WO2002016443A1 - Nouveaux composes polymeres - Google Patents

Nouveaux composes polymeres Download PDF

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Publication number
WO2002016443A1
WO2002016443A1 PCT/US2000/023104 US0023104W WO0216443A1 WO 2002016443 A1 WO2002016443 A1 WO 2002016443A1 US 0023104 W US0023104 W US 0023104W WO 0216443 A1 WO0216443 A1 WO 0216443A1
Authority
WO
WIPO (PCT)
Prior art keywords
ester
polyanionic polymer
moieties
linking
amide
Prior art date
Application number
PCT/US2000/023104
Other languages
English (en)
Inventor
Richard Franklin
Didier S. P. Cowling
Jeffrey A. Hubbell
Petra Van De Wetering
Original Assignee
Phairson Medical Inc.
Eidgenossische Technische Hochschule Zurich
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 Phairson Medical Inc., Eidgenossische Technische Hochschule Zurich filed Critical Phairson Medical Inc.
Priority to JP2002521538A priority Critical patent/JP2004522808A/ja
Priority to AU2000269277A priority patent/AU2000269277A1/en
Priority to PCT/US2000/023104 priority patent/WO2002016443A1/fr
Priority to CA002425212A priority patent/CA2425212A1/fr
Priority to EP00957695A priority patent/EP1320553A4/fr
Publication of WO2002016443A1 publication Critical patent/WO2002016443A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00—Processes of polymerisation
    • C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F246/00—Copolymers in which the nature of only the monomers in minority is defined

Definitions

  • R 1 , R 2 and R 3 can be independently hydrogen or C C 3 alkyl and X is a direct bond or -C 3 alkylene.
  • the cleavage permitting group can include, in some embodiments, one or more Ci to C 6 normal or branched alkyl, phenyl or benzyl groups.
  • aryl means phenyl or a 5 or 6-membered heteroaryl group having up to Q - 2 heteroatoms independently selected from O, S, and N; wherein Q is the total number of atoms in the ring.
  • the ethylenically unsaturated linking agent can be, for example, an allyl ether of pentaerythritol or pentaerythritol triacrylate.
  • the unsaturated linking agent is an acrylate of pentaerythritol.
  • the unsaturated linking agent can be an acrylate- ester-acrylate pentaerythritol.
  • the polymers of the invention can be used in a microgel wherein the ratio of macroviscosity of the microgel to the microviscosity is 10,000 or less.
  • polyanionic polymer means a polymer having an acyclic backbone and having ionizable functional groups, for example carboxy groups, that become negatively charged functional groups, for example carboxylate anions, at physiological pH.
  • a gram of polyanionic polymer has 0.001 moles or more of functional groups that can be titrated with KOH.
  • the ionizable functional groups can be directly chemically bonded to the polymer backbone or they can be chemically bonded to a side group or side chain that is in turn chemically bonded to the main chain.
  • Carboxypolymethylene is an example of a polyanionic polymer in which the ionizable functional group is directly bonded to the main chain.
  • ⁇ -Poly(glutamic acid) is an example of a polyanionic polymer in which the ionizable functional group is bonded to a side group that is an ethylene group.
  • a polyanionic polymer segment is a linear polymerization product that is incorporated into a larger polymer via crosslinks; each such segment meets the definition for polyanionic polymer.
  • the above can be made from a variety of cores, such as 1,2-ethanediol, or from glycerol, or from triethanolamine, or from other cores that can be identified by those skilled in the art.
  • cores such as 1,2-ethanediol, or from glycerol, or from triethanolamine, or from other cores that can be identified by those skilled in the art.
  • lactyl esters i.e. dimers of lactic acid, or dimers of other hydroxy acids.
  • ester-containing group can be obtained by reacting PAO with acryloylchloride to obtain (21)
  • lactic acid esters such as be reacting PAO diol with lactic acid and phosgene to form (22):
  • the hydroxyl side groups can be cross-linked by reaction with PAO diol activated with phosgene to yield (29):
  • PAP derivatize some of side-chain carboxyl groups (or analogous groups) with aminoethane thiolgroups, and cross-links these with a degradable diacrylate linking agent, for example, (21) to yield (30):
  • (44) can be coupled to (41) in this way, yielding (46):
  • X is a direct bond or is a straight or branched alkylene group, preferably having two to six carbon atoms, one or more of which can be replaced with O, S, or N heteroatoms, provided that there is no heteroatom in a position ⁇ or ⁇ to Y.
  • Phenylene, oxazolylene, isoxazolylene, pyridazinylene, pyrimidinylene are examples of preferred arylenes.
  • linking moieties of the invention can be written according to the following formulas, wherein A, B, C Volunteer, D, D', X, X', X", Y, Y', Y", Y'", P, m, n, q or r are as defined above, wherein HO is a terminal hydroxymethyl group and wherein P' is any polymer described in the invention: P-X-D-Y-D'
  • This example sets forth methods for preparing hydrogel and microgel used in the context of the invention.
  • the chemicals and materials used therefor were: Glycerol (Merck, Darmstadt,
  • the carbopol was mixed in small amounts with distilled water under slow agitation with a propeller stirrer. The stirring continued until the powder was dissolved. Any trapped air was removed by reducing the pressure (water operated vacuum gauge). Glycerol was added under slow stirring and the pH was measured, and the 10% NaOH solution or the diisopropanol amine was used to adjust the composition to pH 7.4. Gelation occurred, resulting in a clear, transparent microgel. The resultant microgel was stored at 4°C.
  • Example 3 Reaction scheme for the preparation of compounds (21), (24), (25), (26), and (27)
  • Compound (30) was prepared by coupling PEG diacrylate via Michael-type addition to a thiol-functionalized PAA.
  • the thiol group of cysteamine hydrochloride (Fluka) was protected with a triphenyl methyl (trityl) group essentially according to Bodanszky and Bodanszky.
  • 1 eq cysteamine hydrochloride was dissolved in DMF under heating (to 60°C). After cooling the solution to 40°C, 1.1 eq triphenylmethanol (Fluka) was added. The reaction mixture was stirred at 60°C for 30 min, and then allowed to cool to room temperature. After addition of 1.1 eq boron trifluoride etherate, the reaction mixture was stirred at 80°C. After the reaction was complete according to TLC the solvent was removed in vacuo.
  • the solid product was dispersed in 5 % NaHCO 3 and extracted with ethyl acetate until no solid was present in the water layer.
  • the organic layer was washed with brine, dried over Na SO 4 , and concentrated in vacuo, yielding 87 % crude product.
  • the product was dissolved in water, slightly acidified with 1 M KHSO4, resulting in a precipitate which was recrystallized in EtOAc/MeOH obtaining white crystals in a 75% yield.
  • Thiol-derivatized PAA was obtained by radical copolymerization of acrylic acid (AA, 19 eq) and S-trityl-2-mercaptoethylacrylamide (1 eq) in toluene using 2,2'- azobisisobutyronitrile ("AIBN") as initiator (monomer/initiator 100/1, mol/mol) in the presence of 19 eq TEA. After stirring overnight at 60°C, the reaction mixture was concentrated in vacuo. The product was purified by dialysis against aqueous NaOH, and water. After lyophilization P(AA-co-S-trityl-2-mercaptoethylacrylamide) was obtained.
  • AIBN 2,2'- azobisisobutyronitrile
  • PAA crosslinked via ethylene glycol linkers can be obtained by radical copolymerization of AA and ethylene glycol diacrylate (Polysciences), e.g. in the ratio 500/1 (mol/mol). This copolymerization can be performed in an organic solvent (toluene) using AIBN as initiator. The polymer is purified by precipitation in icecold ether and dried in vacuo.
  • Ethylene glycol (1 eq OH) is dissolved in toluene and dried by azeotropic distillation for 1 h using a Dean Stark water separator. After the reaction mixture is allowed to cool to 50°C, L-lactide (1 eq) is added. The mixture is dried by azeotropic distillation for 1 h, and allowed to cool. When the temperature of the reaction mixture is about 50°C 1 eq CaH is added, and the reaction mixture is refluxed overnight. The reaction mixture is filtrated, and concentrated in vacuo, yielding compound (38).

Abstract

L'invention concerne une composition comprenant un polymère polyanionique qui n'est pas un polymère d'addition et pet être hydrolysé, qui comprend des brins de polymères formés à partir d'au moins un monomère éthyléniquement insaturé, les brins polymères étant liés par au moins un groupe fonctionnel de liaison comprenant un lien pouvant être hydrolysé. Au moins un des monomères possède: i) un ou plusieurs groupes fonctionnels qui peuvent être titrés avec une base pour former des groupes fonctionnels chargés négativement; ou ii) un ou plusieurs groupes précurseurs qui sont des précurseurs des groupes fonctionnels qui peuvent être titrés avec une base; ces groupes précurseurs sont transformés en groupes fonctionnels.
PCT/US2000/023104 2000-08-23 2000-08-23 Nouveaux composes polymeres WO2002016443A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2002521538A JP2004522808A (ja) 2000-08-23 2000-08-23 新規のポリマー化合物
AU2000269277A AU2000269277A1 (en) 2000-08-23 2000-08-23 Novel polymer compounds
PCT/US2000/023104 WO2002016443A1 (fr) 2000-08-23 2000-08-23 Nouveaux composes polymeres
CA002425212A CA2425212A1 (fr) 2000-08-23 2000-08-23 Nouveaux composes polymeres
EP00957695A EP1320553A4 (fr) 2000-08-23 2000-08-23 Nouveaux composes polymeres

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2000/023104 WO2002016443A1 (fr) 2000-08-23 2000-08-23 Nouveaux composes polymeres

Publications (1)

Publication Number Publication Date
WO2002016443A1 true WO2002016443A1 (fr) 2002-02-28

Family

ID=21741704

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/023104 WO2002016443A1 (fr) 2000-08-23 2000-08-23 Nouveaux composes polymeres

Country Status (5)

Country Link
EP (1) EP1320553A4 (fr)
JP (1) JP2004522808A (fr)
AU (1) AU2000269277A1 (fr)
CA (1) CA2425212A1 (fr)
WO (1) WO2002016443A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6652883B2 (en) 2000-03-13 2003-11-25 Biocure, Inc. Tissue bulking and coating compositions
US6676971B2 (en) 2000-03-13 2004-01-13 Biocure, Inc. Embolic compositions
US7070809B2 (en) 2000-03-13 2006-07-04 Biocure, Inc. Hydrogel biomedical articles
US7666225B2 (en) 2004-06-29 2010-02-23 Hassan Chaouk Spinal disc nucleus pulposus implant
US9232805B2 (en) 2010-06-29 2016-01-12 Biocure, Inc. In-situ forming hydrogel wound dressings containing antimicrobial agents
CN109225324A (zh) * 2018-08-15 2019-01-18 太原理工大学 固载l-脯氨酸温度响应性核壳微凝胶及其制备和应用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112016005768B1 (pt) * 2013-09-19 2021-09-21 Microvention, Inc Películas de polímero
US10155879B2 (en) * 2015-12-21 2018-12-18 AZ Electronic Materials (Luxembourg) S.à.r.l. Compositions and use thereof for modification of substrate surfaces

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4596858A (en) * 1981-11-27 1986-06-24 Gregor Harry P Solid state cross-linked polymer
US4666983A (en) * 1982-04-19 1987-05-19 Nippon Shokubai Kagaku Kogyo Co., Ltd. Absorbent article
US5126409A (en) * 1991-01-08 1992-06-30 Rohm And Haas Company Polyglutarimides with improved properties
US5229466A (en) * 1991-05-18 1993-07-20 Chemische Fabrik Stockhausen Gmbh Powdery absorbing material for aqueous liquids based on water-swellable carboxylate polymers
US5385983A (en) * 1992-11-12 1995-01-31 The Dow Chemical Company Process for preparing a water-absorbent polymer

Family Cites Families (4)

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EP0614468B1 (fr) * 1991-11-25 1997-09-17 Exxon Chemical Patents Inc. Composition polyionique de catalyseur de metaux de transition
US6030612A (en) * 1994-11-22 2000-02-29 Phairson Medical Inc. Antimicrobial uses of multifunctional enzyme
EP1100834B1 (fr) * 1998-04-28 2006-06-28 Inex Pharmaceuticals Corp. polymères polyanioniques à fusogénicité améliorée
JP2002537069A (ja) * 1999-02-23 2002-11-05 ファーソン メジカル インク． 損傷の治療方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4596858A (en) * 1981-11-27 1986-06-24 Gregor Harry P Solid state cross-linked polymer
US4666983A (en) * 1982-04-19 1987-05-19 Nippon Shokubai Kagaku Kogyo Co., Ltd. Absorbent article
US5126409A (en) * 1991-01-08 1992-06-30 Rohm And Haas Company Polyglutarimides with improved properties
US5229466A (en) * 1991-05-18 1993-07-20 Chemische Fabrik Stockhausen Gmbh Powdery absorbing material for aqueous liquids based on water-swellable carboxylate polymers
US5385983A (en) * 1992-11-12 1995-01-31 The Dow Chemical Company Process for preparing a water-absorbent polymer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1320553A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6652883B2 (en) 2000-03-13 2003-11-25 Biocure, Inc. Tissue bulking and coating compositions
US6676971B2 (en) 2000-03-13 2004-01-13 Biocure, Inc. Embolic compositions
US7070809B2 (en) 2000-03-13 2006-07-04 Biocure, Inc. Hydrogel biomedical articles
US8221735B2 (en) 2000-03-13 2012-07-17 Biocure, Inc. Embolic compositions
USRE47121E1 (en) 2000-03-13 2018-11-13 Biocure, Inc. Embolic compositions
USRE47873E1 (en) 2000-03-13 2020-02-25 Biocompatibles Uk Limited Embolic compositions
USRE48302E1 (en) 2000-03-13 2020-11-10 Biocure, Inc. Embolic compositions
US7666225B2 (en) 2004-06-29 2010-02-23 Hassan Chaouk Spinal disc nucleus pulposus implant
US9232805B2 (en) 2010-06-29 2016-01-12 Biocure, Inc. In-situ forming hydrogel wound dressings containing antimicrobial agents
CN109225324A (zh) * 2018-08-15 2019-01-18 太原理工大学 固载l-脯氨酸温度响应性核壳微凝胶及其制备和应用

Also Published As

Publication number Publication date
CA2425212A1 (fr) 2002-02-28
EP1320553A4 (fr) 2006-03-15
JP2004522808A (ja) 2004-07-29
EP1320553A1 (fr) 2003-06-25
AU2000269277A1 (en) 2002-03-04

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