for 3o effective denervation of other tissues. Thus, the amount of botulinum A to be injected is proportional to the mass and level of activity of the tissue to be treated. Generally, between about 0.01 units per kilogram to about 35 units per kg of patient weight of a botulinum toxin, such as botulinum toxin type A, can be released by the present implant per unit time period (i.e. over a period s of or once every 2-4 months) to effectively accomplish a desired muscle paralysis. Less than about 0.01 U/kg of a botulinum toxin does not have a significant therapeutic effect upon a muscle, while more than about 35 U/kg of a botulinum toxin approaches a toxic dose of a neurotoxin, such as a botulinum toxin type A. Careful preparation and placement of the implant io prevents significant amounts of a botulinum toxin from appearing systemically. A more preferred dose range is from about 0.01 U/kg to about 25 U/kg of a botulinum toxin, such as that formulated as BOTOX°. The actual amount of U/kg of a botulinum toxin to be administered depends upon factors such as the extent (mass) and level of activity of the tissue to be treated and is the administration route chosen. Botulinum toxin type A is a preferred botulinum toxin serotype for use in the methods of the present invention.
Preferably, a neurotoxin used to practice a method within the scope of the present invention is a botulinum toxin, such as one of the serotype A, B, C, D, 2o E, F or G botulinum toxins. Preferably, the botulinum toxin used is botulinum toxin type A, because of its high potency in humans, ready availability, and known safe and efficacious use for the treatment of skeletal muscle and smooth muscle disorders when locally administered by intramuscular injection.
zs The present invention includes within its scope the use of any neurotoxin which has a long duration therapeutic effect when used to treat a movement disorder or an affliction influenced by cholinergic innervation. For example, neurotoxins made by any of the species of the toxin producing Clostridium 3o bacteria, such as Clostridium botulinum, Clostridium butyricum, and Clostridium beratti can be used or adapted for use in the methods of the present invention. Additionally, all of the botulinum serotypes A, B, C, D, E
, F and G can be advantageously used in the practice of the present invention, although type A is the most preferred serotype, as explained above. Practice s of the present invention can provide effective relief for from 1 month to about or 6 years.
The present invention includes within its scope: (a) neurotoxin complex as well as pure neurotoxin obtained or processed by bacterial culturing, toxin io extraction, concentration, preservation, freeze drying and/or reconstitution and; (b) modified or recombinant neurotoxin, that is neurotoxin that has had one or more amino acids or amino acid sequences deliberately deleted, modified or replaced by known chemical/biochemical amino acid modification procedures or by use of known host cell/recombinant vector recombinant is technologies, as well as derivatives or fragments of neurotoxins so made, and includes neurotoxins with one or more attached targeting moieties for a cell surface receptor present on a cell.
Botulinum toxins for use according to the present invention can be stored 2o in lyophilized or vacuum dried form in containers under vacuum pressure.
Prior to lyophilization the botulinum toxin can be combined with pharmaceutically acceptable excipients, stabilizers and/or carriers, such as albumin. The lyophilized or vacuum dried material can be reconstituted with saline or water.
Our invention also includes within its scope the use of an implanted controlled release neurotoxin complex so as to provide therapeutic relief from a chronic disorder such as movement disorder. Thus, the neurotoxin can be imbedded within, absorbed, or carried by a suitable polymer matrix which can 3o be implanted or embedded subdermally so as to provide a year or more of delayed and controlled release of the neurotoxin to the desired target tissue.
Implantable polymers which permit controlled release of polypeptide drugs are known, and can be used to prepare a botulinum toxin implant suitable for insertion or subdermal attachment. See e.g. Pain 1999;82(1):49-55;
s Biomaterials 1994;15(5):383-9; Brain Res 1990;515(1-2):309-11 and United States patents numbers 6,022,554; 6,011,011; 6,007,843; 5,667,808, and;
5,980,945.
Methods for determining the appropriate route of administration and to dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill in the art (see for example, Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci et al., 14'" edition, published by McGraw Hill).
is EXAMPLES
The following examples set forth specific compositions and methods encompassed by the present invention and are not intended to limit the scope of our invention.
Example 1 Formation of Zinc Stabilized Neurotoxin One hundred units of a neurotoxin, such as unreconstituted Botox~, is 2s dissolved in sodium bicarbonate buffer (pH 6.0) to form a neurotoxin solution.
A Zn~ solution is prepared from deionized water and zinc acetate dehydrate and then added with gentle mixing to the neurotoxin solution to form a Zn neurotoxin complex. The pH of the Zn~neurotoxin complex is then adjusted to between 6.5 and 6.9 by adding 1 % acetic acid. A cloudy suspended 3o precipitate, comprising insoluble Zn~"stabilized neurotoxin is thereby formed.
There is thereby made a neurotoxin (such as a botulinum toxin type A) complex stabilized against significant aggregation upon subsequent incorporation into a polymeric implant matrix.
Example 2 Neurotoxin Controlled Release Pellet s A neurotoxin suitable for incorporation into a polymer or polymerizable solution can be a botulinum toxin type A (such as Botox~), which is commercially available as a freeze dried powder. Additionally, various polymers and copolymers can be mixed and stored in a dry state with no io effect on final implant performance. For example, an acrylate copolymer using an UV cured initiator. The neurotoxin can be complexed with Zn~" as set forth in Example 1 above. The Zn~stabifized neurotoxin complex is then mixed with uncured acrylate copolymer, UV initiator and an acid (pH between 5.5 and 6.8). The mixture is placed into a glass or clear plastic pellet mold is which allows penetration of UV light. The mold is placed into a temperature controlled water bath held at 20 C. The pellet is cured with UV light for approximately 50 seconds, packaged and sterilized. The duration and intensity of the UV curing are such that insignificant amount of neurotoxin are disrupted or denatured.
The size of the pellet and the concentration of the amount of neurotoxin inside of the pellet are defined by the desired application. When the pellet is implanted, the pellet is hydrated inside of the body, which slightly delays the initial burst of the neurotoxin from inside of the implant. Coating the outside 2s of the pellet with a portion of the desired initial burst concentration of neurotoxin can offset this delay. In this example the pellet effectiveness would be for approximately about 4 to about 6 months.

Example 3 Neurotoxin Controlled Release Formulations To increase the amount of time the pellet can effectively deliver s neurotoxin, multiple layers of materials can be used. Thus, the inner material can be made from a polyvinylpyrrolidonelmethylmethacrylate copolymer. This material allows for sustaining a high concentration of neurotoxin complex. A
suitable amount of neurotoxin is complexed with Zn~"as set forth in Example 1 above and this complex is then mixed with uncured copolymer, low to temperature initiator and an acid (pH between 5.5 and 6.8). The mixture is placed into a glass or plastic pellet mold. The mold is placed into a temperature controlled water bath at about 35 degrees C. for between about
6 hours and about 8 hours. This forms the reservoir of neurotoxin required for a prolonged, controlled release.
is In order to prolong the release of the neurotoxin a second material is then cured around the initial pellet. This material is chosen for high molecular density and biocompatibility. Polymethylmethacrylate (PMMA) is an example of a material with this characteristic. The pellet (above) is placed into a mold 20 (insertion molding) with uncured PMMAIIow temperature initiator. A
secondary coating of the uncured PMMA maybe necessary to assure uniform coating of the pellet. Preferably, the PMMA thickness is 0.5 mm. After forming, the outside of the pellet is coated with the desired initial burst concentration of neurotoxin. The PMMA layer will be sufficiently thick to allow 2s foi- a delay (up to 3 months) of the neurotoxin in the reservoir. When the neurotoxin reaches the surface of the implant a second large burst of neurotoxin is obtained. This secondary burst will then be followed by a slowly decreasing release rate of the neurotoxin for approximately 3 months. In this example the pellet effectiveness is for about 7 to about 9 months.
7 PCT/USO1/17164 Example 4 Multi Layer Neurotoxin Controlled Release Implant By utilizing multiple layers - high density polymer/ low density polymer s w/neurotoxin - the temporal extent of the controlled release of a neurotoxin can be increased, but the size of the implant can also increase. As the size of the implant is increased the neurotoxin disperses over a greater area inside of the body, which can decrease the efFectiveness of the implant. In order to avoid this, the implant is encased by a non-permeable material such as io titanium. A small opening is kept to allow for pinpoint release of the neurotoxin through the encased pellet. This effectively can generally allow the implant to have significantly different release characteristics.
Essentially this can also allow for thicker section of polymer the neurotoxin will pass, effectively increasing the duration of the neurotoxin release.
is The inner material can be made from a material such as polyvinylpyrrolidone/methylmethacrylate copolymer. This material allows for sustaining a high concentration of neurotoxin complex. The neurotoxin is complexed with ~n~. The complex is then mixed with uncured copolymer, low 2o temperature initiator and an acid (pH between 5.5 and 6.8). The mixture is placed into a glass or plastic pellet mold. The mold is placed into a temperature controlled water bath at 35 degrees C. for between about 6 and about 8 hours. This forms the reservoir of neurotoxin required for a prolonged controlled release.
In order to prolong the release of the neurotoxin a second material is then cured around the initial pellet. The pellet (above) is placed into a mold (insertion molding) with uncured PMMA/low temperature initiator. A
secondary coating of the uncured PMMA maybe necessary to assure uniform 3o coating of the pellet. Ideally the PMMA thickness is 0.5 mm. To form multiple layers, the same insertion molding technique is applied as described above.

When the last layer of high density polymer is to be applied, a titanium pellet is used as the mold. The pellet is placed inside of the titanium pellet with uncured PMMA. The lid to the pellet is secured and the pellet is placed s into a forced air oven at about 35 degrees C. for about 6 hours to about 8 hours. The lid of the pellet has a 22 gauge opening to allow for release of the neurotoxin. In this example the pellet effectiveness can be for about 10 months to about 24 months.
to Example 5 Neurotoxin Implant With Layered Column In order to sustain release for prolonged periods of time an alternative approach is to place a layers of the - high density polymer/ low density is polymer w/neurotoxin inside of the titanium pellet described above. Curing can be carried out in a forced air oven at about 35 degrees C. for between about 6 hours and about 8 hours for each layer applied. The diameter of the pellet would be key determinant on the amount of neurotoxin applied. The number of layers can determine how long the implant will sustain 2o effectiveness. For each layer the thickness of the PMMA layer can be about 0.5 mm and the low density polymer w/neurotoxin can be about 0.3 mm. For each layer added, an approximately 3-month increase in efFectiveness is obtained. An implant with a 2 year life can be made by increasing the length of the implant to about 6.4 mm plus the size of the titanium shell cross section zs about 1 mm for a total of about 7.4 mm.
Compositions and methods according to the invention disclosed herein has many advantages, including the following:

1. a single implant can be used to provide therapeutically effective continuous or pulsatile administration of a neurotoxin over a period of one year or longer.
s 2. the neurotoxin is delivered to a localized tissue area without a significant amount of neurotoxin appearing systemically.
3. reduced need for patient follow up care.
l0 4. reduced need for periodic injections of neurotoxin to treat a condition, such as a neuromuscular disorder.
5. increased patent comfort due to the reduced number of injections required.
is 6. improved patient compliance.
An advantage of our controlled release formulations for neurotoxins include long term, consistent therapeutic levels of neurotoxin at the target 2o tissue. The advantages also include increased patient compliance and acceptance by reducing the required number of injections.
All references, articles, publications and patents and patent applications cited herein are incorporated by reference in their entireties.
Although the present invention has been described in detail with regard to certain preferred methods, other embodiments, versions, and modifications within the scope of the present invention are possible. For example, a wide variety of neurotoxins can be effectively used in the methods of the present 3o invention. Additionally, the present invention includes local (i.e.

intramuscular, intraglandular, subcutaneous, and intracranial) administration methods wherein two or more neurotoxins, such as two or more botulinum toxins, are administered concurrently or consecutively via implant. For example, botulinum toxin type A can be administered via implant until a loss s of clinical response or neutralizing antibodies develop, followed by administration via implant of a botulinum toxin type B or E. Alternately, a combination of any two or more of the botulinum serotypes A-G can be locally administered to control the onset and duration of the desired therapeutic result. Furthermore, non-neurotoxin compounds can be administered prior to, io concurrently with or subsequent to administration of the neurotoxin via implant so as to provide an adjunct effect such as enhanced or a more rapid onset of denervation before the neurotoxin, such as a botulinum toxin, begins to exert its therapeutic effect.
is Our invention also includes within its scope the use of a neurotoxin, such as a botulinum toxin, in the preparation of a medicament, such as a controlled release implant, for the treatment of a movement disorder, and/or a disorder influenced by cholinergic innervation, by local administration via the implant of the neurotoxin.
Accordingly, the spirit and scope of the following claims should not be limited to the descriptions of the preferred embodiments set forth above.
s2

Claims (15)

We claim:
1. A controlled release system, comprising:
(a) a polymeric matrix, and:
(b) a quantity of botulinum toxin located within the polymeric matrix, wherein fractional amounts of the botulinum toxin can be released from the polymeric matrix over a prolonged period of time without a significant immune system response.
2. The controlled release system of claim 1, wherein botulinum toxin is released from the polymeric matrix in a substantially continuous or monophasic manner.
3. The controlled release system of claim 1, wherein the prolonged period of time during which botulinum toxin is released from the polymeric matrix extends over of time of from about 10 days to about 6 years.
4. The controlled release system of claim 1, wherein the polymeric matrix is comprised of a substance which is substantially non-biodegradable.
5. The, controlled release system of claim 1, wherein the botulinum toxin is a botulinum toxin selected from the group consisting of botulinum toxin types A, B, C1, D, E, F and G.
6. The controlled release system of claim 1, wherein the botulinum toxin is a botulinum toxin type A.
7. The controlled release system of claim 1, wherein the polymer which comprises the polymeric matrix is selected from the group consisting of methacrylate, vinyl pyrrolidone, vinyl alcohol, acrylic acid, polymethylmethacrylate, siloxane, vinyl acetate, lactic acid, glycolic acid, collagen, and bioceramic polymers and copolymers thereof.
8. The controlled release system of claim 1, wherein the quantity of the botulinum toxin is between about 1 unit and about 50,000 units of a botulinum toxin.
9. The controlled release system of claim 1, wherein the quantity of the botulinum toxin is between about 10 units and about 2,000 units of a botulinum toxin type A.
10. The controlled release system of claim 1, wherein the quantity of the botulinum toxin is between about 100 units and about 30,000 units of a botulinum toxin type B.
11. The controlled release system of claim 1 wherein the botulinum toxin is released in an amount effective to cause flaccid muscular paralysis of a muscle or muscle group at or in the vicinity of the implanted system.
12. A controlled release system, comprising:
(a) a polymeric matrix, and;
(b) between about 10 units and about 20,000 units of a botulinum toxin within the polymeric matrix, wherein fractional amounts of the botulinum toxin can be released from the polymeric matrix over a prolonged period of time extending from about 2 months to about 5 years without a significant immune system response.
13. A method for making a controlled release system, the method comprising the steps of:
(a) dissolving a polymer in a solvent to form a polymer solution;
(b) mixing or dispersing a botulinum toxin in the polymer solution to form a polymer-botulinum toxin mixture, and;
(c) allowing the polymer-botulinum toxin mixture to set or cure, thereby making a controlled release system from which fractional amounts of the botulinum toxin can be released over a prolonged period of time without a significant immune system response.
14. The method of claim 13, further comprising the step after the mixing step of evaporating solvent.
15. Use af a continuous release system which includes a polymeric matrix and a botulinum toxin in the manufacture of a medicament for treating a movement disorder without a significant immune system response.
CA002411277A 2000-06-02 2001-05-25 Neurotoxin implant Expired - Fee Related CA2411277C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US09/587,250 2000-06-02
US09/587,250 US6306423B1 (en) 2000-06-02 2000-06-02 Neurotoxin implant
PCT/US2001/017164 WO2001093827A2 (en) 2000-06-02 2001-05-25 Neurotoxin implant

Publications (2)

Publication Number Publication Date
CA2411277A1 CA2411277A1 (en) 2001-12-13
CA2411277C true CA2411277C (en) 2007-07-24

Family

ID=24349017

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002411277A Expired - Fee Related CA2411277C (en) 2000-06-02 2001-05-25 Neurotoxin implant

Country Status (15)

Country Link
US (5) US6306423B1 (en)
EP (2) EP1655023A1 (en)
JP (2) JP2003535117A (en)
KR (1) KR100732810B1 (en)
CN (1) CN100536915C (en)
AR (1) AR028669A1 (en)
AT (1) ATE322251T1 (en)
AU (3) AU2001265043A1 (en)
BR (1) BR0111300A (en)
CA (1) CA2411277C (en)
DE (1) DE60118550T2 (en)
ES (1) ES2259665T3 (en)
NZ (1) NZ522611A (en)
TW (1) TWI250020B (en)
WO (2) WO2001093890A2 (en)

Families Citing this family (566)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6974578B1 (en) * 1993-12-28 2005-12-13 Allergan, Inc. Method for treating secretions and glands using botulinum toxin
US7455845B2 (en) * 1997-07-15 2008-11-25 The Regents Of The University Of Colorado Use of neurotoxin therapy for treatment of urologic and related disorders related to lowering elevated bladder pressure
ES2256945T5 (en) * 1997-07-15 2010-03-26 The Regents Of The University Of Colorado USE OF NEUROTOXIN THERAPY FOR THE TREATMENT OF LA PROSTATA DISORDERS.
US7449192B2 (en) 1997-07-15 2008-11-11 The Regents Of The University Of Colorado Use of neurotoxin therapy for treatment of urologic and related disorders related to neurogenic bladder dysfunction
US7470431B2 (en) * 1997-07-15 2008-12-30 The Regents Of The University Of Colorado Use of neurotoxin therapy for treatment of urological-neurological disorders associated with prostate cancer
US9066943B2 (en) * 1997-07-15 2015-06-30 The Regents Of The University Of Colorado Use of botulinum toxin therapy for treatment of urological neurological conditions
US20060216313A1 (en) 1999-08-10 2006-09-28 Allergan, Inc. Methods for treating a stricture with a botulinum toxin
US6767544B2 (en) * 2002-04-01 2004-07-27 Allergan, Inc. Methods for treating cardiovascular diseases with botulinum toxin
US7838008B2 (en) 1999-12-07 2010-11-23 Allergan, Inc. Methods for treating diverse cancers
US7838007B2 (en) * 1999-12-07 2010-11-23 Allergan, Inc. Methods for treating mammary gland disorders
US7780967B2 (en) * 2000-02-08 2010-08-24 Allergan, Inc. Reduced toxicity Clostridial toxin pharmaceutical compositions
US6306423B1 (en) * 2000-06-02 2001-10-23 Allergan Sales, Inc. Neurotoxin implant
US20040170665A1 (en) * 2000-06-02 2004-09-02 Allergan, Inc. Intravitreal botulinum toxin implant
US20050214327A1 (en) * 2000-06-02 2005-09-29 Allergan, Inc. Neurotoxin-containing suppositories and related methods
US20040033241A1 (en) * 2000-06-02 2004-02-19 Allergan, Inc. Controlled release botulinum toxin system
US6306403B1 (en) * 2000-06-14 2001-10-23 Allergan Sales, Inc. Method for treating parkinson's disease with a botulinum toxin
US6692759B1 (en) * 2000-06-28 2004-02-17 The Regents Of The University Of California Methods for preparing and using implantable substance delivery devices
WO2002007773A2 (en) * 2000-07-21 2002-01-31 Essentia Biosystems, Inc. Multi-component biological transport systems
US20040219619A1 (en) * 2000-07-21 2004-11-04 Ester Fernandez-Salas Methods of identifying compounds that alter toxin persistence and/or protease activity
US7691983B2 (en) 2000-07-21 2010-04-06 Allergan, Inc. Chimera botulinum toxin type E
US6903187B1 (en) * 2000-07-21 2005-06-07 Allergan, Inc. Leucine-based motif and clostridial neurotoxins
US20040220100A1 (en) * 2000-07-21 2004-11-04 Essentia Biosystems, Inc. Multi-component biological transport systems
US7491799B2 (en) * 2000-07-21 2009-02-17 Allergan, Inc. Modified botulinum neurotoxins
US7273722B2 (en) * 2000-11-29 2007-09-25 Allergan, Inc. Neurotoxins with enhanced target specificity
US20020086036A1 (en) 2000-12-05 2002-07-04 Allergan Sales, Inc. Methods for treating hyperhidrosis
GB0100761D0 (en) 2001-01-11 2001-02-21 Biocompatibles Ltd Drug delivery from stents
JP4707254B2 (en) * 2001-04-24 2011-06-22 クミアイ化学工業株式会社 Granular composition and method for producing the same
US6887857B2 (en) * 2001-04-27 2005-05-03 Scimed Life Systems, Inc. Microparticle protection of therapeutic agents
US7592016B2 (en) * 2001-06-28 2009-09-22 Regents Of The University Of California Methods for preparing and using implantable substance delivery devices
US20100104631A1 (en) * 2001-08-13 2010-04-29 Lipella Pharmaceuticals Inc. Method of treatment for bladder dysfunction
CN102349914B (en) 2001-11-15 2015-01-28 微观藻类公司 Pharmaceutical compositions containing 3, 4-propinoperhydropurines and uses thereof for blocking neuronal transmission
US7763663B2 (en) * 2001-12-19 2010-07-27 University Of Massachusetts Polysaccharide-containing block copolymer particles and uses thereof
AU2002360712A1 (en) * 2001-12-21 2003-07-30 The Trustees Of Columbia University In The City Of New York C3 exoenzyme-coated stents and uses thereof for treating and preventing restenosis
US7140371B2 (en) * 2002-03-14 2006-11-28 Allergan, Inc. Surface topography method for determining effects of a botulinum toxin upon a muscle and for comparing botulinum toxins
US8145317B2 (en) 2002-04-08 2012-03-27 Ardian, Inc. Methods for renal neuromodulation
US8150520B2 (en) 2002-04-08 2012-04-03 Ardian, Inc. Methods for catheter-based renal denervation
US7162303B2 (en) 2002-04-08 2007-01-09 Ardian, Inc. Renal nerve stimulation method and apparatus for treatment of patients
US8145316B2 (en) 2002-04-08 2012-03-27 Ardian, Inc. Methods and apparatus for renal neuromodulation
US20080213331A1 (en) 2002-04-08 2008-09-04 Ardian, Inc. Methods and devices for renal nerve blocking
US8774922B2 (en) 2002-04-08 2014-07-08 Medtronic Ardian Luxembourg S.A.R.L. Catheter apparatuses having expandable balloons for renal neuromodulation and associated systems and methods
US6978174B2 (en) 2002-04-08 2005-12-20 Ardian, Inc. Methods and devices for renal nerve blocking
US8131371B2 (en) 2002-04-08 2012-03-06 Ardian, Inc. Methods and apparatus for monopolar renal neuromodulation
US9308043B2 (en) 2002-04-08 2016-04-12 Medtronic Ardian Luxembourg S.A.R.L. Methods for monopolar renal neuromodulation
US20140018880A1 (en) 2002-04-08 2014-01-16 Medtronic Ardian Luxembourg S.A.R.L. Methods for monopolar renal neuromodulation
US8347891B2 (en) 2002-04-08 2013-01-08 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for performing a non-continuous circumferential treatment of a body lumen
US7756583B2 (en) 2002-04-08 2010-07-13 Ardian, Inc. Methods and apparatus for intravascularly-induced neuromodulation
US20070129761A1 (en) 2002-04-08 2007-06-07 Ardian, Inc. Methods for treating heart arrhythmia
US9636174B2 (en) 2002-04-08 2017-05-02 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation
US7653438B2 (en) 2002-04-08 2010-01-26 Ardian, Inc. Methods and apparatus for renal neuromodulation
US8150519B2 (en) 2002-04-08 2012-04-03 Ardian, Inc. Methods and apparatus for bilateral renal neuromodulation
US7620451B2 (en) 2005-12-29 2009-11-17 Ardian, Inc. Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach
US7617005B2 (en) 2002-04-08 2009-11-10 Ardian, Inc. Methods and apparatus for thermally-induced renal neuromodulation
US7853333B2 (en) 2002-04-08 2010-12-14 Ardian, Inc. Methods and apparatus for multi-vessel renal neuromodulation
US8774913B2 (en) 2002-04-08 2014-07-08 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for intravasculary-induced neuromodulation
US20070135875A1 (en) 2002-04-08 2007-06-14 Ardian, Inc. Methods and apparatus for thermally-induced renal neuromodulation
US9308044B2 (en) 2002-04-08 2016-04-12 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation
US6921538B2 (en) * 2002-05-10 2005-07-26 Allergan, Inc. Therapeutic treatments for neuropsychiatric disorders
US7691394B2 (en) * 2002-05-28 2010-04-06 Botulinum Toxin Research Associates, Inc. High-potency botulinum toxin formulations
AU2003237346A1 (en) * 2002-05-31 2003-12-19 Thomas Jefferson University Compositions and methods for transepithelial molecular transport
AU2003231878A1 (en) * 2002-05-31 2003-12-19 Solux Corporation Pharmaceutical preparation of botulinum neurotoxin, methods of synthesis and methods of clinical use
US6776991B2 (en) * 2002-06-26 2004-08-17 Allergan, Inc. Methods for treating priapism
US20040009180A1 (en) * 2002-07-11 2004-01-15 Allergan, Inc. Transdermal botulinum toxin compositions
WO2004010934A2 (en) * 2002-07-29 2004-02-05 Rajiv Doshi Methods for the use of neurotoxin in the treatment of urologic disorders
DE10235556A1 (en) * 2002-08-03 2004-02-19 Hf Arzneimittelforschung Gmbh Medicament for treating substance cravings, especially alcohol and/or tobacco abuse, comprising separate dosage forms for continuous release of nicotinic receptor modulator and rapid delivery of galanthamine
CA2495582C (en) 2002-08-13 2016-07-12 Medical Instill Technologies, Inc. Container and valve assembly for storing and dispensing substances, and related method
KR20050061541A (en) * 2002-10-15 2005-06-22 알러간, 인코포레이티드 Botulinum toxin dental therapies and procedures
USD650067S1 (en) 2002-10-16 2011-12-06 Medical Instill Technologies, Inc. Dispenser
WO2004034888A2 (en) * 2002-10-18 2004-04-29 Ellis Charles N Method for rating severity of psoriasis
US20040086532A1 (en) * 2002-11-05 2004-05-06 Allergan, Inc., Botulinum toxin formulations for oral administration
US7238357B2 (en) * 2002-11-05 2007-07-03 Allergan, Inc. Methods for treating ulcers and gastroesophageal reflux disease
ATE426408T1 (en) * 2002-12-20 2009-04-15 Botulinum Toxin Res Ass Inc PHARMACEUTICAL COMPOSITIONS CONTAINING BOTULINUM TOXIN AND HUMAN SERUM ALBUMINE
US7167750B2 (en) 2003-02-03 2007-01-23 Enteromedics, Inc. Obesity treatment with electrically induced vagal down regulation
US20040172084A1 (en) 2003-02-03 2004-09-02 Knudson Mark B. Method and apparatus for treatment of gastro-esophageal reflux disease (GERD)
US7844338B2 (en) 2003-02-03 2010-11-30 Enteromedics Inc. High frequency obesity treatment
US7613515B2 (en) 2003-02-03 2009-11-03 Enteromedics Inc. High frequency vagal blockage therapy
US8071550B2 (en) * 2003-03-03 2011-12-06 Allergan, Inc. Methods for treating uterine disorders
EP1599221B1 (en) * 2003-03-06 2011-12-28 Botulinum Toxin Research Associates, Inc. Treatment of sinusitis related chronic facial pain and headache with botulinum toxin
WO2004108792A2 (en) * 2003-04-10 2004-12-16 Vinod Chintamani Malshe Novel biodegradable aliphatic polyesters and pharmaceutical compositions and applications thereof
US20070207211A1 (en) * 2003-04-10 2007-09-06 Pr Pharmaceuticals, Inc. Emulsion-based microparticles and methods for the production thereof
WO2005003180A2 (en) * 2003-04-10 2005-01-13 Pr Pharmaceuticals A method for the production of emulsion-based micro particles
US7396535B2 (en) * 2003-04-25 2008-07-08 Ackerman Alan H Therapy for obsessive compulsive head banging
US7393538B2 (en) * 2003-04-25 2008-07-01 Ackerman Alan H Clostridial toxin treatment for dermatillomania
US7393537B2 (en) * 2003-04-25 2008-07-01 Allergan, Inc. Botulinum toxin for treatment of obsessive compulsive finger biting disorder
US7422753B2 (en) * 2003-04-25 2008-09-09 Allergan, Inc. Methods for treating trichotillomania
US7390496B2 (en) * 2003-04-25 2008-06-24 Allergan, Inc. Therapeutic treatments for repetitive hand washing
WO2004096113A2 (en) 2003-04-28 2004-11-11 Medical Instill Technologies, Inc. Container with valve assembly for filling and dispensing substances, and apparatus and method for filling
US6838434B2 (en) * 2003-05-02 2005-01-04 Allergan, Inc. Methods for treating sinus headache
US7279174B2 (en) * 2003-05-08 2007-10-09 Advanced Cardiovascular Systems, Inc. Stent coatings comprising hydrophilic additives
EP1636091A2 (en) * 2003-05-12 2006-03-22 Medical Instill Technologies, Inc. Dispenser and apparatus for filling a dispenser
US20040226556A1 (en) * 2003-05-13 2004-11-18 Deem Mark E. Apparatus for treating asthma using neurotoxin
US7220422B2 (en) * 2003-05-20 2007-05-22 Allergan, Inc. Methods and compositions for treating eye disorders
US9060770B2 (en) 2003-05-20 2015-06-23 Ethicon Endo-Surgery, Inc. Robotically-driven surgical instrument with E-beam driver
US20070084897A1 (en) 2003-05-20 2007-04-19 Shelton Frederick E Iv Articulating surgical stapling instrument incorporating a two-piece e-beam firing mechanism
WO2004105485A2 (en) 2003-05-30 2004-12-09 Nederlandse Organisatie Voor Toegepast-Natuurwet Enschappelijk Onderzoek Tno Inducible release vehicles
US20040253274A1 (en) * 2003-06-11 2004-12-16 Allergan, Inc. Use of a clostridial toxin to reduce appetite
NL1023720C2 (en) * 2003-06-23 2004-12-28 Univ Eindhoven Tech Method for changing the transport properties of a material, method for releasing a drug from an implant, as well as implant with drug.
CN1568999A (en) * 2003-07-14 2005-01-26 南宁枫叶药业有限公司 Stable freeze dried formulation of spheroidine for medical use
BRPI0412059A (en) * 2003-07-15 2006-09-05 Pr Pharmaceuticals Inc Method for preparing controlled release formulation
US20050013850A1 (en) * 2003-07-15 2005-01-20 Caers Jan K. Device to assist hyperhydrosis therapy
US7226231B2 (en) 2003-07-17 2007-06-05 Medical Instill Technologies, Inc. Piston-type dispenser with one-way valve for storing and dispensing metered amounts of substances
EP2444069B1 (en) * 2003-07-23 2019-06-05 Evonik Corporation Controlled release compositions
US8734810B2 (en) * 2003-10-29 2014-05-27 Allergan, Inc. Botulinum toxin treatments of neurological and neuropsychiatric disorders
US7172764B2 (en) * 2003-11-17 2007-02-06 Allergan, Inc. Rescue agents for treating botulinum toxin intoxications
GB0328060D0 (en) * 2003-12-04 2004-01-07 Sod Conseils Rech Applic Botulinum toxin treatment
US8048423B2 (en) * 2003-12-09 2011-11-01 Allergan, Inc. Botulinum toxin therapy for skin disorders
US8871224B2 (en) 2003-12-09 2014-10-28 Allergan, Inc. Botulinum toxin therapy for skin disorders
US20050129677A1 (en) * 2003-12-10 2005-06-16 Shengwen Li Lipid rafts and clostridial toxins
US7845517B2 (en) * 2003-12-10 2010-12-07 Medical Instill Technologies Inc. Container and one-way valve assembly for storing and dispensing substances, and related method
US20050148935A1 (en) * 2003-12-29 2005-07-07 Rozalina Dimitrova Botulinum toxin injection guide
US7270287B2 (en) * 2004-01-06 2007-09-18 Allergan, Inc. Botulinum toxin treatment for kinesia
US6974579B2 (en) * 2004-01-08 2005-12-13 Allergan, Inc. Methods for treating vascular disorders
US7264142B2 (en) 2004-01-27 2007-09-04 Medical Instill Technologies, Inc. Dispenser having variable-volume storage chamber and depressible one-way valve assembly for dispensing creams and other substances
US20050191321A1 (en) 2004-02-26 2005-09-01 Allergan, Inc. Methods for treating headache
US20100266638A1 (en) 2004-02-26 2010-10-21 Allergan, Inc. Headache treatment method
US9078892B2 (en) * 2004-02-26 2015-07-14 Allergan, Inc. Methods for treating pain and for treating a medication overuse disorder
PT2985039T (en) 2004-03-03 2018-11-09 Revance Therapeutics Inc Topical application and transdermal delivery of botulinum toxins
US9211248B2 (en) 2004-03-03 2015-12-15 Revance Therapeutics, Inc. Compositions and methods for topical application and transdermal delivery of botulinum toxins
BRPI0508440A (en) 2004-03-03 2007-07-24 Revance Therapeutics Inc compositions and methods for topical diagnosis and therapeutic transport
US20050220821A1 (en) * 2004-03-31 2005-10-06 Allergan, Inc. Pressure sore treatment
US20050220734A1 (en) * 2004-04-02 2005-10-06 Allergan, Inc. Therapy for melanin related afflictions
US7691381B2 (en) * 2004-04-15 2010-04-06 Allergan, Inc. Stabilized biodegradable neurotoxin implants
AU2011253655B2 (en) * 2004-04-15 2013-09-05 Allergan, Inc. Stabilized biodegradable neurotoxin implants
TW200603843A (en) * 2004-04-20 2006-02-01 Technology Dev Company Ltd Tissue enhancement implant and method
EP1802250A4 (en) * 2004-05-07 2008-07-02 Phytotox Ltd Methods of treating wounds with gonyautoxins
US8377951B2 (en) * 2004-05-07 2013-02-19 Phytotox Limited Transdermal administration of phycotoxins
US6991789B2 (en) * 2004-06-29 2006-01-31 Allergas, Inc. Methods of modulating intracellular degradation rates of toxins
GB2416122A (en) * 2004-07-12 2006-01-18 Ipsen Ltd Botulinum neurotoxin composition
WO2006130161A2 (en) * 2004-07-21 2006-12-07 The Cornell Research Foundation, Inc. Therapeutic compounds derived from spider venom and their method of use
US11890012B2 (en) 2004-07-28 2024-02-06 Cilag Gmbh International Staple cartridge comprising cartridge body and attached support
US20060024794A1 (en) * 2004-07-30 2006-02-02 Shengwen Li Novel methods for production of di-chain botulinum toxin
US20060024331A1 (en) * 2004-08-02 2006-02-02 Ester Fernandez-Salas Toxin compounds with enhanced membrane translocation characteristics
PT1781264E (en) 2004-08-04 2013-10-16 Evonik Corp Methods for manufacturing delivery devices and devices thereof
US20060034891A1 (en) * 2004-08-12 2006-02-16 Laurie Lawin Biodegradable controlled release bioactive agent delivery device
US7179474B2 (en) * 2004-09-03 2007-02-20 Allergan, Inc. Methods for treating a buttock deformity
US7429386B2 (en) * 2004-09-03 2008-09-30 Allergan, Inc. Stretch mark treatment
US9011831B2 (en) * 2004-09-30 2015-04-21 Advanced Cardiovascular Systems, Inc. Methacrylate copolymers for medical devices
US20060073208A1 (en) * 2004-10-01 2006-04-06 Allergan, Inc. Cosmetic neurotoxin compositions and methods
US8221397B2 (en) 2004-10-15 2012-07-17 Baxano, Inc. Devices and methods for tissue modification
US7918849B2 (en) 2004-10-15 2011-04-05 Baxano, Inc. Devices and methods for tissue access
US8048080B2 (en) * 2004-10-15 2011-11-01 Baxano, Inc. Flexible tissue rasp
US7738969B2 (en) 2004-10-15 2010-06-15 Baxano, Inc. Devices and methods for selective surgical removal of tissue
US8617163B2 (en) 2004-10-15 2013-12-31 Baxano Surgical, Inc. Methods, systems and devices for carpal tunnel release
US9247952B2 (en) 2004-10-15 2016-02-02 Amendia, Inc. Devices and methods for tissue access
US7938830B2 (en) 2004-10-15 2011-05-10 Baxano, Inc. Powered tissue modification devices and methods
US9101386B2 (en) 2004-10-15 2015-08-11 Amendia, Inc. Devices and methods for treating tissue
US8257356B2 (en) 2004-10-15 2012-09-04 Baxano, Inc. Guidewire exchange systems to treat spinal stenosis
US8430881B2 (en) 2004-10-15 2013-04-30 Baxano, Inc. Mechanical tissue modification devices and methods
US20080312660A1 (en) * 2007-06-15 2008-12-18 Baxano, Inc. Devices and methods for measuring the space around a nerve root
US7555343B2 (en) 2004-10-15 2009-06-30 Baxano, Inc. Devices and methods for selective surgical removal of tissue
US7887538B2 (en) * 2005-10-15 2011-02-15 Baxano, Inc. Methods and apparatus for tissue modification
US20110190772A1 (en) 2004-10-15 2011-08-04 Vahid Saadat Powered tissue modification devices and methods
US20100331883A1 (en) 2004-10-15 2010-12-30 Schmitz Gregory P Access and tissue modification systems and methods
US7857813B2 (en) * 2006-08-29 2010-12-28 Baxano, Inc. Tissue access guidewire system and method
US7578819B2 (en) 2005-05-16 2009-08-25 Baxano, Inc. Spinal access and neural localization
US20080103504A1 (en) * 2006-10-30 2008-05-01 Schmitz Gregory P Percutaneous spinal stenosis treatment
US20070213734A1 (en) * 2006-03-13 2007-09-13 Bleich Jeffery L Tissue modification barrier devices and methods
US8062300B2 (en) 2006-05-04 2011-11-22 Baxano, Inc. Tissue removal with at least partially flexible devices
US7897147B2 (en) * 2004-10-20 2011-03-01 Allergan, Inc. Treatment of premenstrual disorders
US7937143B2 (en) 2004-11-02 2011-05-03 Ardian, Inc. Methods and apparatus for inducing controlled renal neuromodulation
US7637400B2 (en) * 2004-12-10 2009-12-29 Medical Instill Technologies, Inc. Container and valve assembly for storing and dispensing substances, and related method
FR2879462B1 (en) * 2004-12-21 2008-12-26 Sod Conseils Rech Applic USE OF BOTULINUM TOXIN FOR PROLONGED LOCAL INSENSITION
US8192979B2 (en) * 2005-01-03 2012-06-05 Botulinum Toxin Research Associates, Inc. Compositions, methods and devices for preparing less painful Botulinum toxin formulations
US7749515B2 (en) * 2005-02-01 2010-07-06 Allergan, Inc. Targeted delivery of botulinum toxin to the sphenopalatine ganglion
US7655244B2 (en) 2005-02-01 2010-02-02 Allergan, Inc. Targeted delivery of botulinum toxin for the treatment and prevention of trigeminal autonomic cephalgias, migraine and vascular conditions
US7727537B2 (en) * 2005-02-14 2010-06-01 Dpm Therapeutics Corp. Stabilized compositions for topical administration and methods of making same
US7838011B2 (en) * 2005-02-14 2010-11-23 Pankaj Modi Stabilized protein compositions for topical administration and methods of making same
EP1853622B1 (en) 2005-03-03 2014-07-16 Allergan, Inc. Processes for obtaining a clostridial toxin
SG160357A1 (en) 2005-03-03 2010-04-29 Revance Therapeutics Inc Compositions and methods for topical application and transdermal delivery of botulinum toxins
EP1856139B1 (en) * 2005-03-03 2011-04-27 Revance Therapeutics, Inc. Compositions and methods for topical application and transdermal delivery of an oligopeptide
US7700659B2 (en) * 2005-03-24 2010-04-20 Advanced Cardiovascular Systems, Inc. Implantable devices formed of non-fouling methacrylate or acrylate polymers
US7419675B2 (en) * 2005-05-26 2008-09-02 Allergan, Inc. Method for treating peritoneal adhesions
US8105611B2 (en) 2005-06-17 2012-01-31 Allergan, Inc. Treatment of autoimmune disorder with a neurotoxin
CN101384247B (en) * 2005-07-18 2013-05-22 麻萨诸塞州洛厄尔大学 Compositions and methods for making and using nanoemulsions
US10052465B2 (en) 2005-07-22 2018-08-21 The Foundry, Llc Methods and systems for toxin delivery to the nasal cavity
US7655243B2 (en) 2005-07-22 2010-02-02 The Foundry, Llc Methods and systems for toxin delivery to the nasal cavity
EP1906923B1 (en) * 2005-07-22 2018-01-24 The Foundry, LLC Systems and methods for delivery of a therapeutic agent
US8323666B2 (en) * 2005-08-01 2012-12-04 Allergan, Inc. Botulinum toxin compositions
US7822486B2 (en) 2005-08-17 2010-10-26 Enteromedics Inc. Custom sized neural electrodes
US7672727B2 (en) 2005-08-17 2010-03-02 Enteromedics Inc. Neural electrode treatment
US7910116B2 (en) * 2005-08-24 2011-03-22 Allergan, Inc. Use of a botulinum toxin to improve gastric emptying and/or to treat GERD
US11484312B2 (en) 2005-08-31 2022-11-01 Cilag Gmbh International Staple cartridge comprising a staple driver arrangement
US7934630B2 (en) 2005-08-31 2011-05-03 Ethicon Endo-Surgery, Inc. Staple cartridges for forming staples having differing formed staple heights
US10159482B2 (en) 2005-08-31 2018-12-25 Ethicon Llc Fastener cartridge assembly comprising a fixed anvil and different staple heights
US7669746B2 (en) 2005-08-31 2010-03-02 Ethicon Endo-Surgery, Inc. Staple cartridges for forming staples having differing formed staple heights
US11246590B2 (en) 2005-08-31 2022-02-15 Cilag Gmbh International Staple cartridge including staple drivers having different unfired heights
EP1945234B1 (en) * 2005-09-23 2012-12-19 Gwangju Institute of Science and Technology Composition for preventing or treating arthritis comprising lactic acid bacteria and collangen as active ingredients
AU2013202329B2 (en) * 2005-10-06 2016-04-14 Allergan, Inc. Non-protein stabilized clostridial toxin pharmaceutical compositions
US8137677B2 (en) 2005-10-06 2012-03-20 Allergan, Inc. Non-protein stabilized clostridial toxin pharmaceutical compositions
US8168206B1 (en) 2005-10-06 2012-05-01 Allergan, Inc. Animal protein-free pharmaceutical compositions
US8092456B2 (en) 2005-10-15 2012-01-10 Baxano, Inc. Multiple pathways for spinal nerve root decompression from a single access point
US8366712B2 (en) 2005-10-15 2013-02-05 Baxano, Inc. Multiple pathways for spinal nerve root decompression from a single access point
US8062298B2 (en) 2005-10-15 2011-11-22 Baxano, Inc. Flexible tissue removal devices and methods
US20070106317A1 (en) 2005-11-09 2007-05-10 Shelton Frederick E Iv Hydraulically and electrically actuated articulation joints for surgical instruments
NZ568216A (en) * 2005-11-17 2012-09-28 Revance Therapeutics Inc Compositions and methods of topical application and transdermal delivery of botulinum toxins with reduced non-toxin proteins
US9486408B2 (en) 2005-12-01 2016-11-08 University Of Massachusetts Lowell Botulinum nanoemulsions
HUE054852T2 (en) 2005-12-01 2021-10-28 Univ Massachusetts Lowell Botulinum nanoemulsions
WO2007130134A2 (en) * 2005-12-02 2007-11-15 (Osi) Eyetech, Inc. Controlled release microparticles
US7824694B2 (en) * 2006-01-12 2010-11-02 Allergan, Inc. Methods for enhancing therapeutic effects of a neurotoxin
US20070178121A1 (en) * 2006-01-27 2007-08-02 Allergan, Inc. Methods for enhancing skin treatments
US11793518B2 (en) 2006-01-31 2023-10-24 Cilag Gmbh International Powered surgical instruments with firing system lockout arrangements
US7753904B2 (en) 2006-01-31 2010-07-13 Ethicon Endo-Surgery, Inc. Endoscopic surgical instrument with a handle that can articulate with respect to the shaft
US8708213B2 (en) 2006-01-31 2014-04-29 Ethicon Endo-Surgery, Inc. Surgical instrument having a feedback system
US20120292367A1 (en) 2006-01-31 2012-11-22 Ethicon Endo-Surgery, Inc. Robotically-controlled end effector
US8820603B2 (en) 2006-01-31 2014-09-02 Ethicon Endo-Surgery, Inc. Accessing data stored in a memory of a surgical instrument
US7756524B1 (en) 2006-01-31 2010-07-13 Nextel Communications Inc. System and method for partially count-based allocation of vocoder resources
US8186555B2 (en) 2006-01-31 2012-05-29 Ethicon Endo-Surgery, Inc. Motor-driven surgical cutting and fastening instrument with mechanical closure system
US7845537B2 (en) 2006-01-31 2010-12-07 Ethicon Endo-Surgery, Inc. Surgical instrument having recording capabilities
US11224427B2 (en) 2006-01-31 2022-01-18 Cilag Gmbh International Surgical stapling system including a console and retraction assembly
US11278279B2 (en) 2006-01-31 2022-03-22 Cilag Gmbh International Surgical instrument assembly
US20110290856A1 (en) 2006-01-31 2011-12-01 Ethicon Endo-Surgery, Inc. Robotically-controlled surgical instrument with force-feedback capabilities
US20070178138A1 (en) * 2006-02-01 2007-08-02 Allergan, Inc. Biodegradable non-opthalmic implants and related methods
US7794386B2 (en) 2006-03-15 2010-09-14 Allergan, Inc. Methods for facilitating weight loss
US8992422B2 (en) 2006-03-23 2015-03-31 Ethicon Endo-Surgery, Inc. Robotically-controlled endoscopic accessory channel
EP2013113B1 (en) 2006-04-24 2018-03-21 Medical Instill Technologies, Inc. Needle penetrable and resealable lyophilization device and related method
US7811586B2 (en) * 2006-05-02 2010-10-12 Allergan, Inc. Methods for alleviating testicular pain
CN101074935B (en) * 2006-05-19 2011-03-23 清华大学 Detector array and its apparatus
US20080095918A1 (en) * 2006-06-14 2008-04-24 Kleiner Lothar W Coating construct with enhanced interfacial compatibility
US8322455B2 (en) 2006-06-27 2012-12-04 Ethicon Endo-Surgery, Inc. Manually driven surgical cutting and fastening instrument
AR061669A1 (en) * 2006-06-29 2008-09-10 Merz Pharma Gmbh & Co Kgaa HIGH FREQUENCY THERAPY APPLICATION WITH BOTULIN TOXIN
US10792344B2 (en) 2006-06-29 2020-10-06 Merz Pharma Gmbh & Co. Kgaa High frequency application of botulinum toxin therapy
US8956640B2 (en) * 2006-06-29 2015-02-17 Advanced Cardiovascular Systems, Inc. Block copolymers including a methoxyethyl methacrylate midblock
US20080008736A1 (en) * 2006-07-06 2008-01-10 Thierry Glauser Random copolymers of methacrylates and acrylates
US20080075777A1 (en) * 2006-07-31 2008-03-27 Kennedy Michael T Apparatus and methods for preparing solid particles
US9061025B2 (en) * 2006-08-31 2015-06-23 Allergan, Inc. Methods for selecting headache patients responsive to botulinum toxin therapy
WO2008079464A2 (en) * 2006-09-08 2008-07-03 Becton, Dickinson And Company Stable powder formulations of alum-adsorbed vaccines
US10568652B2 (en) 2006-09-29 2020-02-25 Ethicon Llc Surgical staples having attached drivers of different heights and stapling instruments for deploying the same
US20080092910A1 (en) * 2006-10-18 2008-04-24 Allergan, Inc. Apparatus and method for treating obesity using neurotoxins in conjunction with bariatric procedures
US20080113051A1 (en) * 2006-11-13 2008-05-15 Allergan, Inc. Methods for alleviating tattoo pain
US7713541B1 (en) * 2006-11-21 2010-05-11 Abbott Cardiovascular Systems Inc. Zwitterionic terpolymers, method of making and use on medical devices
JP5557373B2 (en) * 2006-11-21 2014-07-23 アボット ラボラトリーズ Use of terpolymers of tetrafluoroethylene, hexafluoropropylene, and vinylidene fluoride in drug-eluting coatings
US20080118541A1 (en) * 2006-11-21 2008-05-22 Abbott Laboratories Use of a terpolymer of tetrafluoroethylene, hexafluoropropylene, and vinylidene fluoride in drug eluting coatings on medical devices
KR101518077B1 (en) 2006-12-01 2015-05-28 안테리오스, 인코퍼레이티드 Peptide nanoparticles and uses therefor
KR20090106493A (en) 2006-12-01 2009-10-09 안테리오스, 인코퍼레이티드 Micellar nanoparticles comprising botulinum toxin
US8017141B2 (en) * 2006-12-15 2011-09-13 Advanced Cardiovascular Systems, Inc. Coatings of acrylamide-based copolymers
US20100021502A1 (en) * 2006-12-28 2010-01-28 Waugh Jacob M Compositions and Methods of Topical Application and Transdermal Delivery of Botulinum Toxins Stabililzed with Polypeptide Fragments Derived from HIV-TAT
CN101616682A (en) * 2006-12-29 2009-12-30 雷文斯治疗公司 With the stable botulinal compositions of the polypeptide fragment of derived from hiv-tat and the method for local application and transdermal delivery thereof
CA2672886C (en) * 2006-12-29 2015-02-10 Revance Therapeutics, Inc. Transport molecules using reverse sequence hiv-tat polypeptides
US8684253B2 (en) 2007-01-10 2014-04-01 Ethicon Endo-Surgery, Inc. Surgical instrument with wireless communication between a control unit of a robotic system and remote sensor
US11291441B2 (en) 2007-01-10 2022-04-05 Cilag Gmbh International Surgical instrument with wireless communication between control unit and remote sensor
US8652120B2 (en) 2007-01-10 2014-02-18 Ethicon Endo-Surgery, Inc. Surgical instrument with wireless communication between control unit and sensor transponders
US20080169332A1 (en) 2007-01-11 2008-07-17 Shelton Frederick E Surgical stapling device with a curved cutting member
WO2008101098A2 (en) 2007-02-15 2008-08-21 Allergan, Inc. Use of botulinum toxin and enzymes for treating bladder or prostata disorders, or hyperhydrosis
US20090001130A1 (en) 2007-03-15 2009-01-01 Hess Christopher J Surgical procedure using a cutting and stapling instrument having releasable staple-forming pockets
WO2008151022A2 (en) 2007-05-31 2008-12-11 Anterios, Inc. Nucleic acid nanoparticles and uses therefor
US11857181B2 (en) 2007-06-04 2024-01-02 Cilag Gmbh International Robotically-controlled shaft based rotary drive systems for surgical instruments
US8931682B2 (en) 2007-06-04 2015-01-13 Ethicon Endo-Surgery, Inc. Robotically-controlled shaft based rotary drive systems for surgical instruments
US11849941B2 (en) 2007-06-29 2023-12-26 Cilag Gmbh International Staple cartridge having staple cavities extending at a transverse angle relative to a longitudinal cartridge axis
WO2009032363A1 (en) 2007-09-06 2009-03-12 Baxano, Inc. Method, system and apparatus for neural localization
CN101450035B (en) * 2007-12-07 2010-09-29 福建医科大学附属协和医院 Double sustained release biological agent for tumor local ablation therapy
US8192436B2 (en) 2007-12-07 2012-06-05 Baxano, Inc. Tissue modification devices
US9044477B2 (en) * 2007-12-12 2015-06-02 Allergan, Inc. Botulinum toxin formulation
US8728528B2 (en) 2007-12-20 2014-05-20 Evonik Corporation Process for preparing microparticles having a low residual solvent volume
US8437938B2 (en) * 2008-01-15 2013-05-07 GM Global Technology Operations LLC Axle torque based cruise control
JP5410110B2 (en) 2008-02-14 2014-02-05 エシコン・エンド−サージェリィ・インコーポレイテッド Surgical cutting / fixing instrument with RF electrode
US7819298B2 (en) 2008-02-14 2010-10-26 Ethicon Endo-Surgery, Inc. Surgical stapling apparatus with control features operable with one hand
US7866527B2 (en) 2008-02-14 2011-01-11 Ethicon Endo-Surgery, Inc. Surgical stapling apparatus with interlockable firing system
US8636736B2 (en) 2008-02-14 2014-01-28 Ethicon Endo-Surgery, Inc. Motorized surgical cutting and fastening instrument
US9179912B2 (en) 2008-02-14 2015-11-10 Ethicon Endo-Surgery, Inc. Robotically-controlled motorized surgical cutting and fastening instrument
US8483831B1 (en) 2008-02-15 2013-07-09 Holaira, Inc. System and method for bronchial dilation
US9770245B2 (en) 2008-02-15 2017-09-26 Ethicon Llc Layer arrangements for surgical staple cartridges
US9107815B2 (en) 2008-02-22 2015-08-18 Allergan, Inc. Sustained release poloxamer containing pharmaceutical compositions
US8470337B2 (en) * 2008-03-13 2013-06-25 Allergan, Inc. Therapeutic treatments using botulinum neurotoxin
US8617571B2 (en) 2008-04-03 2013-12-31 Allergan, Inc. Suture line administration technique using botulinum toxin
EP2662046B1 (en) 2008-05-09 2023-03-15 Nuvaira, Inc. Systems and assemblies for treating a bronchial tree
CN105147608B (en) 2008-06-26 2019-12-10 安特里奥公司 Dermal delivery
US9314253B2 (en) 2008-07-01 2016-04-19 Amendia, Inc. Tissue modification devices and methods
US8398641B2 (en) 2008-07-01 2013-03-19 Baxano, Inc. Tissue modification devices and methods
US8409206B2 (en) 2008-07-01 2013-04-02 Baxano, Inc. Tissue modification devices and methods
CA2730732A1 (en) 2008-07-14 2010-01-21 Baxano, Inc. Tissue modification devices
US20100028385A1 (en) * 2008-08-04 2010-02-04 Allergan, Inc. Treatment of excess cerumen secretion
US9005230B2 (en) 2008-09-23 2015-04-14 Ethicon Endo-Surgery, Inc. Motorized surgical instrument
US9386983B2 (en) 2008-09-23 2016-07-12 Ethicon Endo-Surgery, Llc Robotically-controlled motorized surgical instrument
US8210411B2 (en) 2008-09-23 2012-07-03 Ethicon Endo-Surgery, Inc. Motor-driven surgical cutting instrument
US11648005B2 (en) 2008-09-23 2023-05-16 Cilag Gmbh International Robotically-controlled motorized surgical instrument with an end effector
US8608045B2 (en) 2008-10-10 2013-12-17 Ethicon Endo-Sugery, Inc. Powered surgical cutting and stapling apparatus with manually retractable firing system
US9066851B2 (en) 2008-12-04 2015-06-30 Botulinum Toxin Research Associates, Inc. Extended length botulinum toxin formulation for human or mammalian use
WO2010078403A2 (en) * 2008-12-30 2010-07-08 Lipella Pharmaceuticals Inc. Methods and compositions for diagnosing urological disorders
RU2011125775A (en) 2008-12-31 2013-02-10 Реванс Терапьютикс, Инк. COMPOSITIONS BASED ON BOTULOTOXIN FOR INJECTION
US8652129B2 (en) 2008-12-31 2014-02-18 Medtronic Ardian Luxembourg S.A.R.L. Apparatus, systems, and methods for achieving intravascular, thermally-induced renal neuromodulation
JP5582619B2 (en) 2009-03-13 2014-09-03 バクサノ,インク. Flexible nerve position determination device
US8591884B2 (en) 2009-06-24 2013-11-26 CNSS IP Holdings, Inc Compositions and methods for enhancing metal ion dependent drug therapies
US8394102B2 (en) 2009-06-25 2013-03-12 Baxano, Inc. Surgical tools for treatment of spinal stenosis
JP6043627B2 (en) 2009-06-25 2016-12-14 ルバンス セラピュティックス インク.Revance Therapeutics,Inc. Botulinum toxin preparation without albumin
WO2011011497A1 (en) 2009-07-21 2011-01-27 North Richard B Spinal cord stimulation lead anchor
RU2545865C2 (en) * 2009-09-22 2015-04-10 Евоник Корпорейшн Implanted devices with various versions of biologically active ingredient loading
WO2011038015A1 (en) 2009-09-24 2011-03-31 Allergan, Inc. Method of treating osteoporosis with a neurotoxin
CN102639077B (en) 2009-10-27 2015-05-13 赫莱拉公司 Delivery devices with coolable energy emitting assemblies
US20110106076A1 (en) * 2009-11-04 2011-05-05 Gregorio Hernandez Zendejas Myoablation system
US8911439B2 (en) 2009-11-11 2014-12-16 Holaira, Inc. Non-invasive and minimally invasive denervation methods and systems for performing the same
EP4111995A1 (en) 2009-11-11 2023-01-04 Nuvaira, Inc. Device for treating tissue and controlling stenosis
US20110137305A1 (en) * 2009-12-06 2011-06-09 Gregorio Hernandez Zendejas Thermal neuroablator
US8851354B2 (en) 2009-12-24 2014-10-07 Ethicon Endo-Surgery, Inc. Surgical cutting instrument that analyzes tissue thickness
US8825164B2 (en) 2010-06-11 2014-09-02 Enteromedics Inc. Neural modulation devices and methods
US8865220B2 (en) * 2010-06-14 2014-10-21 Kaohsiung Medical University Method for controlled release of parathyroid hormone from encapsulated poly(lactic-glycolic)acid microspheres
US8783543B2 (en) 2010-07-30 2014-07-22 Ethicon Endo-Surgery, Inc. Tissue acquisition arrangements and methods for surgical stapling devices
US8777004B2 (en) 2010-09-30 2014-07-15 Ethicon Endo-Surgery, Inc. Compressible staple cartridge comprising alignment members
US9241714B2 (en) 2011-04-29 2016-01-26 Ethicon Endo-Surgery, Inc. Tissue thickness compensator and method for making the same
US11812965B2 (en) 2010-09-30 2023-11-14 Cilag Gmbh International Layer of material for a surgical end effector
US11925354B2 (en) 2010-09-30 2024-03-12 Cilag Gmbh International Staple cartridge comprising staples positioned within a compressible portion thereof
US9788834B2 (en) 2010-09-30 2017-10-17 Ethicon Llc Layer comprising deployable attachment members
US10945731B2 (en) 2010-09-30 2021-03-16 Ethicon Llc Tissue thickness compensator comprising controlled release and expansion
US9629814B2 (en) 2010-09-30 2017-04-25 Ethicon Endo-Surgery, Llc Tissue thickness compensator configured to redistribute compressive forces
US11298125B2 (en) 2010-09-30 2022-04-12 Cilag Gmbh International Tissue stapler having a thickness compensator
US9320523B2 (en) 2012-03-28 2016-04-26 Ethicon Endo-Surgery, Llc Tissue thickness compensator comprising tissue ingrowth features
US8695866B2 (en) 2010-10-01 2014-04-15 Ethicon Endo-Surgery, Inc. Surgical instrument having a power control circuit
EP2632373B1 (en) 2010-10-25 2018-07-18 Medtronic Ardian Luxembourg S.à.r.l. System for evaluation and feedback of neuromodulation treatment
WO2012103415A1 (en) 2011-01-28 2012-08-02 Allergan, Inc. Dosage regimen for the treatment of multiple disorders with botulinum toxins
JP2014510045A (en) 2011-02-08 2014-04-24 ハロザイム インコーポレイテッド Hyaluronan degrading enzyme composition and lipid preparation and its use for the treatment of benign prostatic hypertrophy
BR112013027794B1 (en) 2011-04-29 2020-12-15 Ethicon Endo-Surgery, Inc CLAMP CARTRIDGE SET
US8697090B2 (en) 2011-05-05 2014-04-15 Allergan, Inc. Method of treating persistent genital arousal disorder with a neurotoxin
US11207064B2 (en) 2011-05-27 2021-12-28 Cilag Gmbh International Automated end effector component reloading system for use with a robotic system
US9072535B2 (en) 2011-05-27 2015-07-07 Ethicon Endo-Surgery, Inc. Surgical stapling instruments with rotatable staple deployment arrangements
WO2013009625A1 (en) 2011-07-08 2013-01-17 Allergan, Inc. Method for treatment of autonomic nervous system disorders
US8992941B2 (en) 2011-07-08 2015-03-31 Allergan, Inc. Method for treatment of esophageal spasm
WO2013010100A1 (en) 2011-07-14 2013-01-17 Allergan, Inc. Methods for treatment of incontinence associated with sexual activity
KR20140082956A (en) 2011-07-20 2014-07-03 알러간, 인코포레이티드 Botulinum toxins for use in a method for treatment of adipose deposits
US9750568B2 (en) 2012-03-08 2017-09-05 Medtronic Ardian Luxembourg S.A.R.L. Ovarian neuromodulation and associated systems and methods
EP3348220A1 (en) 2012-03-08 2018-07-18 Medtronic Ardian Luxembourg S.à.r.l. Biomarker sampling in the context of neuromodulation devices and associated systems
CN104334098B (en) 2012-03-28 2017-03-22 伊西康内外科公司 Tissue thickness compensator comprising capsules defining a low pressure environment
RU2014143258A (en) 2012-03-28 2016-05-20 Этикон Эндо-Серджери, Инк. FABRIC THICKNESS COMPENSATOR CONTAINING MANY LAYERS
US9393291B2 (en) 2012-04-12 2016-07-19 Botulinum Toxin Research Associates, Inc. Use of botulinum toxin for the treatment of cerebrovascular disease, renovascular and retinovascular circulatory beds
US9101358B2 (en) 2012-06-15 2015-08-11 Ethicon Endo-Surgery, Inc. Articulatable surgical instrument comprising a firing drive
BR112014032703B1 (en) * 2012-06-26 2022-04-26 Ethicon Endo-Surgery, Inc Staple cartridge set for use with a surgical stapler
US11202631B2 (en) 2012-06-28 2021-12-21 Cilag Gmbh International Stapling assembly comprising a firing lockout
US20140001231A1 (en) 2012-06-28 2014-01-02 Ethicon Endo-Surgery, Inc. Firing system lockout arrangements for surgical instruments
US9282974B2 (en) 2012-06-28 2016-03-15 Ethicon Endo-Surgery, Llc Empty clip cartridge lockout
US9408606B2 (en) 2012-06-28 2016-08-09 Ethicon Endo-Surgery, Llc Robotically powered surgical device with manually-actuatable reversing system
BR112014032776B1 (en) 2012-06-28 2021-09-08 Ethicon Endo-Surgery, Inc SURGICAL INSTRUMENT SYSTEM AND SURGICAL KIT FOR USE WITH A SURGICAL INSTRUMENT SYSTEM
JP6290201B2 (en) 2012-06-28 2018-03-07 エシコン・エンド−サージェリィ・インコーポレイテッドEthicon Endo−Surgery,Inc. Lockout for empty clip cartridge
US9289256B2 (en) 2012-06-28 2016-03-22 Ethicon Endo-Surgery, Llc Surgical end effectors having angled tissue-contacting surfaces
US9700310B2 (en) 2013-08-23 2017-07-11 Ethicon Llc Firing member retraction devices for powered surgical instruments
US20140110296A1 (en) 2012-10-19 2014-04-24 Medtronic Ardian Luxembourg S.A.R.L. Packaging for Catheter Treatment Devices and Associated Devices, Systems, and Methods
EP2732832A3 (en) 2012-11-14 2015-07-01 Universitair Medisch Centrum Groningen (UMCG) Drug delivery device comprising an active compound and a thermo-sensitive polymeric material
US9398933B2 (en) 2012-12-27 2016-07-26 Holaira, Inc. Methods for improving drug efficacy including a combination of drug administration and nerve modulation
JP6345707B2 (en) 2013-03-01 2018-06-20 エシコン・エンド−サージェリィ・インコーポレイテッドEthicon Endo−Surgery,Inc. Surgical instrument with soft stop
JP6382235B2 (en) 2013-03-01 2018-08-29 エシコン・エンド−サージェリィ・インコーポレイテッドEthicon Endo−Surgery,Inc. Articulatable surgical instrument with a conductive path for signal communication
US9629629B2 (en) 2013-03-14 2017-04-25 Ethicon Endo-Surgey, LLC Control systems for surgical instruments
US20140271717A1 (en) * 2013-03-14 2014-09-18 Kyphon Sarl Devices containing a chemical denervation agent and methods for treating chronic back pain using chemical denervation
US9649110B2 (en) 2013-04-16 2017-05-16 Ethicon Llc Surgical instrument comprising a closing drive and a firing drive operated from the same rotatable output
BR112015026109B1 (en) 2013-04-16 2022-02-22 Ethicon Endo-Surgery, Inc surgical instrument
MX369362B (en) 2013-08-23 2019-11-06 Ethicon Endo Surgery Llc Firing member retraction devices for powered surgical instruments.
US10149893B2 (en) 2013-09-24 2018-12-11 Allergan, Inc. Methods for modifying progression of osteoarthritis
BR112016021943B1 (en) 2014-03-26 2022-06-14 Ethicon Endo-Surgery, Llc SURGICAL INSTRUMENT FOR USE BY AN OPERATOR IN A SURGICAL PROCEDURE
US10013049B2 (en) 2014-03-26 2018-07-03 Ethicon Llc Power management through sleep options of segmented circuit and wake up control
US9980766B1 (en) 2014-03-28 2018-05-29 Medtronic Ardian Luxembourg S.A.R.L. Methods and systems for renal neuromodulation
US10194980B1 (en) 2014-03-28 2019-02-05 Medtronic Ardian Luxembourg S.A.R.L. Methods for catheter-based renal neuromodulation
US10194979B1 (en) 2014-03-28 2019-02-05 Medtronic Ardian Luxembourg S.A.R.L. Methods for catheter-based renal neuromodulation
JP6636452B2 (en) 2014-04-16 2020-01-29 エシコン エルエルシーEthicon LLC Fastener cartridge including extension having different configurations
US20150297223A1 (en) 2014-04-16 2015-10-22 Ethicon Endo-Surgery, Inc. Fastener cartridges including extensions having different configurations
BR112016023807B1 (en) 2014-04-16 2022-07-12 Ethicon Endo-Surgery, Llc CARTRIDGE SET OF FASTENERS FOR USE WITH A SURGICAL INSTRUMENT
CN106456158B (en) 2014-04-16 2019-02-05 伊西康内外科有限责任公司 Fastener cartridge including non-uniform fastener
WO2015183923A1 (en) 2014-05-28 2015-12-03 Allergan, Inc. Methods for reducing the occurrence or preventing formation of bladder calculi
US9901627B2 (en) 2014-07-18 2018-02-27 Revance Therapeutics, Inc. Topical ocular preparation of botulinum toxin for use in ocular surface disease
US11484580B2 (en) 2014-07-18 2022-11-01 Revance Therapeutics, Inc. Topical ocular preparation of botulinum toxin for use in ocular surface disease
US11311294B2 (en) 2014-09-05 2022-04-26 Cilag Gmbh International Powered medical device including measurement of closure state of jaws
US10111679B2 (en) 2014-09-05 2018-10-30 Ethicon Llc Circuitry and sensors for powered medical device
BR112017004361B1 (en) 2014-09-05 2023-04-11 Ethicon Llc ELECTRONIC SYSTEM FOR A SURGICAL INSTRUMENT
AU2015315571A1 (en) 2014-09-12 2017-04-27 Allergan, Inc. Methods for treating osteoarthritis pain
US11523821B2 (en) 2014-09-26 2022-12-13 Cilag Gmbh International Method for creating a flexible staple line
MX2017003960A (en) 2014-09-26 2017-12-04 Ethicon Llc Surgical stapling buttresses and adjunct materials.
US9924944B2 (en) 2014-10-16 2018-03-27 Ethicon Llc Staple cartridge comprising an adjunct material
US10517594B2 (en) 2014-10-29 2019-12-31 Ethicon Llc Cartridge assemblies for surgical staplers
US11141153B2 (en) 2014-10-29 2021-10-12 Cilag Gmbh International Staple cartridges comprising driver arrangements
US9844376B2 (en) 2014-11-06 2017-12-19 Ethicon Llc Staple cartridge comprising a releasable adjunct material
US10736636B2 (en) 2014-12-10 2020-08-11 Ethicon Llc Articulatable surgical instrument system
US10085748B2 (en) 2014-12-18 2018-10-02 Ethicon Llc Locking arrangements for detachable shaft assemblies with articulatable surgical end effectors
US9943309B2 (en) 2014-12-18 2018-04-17 Ethicon Llc Surgical instruments with articulatable end effectors and movable firing beam support arrangements
US9987000B2 (en) 2014-12-18 2018-06-05 Ethicon Llc Surgical instrument assembly comprising a flexible articulation system
US9844375B2 (en) 2014-12-18 2017-12-19 Ethicon Llc Drive arrangements for articulatable surgical instruments
BR112017012996B1 (en) 2014-12-18 2022-11-08 Ethicon Llc SURGICAL INSTRUMENT WITH AN ANvil WHICH IS SELECTIVELY MOVABLE ABOUT AN IMMOVABLE GEOMETRIC AXIS DIFFERENT FROM A STAPLE CARTRIDGE
US9844374B2 (en) 2014-12-18 2017-12-19 Ethicon Llc Surgical instrument systems comprising an articulatable end effector and means for adjusting the firing stroke of a firing member
US11154301B2 (en) 2015-02-27 2021-10-26 Cilag Gmbh International Modular stapling assembly
JP2020121162A (en) 2015-03-06 2020-08-13 エシコン エルエルシーEthicon LLC Time dependent evaluation of sensor data to determine stability element, creep element and viscoelastic element of measurement
US10548504B2 (en) 2015-03-06 2020-02-04 Ethicon Llc Overlaid multi sensor radio frequency (RF) electrode system to measure tissue compression
US9993248B2 (en) 2015-03-06 2018-06-12 Ethicon Endo-Surgery, Llc Smart sensors with local signal processing
WO2016149092A1 (en) 2015-03-13 2016-09-22 Allergan, Inc. Improved injection paradigm for administration of botulinum toxins
US10213201B2 (en) 2015-03-31 2019-02-26 Ethicon Llc Stapling end effector configured to compensate for an uneven gap between a first jaw and a second jaw
US10105139B2 (en) 2015-09-23 2018-10-23 Ethicon Llc Surgical stapler having downstream current-based motor control
US10238386B2 (en) 2015-09-23 2019-03-26 Ethicon Llc Surgical stapler having motor control based on an electrical parameter related to a motor current
US10736633B2 (en) 2015-09-30 2020-08-11 Ethicon Llc Compressible adjunct with looping members
US11890015B2 (en) 2015-09-30 2024-02-06 Cilag Gmbh International Compressible adjunct with crossing spacer fibers
WO2017087677A1 (en) 2015-11-17 2017-05-26 Allergan, Inc. Botulinum toxin administration for treatment of neurogenic detrusor overactivity associated urinary incontinence
US10292704B2 (en) 2015-12-30 2019-05-21 Ethicon Llc Mechanisms for compensating for battery pack failure in powered surgical instruments
US11213293B2 (en) 2016-02-09 2022-01-04 Cilag Gmbh International Articulatable surgical instruments with single articulation link arrangements
JP6911054B2 (en) 2016-02-09 2021-07-28 エシコン エルエルシーEthicon LLC Surgical instruments with asymmetric joint composition
US11224426B2 (en) 2016-02-12 2022-01-18 Cilag Gmbh International Mechanisms for compensating for drivetrain failure in powered surgical instruments
US10448948B2 (en) 2016-02-12 2019-10-22 Ethicon Llc Mechanisms for compensating for drivetrain failure in powered surgical instruments
EP3419652A1 (en) 2016-02-22 2019-01-02 Allergan, Inc. Improved bladder injection paradigm for administration of botulinum toxins
US10828028B2 (en) 2016-04-15 2020-11-10 Ethicon Llc Surgical instrument with multiple program responses during a firing motion
US10357247B2 (en) 2016-04-15 2019-07-23 Ethicon Llc Surgical instrument with multiple program responses during a firing motion
US10426467B2 (en) 2016-04-15 2019-10-01 Ethicon Llc Surgical instrument with detection sensors
US11607239B2 (en) 2016-04-15 2023-03-21 Cilag Gmbh International Systems and methods for controlling a surgical stapling and cutting instrument
US11179150B2 (en) 2016-04-15 2021-11-23 Cilag Gmbh International Systems and methods for controlling a surgical stapling and cutting instrument
US10492783B2 (en) 2016-04-15 2019-12-03 Ethicon, Llc Surgical instrument with improved stop/start control during a firing motion
US10456137B2 (en) 2016-04-15 2019-10-29 Ethicon Llc Staple formation detection mechanisms
US20170296173A1 (en) 2016-04-18 2017-10-19 Ethicon Endo-Surgery, Llc Method for operating a surgical instrument
US11317917B2 (en) 2016-04-18 2022-05-03 Cilag Gmbh International Surgical stapling system comprising a lockable firing assembly
US10433840B2 (en) 2016-04-18 2019-10-08 Ethicon Llc Surgical instrument comprising a replaceable cartridge jaw
US20170342383A1 (en) 2016-05-27 2017-11-30 Corning Incorporated Lithium disilicate glass-ceramic compositions and methods thereof
US10059621B2 (en) 2016-05-27 2018-08-28 Corning Incorporated Magnetizable glass ceramic composition and methods thereof
US10676713B2 (en) 2016-05-27 2020-06-09 Corning Incorporated Bioactive borophosphate glasses
US10751367B2 (en) 2016-05-27 2020-08-25 Corning Incorporated Bioactive glass microspheres
US10647962B2 (en) 2016-05-27 2020-05-12 Corning Incorporated Bioactive aluminoborate glasses
US10925837B2 (en) 2016-08-26 2021-02-23 Akina, Inc. Biodegradable polymer formulations for extended efficacy of botulinum toxin
WO2018038301A1 (en) 2016-08-26 2018-03-01 Hugel Inc. Stabilized liquid formulation of botulinum toxin and preparation method thereof
DK3436054T4 (en) 2016-09-13 2022-08-29 Allergan Inc STABILIZED NON-PROTEIN CLOSTRID TOXIN COMPOSITIONS
WO2018089640A1 (en) 2016-11-10 2018-05-17 Allergan, Inc. Methods for alleviating histamine-independent pruritus using neurotoxins
MX2019005833A (en) 2016-11-21 2019-10-30 Eirion Therapeutics Inc Transdermal delivery of large agents.
US10524789B2 (en) 2016-12-21 2020-01-07 Ethicon Llc Laterally actuatable articulation lock arrangements for locking an end effector of a surgical instrument in an articulated configuration
JP7010956B2 (en) 2016-12-21 2022-01-26 エシコン エルエルシー How to staple tissue
US10980536B2 (en) 2016-12-21 2021-04-20 Ethicon Llc No-cartridge and spent cartridge lockout arrangements for surgical staplers
JP6983893B2 (en) 2016-12-21 2021-12-17 エシコン エルエルシーEthicon LLC Lockout configuration for surgical end effectors and replaceable tool assemblies
US10675026B2 (en) 2016-12-21 2020-06-09 Ethicon Llc Methods of stapling tissue
JP2020501779A (en) 2016-12-21 2020-01-23 エシコン エルエルシーEthicon LLC Surgical stapling system
US10588631B2 (en) 2016-12-21 2020-03-17 Ethicon Llc Surgical instruments with positive jaw opening features
US20180168615A1 (en) 2016-12-21 2018-06-21 Ethicon Endo-Surgery, Llc Method of deforming staples from two different types of staple cartridges with the same surgical stapling instrument
US10588632B2 (en) 2016-12-21 2020-03-17 Ethicon Llc Surgical end effectors and firing members thereof
US11419606B2 (en) 2016-12-21 2022-08-23 Cilag Gmbh International Shaft assembly comprising a clutch configured to adapt the output of a rotary firing member to two different systems
US10675025B2 (en) 2016-12-21 2020-06-09 Ethicon Llc Shaft assembly comprising separately actuatable and retractable systems
BR112019025402A2 (en) 2017-05-31 2020-06-23 Allergan, Inc. BOTULINIC NEUROTOXIN FOR TREATING DISORDERS ASSOCIATED WITH HYPERACTIVITY OF MELANOCYTE AND / OR EXCESS MELANINE
US11517325B2 (en) 2017-06-20 2022-12-06 Cilag Gmbh International Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured displacement distance traveled over a specified time interval
US10779820B2 (en) 2017-06-20 2020-09-22 Ethicon Llc Systems and methods for controlling motor speed according to user input for a surgical instrument
US10881399B2 (en) 2017-06-20 2021-01-05 Ethicon Llc Techniques for adaptive control of motor velocity of a surgical stapling and cutting instrument
US11653914B2 (en) 2017-06-20 2023-05-23 Cilag Gmbh International Systems and methods for controlling motor velocity of a surgical stapling and cutting instrument according to articulation angle of end effector
US11382638B2 (en) 2017-06-20 2022-07-12 Cilag Gmbh International Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified displacement distance
US10307170B2 (en) 2017-06-20 2019-06-04 Ethicon Llc Method for closed loop control of motor velocity of a surgical stapling and cutting instrument
US10993716B2 (en) 2017-06-27 2021-05-04 Ethicon Llc Surgical anvil arrangements
US11324503B2 (en) 2017-06-27 2022-05-10 Cilag Gmbh International Surgical firing member arrangements
US11266405B2 (en) 2017-06-27 2022-03-08 Cilag Gmbh International Surgical anvil manufacturing methods
US11246592B2 (en) 2017-06-28 2022-02-15 Cilag Gmbh International Surgical instrument comprising an articulation system lockable to a frame
US20190000461A1 (en) 2017-06-28 2019-01-03 Ethicon Llc Surgical cutting and fastening devices with pivotable anvil with a tissue locating arrangement in close proximity to an anvil pivot axis
US11058424B2 (en) 2017-06-28 2021-07-13 Cilag Gmbh International Surgical instrument comprising an offset articulation joint
US11564686B2 (en) 2017-06-28 2023-01-31 Cilag Gmbh International Surgical shaft assemblies with flexible interfaces
EP4070740A1 (en) 2017-06-28 2022-10-12 Cilag GmbH International Surgical instrument comprising selectively actuatable rotatable couplers
US10765427B2 (en) 2017-06-28 2020-09-08 Ethicon Llc Method for articulating a surgical instrument
US10932772B2 (en) 2017-06-29 2021-03-02 Ethicon Llc Methods for closed loop velocity control for robotic surgical instrument
US11471155B2 (en) 2017-08-03 2022-10-18 Cilag Gmbh International Surgical system bailout
US11304695B2 (en) 2017-08-03 2022-04-19 Cilag Gmbh International Surgical system shaft interconnection
US11399829B2 (en) 2017-09-29 2022-08-02 Cilag Gmbh International Systems and methods of initiating a power shutdown mode for a surgical instrument
EP3470054B1 (en) 2017-10-11 2023-09-20 Hugel Inc. Microstructure formulation techniques for botulinum toxin
US10525111B2 (en) 2017-10-12 2020-01-07 Hugel, Inc. Microstructure formulation techniques for botulinum toxin
US10792400B2 (en) 2017-10-12 2020-10-06 Hugel Inc. Microstructure formulation techniques for botulinum toxin
US10842490B2 (en) 2017-10-31 2020-11-24 Ethicon Llc Cartridge body design with force reduction based on firing completion
EP3717030A1 (en) 2017-11-28 2020-10-07 Corning Incorporated Bioactive glass compositions and dentin hypersensitivity remediation
WO2019108558A1 (en) 2017-11-28 2019-06-06 Corning Incorporated High liquidus viscosity bioactive glass
CN111417603B (en) 2017-11-28 2023-10-31 康宁股份有限公司 Bioactive borate glass and method thereof
CN111417601A (en) 2017-11-28 2020-07-14 康宁股份有限公司 Chemically strengthened bioactive glass-ceramics
US10779826B2 (en) 2017-12-15 2020-09-22 Ethicon Llc Methods of operating surgical end effectors
US10835330B2 (en) 2017-12-19 2020-11-17 Ethicon Llc Method for determining the position of a rotatable jaw of a surgical instrument attachment assembly
WO2019126542A1 (en) 2017-12-20 2019-06-27 Allergan, Inc. Botulinum toxin cell binding domain polypeptides and methods of use for treatments of fibrosis associated disorders
US11311290B2 (en) 2017-12-21 2022-04-26 Cilag Gmbh International Surgical instrument comprising an end effector dampener
US10682134B2 (en) 2017-12-21 2020-06-16 Ethicon Llc Continuous use self-propelled stapling instrument
JP2021523176A (en) 2018-05-11 2021-09-02 アラーガン、インコーポレイテッドAllergan,Incorporated How to deliver a biopharmaceutical from a topical product
US20210275691A1 (en) 2018-05-30 2021-09-09 Allergan, Inc. Screening assay to assess topical delivery of biological therapeutic agents
TW202019459A (en) 2018-07-05 2020-06-01 愛爾蘭商歐樂根製藥國際有限公司 Combination therapy with cgrp antagonists and clostridial derivatives
US11324501B2 (en) 2018-08-20 2022-05-10 Cilag Gmbh International Surgical stapling devices with improved closure members
MX2021002993A (en) 2018-09-13 2021-08-11 Allergan Inc Methods for treatment of masseter muscle hypertrophy.
EP3660509B1 (en) 2018-11-29 2022-03-09 Hugel Inc. A cell-based method for determining an activity of botulinum toxin
JP2022510007A (en) 2018-12-03 2022-01-25 エイリオン セラピューティクス, インコーポレイテッド Improved delivery of large drugs
US11147553B2 (en) 2019-03-25 2021-10-19 Cilag Gmbh International Firing drive arrangements for surgical systems
US11696761B2 (en) 2019-03-25 2023-07-11 Cilag Gmbh International Firing drive arrangements for surgical systems
US11172929B2 (en) 2019-03-25 2021-11-16 Cilag Gmbh International Articulation drive arrangements for surgical systems
US11452528B2 (en) 2019-04-30 2022-09-27 Cilag Gmbh International Articulation actuators for a surgical instrument
US11432816B2 (en) 2019-04-30 2022-09-06 Cilag Gmbh International Articulation pin for a surgical instrument
US11253254B2 (en) 2019-04-30 2022-02-22 Cilag Gmbh International Shaft rotation actuator on a surgical instrument
US11426251B2 (en) 2019-04-30 2022-08-30 Cilag Gmbh International Articulation directional lights on a surgical instrument
US11648009B2 (en) 2019-04-30 2023-05-16 Cilag Gmbh International Rotatable jaw tip for a surgical instrument
US11471157B2 (en) 2019-04-30 2022-10-18 Cilag Gmbh International Articulation control mapping for a surgical instrument
US11903581B2 (en) 2019-04-30 2024-02-20 Cilag Gmbh International Methods for stapling tissue using a surgical instrument
US11298132B2 (en) 2019-06-28 2022-04-12 Cilag GmbH Inlernational Staple cartridge including a honeycomb extension
US11361176B2 (en) 2019-06-28 2022-06-14 Cilag Gmbh International Surgical RFID assemblies for compatibility detection
US11771419B2 (en) 2019-06-28 2023-10-03 Cilag Gmbh International Packaging for a replaceable component of a surgical stapling system
US11376098B2 (en) 2019-06-28 2022-07-05 Cilag Gmbh International Surgical instrument system comprising an RFID system
US11224497B2 (en) 2019-06-28 2022-01-18 Cilag Gmbh International Surgical systems with multiple RFID tags
US11426167B2 (en) 2019-06-28 2022-08-30 Cilag Gmbh International Mechanisms for proper anvil attachment surgical stapling head assembly
US11241235B2 (en) 2019-06-28 2022-02-08 Cilag Gmbh International Method of using multiple RFID chips with a surgical assembly
US11259803B2 (en) 2019-06-28 2022-03-01 Cilag Gmbh International Surgical stapling system having an information encryption protocol
US11246678B2 (en) 2019-06-28 2022-02-15 Cilag Gmbh International Surgical stapling system having a frangible RFID tag
US11478241B2 (en) 2019-06-28 2022-10-25 Cilag Gmbh International Staple cartridge including projections
US11399837B2 (en) 2019-06-28 2022-08-02 Cilag Gmbh International Mechanisms for motor control adjustments of a motorized surgical instrument
US11627959B2 (en) 2019-06-28 2023-04-18 Cilag Gmbh International Surgical instruments including manual and powered system lockouts
US11853835B2 (en) 2019-06-28 2023-12-26 Cilag Gmbh International RFID identification systems for surgical instruments
US11464601B2 (en) 2019-06-28 2022-10-11 Cilag Gmbh International Surgical instrument comprising an RFID system for tracking a movable component
US11298127B2 (en) 2019-06-28 2022-04-12 Cilag GmbH Interational Surgical stapling system having a lockout mechanism for an incompatible cartridge
US11684434B2 (en) 2019-06-28 2023-06-27 Cilag Gmbh International Surgical RFID assemblies for instrument operational setting control
US11497492B2 (en) 2019-06-28 2022-11-15 Cilag Gmbh International Surgical instrument including an articulation lock
US11553971B2 (en) 2019-06-28 2023-01-17 Cilag Gmbh International Surgical RFID assemblies for display and communication
US11638587B2 (en) 2019-06-28 2023-05-02 Cilag Gmbh International RFID identification systems for surgical instruments
US11523822B2 (en) 2019-06-28 2022-12-13 Cilag Gmbh International Battery pack including a circuit interrupter
US11660163B2 (en) 2019-06-28 2023-05-30 Cilag Gmbh International Surgical system with RFID tags for updating motor assembly parameters
US11291451B2 (en) 2019-06-28 2022-04-05 Cilag Gmbh International Surgical instrument with battery compatibility verification functionality
WO2021005497A1 (en) 2019-07-05 2021-01-14 Allergan Pharmaceuticals International Limited Cgrp antagonists and clostridial derivatives for the treatment of cortical spreading depression associated disorders
WO2021005494A1 (en) 2019-07-05 2021-01-14 Allergan Pharmaceuticals International Limited Cgrp antagonists and clostridial derivatives for the treatment of neuropsychiatric and neurological disorders
CN114258306A (en) 2019-07-05 2022-03-29 阿勒根公司 Methods of treating and inhibiting the development of seizures
US20210130445A1 (en) 2019-07-05 2021-05-06 Allergan Pharmaceuticals International Limited CGRP Antagonists and Botulinum Toxins for the Treatment of Inflammatory and Neurologic Disorders
US11464512B2 (en) 2019-12-19 2022-10-11 Cilag Gmbh International Staple cartridge comprising a curved deck surface
US11304696B2 (en) 2019-12-19 2022-04-19 Cilag Gmbh International Surgical instrument comprising a powered articulation system
US11529139B2 (en) 2019-12-19 2022-12-20 Cilag Gmbh International Motor driven surgical instrument
US11234698B2 (en) 2019-12-19 2022-02-01 Cilag Gmbh International Stapling system comprising a clamp lockout and a firing lockout
US11291447B2 (en) 2019-12-19 2022-04-05 Cilag Gmbh International Stapling instrument comprising independent jaw closing and staple firing systems
US11559304B2 (en) 2019-12-19 2023-01-24 Cilag Gmbh International Surgical instrument comprising a rapid closure mechanism
US11607219B2 (en) 2019-12-19 2023-03-21 Cilag Gmbh International Staple cartridge comprising a detachable tissue cutting knife
US11844520B2 (en) 2019-12-19 2023-12-19 Cilag Gmbh International Staple cartridge comprising driver retention members
US11529137B2 (en) 2019-12-19 2022-12-20 Cilag Gmbh International Staple cartridge comprising driver retention members
US11701111B2 (en) 2019-12-19 2023-07-18 Cilag Gmbh International Method for operating a surgical stapling instrument
US11911032B2 (en) 2019-12-19 2024-02-27 Cilag Gmbh International Staple cartridge comprising a seating cam
US11446029B2 (en) 2019-12-19 2022-09-20 Cilag Gmbh International Staple cartridge comprising projections extending from a curved deck surface
US11504122B2 (en) 2019-12-19 2022-11-22 Cilag Gmbh International Surgical instrument comprising a nested firing member
US11576672B2 (en) 2019-12-19 2023-02-14 Cilag Gmbh International Surgical instrument comprising a closure system including a closure member and an opening member driven by a drive screw
USD975850S1 (en) 2020-06-02 2023-01-17 Cilag Gmbh International Staple cartridge
USD974560S1 (en) 2020-06-02 2023-01-03 Cilag Gmbh International Staple cartridge
USD975278S1 (en) 2020-06-02 2023-01-10 Cilag Gmbh International Staple cartridge
USD966512S1 (en) 2020-06-02 2022-10-11 Cilag Gmbh International Staple cartridge
USD967421S1 (en) 2020-06-02 2022-10-18 Cilag Gmbh International Staple cartridge
USD976401S1 (en) 2020-06-02 2023-01-24 Cilag Gmbh International Staple cartridge
USD975851S1 (en) 2020-06-02 2023-01-17 Cilag Gmbh International Staple cartridge
US20220031351A1 (en) 2020-07-28 2022-02-03 Cilag Gmbh International Surgical instruments with differential articulation joint arrangements for accommodating flexible actuators
USD980425S1 (en) 2020-10-29 2023-03-07 Cilag Gmbh International Surgical instrument assembly
US11534259B2 (en) 2020-10-29 2022-12-27 Cilag Gmbh International Surgical instrument comprising an articulation indicator
USD1013170S1 (en) 2020-10-29 2024-01-30 Cilag Gmbh International Surgical instrument assembly
US11617577B2 (en) 2020-10-29 2023-04-04 Cilag Gmbh International Surgical instrument comprising a sensor configured to sense whether an articulation drive of the surgical instrument is actuatable
US11844518B2 (en) 2020-10-29 2023-12-19 Cilag Gmbh International Method for operating a surgical instrument
US11452526B2 (en) 2020-10-29 2022-09-27 Cilag Gmbh International Surgical instrument comprising a staged voltage regulation start-up system
US11717289B2 (en) 2020-10-29 2023-08-08 Cilag Gmbh International Surgical instrument comprising an indicator which indicates that an articulation drive is actuatable
US11779330B2 (en) 2020-10-29 2023-10-10 Cilag Gmbh International Surgical instrument comprising a jaw alignment system
US11517390B2 (en) 2020-10-29 2022-12-06 Cilag Gmbh International Surgical instrument comprising a limited travel switch
US11896217B2 (en) 2020-10-29 2024-02-13 Cilag Gmbh International Surgical instrument comprising an articulation lock
US11744581B2 (en) 2020-12-02 2023-09-05 Cilag Gmbh International Powered surgical instruments with multi-phase tissue treatment
US11737751B2 (en) 2020-12-02 2023-08-29 Cilag Gmbh International Devices and methods of managing energy dissipated within sterile barriers of surgical instrument housings
US11653920B2 (en) 2020-12-02 2023-05-23 Cilag Gmbh International Powered surgical instruments with communication interfaces through sterile barrier
US11653915B2 (en) 2020-12-02 2023-05-23 Cilag Gmbh International Surgical instruments with sled location detection and adjustment features
US11678882B2 (en) 2020-12-02 2023-06-20 Cilag Gmbh International Surgical instruments with interactive features to remedy incidental sled movements
US11890010B2 (en) 2020-12-02 2024-02-06 Cllag GmbH International Dual-sided reinforced reload for surgical instruments
US11627960B2 (en) 2020-12-02 2023-04-18 Cilag Gmbh International Powered surgical instruments with smart reload with separately attachable exteriorly mounted wiring connections
US11849943B2 (en) 2020-12-02 2023-12-26 Cilag Gmbh International Surgical instrument with cartridge release mechanisms
US11925349B2 (en) 2021-02-26 2024-03-12 Cilag Gmbh International Adjustment to transfer parameters to improve available power
US11723657B2 (en) 2021-02-26 2023-08-15 Cilag Gmbh International Adjustable communication based on available bandwidth and power capacity
US11749877B2 (en) 2021-02-26 2023-09-05 Cilag Gmbh International Stapling instrument comprising a signal antenna
US11696757B2 (en) 2021-02-26 2023-07-11 Cilag Gmbh International Monitoring of internal systems to detect and track cartridge motion status
US11812964B2 (en) 2021-02-26 2023-11-14 Cilag Gmbh International Staple cartridge comprising a power management circuit
US11751869B2 (en) 2021-02-26 2023-09-12 Cilag Gmbh International Monitoring of multiple sensors over time to detect moving characteristics of tissue
US11701113B2 (en) 2021-02-26 2023-07-18 Cilag Gmbh International Stapling instrument comprising a separate power antenna and a data transfer antenna
US11744583B2 (en) 2021-02-26 2023-09-05 Cilag Gmbh International Distal communication array to tune frequency of RF systems
US11730473B2 (en) 2021-02-26 2023-08-22 Cilag Gmbh International Monitoring of manufacturing life-cycle
US11793514B2 (en) 2021-02-26 2023-10-24 Cilag Gmbh International Staple cartridge comprising sensor array which may be embedded in cartridge body
US11717291B2 (en) 2021-03-22 2023-08-08 Cilag Gmbh International Staple cartridge comprising staples configured to apply different tissue compression
US11806011B2 (en) 2021-03-22 2023-11-07 Cilag Gmbh International Stapling instrument comprising tissue compression systems
US11737749B2 (en) 2021-03-22 2023-08-29 Cilag Gmbh International Surgical stapling instrument comprising a retraction system
US11826042B2 (en) 2021-03-22 2023-11-28 Cilag Gmbh International Surgical instrument comprising a firing drive including a selectable leverage mechanism
US11723658B2 (en) 2021-03-22 2023-08-15 Cilag Gmbh International Staple cartridge comprising a firing lockout
US11759202B2 (en) 2021-03-22 2023-09-19 Cilag Gmbh International Staple cartridge comprising an implantable layer
US11826012B2 (en) 2021-03-22 2023-11-28 Cilag Gmbh International Stapling instrument comprising a pulsed motor-driven firing rack
US11786239B2 (en) 2021-03-24 2023-10-17 Cilag Gmbh International Surgical instrument articulation joint arrangements comprising multiple moving linkage features
US11896219B2 (en) 2021-03-24 2024-02-13 Cilag Gmbh International Mating features between drivers and underside of a cartridge deck
US11849945B2 (en) 2021-03-24 2023-12-26 Cilag Gmbh International Rotary-driven surgical stapling assembly comprising eccentrically driven firing member
US11849944B2 (en) 2021-03-24 2023-12-26 Cilag Gmbh International Drivers for fastener cartridge assemblies having rotary drive screws
US11903582B2 (en) 2021-03-24 2024-02-20 Cilag Gmbh International Leveraging surfaces for cartridge installation
US11786243B2 (en) 2021-03-24 2023-10-17 Cilag Gmbh International Firing members having flexible portions for adapting to a load during a surgical firing stroke
US11744603B2 (en) 2021-03-24 2023-09-05 Cilag Gmbh International Multi-axis pivot joints for surgical instruments and methods for manufacturing same
US11793516B2 (en) 2021-03-24 2023-10-24 Cilag Gmbh International Surgical staple cartridge comprising longitudinal support beam
US11896218B2 (en) 2021-03-24 2024-02-13 Cilag Gmbh International Method of using a powered stapling device
US11857183B2 (en) 2021-03-24 2024-01-02 Cilag Gmbh International Stapling assembly components having metal substrates and plastic bodies
US11832816B2 (en) 2021-03-24 2023-12-05 Cilag Gmbh International Surgical stapling assembly comprising nonplanar staples and planar staples
US20220378424A1 (en) 2021-05-28 2022-12-01 Cilag Gmbh International Stapling instrument comprising a firing lockout
US11877745B2 (en) 2021-10-18 2024-01-23 Cilag Gmbh International Surgical stapling assembly having longitudinally-repeating staple leg clusters
WO2023091469A1 (en) * 2021-11-17 2023-05-25 The Board Of Trustees Of The Leland Stanford Junior University Targeting periosteal tissue for delivery of therapeutics

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE634668A (en) 1962-07-11
JPS505801B1 (en) 1964-07-10 1975-03-07
BE744162A (en) 1969-01-16 1970-06-15 Fuji Photo Film Co Ltd ENCAPSULATION PROCESS
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
DE2010115A1 (en) 1970-03-04 1971-09-16 Farbenfabriken Bayer Ag, 5090 Leverkusen Process for the production of micro-granules
US4389330A (en) 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
IE52535B1 (en) 1981-02-16 1987-12-09 Ici Plc Continuous release pharmaceutical compositions
US4474572A (en) 1981-09-29 1984-10-02 Syntex (U.S.A.) Inc. Implanting device and implant magazine
US5019400A (en) 1989-05-01 1991-05-28 Enzytech, Inc. Very low temperature casting of controlled release microspheres
US5401243A (en) 1990-08-21 1995-03-28 Associated Synapse Biologics Controlled administration of chemodenervating pharmaceuticals
US5183462A (en) 1990-08-21 1993-02-02 Associated Synapse Biologics Controlled administration of chemodenervating pharmaceuticals
DK0661989T3 (en) 1992-09-21 1998-03-02 Upjohn Co Prolonged release protein compositions
EP1013270A3 (en) 1992-12-02 2001-03-28 Alkermes Controlled Therapeutics, Inc. Controlled release growth hormone containing microspheres
CA2153781A1 (en) 1993-01-15 1994-07-21 Gary E. Borodic Method for treating myofascial pain syndrome
EP0702561B1 (en) * 1993-06-10 2002-01-09 Allergan, Inc. Treatment of neuromuscular disorders and conditions with botulinum serotyp e
US5902565A (en) 1993-12-24 1999-05-11 Csl Limited Spray dried vaccine preparation comprising aluminium adsorbed immunogens
US5538733A (en) * 1994-07-07 1996-07-23 Willmar Poultry Company, Inc. Method of priming an immune response in a one-day old animal
GB9508204D0 (en) 1995-04-21 1995-06-07 Speywood Lab Ltd A novel agent able to modify peripheral afferent function
US5773019A (en) 1995-09-27 1998-06-30 The University Of Kentucky Research Foundation Implantable controlled release device to deliver drugs directly to an internal portion of the body
US6063405A (en) 1995-09-29 2000-05-16 L.A.M. Pharmaceuticals, Llc Sustained release delivery system
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US5980948A (en) 1996-08-16 1999-11-09 Osteotech, Inc. Polyetherester copolymers as drug delivery matrices
US6063768A (en) * 1997-09-04 2000-05-16 First; Eric R. Application of botulinum toxin to the management of neurogenic inflammatory disorders
US6022554A (en) 1997-12-15 2000-02-08 American Home Products Corporation Polymeric microporous film coated subcutaneous implant
CA2319113A1 (en) * 1998-01-26 1999-07-29 University Of Massachusetts Biologically active hemagglutinin from type a clostridium botulinum and methods of use
US6306423B1 (en) * 2000-06-02 2001-10-23 Allergan Sales, Inc. Neurotoxin implant

Also Published As

Publication number Publication date
US20020028216A1 (en) 2002-03-07
AR028669A1 (en) 2003-05-21
AU7292701A (en) 2001-12-17
WO2001093890A2 (en) 2001-12-13
KR20030066330A (en) 2003-08-09
DE60118550T2 (en) 2007-02-08
AU2001265043A1 (en) 2001-12-17
BR0111300A (en) 2003-06-10
ES2259665T3 (en) 2006-10-16
US6585993B2 (en) 2003-07-01
JP2012067144A (en) 2012-04-05
WO2001093890B1 (en) 2002-05-10
AU2001272927B8 (en) 2006-03-16
WO2001093890A3 (en) 2002-03-14
EP1655023A1 (en) 2006-05-10
DE60118550D1 (en) 2006-05-18
NZ522611A (en) 2004-07-30
WO2001093827B1 (en) 2002-05-10
KR100732810B1 (en) 2007-06-27
WO2001093827A2 (en) 2001-12-13
EP1289504A2 (en) 2003-03-12
AU2001272927B2 (en) 2006-01-05
JP2003535117A (en) 2003-11-25
US20020028244A1 (en) 2002-03-07
CN1446081A (en) 2003-10-01
CA2411277A1 (en) 2001-12-13
US6506399B2 (en) 2003-01-14
EP1289504B1 (en) 2006-04-05
US6383509B1 (en) 2002-05-07
US6312708B1 (en) 2001-11-06
CN100536915C (en) 2009-09-09
US20020098237A1 (en) 2002-07-25
US6306423B1 (en) 2001-10-23
WO2001093827A3 (en) 2002-03-14
TWI250020B (en) 2006-03-01
ATE322251T1 (en) 2006-04-15

Similar Documents

Publication Publication Date Title
CA2411277C (en) Neurotoxin implant
AU2001272927A1 (en) Neurotoxin implant
US20040033241A1 (en) Controlled release botulinum toxin system
US8007828B2 (en) Stabilized biodegradable neurotoxin implants
US9265722B2 (en) Botulinum toxin formulation for oral administration
US20040170665A1 (en) Intravitreal botulinum toxin implant
US20040253274A1 (en) Use of a clostridial toxin to reduce appetite
US20050214327A1 (en) Neurotoxin-containing suppositories and related methods
AU2011253655B2 (en) Stabilized biodegradable neurotoxin implants

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed

Effective date: 20140527