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WO1978000011A1 - Forme d'implant medicamenteux et procede de preparation - Google Patents

Forme d'implant medicamenteux et procede de preparation Download PDF

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Publication number
WO1978000011A1
WO1978000011A1 PCT/DE1978/000003 DE7800003W WO7800011A1 WO 1978000011 A1 WO1978000011 A1 WO 1978000011A1 DE 7800003 W DE7800003 W DE 7800003W WO 7800011 A1 WO7800011 A1 WO 7800011A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
polycondensate
medicament
matrix
depot
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.)
Ceased
Application number
PCT/DE1978/000003
Other languages
German (de)
English (en)
Inventor
H Bisson
P Speiser
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.)
Garching Instrumente
Original Assignee
Garching Instrumente
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
Application filed by Garching Instrumente filed Critical Garching Instrumente
Publication of WO1978000011A1 publication Critical patent/WO1978000011A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/2045—Polyamides; Polyaminoacids, e.g. polylysine
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the invention relates to a depot pharmaceutical form for oral and / or parenteral administration from one or more medicaments enclosed in a polymer matrix, the matrix produced by polycondensation of at least bifunctional carboxylic acids with polyols slowly hydrolyzing into non-toxic, excretable compounds under physiological conditions and thereby releases the drug or drugs.
  • the matrix consists of polymeric condensation products which, by reacting di- and tricarboxylic acids of the type that occur in the citric acid cycle, be produced with physiologically compatible polyols.
  • citric acid, cis-aconitic acid, isocitric acid, ⁇ -ketoglutaric acid, succinic acid, fumaric acid, malic acid and oxaloacetic acid or glycerol, mannitol, sorbitol and glycerol esters are used as starting components for the polymer matrix.
  • a process for the production of such depot pharmaceutical forms is also known from the cited US patent, in which a polyester, which forms the polymer matrix, is first known from one of the di- or tricarboxylic acids and one of the polyols mentioned by polycondensation in a manner known per se.
  • the powdered or finely ground drug desired as active ingredient is then ground together with the solid polyester in a ball mill, and the uniformly ground mixture is then sintered under pressure and at elevated temperature to a desired external shape.
  • the known depot pharmaceuticals have the disadvantage that they often hydrolyze too quickly under physiological conditions, ie they release the active substance enclosed in the polymer matrix too quickly.
  • the known method for producing the depot pharmaceutical forms has the disadvantage that only very temperature-resistant active ingredients can be incorporated into the polymeric matrix, since active ingredients that are sensitive to temperature would be destroyed during sintering.
  • the object of the invention is to avoid these disadvantages and to create a depot pharmaceutical form which is more hydrolysis-resistant, simple to manufacture and easily brought into any external form suitable for oral and, above all, parenteral administration.
  • Another object of the invention is to provide a method for producing depot pharmaceutical forms of the initially to create named genus, which also makes it possible to incorporate very temperature-sensitive active ingredients into the polycondensation products used as the matrix.
  • the matrix of the polycondensation product from a dicarboxylic acid, hydroxymonocarboxylic acid and / or a physiologically compatible amino acid or from several of these acids and optionally from one or more of the polyols, 1,2-propanediol , Inositol, pyridoxol, D-panthenol, pentaerythritol, adonit.
  • particularly advantageous depot pharmaceutical forms are characterized in that the matrix of polylactic acid or the self-condensation product of. p-aminobenzoic acid exists.
  • the matrix consisting of polylactic acid has the advantage that the desired active ingredient is light and very uniform, even with very fine distribution and very small particle sizes
  • the polycondensate made from p-aminobenzoic acid is also special because of its particularly simple and inexpensive manufacture can be used advantageously.
  • micropellets with an average diameter of 10 -9 to 10 m ie their average diameters are in the nanometer or micrometer range. They can then not only be implanted during parenteral administration, such as the depot medication known from US Pat. No. 3,978,2-03, but they can even be suspended directly in ⁇ in a suitable physiologically compatible liquid jit.
  • the object on which the invention is based is further achieved by a process for the preparation of the depot drug form according to the invention by producing a polycondensate soluble in organic solvents in a manner known per se and adding the desired drug (s) to the polycondensate, which is characterized in that the still water-soluble polycondensate together with. the drug is dispersed in a weakly polar dispersant with stirring and the condensation is completed until the polycondensate is insoluble in water.
  • Advantageous embodiments of the method according to the invention consist in that silicone oil is used as the dispersant, that the condensation is carried out at a temperature of 120 to 200 ° C. and that the condensation is carried out under a pressure of 10 to 14 mm Hg .
  • depot pharmaceutical forms can be produced which can be administered not only orally or by implantation, which always requires a surgical procedure involving risk, but also subcutaneously, intramuscularly or can be applied peritoneally by simple injection.
  • a further development of the method according to the invention which also allows very temperature-sensitive active ingredients to be incorporated into the matrix, consists in the polycondensate being solubilized together with the medicament in an aqueous surfactant solution, heated to a temperature of 20 to 60 ° C. with stirring and from the Solution fails.
  • dicarboxylic acid fumaric acid, succinic acid, glutaric acid, adipic acid, sugar acid, tartaric acid; as hydroxymonocarboxylic acid: lactic acid, ß-hydroxybutyric acid, p-hydroxybenzoic acid, cholic acid, gluconic acid, glucuronic acid, glucoheptonic acid; as amino acid: serine, hydroxyproline, homoserine, aminosuccinic acid, glutamic acid, lysine, p-aminobenzoic acid, and all other amino acids in the body in the corresponding physiological form; as polyol: 1, 2-propanediol, inositol, pyridoxol, D-panthenol, pentaerythritol, adonite.
  • acids mentioned can also be in the form of their Anhydrides, acid chlorides, esters or lactones are polycondensed.
  • pentaerythritol and 1,2-propanediol are preferred, since pentaerythritol, owing to its four primary hydroxyl groups, which ensure a high esterification rate, leads quickly to crosslinked, water-insoluble polyesters upon condensation with one of the acids mentioned while 1,2-propanediol, whose toxicological properties correspond to glycerol, forms much more hydrolysis-resistant polyester than glycerol.
  • the tricarboxylic acids known per se for the production of depot medicinal forms citric acid, cis-azonitic acid, isocitric acid and the like with the above-mentioned polyols, preferably pentaerythritol and 1,2-propanediol, can also be used to produce the polymeric matrix.
  • condensation components By varying the condensation components, polymer matrices with a wide variety of properties can be achieved which influence the release of the active ingredient or ingredients incorporated therein.
  • a polycondensate which is soluble in organic solvents is first prepared by conventional methods, and the drug selected as active ingredient is added to this polymer in solid form or in a suitable solvent with constant stirring and condensed until the polycondensate formed is insoluble in water.
  • the pole condensate obtained in this way can be pulverized in a suitable manner to the desired grain size and, for example, injected intramuscularly after sterilization in physiological saline
  • the powder obtained in this way can also be tablet-coated directly or moistened in small proportions by means of an appropriate organic solvent and processed further to form crust granules. Tablets or any other desired shape can be pressed from this granulate without additional auxiliaries.
  • the compressed products produced in this way are suitable for implantation in the human or animal body.
  • the silicone oil which is preferably used as a weakly polar dispersant in the process according to the invention can, for example, be of the dimethylpolysiloxane type.
  • Polycondensates which are soluble in organic solvents and in which at least one starting component is unsaturated, for example fumaric acid can, after incorporation of the active ingredient and solubilization in an aqueous surfactant solution, for example in 15% polyoxyethylene-sorbitan-mbnolaurate solution, at temperatures between 20 ° and 60 ° C. that is, they can also be polymerized at room temperature, so that even temperature-sensitive active ingredients can be easily incorporated into the polycondensates without decomposition and without losing their effectiveness.
  • an aqueous surfactant solution for example in 15% polyoxyethylene-sorbitan-mbnolaurate solution
  • polylactic acid with a melting point of approx. 160 ° C. and an average molecular weight of 9000 are obtained.
  • the polycondensate has film-forming properties.
  • the dispersion is now quickly cooled, diluted with hexane and the resulting polycondensate micropellets are separated from the silicone oil by centrifugation.
  • the silicon residues are removed by resuspending the microspheres in hexane and then centrifuging.
  • the silicone oil can be reused after distilling off the hexane.
  • a fine powder of micropellets is obtained, the diameter of which does not exceed 50 ⁇ m.
  • the active substance is released with a delay.
  • Example 1 Under vacuum and rapid stirring (high-speed stirrer Tornado), the polymer drug solution in 50 g of silicone oil (of the same quality as in Example 1) is then slowly dripped from 150 to 170 ° C. and the procedure is then continued as in Example 1.
  • Micropellets containing active ingredient are obtained, the size of which can be changed by varying the amounts of solvent and silicone used and the stirring speed of the high-speed stirrer.
  • the active ingredient is released from the pellets with a delay.
  • the hose ends are welded and subjected to a heat treatment of 120 ° C for 100 minutes.
  • the polymerized polyester can then be easily “peeled” out of the tube.
  • the active substance-containing polyester stick can be applied parenterally with an appropriate device without a major surgical intervention being necessary.
  • Theophylline substance stirred in and condensed for a further 15 minutes under vacuum at 170 ° C and then the temperature raised to 190 to 200 ° C. At this temperature, the vacuum is maintained for a further 20 minutes. You get 17.5 g of a very hard polycondensate at room temperature. with theophylline, which can be pulverized and releases the active ingredient with a delay.
  • the pulverized polycondensate can easily be briquetted and, after treatment in a dry granulator, can be tabletted directly without the aid of an additive. In this way, implant tablets are obtained which contain only active ingredient and polyester and are characterized by a delayed release of active ingredient.
  • Example 2 After working up the dispersion as in Example 1, a fine powder of micropellets is obtained, the diameter of which is less than 100 ⁇ m.
  • the clear solubilizate is mixed with 0.1 g ammonium persulfate and 0.001 g tetramethyl. ethylenediamine added and with constant stirring and nitrogen fumigation . Heated to 40 ° C for 12 hours.
  • the polymer particles are precipitated by adding methanol, which are then centrifuged and washed several times. The aqueous suspension of these polymer particles is lyophilized.
  • particles in the nanometer range are obtained which contain testosterone as a pharmacologically active substance and release them with a delay. These nanoparticles are suitable for parenteral administration.
  • 1 g of a polyester made of fumaric acid and 1,2-propanediol with a molecular weight of 1300 is dissolved together with 0.05 g of benzoyl peroxide and 0.2 g of norgestrel in 10.0 g of methylene chloride.
  • This solution is mixed thoroughly with 5.0 g of Tween 80 and then slowly added dropwise from a burette in 50 ml of aqua destillata, which is constantly stirred. After the solubilization, the temperature is raised to 50 to 60 ° C. and the mixture is stirred for 6 to 8 hours while gassing with nitrogen. 0.03 g of a tert-arylalkylamine is then added to the outer phase and the mixture is stirred at 40 to 50 ° C. for a further 12 hours.
  • Polyester pellets in the nanometer range are obtained.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Physics & Mathematics (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Forme d'implant medicamenteux pour administration par voie orale et/ou parenterale comportant un ou plusieurs medicaments inclus dans une matrice de polymere. Dans des conditions physiologiques la substance s'hydrolyse lentement en elements non toxiques, physiologiquement eliminables et, ce faisant, libere le ou les medicaments. Elle est le produit de la polycondensation d'un acide dicarboxylique, d'un acide hydroxy monocarboxylique et/ou d'un acide amine bien tolere, ou constituee de plusieurs de ces acides et, si necessaire, d'un ou plusieurs des polyols propanediol-1, 2, inosite, pyridoxal, D-penthenol, pentaerythrite, adonite. Preparation de l'implant medicamenteux consistant a disperser le polycondensat encore soluble dans l'eau avec le medicament par agitation dans un milieu de dispersion legerement polaire, et a poursuivre la condensation du polycondensat jusqu'a l'obtention d'une insolubilite totale dans l'eau.
PCT/DE1978/000003 1977-06-07 1978-06-07 Forme d'implant medicamenteux et procede de preparation Ceased WO1978000011A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH7082/77 1977-06-07
CH708277 1977-06-07

Publications (1)

Publication Number Publication Date
WO1978000011A1 true WO1978000011A1 (fr) 1978-12-21

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PCT/DE1978/000003 Ceased WO1978000011A1 (fr) 1977-06-07 1978-06-07 Forme d'implant medicamenteux et procede de preparation

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EP (1) EP0006853A1 (fr)
DE (1) DE2856901D2 (fr)
WO (1) WO1978000011A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0086627A1 (fr) * 1982-02-12 1983-08-24 Unitika Ltd. Produit anti-cancéreux
US4491575A (en) * 1982-10-15 1985-01-01 Chemie Linz Aktiengesellschaft Compressed products with retarded release of active substance, a process for their preparation and a process for the long-term administration of medicaments
DE3430852A1 (de) * 1983-08-26 1985-03-14 Sandoz-Patent-GmbH, 7850 Lörrach Neue ester, deren herstellung und verwendung
DE3538429A1 (de) * 1984-10-30 1986-04-30 Elan Corp. P.L.C., Athlone, County Westmeath Pulver mit gesteuerter freisetzung, verfahren zu dessen herstellung und dieses enthaltende pharmazeutische zusammensetzung
EP0245840A3 (en) * 1986-05-15 1989-03-22 Hoechst Aktiengesellschaft Biodegradable polymers for retarding preparations with controlled release
DE3835099A1 (de) * 1987-10-14 1989-04-27 Debiopharm Sa Pharmazeutische zusammensetzung
EP0474098A1 (fr) * 1990-08-30 1992-03-11 Senju Pharmaceutical Co., Ltd. Composition pour la libération contrôlée de médicaments
US5128144A (en) * 1989-10-16 1992-07-07 Pcd Polymere Gesellschaft M.B.H. Pressing having sustained release of active compound
EP0520888A1 (fr) * 1991-06-28 1992-12-30 Aventis Pharma S.A. Nanoparticules à base d'un copolymère à blocs de polyoxyde d'éthylène et acide polylactique
US5187150A (en) * 1987-10-14 1993-02-16 Debiopharm S.A. Polyester-based composition for the controlled release of polypeptide medicinal substances
EP0603889A3 (fr) * 1992-12-25 1994-07-20 MITSUI TOATSU CHEMICALS, Inc. Procédé pour la préparation de polyesters d'acide lactique
AT397804B (de) * 1987-03-07 1994-07-25 Hoechst Ag Biologisch abbaubare polymere für depotzubereitungen mit kontrollierter wirkstoffabgabe, verfahren zu ihrer herstellung und ihre verwendung
US5698291A (en) * 1994-03-14 1997-12-16 Kimberly-Clark Corporation Crimp-bonded fibrous cellulosic laminate
US6174299B1 (en) 1991-09-09 2001-01-16 Harvey B. Pollard Method for treating hemophilia A and B and AIDS and devices used therein
WO2002072662A1 (fr) * 2001-03-12 2002-09-19 Schwarz Pharma Ag Procede de production de polyesters a partir d'acides hydroxycarboxyliques et de polyols par polycondensation
WO2004096178A1 (fr) * 2003-05-02 2004-11-11 The University Of Nottingham Systemes de relargage de medicaments nanoparticulaires et microparticulaires a base de polyesters contenant des residus dicarboxylate aliphatique et des residus polyols aliphatiques

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3297033A (en) * 1963-10-31 1967-01-10 American Cyanamid Co Surgical sutures
DE2051580A1 (de) * 1969-10-23 1971-05-06 E I Du Pont de Nemours and Co, Wilmington, Del (V St A ) Polylactid Arzneimittel Mischungen
FR2126270A1 (fr) * 1971-02-23 1972-10-06 Du Pont
US3880991A (en) * 1969-03-24 1975-04-29 Brook David E Polymeric article for dispensing drugs
FR2287242A1 (fr) * 1973-05-17 1976-05-07 Little Inc A Dispositif biodegradable et implantable pour la liberation d'un produit actif

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3297033A (en) * 1963-10-31 1967-01-10 American Cyanamid Co Surgical sutures
US3880991A (en) * 1969-03-24 1975-04-29 Brook David E Polymeric article for dispensing drugs
DE2051580A1 (de) * 1969-10-23 1971-05-06 E I Du Pont de Nemours and Co, Wilmington, Del (V St A ) Polylactid Arzneimittel Mischungen
FR2126270A1 (fr) * 1971-02-23 1972-10-06 Du Pont
FR2287242A1 (fr) * 1973-05-17 1976-05-07 Little Inc A Dispositif biodegradable et implantable pour la liberation d'un produit actif

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 82, Nr. 8, 21. April 1975 Columbus, Ohio, USA. YOLLES, SEYMOUR; LAFE, THOMAS D.; MEYER, FRANCIS J.: "Timed-release depot for anticance r agents" Seite 355, Auszug Nr.103110h - J.PHARM. SCI 1975, 64 (1) 115-16 (Eng.). *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0086627A1 (fr) * 1982-02-12 1983-08-24 Unitika Ltd. Produit anti-cancéreux
US4491575A (en) * 1982-10-15 1985-01-01 Chemie Linz Aktiengesellschaft Compressed products with retarded release of active substance, a process for their preparation and a process for the long-term administration of medicaments
DE3430852A1 (de) * 1983-08-26 1985-03-14 Sandoz-Patent-GmbH, 7850 Lörrach Neue ester, deren herstellung und verwendung
DE3430852C2 (de) * 1983-08-26 2003-08-14 Novartis Ag Neue Ester, deren Herstellung und Verwendung
US4952402A (en) * 1984-10-30 1990-08-28 Elan Corporation, P.L.C. Controlled release powder and process for its preparation
DE3538429A1 (de) * 1984-10-30 1986-04-30 Elan Corp. P.L.C., Athlone, County Westmeath Pulver mit gesteuerter freisetzung, verfahren zu dessen herstellung und dieses enthaltende pharmazeutische zusammensetzung
FR2572282A1 (fr) * 1984-10-30 1986-05-02 Elan Corp Plc Formulations a liberation progressive, procede pour leur preparation et compositions les renfermant
US4940588A (en) * 1984-10-30 1990-07-10 Elan Corporation Controlled release powder and process for its preparation
EP0245840A3 (en) * 1986-05-15 1989-03-22 Hoechst Aktiengesellschaft Biodegradable polymers for retarding preparations with controlled release
AT397804B (de) * 1987-03-07 1994-07-25 Hoechst Ag Biologisch abbaubare polymere für depotzubereitungen mit kontrollierter wirkstoffabgabe, verfahren zu ihrer herstellung und ihre verwendung
GR1000266B (el) * 1987-10-14 1992-05-12 Debiopharm Sa Μεθοδος παρασκευης μιας συνθεσης βασισμενης σε πολυεστερα για την ελεγχομενη εκλυση φαρμακευτικων ουσιων.
US5187150A (en) * 1987-10-14 1993-02-16 Debiopharm S.A. Polyester-based composition for the controlled release of polypeptide medicinal substances
BE1001687A5 (fr) * 1987-10-14 1990-02-06 Debio Rech Pharma Sa Composition a base de polyesters pour la liberation controlee de substances medicamenteuses.
DE3835099A1 (de) * 1987-10-14 1989-04-27 Debiopharm Sa Pharmazeutische zusammensetzung
FR2622105A1 (fr) * 1987-10-14 1989-04-28 Debiopharm Sa Composition a base de polyesters pour la liberation controlee de substances medicamenteuses
US5128144A (en) * 1989-10-16 1992-07-07 Pcd Polymere Gesellschaft M.B.H. Pressing having sustained release of active compound
EP0474098A1 (fr) * 1990-08-30 1992-03-11 Senju Pharmaceutical Co., Ltd. Composition pour la libération contrôlée de médicaments
FR2678168A1 (fr) * 1991-06-28 1992-12-31 Rhone Poulenc Rorer Sa Nanoparticules ayant un temps de capture par le dysteme reticulo endothelial allonge.
WO1993000101A1 (fr) * 1991-06-28 1993-01-07 Rhone-Poulenc Rorer S.A. Nanoparticules a base d'un copolymere a blocs de polyoxyethylene et acide polylactique
EP0520888A1 (fr) * 1991-06-28 1992-12-30 Aventis Pharma S.A. Nanoparticules à base d'un copolymère à blocs de polyoxyde d'éthylène et acide polylactique
US6174299B1 (en) 1991-09-09 2001-01-16 Harvey B. Pollard Method for treating hemophilia A and B and AIDS and devices used therein
EP0603889A3 (fr) * 1992-12-25 1994-07-20 MITSUI TOATSU CHEMICALS, Inc. Procédé pour la préparation de polyesters d'acide lactique
US5444143A (en) * 1992-12-25 1995-08-22 Mitsui Toatsu Chemicals, Inc. Preparation process of polyhydroxycarboxylic acid
US5512653A (en) * 1992-12-25 1996-04-30 Mitsui Toatsu Chemicals, Inc. Lactic acid containing hydroxycarboxylic acid for the preparation of polhydroxycarboxylic acid
US5698291A (en) * 1994-03-14 1997-12-16 Kimberly-Clark Corporation Crimp-bonded fibrous cellulosic laminate
WO2002072662A1 (fr) * 2001-03-12 2002-09-19 Schwarz Pharma Ag Procede de production de polyesters a partir d'acides hydroxycarboxyliques et de polyols par polycondensation
WO2004096178A1 (fr) * 2003-05-02 2004-11-11 The University Of Nottingham Systemes de relargage de medicaments nanoparticulaires et microparticulaires a base de polyesters contenant des residus dicarboxylate aliphatique et des residus polyols aliphatiques

Also Published As

Publication number Publication date
EP0006853A1 (fr) 1980-01-23
DE2856901D2 (de) 1980-11-13

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