WO1989005138A1 - Procede de production d'implants bioerodables pour l'amelioration de la liberation controlee de medicaments - Google Patents

Procede de production d'implants bioerodables pour l'amelioration de la liberation controlee de medicaments Download PDF

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Publication number
WO1989005138A1
WO1989005138A1 PCT/US1988/004342 US8804342W WO8905138A1 WO 1989005138 A1 WO1989005138 A1 WO 1989005138A1 US 8804342 W US8804342 W US 8804342W WO 8905138 A1 WO8905138 A1 WO 8905138A1
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Prior art keywords
polymer
drug
solvent
bioerodible
solution
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Application number
PCT/US1988/004342
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English (en)
Inventor
Mark Chasin
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Mark Chasin
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Publication of WO1989005138A1 publication Critical patent/WO1989005138A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G67/00—Macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing oxygen or oxygen and carbon, not provided for in groups C08G2/00 - C08G65/00
    • C08G67/04—Polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation

Definitions

  • the present invention relates to a method of producing bioerodible implants and the resultant bioerodible implant having a medicament uniformly dispersed throughout a polymeric matrix. More particularly the invention is directed to sustained drug release polymeric implants which approach zero order release.
  • Bioerodible polymeric controlled drug release systems have the major advantage of not requiring removal of the device after depletion of the drug since the polymers degrade completely into nontoxic components. Further advantages include the ability to surgically implant the device at a preselected site to deliver the drug only to that desired site and at the desired concentration.
  • An i plantable controlled drug release device formed from a bioerodible polymer is able to release a drug to a selected site at concentrations much higher than could ever be achieved by conventional intraveneous or intramuscular administration.
  • the ideal implantable controlled drug release device is formed from a polymer which exhibits a constant erosion rate over time and is able to release the drug at a constant rate.
  • True zero order release is the linear release of a drug in relation to the rate of erosion of the polymeric matrix .
  • the rate of surface erosion of the polymer is the primary factor in controlling the rate of release of the drug.
  • the rate of release of the drug in a homogeneous mixture should be proportional to the surface area of the system.
  • the optimum controlled release device erodes at a constant preselected rate with only minimal diffusion from the inner body of the polymer matrix.
  • the fluctuating release rate of the prior art compression molded implants is believed to be due primarily to the relatively large particles of the drug imbedded in or surrounded by the polymeric matrix. As such, there tends to be distinct particles of the drug of different sizes randomly dispersed throughout the matrix.
  • the powdered composition When the powdered composition is formed by simply mixing a powdered drug with a powdered polymer and compressing the mixture, the resulting implant does not show a completely uniform distribution of the drug throughout the polymer matrix.
  • the outer surface of the polymer erodes to expose these randomly dispersed particles which then dissolve in the surrounding fluid environment. Since the drug particles are . not uniformly but rather randomly dispersed throughout the polymer there are times when no drug particles are exposed to be released and other times when, undesi rably large numbers of the drug particles are exposed and are released. The result is that as the polymer erodes the rate of release of the drug is uncontrolled and continuously rises and falls.
  • This prior art process of manufacturing bioerodible drug release implants accordingly does not produce a satisfactory implant which exhibits or more closely approaches zero order release of the drug.
  • injection molding processes involve essentially heating the polymer to the glass transition point or melting point and injecting the fluid polymer and drug into a suitable mold.
  • the drug can be mixed i powder form with the polymer prior to melting or it can be added as a dispersion or suspension to the melted polymer.
  • Injection molding does not produce a suitable implant which sufficiently exhibits or approaches zero order release.
  • the melt dispersion of polymer and drug as with the mixing of the powders does not produce a sufficiently uniform distribution of the drug throughout the polymer matrix to enable a constant rate of release.
  • some of the drug may be dissolved in the melted polymer a large number of drug particles remain undissolved which when exposed upon erosion of the surrounding polymer cause a sudden release of an undesirably large amount of the drug to the surrounding ti ssue or fluid .
  • Further disadvantages of the melting step result when the heat required to reach the melting point of the polymer causes the drug or the polymer to degrade. At these higher temperatures the probability of drug to polymer interaction is much greater which further reduces the effectiveness of the bioerodible implant.
  • solvent is . evaporated to form a thin film of the polymer drug matrix.
  • Solvent casting generally results in a distribution of the polymer and drug which is more uniform than compression molding or injection molding technigues and has the advantage over injection molding of avoiding the possibility of degradation of the drug or polymer.
  • Solvent casting is suitable, however, only for making thin flexible films and is generally not used for larger implants or prosthesis where thicker or larger devices are required. Since ' the solvent casting technique is limited to the formation of thin films which must be cut into a desired shape to obtain a suitable implant high volume production is not cost effective and the size and shape of the implant is unduly restricted. In addition the cutting of an implantable device from a thin film or sheet inherently results in some waste and scrap which must be redissolved and recast to make the process economically feasible. Since solvent casting is only suitable for thin films the resulting implant will generally be rather small and as such capable of releasing a rather small amount of a drug for only a limited time.
  • the present invention accordingly relates to a bioerodible device which is able to deliver a drug at a predetermined continuous rate for extended periods of time. Moreover, the invention is - directed to a method of preparing bioerodible implants in any desired shape without degradation to the drug and polymer and which is cost effective and capable of producing large quantities of the devices in rapid, succession.
  • the present invention relates primarily to a method of manufacturing bioerodible implants in a manner in which the drug is dispersed evenly and uniformly throughout the polymeric matrix.
  • the polymer is first dissolved in a suitable solvent.
  • the desired drug is then added to the polymer solution in the desired proportion and mixed until completely dissolved.
  • the solution is either spray dried to a powder or poured into a suitable vessel where the solvent is removed, preferrably by evaporation under vacuum. Once dried the polymer-drug matix is ground to a powder where it can be formed by compression molding into the desired shape and size.
  • the resulting implantable article possesses superior release rates over extended periods of time compared to the prior art devices since the drug is evenly dispersed throughout the polymer matrix.
  • the drug By dissolving the drug in solution with the dissolved polymer the drug tends to be dissolved in the polymer and dispersed throughout the polymer matrix on a molecular level as the solvent is removed.
  • the polymer/drug matrix in a powder form can be used to produce implantable articles of any desired shape using standard compression molding techniques.
  • the molded articles formed from discrete particles display a uniform distribution of the drug throughout the article resulting in an implantable bioerodible article which releases the drugs to the surroundings at a constant and uniform rate.
  • FIGURE 1 is a representation of the drug distribution in a prior art controlled drug release device.
  • FIGURE 2 is a representation of the drug distribution in a controlled drug release device formed according to the present invention.
  • FIGURE 3 is a graph of samples showing the distribution of BCNU throughout the polymer matrix produced according to the present invention.
  • FIGURE 4 is a graph of samples showing the distribution of BCNU throughout the polymer matrix produced according the prior art method.
  • FIGURE 5 is Differential Scanning Calorimetry curve for pure BCNU.
  • FIGURE 6 is a Differential Scanning Calorimetry curve for pure PCPP.SA (20:80).
  • FIGURE 7 is a Differential Scanning Calorimetry curve for a BCNU/PCPP:SA powdered mixture prepared by the prior art methods.
  • FIGURE 8 is a Differential Scanning Calorimetry curve for a BCNU/PCPP:SA matrix prepared according to the present invention.
  • FIGURE 9 is a Differential Scanning Calorimetry curve for Examples VI-IX of a BCNU/PCPP:SA matrix prepared according to the present invention.
  • FIGURE 10 is a Differential Scanning Calorimetry curve for Examples X-XIII of BCNU/PCPP:SA prepared according to the pr i or art .
  • FIGURE 11 is a comparison graph plotting the % of BCNU released over time for wafers containing 2.5% BCNU formed according to the prior art and the novel methods.
  • FIGURE 12 is a comparison graph plotting the % BCNU released over time from wafers containing 10% by weight BCNU according to the prior art and the novel method.
  • a drug containing bioerodible polymeric matrix having a uniform composition throughout the implant has been developed which can be formed by compression molding techniques into implantable articles which approach a zero order release rate of the drug over an extended period of time.
  • the polymer employed can be any suitable polymer which degrades iji vivo into non-toxic components and degrades at a steady rate from the outermost surface inwardly.
  • the ideal polymers are those which undergo surface erosion with a steady state of hydrolytic degradation at the surface at a faster rate than the rate of water penetration onto the bulk of the matrix.
  • the ideal polymers for bioerodible articles generally have a hydrophilic backbone with water labile linkages.
  • Polymers which have been studied with varying success for bioerodible controlled delivery articles include polyesters, polyorthoesters , polyamides, polyurethanes , polyacrylonitri 1 es and polyphosphazenes .
  • Presently the most promising bioerodible polymers appear to be the polyanhydrides and particularly the high molecular weight polyanhydrides as described in Rosen, et al Biomater . Vol 4,
  • Polyanhydrides which have been shown to demonstrat superior bioerodible qualities include, polysebacic acid, 1,3-bis ( p-carboxyphenoxy) propane, polyterephthal ate and polymers from other aliphatic and aromatic dicarboxylic acid and copoly ers of these acids.
  • the rates of the erosion and rate of release of the drug can be controlled or altered by the specific polymer.
  • By controlling the ratio of aliphatic and aromatic nonomers and the molecular weight of the polyme as is known in the prior art the erosion rates and uniformit of erosion can be controlled as desired depending on the intended location of the device and the type of treatment needed .
  • the method according to the present invention includes the steps of dissolving the polymer in a suitable solvent while stirring continuously.
  • the preferred solvent is methylene chloride although any nonreactive solvent can b used.
  • suitable solvents include but are not limited to carbontetrachloride, tetrahydrofuran and ethyl acetate . It is of course essential that the polymer is not reactive with the solvent and that the particular drug selected is soluble or miscible in the resulting polyanhydri de and solvent solution.
  • a predetermined quantity of a drug is added to the polymer solution and stirred until completely dissolved.
  • the solution is spray dried using conventional techniques. This method generally sprays the drug polymer solution into a heated chamber maintained at reduced pressure to remove the solvent. The resulting product is a fine powder or granular composition which does not require further processing.
  • the drug:polymer solution may be transferred to a suitable evaporation vessel such as a roto- evaporatior where a vacuum i's applied to remove the solvent.
  • a suitable evaporation vessel such as a roto- evaporatior where a vacuum i's applied to remove the solvent.
  • This drying method is, however, more time consumming and requires a further grinding step to reduce the dried material to a powder.
  • the powdered drug polymer composition can be stored or transferred to a suitable molding apparatus.
  • the powdered drug polymer composition is particularly useful for compression molding techniques where the powder can be formed at a commercially acceptable rate into any desired shape or size.
  • the drug polymer composition can be redissolved in a suitable solvent and cast using standard solvent casting or film forming procedures.
  • any number of suitable solvents which are easily removed from the solution and nonreactive with the drug or polymer can be employed in practicing the present invention.
  • the solvent is selected where both the desired polymer and the drug are readily soluble.
  • the polymer can be first dissolved in the solvent followed by the addition of the pure drug.
  • the drug can alternatively be added in the form of a suitable pharmaceutical preparation formed by dissolving a predetermined amount of the drug in the solvent.
  • bioerodible drug release implants produced according to the present invention have been found useful for treating a variety ,of disorders.
  • types of drugs which can be employed in the implant include anticonvul sants, antiepi 1eptics , anticancer, anti- parkinsonism agents, anti hypertensi ves , antibacteri al s , antiviral, antifungal, narcotic antagonists, vascular agents, stimulants, agents for treating Alzheimer's disease and phamaceutical s used to treat other disorders of the central nervous system.
  • the uniform release rates of bioerodible drug release implants when prepared according to the present invention are due in part to the uniform distribution of the drug throughout the polymeric matrix.
  • the method of forming bioerodible implants according to the present invention results in a uniform distribution of the drug with the polymer matrix. This uniform distribution is due in part to the drug actuall-y being dissolved in the polymer as represented generally in
  • PCPP:SA poly 1 ,3-bis ( p-carboxyphenoxy) propane : sebacic acid copolymer
  • the prior art method of forming implantable articles was carried out by mechanically mixing 0.18 grams of dry powdered PCPP:SA polymer with 0.02 grams of BCNU.
  • the mixture of dry powdered polymer and powdered BCNU was transferred to a similar mold and compressed into a wafer suitable for in vivo implantation.
  • the device formed by this prior art method contained a theoretical average of 10% BCNU by weight.
  • the prior art wafer was divided into 10 portions in the manner as described above and each portion was subjected to HPLC to determine the BCNU content of each portion revealing an average of 9.82% BCNU by weight for each portion.
  • the distribution between the portions is shown in Fig. 4 exhibiting a standard deviation of 1.14.
  • the percent standard deviation of this prior, art method showed a variation of 11.6% between the segmented portions.
  • DSC Differential Scanning Calorimetry
  • Fig. 5 the DSC curve is shown for pure 5 BCNU which shows a sharp melting point between 30 and 32 degrees C.
  • Fig. 6 shows a similar DSC curve for the pure PCPP:SA (20:80) polyanhydride copolymer having a broad band between 32 and 60 degrees C. This broad range represents the glass transition range of PCPP:SA (20:80) while the sharper 10 peak represents the melting point between 60 and 65 degrees C.
  • the DSC of a PCPP:SA/BCNU wafer produced according to the prior art method of Example II by mechanically mixing 15 dry powders is shown in Fig. 7.
  • the prior art method of preparing wafers for implantation shows two distinct peaks . far the melting point of BCNU and the polymer in an essentially additive manner. The existence of the two peaks demonstrates the presence of discrete particles of the drug 2 surrounded by the polymer. It is important to recognize that since the content uniformity of the prior art wafers are so poor the relative heights of the peaks of the BCNU and the polymer melting points will differ from sample to sample.
  • EXAMPLE V z Referring to Fig. 8 the wafer of BCNU and PCPP:SA prepared according to the novel method of Example I displays unique and unexpected results.
  • the DSC curve does not show distinct melting points for the drug and polymer as with the prior art article. There is no melting point peak for the BCNU but rather a shift in the melting point of the PCPP:SA and a substantial broadening of the peak. The melting point peak of the novel polymer/drug matrix is shifted slightly lower than the polyanhydride peak of the prior art article.
  • the above data demonstrate that substantial differences exist between the novel polymer/drug matrix and the prior art.
  • the DSC data shows that the BCNU is actually dissolved in the PCPP:SA which causes the shift in the melting point peak.
  • the absence of a peak at the melting point of BCNU demonstrates that essentially no distinct particles of BCNU remain undissolved in the polymeric matrix. Since the drug is dissolved or at least partially dissolved in the polymer a more uniform distribution of the drug occurs.
  • a second sample was prepared which included 10% BCNU by weight of the PCPP:SA polymer using the prior art method of Example II and the method according to the invention of Example I.
  • the jji vitro release rate of the novel controlled drug release device also approaches zero order release when compared to the prior art as indicated by the more gradual slope of the curve.
  • any combination of polymers and drugs can be implemented using the teachings of the invention to achieve superior drug release rates.
  • the choice of the polymer which can be used is not limited to polyanhydrides as any suitable bioerodible polymeric material can be used.
  • the selection of the appropriate polymer is made by one skilled in the art according to the intended use. Factors which determine the selection of the polymer include the type of drug to be released, the location of the implant and desired duration and rate of release.
  • the solvent can be selected from any nonreactive solvent although methylene chloride is the preferred solvent.
  • the solvent is selected to ensure the particular polymer and the drug are soluble therein. In the case of the drug being in liquid form the drug should be readily miscible in the solvent with no phase separation. Moreover, the drug must not react with the solvent or the polymer once in solution.
  • the method according to the present invention enables a relatively shelf stable powder of the polymer and drug to be prepared in larger quantities and which can be readily formed by standard compression molding techniques into any desired shape and size of implantable article. More importantly the method of the present invention can be used to prepare bioerodible controlled drug release devices which demonstrate superior rates of release of the drug.

Abstract

Un implant bioérodable de libération contrôlée de médicaments contient un composé approprié pharmaceutiquement actif uniformément dispersé dans une matrice polymère. On prépare l'implant en dissolvant un polymère bioérodable approprié dans une solvant organique, puis en ajoutant une quantité prédéterminée d'une composition pharmaceutique. On agite la solution jusqu'à ce que le polymère et le médicament soient complètement dissous. On sèche ensuite la solution par évaporation et on réduit en granules la composition sèche de polymère/médicament, que l'on moule par compression afin d'obtenir la forme voulue. La composition pharmaceutique peut être un médicament à l'état pur ou une solution d'un médicament dans un solvant appropré. Lorsque la solution du médicament est immiscible avec la solution polymère, on ajoute à la solution du médicament un agent dispersant approprié afin de disperser le médicament dans le polymère. Les dispositifs formés selon ce procédé conviennent pour des dispositifs de libération contrôlée de médicaments, prothèses osseuses ou autres.
PCT/US1988/004342 1987-12-08 1988-12-06 Procede de production d'implants bioerodables pour l'amelioration de la liberation controlee de medicaments WO1989005138A1 (fr)

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US13019387A 1987-12-08 1987-12-08
US130,193 1987-12-08

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0414416A2 (fr) * 1989-08-25 1991-02-27 Massachusetts Institute Of Technology Compositions de polyanhydrides aromatiques
EP0473223A1 (fr) * 1990-08-22 1992-03-04 Merck & Co. Inc. Implants bioérodibles
EP0626854A4 (fr) * 1990-07-12 1993-09-02 Sterilization Techn Serv Composition antithrombogene et/ou antimicrobienne.
US5525348A (en) * 1989-11-02 1996-06-11 Sts Biopolymers, Inc. Coating compositions comprising pharmaceutical agents
WO1997042940A1 (fr) * 1996-05-14 1997-11-20 Alkermes Controlled Therapeutics, Inc. Procede de preparation de dispositifs a liberation retardee a base de polymeres
US5989463A (en) * 1997-09-24 1999-11-23 Alkermes Controlled Therapeutics, Inc. Methods for fabricating polymer-based controlled release devices
JP2001510078A (ja) * 1997-07-17 2001-07-31 マサチューセッツ インスティテュート オブ テクノロジー 半相互浸透性重合体ネットワーク
WO2007147010A2 (fr) * 2006-06-15 2007-12-21 Medtronic Vascular Inc. Appareils médicaux implantables et méthodes pour les fabriquer
US7658998B2 (en) 2003-01-22 2010-02-09 Alkermes Controlled Therapeutics, Inc. Method of preparing sustained release microparticles
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US20140363484A1 (en) * 2012-02-21 2014-12-11 Amrita Vishwa Vidyapeetham Fibrous bio-degradable polymeric wafers system for the local delivery of therapeutic agents in combinations
US10646622B2 (en) 1998-09-11 2020-05-12 Gerhard Schmidmaier Biologically active implants

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4357312A (en) * 1981-07-16 1982-11-02 The Children's Hospital Medical Center Method of making prolonged release body
EP0158277A2 (fr) * 1984-04-11 1985-10-16 Hoechst Aktiengesellschaft Préparations implantables à libération contrôlée de peptides régulateurs et procédé pour leur fabrication
US4767627A (en) * 1985-05-29 1988-08-30 Merck & Co., Inc. Drug delivery device which can be retained in the stomach for a controlled period of time

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4357312A (en) * 1981-07-16 1982-11-02 The Children's Hospital Medical Center Method of making prolonged release body
EP0158277A2 (fr) * 1984-04-11 1985-10-16 Hoechst Aktiengesellschaft Préparations implantables à libération contrôlée de peptides régulateurs et procédé pour leur fabrication
US4767627A (en) * 1985-05-29 1988-08-30 Merck & Co., Inc. Drug delivery device which can be retained in the stomach for a controlled period of time

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0414416A3 (en) * 1989-08-25 1991-07-03 Nova Pharmaceutical Corporation Aromatic polyanhydride compositions
EP0414416A2 (fr) * 1989-08-25 1991-02-27 Massachusetts Institute Of Technology Compositions de polyanhydrides aromatiques
US5525348A (en) * 1989-11-02 1996-06-11 Sts Biopolymers, Inc. Coating compositions comprising pharmaceutical agents
EP0626854A4 (fr) * 1990-07-12 1993-09-02 Sterilization Techn Serv Composition antithrombogene et/ou antimicrobienne.
EP0626854A1 (fr) * 1990-07-12 1994-12-07 STS Biopolymers, Inc. Composition antithrombogene et/ou antimicrobienne
EP0473223A1 (fr) * 1990-08-22 1992-03-04 Merck & Co. Inc. Implants bioérodibles
US5837228A (en) * 1990-08-22 1998-11-17 Merck & Co., Inc. Bioerodible implants
US6183781B1 (en) 1996-05-14 2001-02-06 Alkermes Controlled Therapeutics, Inc. Method for fabricating polymer-based controlled-release devices
WO1997042940A1 (fr) * 1996-05-14 1997-11-20 Alkermes Controlled Therapeutics, Inc. Procede de preparation de dispositifs a liberation retardee a base de polymeres
JP2001510078A (ja) * 1997-07-17 2001-07-31 マサチューセッツ インスティテュート オブ テクノロジー 半相互浸透性重合体ネットワーク
US5989463A (en) * 1997-09-24 1999-11-23 Alkermes Controlled Therapeutics, Inc. Methods for fabricating polymer-based controlled release devices
US10646622B2 (en) 1998-09-11 2020-05-12 Gerhard Schmidmaier Biologically active implants
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US7658998B2 (en) 2003-01-22 2010-02-09 Alkermes Controlled Therapeutics, Inc. Method of preparing sustained release microparticles
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8309613B2 (en) 2003-08-28 2012-11-13 Abbvie Inc. Solid pharmaceutical dosage form
US8333990B2 (en) 2003-08-28 2012-12-18 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8399015B2 (en) 2003-08-28 2013-03-19 Abbvie Inc. Solid pharmaceutical dosage form
US8691878B2 (en) 2003-08-28 2014-04-08 Abbvie Inc. Solid pharmaceutical dosage form
WO2007147010A3 (fr) * 2006-06-15 2008-10-23 Medtronic Vascular Inc Appareils médicaux implantables et méthodes pour les fabriquer
WO2007147010A2 (fr) * 2006-06-15 2007-12-21 Medtronic Vascular Inc. Appareils médicaux implantables et méthodes pour les fabriquer
US20140363484A1 (en) * 2012-02-21 2014-12-11 Amrita Vishwa Vidyapeetham Fibrous bio-degradable polymeric wafers system for the local delivery of therapeutic agents in combinations

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