IE60475B1 - Polyester-based composition for the controlled release of medicinal substances - Google Patents

Polyester-based composition for the controlled release of medicinal substances

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Publication number
IE60475B1
IE60475B1 IE311088A IE311088A IE60475B1 IE 60475 B1 IE60475 B1 IE 60475B1 IE 311088 A IE311088 A IE 311088A IE 311088 A IE311088 A IE 311088A IE 60475 B1 IE60475 B1 IE 60475B1
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IE
Ireland
Prior art keywords
composition according
copolymer
medicinal substance
polymer
hormone
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Application number
IE311088A
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IE883110L (en
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Debiopharm Sa
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Publication of IE883110L publication Critical patent/IE883110L/en
Publication of IE60475B1 publication Critical patent/IE60475B1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Transplantation (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The pharmaceutical composition is intended in particular for the sustained and controlled release of an effective dose of a medicinal substance. It comprises, as a carrier for the medicinal substance, a biodegradable polymer or copolymer or a mixture of biodegradable polymers and/or copolymers derived from a dicarboxylic acid selected from the acids of the Krebs cycle, and from an aliphatic diol containing 4 carbon atoms or from cyclohexane-1,4-dimethanol.

Description

The present invention relates to a pharmaceutical composition and more particularly to a composition permitting the sustained and controlled release of an effective dose of a given medicinal substance.
There are numerous examples of therapeutic treatments in which it is desirable to achieve, by means of a single administration, a sustained release of the medicinal substance over a period of time and a controlled release as regards the dose passing into the organism. Ί0 Various solutions have already been proposed in this field, such as subcutaneous implants or injectable suspensions of microparticles or microcapsules. Such compositions are based on biocompatible and biodegradable polymers, for example polymers or copolymers of D.L-lactic acid and/or glycolic acid (see e.g.
Patent Specification Nos. 52003 and 52535).
In practice, interesting results have been obtained from therapeutic treatments with polypeptides, such as LHRH or its analogues, used in the form of injectable microcapsules or microparticles based on a D,L-lactic acid/glycolic acid copolymer (approx. 50:50) with an average molecular weight of the order of about 50 000. As this type of copolymer hydrolyzes relatively easily in vivo, it is essential to use forms of high molecular weight: the synthesis of such copolymers requires the use of organometallic polymerization catalysts and, when the reaction is complete, it is imperative for all traces of these catalysts to be removed for toxicological reasons. Operations of this kind are often very lengthy and very expensive.
More generally, it is found that the techniques of polymerization without the use of organometallic catalysts are rather unsuitable for the preparation of biodegradable polymers having an average molecular weight of the order of 30,000 or more.
Moreover, in order to prevent this type of polymer (lactide/glycolide copolymer) from being degraded too quickly by hydrolysis in vivo, injectable microcapsules or microparticles must have a relatively large mean size: when these are injected, the tissues are very often observed to give an inflammatory response, which is sometimes extremely painful for the subject treated.
It has furthermore been found in some cases that the uniformity of release of a peptide-type medicinal substance in the form of microparticles (see e.g. Patent Specification No. 52535) gives rise to problems, especially where twostage release is^ to be avoided.
The pharmaceutical industry is therefore always looking for biodegradable polymers which are capable of being used as carriers for medicinal substances, especially for a sustained and controlled release of the active substance, and which do not have the above-listed disadvantages inherent in the biodegradable polymers recommended to date.
In fact, certain polyesters or copolyesters are known which are derived from carboxylic acids of the Krebs cycle, such as, for example, succinic, malic, fumaric or oxaloacetic acids, and from polyols such as triols like glycerol, mannitol or sorbitol: according to US-A-3978203, they can be used inter alia as carriers for medicinal substances, mainly steroids, in the form of matrices. The polyesters described have an average molecular weight of between about 20,000 and 200,000.
US-A-4481353 recommends the use of polyesters derived from acids of the Krebs cycle, such as those mentioned above, and from c, to CB aliphatic diols in the preparation £ of surgical reauisites such as, for example, microtubes, ligatures or sutures.
? According to the present invention, a sustainedrelease pharmaceutical composition comprises a medicinal substance and, as a carrier for the medicinal substance, a biodegradable polymer or copolymer derived from a dicarboxylic acid of the Krebs cycle, and a c4 aliphatic diol or cyclohexane-1,4-dimethanol, the composition having the characteristic that, when administered in vivo or placed in an aqueous medium of physiological type, the medicinal substance is released into the surrounding medium at a constant rate over a period of at least l week.
In a composition of the invention, the dicarboxylic acid is preferably fumaric acid or succinic acid. The preferred Cri aliphatic diol is 1,4-butanediol or 2,3~ butanediol. 0 The preferred polymer for use in the invention is poly-1,4-butylene succinate, poly-1,4-butylene fumarate, poly-1,4-cyclohexanedimethylene succinate or fumarate or else poly-2,3-butylene succinate or fumarate. The abovementioned polyesters can be used in the pure state or in the form of mixtures of at least two of the said polyesters. According to the invention, it is also possible to use a copolymer derived from fumaric and succinic acids and from butane-l, 4-diol or butane-2,3-diol, for example. A copolymer derived from fumaric acid and from butane-l,4-diol and butane-2,3-diol can also be used. Interesting results have been obtained using poly-1,4butylene succinate, polv-1,4-cyclohexanedimethylene succinate end poly~2,3~butylene fumarate, although this list does not imply © limitation.
In .a particular embodiment of the invention. 1 a further possibility is to use one of the abovementioned polymers or copolymers mixed with a polymer or copolymer derived from ©n alpha-hydroxycarboxylic acid such as D- or L-lactic acid and from glycolic acid. Interesting results have been obtained issuing mixtures of poly-19A-butylene succinate and D„L-lactide/glycolide copolymer .
The polymers, more precisely the polyesters, used according to the present invention are characterized by a relatively low average molecular weight which is snore generally between about 2000 and 50, 000 and preferably less than 10,000. This has a decisive advantage when it comes to their synthesis, which can be carried out without any need to use organometallic polymerization catalysts. They can easily be obtained by means of the customary techniques such ©s melt phase polymerization in the presence of an organic esterification catalyst (e.g. p-toluenesulphonic acid), or pearl phase polymerization.
The polyesters obtained by these methods are characterized by a lipophilie behaviour which is more pronounced than that of the lactic or glycolic acid polymers or copolymers known hitherto; they are also less sensitive than the latter to degradation by hydrolysis. This feature makes it possible easily to achieve one of the stated aims, namely to prepare injectable roicrocapsules or microparticles with very small dimensions of the order of only a few microns or tens of microns.
The polyesters mentioned above, or mixtures thereof, are suitable for the preparation of any form of carrier for medicinal substances: a matrix in which the active substance is dispersed or solubilized can be considered for this purpose, examples being beads, implants, microspheres or microparticles. These polyesters or mixtures thereof are particularly suitable for carrying Out the techniques of microencapsulation of active substances, such as microencapsulation by phase separation or microencapsulation by evaporation (solvent evaporation microencapsulation). To obtain the carriers in the appropriate form, it is also possible to use processes such as spray drying or spray congealing, which both produce microparticles containing the active substance, or alternatively extrusion, which makes it possible to prepare implants of predetermined shape. These are known techniques: some of them will be described in greater detail in the Examples below.
Microcapsules are preferably prepared using polyesters with an average molecular weight of the order of about 2000 to 5000, for example of the order of about 2500. In a particular embodiment of the invention, a polyester of this type is used in a mixture with a D,L-lactic/glycolic acid copolymer (approx. 50:50) with an average molecular weight of between about 35,000 and 60,000, preferably of the order of about 45,000. However, this is not an exhaustive list.
Depending on the particular case, it is also possible to incorporate into the polymer composition a biocompatible hydrolysis modifier such as a carboxylic acid, like citric acid, or else a salt such as sodium chloride (neutral) or sodium carbonate (alkaline).
Despite their lipophilic character mentioned earlier, the polyesters forming the subject of the present invention have a sufficient affinity for hydrophilic medicinal substances such as polypeptides. Examples of medicinal substances which may be used are natural or synthetic polypeptides containing from 3 to 60 amino acid units, or else a polypeptide derivative such as a non-toxic salt of a polypeptide. For example, it may be advantageous to use a decapeptide such as luteinizing hormone/follicle-stimulating hormone releasing hormone (LH/FSH-RH) or one of its natural or synthetic analogues, or else thyrotropin releasing hormone (TRH), insulin, somatostatin or one of its synthetic analogues, human or animal calcitonin, human or animal growth hormone, growth hormone releasing hormone (GHRH), a cardiopeptide such as AMP (human 1-28) or a natural or recombinant interferon. Such active substances are suitable for the various microencapsulation techniques.
More generally, the medicinal substances which can advantageously be used in the preparation of compositions according to the invention can be selected from substances having an antiinflammatory, antitumoral, immunosuppressive, antithrombotic, neuroleptic, antidepressant or antihypertensive effect or a non-toxic salt of such substances. This is not an exhaustive list.
As a general rule, the pharmaceutical compositions according to the invention contain the chosen medicinal substance in a proportion of about 0,5 to 20% by weight, although these limits can be exceeded in particular cases. One of the preferred forms of such compositions consists of injectable microcapsules or microparticles with a mean size of between about 1 and 500 microns, dispersed in a vehicle intended for parenteral injection.
When administered in vivo or placed in an aqueous environment of physiological type, the pharmaceutical composition according to the invention releases the medicinal substance into the surrounding medium at a constant rate over a period of at least 1 week.
The Examples below serve to illustrate the present invention without thereby implying a limitation.
Example 1 Preparation of a succinic acid polyester 29.25 g (0.25 mol) of succinic acid were mixed with 22.53 g (0.25 mol) of butane-1,4-diol, 0.43 g of p-toluenesulphonic acid (1% by weight, based on the theoretical yield of polyester) and 90 ml of toluene, the mixture being placed in a reactor equipped with a magnetic stirrer. ' 9 a thermometera means for introducing inert gas (N?) and a water separator. The reaction mixture was heated to 110°C and. after 10 hours of heating, a first sample of polymer was taken in order to determine its intrinsic viscosity (I.V.). Samples were taken at regular intervals until the I.V. index had reached 0.34 (measured at 25°C in chloroform): heating was stopped at that point and the reaction mixture was left to cool to room temperature, with stirring.
Example 2 Preparation of a succinic acid polyester 47.24 g (0.40 mol) of succinic acid were mixed with 60.57 g (0.42 mol) of cyc1ohexane-1s4-dimethanol, the mixture being placed in a reactor equipped with a magnetic stirrer, a thermometer and a distillation bridge fitted to a means for introducing inert gas (N^) and to a vacuum pump. With the reaction mixture placed under an inert atmosphere, the temperature was gradually raised to 130 to 170°C over a period of 22 h and then kept at 180°C under a pressure of 1 am Hg. After 72 h of heating at this temperature and cooling to about °C, the desired polymer was collected: it had an I.V. index of 0.27 (measured at 25°C in chloroform).
Example 3 Preparation of a fumaric acid polyester 34.83 g (0.3 mol) of fumaric acid were mixed with 28.4 g (0.315 mol) of butane-2,3~diol and the mixture was placed in a reactor identical to that described in Example 2. With the reaction mixture placed under an inert atmosphere,, the temperature was gradually raised to 130 to 180°C over 6 h and then kept at 170-l80°C for 20 h under a pressure of 5 mm Hg.
The desired polymer was thus collected and had an average molecular weight of about 2000 (measurement of the vapour pressure by osmometry). ' Example 4 Preparation of a polyester-based pharmaceutical composition by microencapsulation 0.10 g of a decapeptide of the formula (pyrolGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH^ (hereafter called LHRH-D-Trp^) was suspended in a solution of 2.0 e of poly-1,4-butylene succinate (I.V. index 0.35; see Example 2) in 100 ml of methylene chloride. The suspension obtained was then emulsified with a solution of 1.35 g of methyl cellulose in 500 ml of distilled water (rotation speed 1900 rpm) and the organic solvent was then removed by rotary evaporation (rotation speed 470 rpm) for 2 h at 40°C under a pressure of 380 mm Hg. The resulting microcapsules were then filtered off, washed with cold H?0 and finally dried under vacuum.
Example 5 Preparation of a polyester-based pharmaceutical composition by microencapsulation 0.037 g of LHRH-D-Trp- was suspended in a solution of 1.0 g of poly-1,4-butylene succinate (average Ο molecular weight 2600) in 36 ml of methylene chloride, and 30 ml of silicone oil were then added gradually to the suspension, at a rate of about 5 ml/min, at room temperature. The resulting suspension, containing the embryonic microcapsules, was then poured, with thorough stirring, into 3000 ral of 1.1.2-trichlorotrifluoroethane (FREON 113) kept at room temperature. After 5 min of stirring, the resulting microcapsules were filtered off and then dried under vacuum.
Analysis of the microcapsules obtained by this method showed that they were totally devoid of all traces of residual solvent, especially FREON 113. By way of comparison, a solvent residue of at least 5% by weight is observed in the preparation of microcapsules from D.L-lactide/glycolide copolymer under identical conditions.
Example 6 Preparation, by microencapsulation, of a pharma ceutical composition based on a mixture of polymer and copolymer 0.037 g of LHRH-D-Trp^ was suspended in 36 ml of methylene chloride containing the following mixture in solution: - 0.40 g of poly-194-butylene succinate (average molecular weight approx. 2600) and - 0.60 g of 50:50 D.L-lactide/glycolide copolymer (average molecular weight approx. 45 000).
After undergoing the treatments described in Example 5, the suspension obtained produced microcapsules having the following characteristics: by means of a solubiliza tion treatment with dimethylformamide, it was demonstra that the D,L-lactide/glycolide copolymer formed the core of the microcapsules and that the poly-1,4-butylen succinate formed the outer wall of these microcapsules.
Furthermore, it was observed that the dried microcapsules had a better flow property than comparable microcapsules prepared either from D,L-lactide/ glycolide copolymer on its own or from poly-ls4butylene succinate on its own» Comparable results were obtained using mixtures containing 0.20 or 0.30 g of poly-1,4-butylene succinate (average molecular weight approx. 2600) and 0.80 or, respectively, 0.70 g of 50:50 D,L-lactide/glycolide copolymer (average molecular weight approx. 45 000).
Example 7 Determination of the activity of a pharmaceutical composition in the form of microcapsules These experiments were carried out using microcapsules of LHRH-D-Trpg prepared by the process of Example 5 and appropriately dried and sterilized.
The microcapsules were injected into rats (laboratory subjects) at a rate of 300 micrograms/kg, in the form of a sterile aqueous suspension (1% TWEEN/ 2% NaCMC). The LHRH-D-Trpg released and the testosterone were determined in the blood by radioimmunoassay according to the standard techniques. The results obtained are collated in the Table below (measurements made on 4 subjects).
Period LHRH-D-Trofi Testosterone (days ) (ng/ml) (ng/ml) 0 0.05 3.58 0.25 7.09 not determined 2 1.53 7.15 4 0.32 1.25 7 0.28 1 .13 11 0.23 1 .07 14 0.07 1.40 ] 18 0.06 1.72 1 21 0.07 1.55 I 25 0.07 I 2.40 _ After an initial stimulation phase (initial burst effect), the LHRH-D-Trp, is released continuously ό and at a constant rate up to day 11 and even beyond.
The testosterone decreases and reaches a castration level as from day 4; this castration level is maintained up to day 21.

Claims (15)

1. A sustained-release pharmaceutical composition comprising a medicinal substance and,, as a carrier for the medicinal substance„ a biodegradable polymer or copolymer ? derived from a dicarboxylic acid of the Krebs cycle, and a C 4 aliphatic diol or cyclohexane-1,4-dimethanol, the composition having the characteristic that, when administered in vivo or placed in an aqueous medium of physiological type, the medicinal substance is released into the surrounding medium at a constant rate over a period of at least 1 week.
2. A composition according to claim 1, wherein the dicarboxylic acid is fumaric acid, or succinic acid.
3. A composition according to claim 1 or claim 2, wherein the C, aliphatic diol is 1,4-butanediol or 2,3-butanediol.
4. A composition according to claim 2, wherein the diol is 1,4-butanediol, 2,3-butanediol or cyclohexane-1,4dimethanol, and which additionally comprises a lactic and/or glycolic acid polymer or copolymer.
5. A composition according to claim 4, wherein the lactic and/or glycolic acid polymer or copolymer has an average molecular weight of between 35,000 and 60,000.
6. A composition according to claim 5, wherein the lactic and/or glycolic acid polymer or copolymer represents from 60 to 80% by weight of the mixture of polymers and/or copolymers.
7. A composition according to any preceding claim, wherein the biodegradable polymer or copolymer has an average molecular weight of between 2,000 and 50,000.
8. A composition according to claim 7, wherein the biodegradable polymer or copolymer has an average molecular weight of between 2,000 and 10,000. I
9. A composition according to any preceding claim, which also comprises an agent for modifying the hydrolysis of the j polymer. XO. A composition according to any preceding claim, wherein the medicinal substance has an anti-inflammatory, anti-tumoral, immuno-suppressive, anti-thrombotic, neuroleptic, anti-depressant or anti-hypertensive effect. 5 ll. A composition according to any preceding claim, wherein the medicinal substance is a polypeptide.
10. 12. A composition according to claim 11, wherein the polypeptide is a decapeptide.
11. 13. A composition according to claim 11, wherein the 10 polypeptide is a luteinxsing hormone/follicle-stimulatxng hormone releasing hormone (LH/FSH-RH) or one of its natural or synthetic analogues, a thyrotropin-releasing hormone (TRH), insulin, somatostatin or one of its synthetic analogues, human or animal calcitonin, human or animal 15 growth hormone, growth hormone-releasing hormone (GHRH), a cardiopeptide or a natural or recombinant interferon.
12. 14. A composition according to any preceding claim, which comprises 0.5 to 20% by weight of the medicinal substance.
13. 15. A composition according to any preceding claim, in the 20 form of a matrix in which the medicinal substance is dispersed or solubilised.
14. 16. A composition according to claim 15, in the form of injectable microcapsules or microparticles having a mean size of between 1 and 500 μπι, dispersed in a vehicle ’ 25 intended for parenteral injection.
15. 17. A composition according to claim l, substantially as exemplified herein.
IE311088A 1987-10-14 1988-10-13 Polyester-based composition for the controlled release of medicinal substances IE60475B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH4022/87A CH672887A5 (en) 1987-10-14 1987-10-14

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IE60475B1 true IE60475B1 (en) 1994-07-13

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JP (1) JP2716747B2 (en)
BE (1) BE1001687A5 (en)
CA (1) CA1332808C (en)
CH (1) CH672887A5 (en)
DE (1) DE3835099A1 (en)
DK (1) DK571488A (en)
ES (1) ES2009347A6 (en)
FR (1) FR2622105B1 (en)
GB (1) GB2211091B (en)
GR (1) GR1000266B (en)
IE (1) IE60475B1 (en)
IT (1) IT1227394B (en)
NL (1) NL8802490A (en)
PT (1) PT88757B (en)

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Publication number Priority date Publication date Assignee Title
HU221294B1 (en) * 1989-07-07 2002-09-28 Novartis Ag Process for producing retarde compositions containing the active ingredient in a polymeric carrier
CH681425A5 (en) * 1990-11-14 1993-03-31 Debio Rech Pharma Sa
CH683149A5 (en) * 1991-07-22 1994-01-31 Debio Rech Pharma Sa Process for the preparation of microspheres of a biodegradable polymeric material.
ZA936692B (en) * 1992-09-12 1994-04-29 Dott Ltd Comp Physiologically active peptide composition
GB9310030D0 (en) * 1993-05-15 1993-06-30 Scras Dry processed particles and process for the preparation of the same
US6440457B1 (en) 1993-05-27 2002-08-27 Alza Corporation Method of administering antidepressant dosage form
FR2777895A1 (en) * 1998-04-28 1999-10-29 Debio Rech Pharma Sa Non crosslinked block polymer useful as support for active agents e.g. antigens and vaccines
WO2004108792A2 (en) * 2003-04-10 2004-12-16 Vinod Chintamani Malshe Novel biodegradable aliphatic polyesters and pharmaceutical compositions and applications thereof

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US3978203A (en) * 1974-07-12 1976-08-31 Dynatech Corporation Sustained release of pharmaceuticals from polyester matrices
DE2856901D2 (en) * 1977-06-07 1980-11-13 Garching Instrumente Form of implant medicament and preparation process
US4186189A (en) * 1977-09-28 1980-01-29 Ethicon, Inc. Absorbable pharmaceutical compositions based on poly(alkylene oxalates)
US4130639A (en) * 1977-09-28 1978-12-19 Ethicon, Inc. Absorbable pharmaceutical compositions based on isomorphic copolyoxalates
US4594407A (en) * 1983-09-20 1986-06-10 Allied Corporation Prosthetic devices derived from krebs-cycle dicarboxylic acids and diols
US4481353A (en) * 1983-10-07 1984-11-06 The Children's Medical Center Corporation Bioresorbable polyesters and polyester composites

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GB2211091A (en) 1989-06-28
NL8802490A (en) 1989-05-01
DE3835099A1 (en) 1989-04-27
JPH01157920A (en) 1989-06-21
DK571488A (en) 1989-04-15
GB2211091B (en) 1991-02-13
CH672887A5 (en) 1990-01-15
FR2622105B1 (en) 1993-05-14
DK571488D0 (en) 1988-10-13
ES2009347A6 (en) 1989-09-16
BE1001687A5 (en) 1990-02-06
GR1000266B (en) 1992-05-12
PT88757B (en) 1993-01-29
GB8823735D0 (en) 1988-11-16
IE883110L (en) 1989-04-14
FR2622105A1 (en) 1989-04-28
JP2716747B2 (en) 1998-02-18
IT1227394B (en) 1991-04-08
CA1332808C (en) 1994-11-01
IT8805224A0 (en) 1988-10-11

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