WO1997029145A1 - Copolymers with polyester polycarbonate blocks containing poly(caprolactone) segments, and use thereof for the preparation of biodegradable matrices - Google Patents

Copolymers with polyester polycarbonate blocks containing poly(caprolactone) segments, and use thereof for the preparation of biodegradable matrices Download PDF

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Publication number
WO1997029145A1
WO1997029145A1 PCT/EP1997/000519 EP9700519W WO9729145A1 WO 1997029145 A1 WO1997029145 A1 WO 1997029145A1 EP 9700519 W EP9700519 W EP 9700519W WO 9729145 A1 WO9729145 A1 WO 9729145A1
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WO
WIPO (PCT)
Prior art keywords
formula
polyester
copolymers
residue
coo
Prior art date
Application number
PCT/EP1997/000519
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English (en)
French (fr)
Inventor
Paolo Ferruti
Maurizio Penco
Elisabetta Ranucci
Original Assignee
Asta Medica Aktiengesellschaft
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 Asta Medica Aktiengesellschaft filed Critical Asta Medica Aktiengesellschaft
Priority to JP9528140A priority Critical patent/JP2000505831A/ja
Priority to EP97902333A priority patent/EP0879258A1/en
Priority to AU16011/97A priority patent/AU1601197A/en
Publication of WO1997029145A1 publication Critical patent/WO1997029145A1/en

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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
    • A61K9/20—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)
    • 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
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/64—Polyesters containing both carboxylic ester groups and carbonate groups

Definitions

  • the present invention relates to block copolymers and to their use as biodegradable matrices for the controlled release of medicaments.
  • the polymers used as supports for controlled-release medicaments must be biocompatible, non-toxic and free of impurities.
  • biodegradable polymers must give non-toxic, non-carcinogenic and non-teratogenic degradation products and must be readily eliminated.
  • the factors which influence the biodegradability are the particle sizes, morphology and chemical structure. Among these factors, the crystallinity has an important role, both from the point of view of the biodegradability and from the technological point of view of working of the polymers.
  • microencapsulation comprises coacervation, evaporation of the emulsified solvent and coextrusion.
  • the latter is the preferred technique since it avoids the use of solvents and consequently poses no toxicological problems arising from residues thereof.
  • Extrudable polymers must be stable at the temperature of coextrusion, and must have a softening temperature which is not too high, to avoid decomposition of the medicament, but not too low either, to avoid problems of conservation.
  • Polycarbonates are polymers which have been known for a long time. Aliphatic polycarbonates are known, for example, from DE 2,546,534, published on 28 April 1977, JP 6224190, published on 22 October 1987 and JP 1009225, published on 12 January 1989, these patents proposing them as plasticizers and intermediates for the preparation of polyurethanes (see also US 4, 105,641 , granted on 8 August 1978).
  • biodegradation time of the material which is usually too short.
  • the rate of degradation is a function of the hydrolytic susceptibility of the polyester blocks.
  • Another problem consists of the presence of crystallinity in the material. Indeed, biodegradable materials having a certain degree of crystallinity have markedly longer degradation times when compared with a completely amorphous analogous material. Therefore, the presence of a crystalline phase allows the development of products which are useful when long degradation times are required. Another appreciable effect of this factor is a substantial increase in the mechanical properties, for example the elastic modulus. This is potentially useful when a use as subcutaneous implants is envisaged. However, this crystallinity is lost when the material comes into contact with an aqueous medium or when it absorbs moisture.
  • the melting range must be such as to be able to work the polymer easily without adversely affecting the active principle contained therein.
  • the products obtained have a degree of crystallinity which can be modified depending on the type of poly(caprolactone) segment used.
  • the working range of the semi-crystalline products is similar to that of the previous products.
  • the reason for this is that both PEG blocks and poly(caprolactone) blocks show melting points in the range 40 - 60°C, this being the optimum range for products used in extrusion processes.
  • One subject of the present invention is block copolymers of general formula (I)
  • a and B which may be the same or different, are blocks which can be obtained by reaction between a bis(chloroformate) of oligomeric poly(caprolactone) and a polyester residue of formula (II)
  • R, and R 2 which may be the same or different, are each an aliphatic hydrocarbon residue with a linear or branched chain having from 1 to 4 carbon atoms; x and y are integers from 1 to 50, in any possible ratio from 0 to 1 ; the groups -RrCOO- and -R 2 -COO- being randomly distributed in the polyester residue.
  • a subject of the present invention is block copolymers of formula (I)
  • a is an integer between 2 and 300 inclusive;
  • a and B which may be the same or different, are polyester blocks of formula (III) -[-Ri-CO-OJx-f-Rz-CO-O-ly-Rg- (III)
  • Ri and R 2 which may be the same or different, are an aliphatic hydrocarbon residue with a linear or branched chain having from 1 to 4 carbon atoms, x and y are integers from 1 to 50, in any possible ratio from 0 to 1 , the groups -Ri-COO- and -R 2 -COO- being randomly distributed in the polyester residue; R 3 is a residue of formula (IV)
  • m is an integer between 1 and 200, preferably between 2 and 100, where R 4 is an aliphatic hydrocarbon residue with a linear or branched chain having from 2 to 18 carbon atoms; or a cycloaliphatic hydrocarbon residue having from 3 to 8 carbon atoms optionally bearing one or more linear or branched alkyl substituents having from 1 to 4 carbon atoms; or alternatively R is a residue of formula (V)
  • R 4 is defined as above, and m and mi, which may be the same or different, are an integer between 1 and 200.
  • aliphatic hydrocarbon residue with a linear or branched chain having from 1 to 4 carbon atoms is understood to refer, for example, to: -CH 2 -; -CH 2 -CH 2 -; -(CH 2 ) 3 -; -(CH 2 ) 4 -; -CH(CH 3 )-; -CH(CH 3 )-CH 2 -; -CH(C 2 H 5 )-.
  • aliphatic hydrocarbon residue with a linear or branched chain having from 2 to 18 carbon atoms is understood to refer, for example, to:
  • cycloaliphatic hydrocarbon residue having from 3 to 8 carbon atoms is understood to refer, for example, to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl.
  • Examples of optional linear or branched alkyl substituents are methyl, ethyl, isopropyl, sec-butyl and tert-butyl.
  • a first group of preferred polymers are those in which, in the polyester blocks (II) and (III), R T and R 2 are
  • polyester blocks consist of lactic acid/glycolic acid, in particular in a 1 :1 molar ratio.
  • a second group of preferred polymers are those with number-average molecular weights of between 10,000 and 400,000.
  • a third group of preferred polymers are those with number-average molecular weights of between 25,000 and 67,000, in particular those of weight 67,400, 48,100, 33,200, 51 ,400, 49,700, 27,600 and 63,800.
  • the polymers of the present invention may be obtained by a chain- extension reaction between a bis(chloroformate) of an oligomeric poiy(caprolactone) with a polyester residue of formula (II) as described above.
  • the polyester block is prepared by reaction under vacuum of a mixture of hydroxy acids of formulae (VI) and (Vll)
  • R ⁇ R 2 , x and y are as defined above.
  • the starting materials are normally commercially available and are, in any case, described in the chemical literature.
  • the formulation of the polyester (II) takes place under at atmosphere of inert gas, for example nitrogen or argon, at a temperature of 170 - 220°C, preferably
  • the oligomer is cooled, while still maintaining the vacuum, and is isolated by precipitation from chloroform/ethyl ether.
  • polyester (II) is then reacted with the poly(caprolactone) bis(chloroformate) of formula (Vlll)
  • R 3 is as in formula (I), in a chlorinated solvent, optionally in the presence of a tertiary amine, at a temperature between -10 and 50°C, preferably 0 - 30°C, followed by application of the vacuum (pressure of 5 - 0.001 mmHg, preferably 1 - 0.01 mmHg), for a period of time between 4 and 30 hours, preferably between 15 and 20 hours.
  • Hydroxy-terminal poly(caprolactones) of the type described by formula (IVa) are commercially available Alternatively, they may be prepared by a reaction of poly(caprolactone) with an excess of diol HO-R 4 -OH
  • the hydroxy-terminal poly(caprolactone) of formula (Va) is obtained according to procedures described in the chemical literature, for example in US 3,654,347 and DE 2,634,211
  • polymers which form the subject of the invention have advantageous physicochemical properties which make them suitable for use as biodegradable matrices
  • these polymers are of modifiable crystallinity and this property imparts good characteristics of biodegradability and of workability thereto, in particular in the coextrusion technique.
  • Another subject of the invention is the use of the polymers described above for the preparation of biodegradable matrices, and the matrices thus obtained.
  • the matrices are preferably prepared by coextrusion of a mixture of the active principle under consideration and the polymer which constitutes the matrix. Several polymers may also be used.
  • the matrix may also contain conventional additives.
  • the matrices according to the present invention can also be prepared by other methods known to those skilled in the art.
  • the present invention provides pharmaceutical compositions with controlled release of the active principle, comprising a biodegradable matrix as described above, optionally mixed with conventional excipients and vehicles.
  • the present invention finds an advantageous application in the production of controlled-release pharmaceutical compositions, for example as subcutaneous implants, and in the production of physiologically active peptides, for example those described in EP 0,531 ,461 and EP 0,593,491.
  • Example 2 In a manner similar to that described in Example 1 , 243.33 g of a 72% by weight solution of D,L-lactic acid were reacted together. 125 g of oligomer were thus obtained having a number-average molecular weight of 2,630 (evaluated by titration in benzyl alcohol with a standard 0.1 N solution of tetrabutylammonium hydroxide in isopropanol) and an intrinsic viscosity of 0.132 dl/g, measured in chloroform at a temperature of 32°C
  • Example 2 In a manner similar to that described in Example 1 , 243.33 g of an 80% by weight solution of L-lactic acid were reacted together. 130 g of oligomer were thus obtained having a number-average molecular weight of 3,020 (evaluated by titration in benzyl alcohol with a standard 0.1 N solution of tetrabutylammonium hydroxide in isopropanol) and an intrinsic viscosity of 0 143 dl/g, measured in chloroform at a temperature of 32°C
  • Example 8 Using a procedure similar to that described in Example 7, 30 g of PLGA oligomer (described in Example 1 ) and 32 g of polycaprolactone diol oligomer having a number-average molecular weight of 2,000 were reacted together. 60 g of polymer were thus obtained having a number- average molecular weight of 48,100, an intrinsic viscosity of 0.823 dl/g, glass transition temperatures of -61 °C and 28°C and a melting point of 60°C Example 8
  • Example 7 Using a procedure similar to that described in Example 7, 30 g of PLGA oligomer (described in Example 1 ) and 8.48 g of polycaprolactone diol oligomer having a number-average molecular weight of 530 were reacted together. 35 g of polymer were thus obtained having a number-average molecular weight of 33,200, an intrinsic viscosity of 0.765 dl/g, and a glass transition temperature of 38°C
  • Example 7 Using a procedure similar to that described in Example 7, 40.64 g of PLGA oligomer (described in Example 2) and 8.48 g of polycaprolactone diol oligomer having a number-average molecular weight of 530 were reacted together. 45 g of polymer were thus obtained having a number-average molecular weight of 51 ,400, an intrinsic viscosity of 0.967 dl/g, and a glass transition temperature of 42°C
  • Example 7 Using a procedure similar to that described in Example 7, 42.1 g of PLGA oligomer (described in Example 3) and 8.48 g of polycaprolactone diol oligomer having a number-average molecular weight of 530 were reacted together. 47 g of polymer were thus obtained having a number-average molecular weight of 49,700, and an intrinsic viscosity of 0.887 dl/g.
  • Example 7 Using a procedure similar to that described in Example 7, 48.3 g of PLGA oligomer (described in Example 5) and 8.48 g of polycaprolactone diol oligomer having a number-average molecular weight of 530 were reacted together. 53 g of polymer were thus obtained having a number-average molecular weight of 63,800, and an intrinsic viscosity of 1.012 dl/g.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Polyesters Or Polycarbonates (AREA)
  • Medicinal Preparation (AREA)
PCT/EP1997/000519 1996-02-08 1997-02-06 Copolymers with polyester polycarbonate blocks containing poly(caprolactone) segments, and use thereof for the preparation of biodegradable matrices WO1997029145A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9528140A JP2000505831A (ja) 1996-02-08 1997-02-06 ポリ（カプロラクトン）セグメントを含有するポリエステルポリカーボネートブロックを有するコポリマーおよび生分解性マトリックスを製造するためのその使用
EP97902333A EP0879258A1 (en) 1996-02-08 1997-02-06 Copolymers with polyester polycarbonate blocks containing poly(caprolactone) segments, and use thereof for the preparation of biodegradable matrices
AU16011/97A AU1601197A (en) 1996-02-08 1997-02-06 Copolymers with polyester polycarbonate blocks containing poly(caprolactone) segments, and use thereof for the preparation of biodegradable matrices

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI96A000238 1996-02-08
IT96MI000238A IT1282585B1 (it) 1996-02-08 1996-02-08 Copolimeri a blocchi poliesterepolicarbonato contenenti segmenti di poli(caprolattone)e loro uso per la preparazione di matrici

Publications (1)

Publication Number Publication Date
WO1997029145A1 true WO1997029145A1 (en) 1997-08-14

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US (1) US5916998A (en])
EP (1) EP0879258A1 (en])
JP (1) JP2000505831A (en])
AU (1) AU1601197A (en])
IT (1) IT1282585B1 (en])
WO (1) WO1997029145A1 (en])
ZA (1) ZA971053B (en])

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1036806A3 (en) * 1999-03-15 2000-12-27 EVC Compounds (Italia) S.p.A. Polymeric materials of the polyester-carbonate family and reactions for the formation of such materials
USRE39713E1 (en) 1996-09-23 2007-07-03 Genzyme Corporation Polymerizable biodegradable polymers including carbonate or dioxanone linkages

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6514193B2 (en) * 2000-11-16 2003-02-04 Microspherix Llc Method of administering a therapeutically active substance
US7776310B2 (en) 2000-11-16 2010-08-17 Microspherix Llc Flexible and/or elastic brachytherapy seed or strand
JP4545428B2 (ja) * 2003-12-16 2010-09-15 株式会社ミツバ 電動モータ
EP1555278A1 (en) * 2004-01-15 2005-07-20 Innocore Technologies B.V. Biodegradable multi-block co-polymers
US7736293B2 (en) * 2005-07-22 2010-06-15 Biocompatibles Uk Limited Implants for use in brachytherapy and other radiation therapy that resist migration and rotation
US8187159B2 (en) 2005-07-22 2012-05-29 Biocompatibles, UK Therapeutic member including a rail used in brachytherapy and other radiation therapy
CN100372881C (zh) * 2006-08-10 2008-03-05 同济大学 一种生物全降解聚酯共聚物的制备方法
JP5694940B2 (ja) 2008-10-11 2015-04-01 ラトガース，ザ ステート ユニバーシティ オブ ニュー ジャージー 医療用途のための相分離した生体適合性ポリマー組成物
JP5944314B2 (ja) 2009-07-31 2016-07-05 ラトガース，ザ ステート ユニバーシティ オブ ニュー ジャージー 医療装置のための生体適合性ポリマー
CA3029961C (en) 2009-10-11 2021-06-22 Rutgers, The State Of University Of New Jersey Biocompatible polymers for medical devices
US11472918B2 (en) 2012-02-03 2022-10-18 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
JP6182159B2 (ja) 2012-02-03 2017-08-16 ラトガース，ザ ステート ユニバーシティ オブ ニュー ジャージー フェノール性単量体から誘導された高分子生体材料およびその医療用途
JP6592437B2 (ja) 2013-08-07 2019-10-16 ラトガース，ザ ステート ユニバーシティ オブ ニュー ジャージー ヒドロキシ酸およびフェノール化合物を含む単量体から誘導された高分子生体材料およびその医療用途
US10774030B2 (en) 2014-12-23 2020-09-15 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
CN107108863B (zh) 2014-12-23 2021-03-19 新泽西鲁特格斯州立大学 生物相容性的碘化二酚单体和聚合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011441A1 (en) * 1992-11-06 1994-05-26 Rijksuniversiteit Te Groningen Rubber-modified polylactide and/or glycolide composition
WO1995012629A1 (en) * 1993-11-05 1995-05-11 Mediolanum Farmaceutici S.P.A. High molecular weight polyesterpolycarbonates and the use thereof for the preparation of bioerosible matrices

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011441A1 (en) * 1992-11-06 1994-05-26 Rijksuniversiteit Te Groningen Rubber-modified polylactide and/or glycolide composition
WO1995012629A1 (en) * 1993-11-05 1995-05-11 Mediolanum Farmaceutici S.P.A. High molecular weight polyesterpolycarbonates and the use thereof for the preparation of bioerosible matrices

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE39713E1 (en) 1996-09-23 2007-07-03 Genzyme Corporation Polymerizable biodegradable polymers including carbonate or dioxanone linkages
EP1036806A3 (en) * 1999-03-15 2000-12-27 EVC Compounds (Italia) S.p.A. Polymeric materials of the polyester-carbonate family and reactions for the formation of such materials

Also Published As

Publication number Publication date
EP0879258A1 (en) 1998-11-25
ITMI960238A1 (it) 1997-08-08
ZA971053B (en) 1997-08-25
ITMI960238A0 (en]) 1996-02-08
JP2000505831A (ja) 2000-05-16
IT1282585B1 (it) 1998-03-31
US5916998A (en) 1999-06-29
AU1601197A (en) 1997-08-28

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