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US20060178477A1 - Degradable biocompatible block copolymer - Google Patents

Degradable biocompatible block copolymer Download PDF

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Publication number
US20060178477A1
US20060178477A1 US10/564,360 US56436004A US2006178477A1 US 20060178477 A1 US20060178477 A1 US 20060178477A1 US 56436004 A US56436004 A US 56436004A US 2006178477 A1 US2006178477 A1 US 2006178477A1
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oligo
block copolymer
hydroxybutyrate
diol
glycolide
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US10/564,360
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Peter Neuenschwander
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EIDGENOSSISCHE TECHNISCHE
Eidgenoessische Technische Hochschule Zurich ETHZ
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Eidgenoessische Technische Hochschule Zurich ETHZ
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Assigned to EIDGENOSSISCHE TECHNISCHE reassignment EIDGENOSSISCHE TECHNISCHE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NEUENSCHWANDER, PETER
Publication of US20060178477A1 publication Critical patent/US20060178477A1/en
Priority to US12/940,786 priority Critical patent/US8362159B2/en
Assigned to AB MEDICA S.P.A. reassignment AB MEDICA S.P.A. LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: SWISS FEDERAL INSTITUTE OF TECHNOLOGY OF ZURICH, UNIVERSITY OF ZURICH
Abandoned legal-status Critical Current

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    • 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
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/73—Polyisocyanates or polyisothiocyanates acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A61L17/105—Polyesters not covered by A61L17/12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A61L17/12—Homopolymers or copolymers of glycolic acid or lactic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
    • C08G18/4283—Hydroxycarboxylic acid or ester
    • 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
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • 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
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • 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
    • C08G63/91—Polymers modified by chemical after-treatment
    • C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
    • 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
    • C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G2261/10—Definition of the polymer structure
    • C08G2261/12—Copolymers
    • C08G2261/126—Copolymers block

Definitions

  • the invention relates to a biocompatible block copolymer comprising the polycondensation product of a diol and of a further component selected from the group of the same diol, an ⁇ , ⁇ -dihydroxypolyester or an ⁇ , ⁇ -dihydroxypolyether.
  • the invention additionally relates, besides the conventional applications of polyurethanes, to a medical implant comprising the block copolymer, to the use of the block copolymer for producing a medical implant, and to a diol and the process for preparing the same. Wherever the term medicine is used, both human and veterinary medicine is meant thereby.
  • biocompatible polymers employed in practice for medical implants is surprisingly small. This is attributable, apart from the problem of compatibility, firstly to the great technical requirements in relation to mechanical strength, sterilizability, biodegradability and secondly to the large number of different administrative regulations in individual countries.
  • the biodegradability of such a polymer in particular poses exacting requirements because the desired rate of degradability depends greatly on the use.
  • EP 0 196 486 discloses a biocompatible block copolymer that can be used as medical implant.
  • This block copolymer has a crystalline and an amorphous component. The degradability of these block copolymers is, however, not fast enough for all applications.
  • An additional object of the present invention is to provide a polymer which is readily degradable outside the body.
  • FIGS. 1 and 2 are graphical representations of decrease in molecular mass as a function of storage in water.
  • the biocompatible block copolymer and the diol have an exceptionally good biocompatibility.
  • the degradability of the block copolymer of the invention outside the body can be increased, besides the incorporation of glycolide or diglycolide units, by (L,L)-dilactide, (D,D)-dilactide, (D,L)-dilactide or mixtures thereof.
  • the diol Since the diol is composed of ⁇ - and/or ⁇ -hydroxy-alkanoates, degradation thereof forms toxicologically unobjectionable metabolites. There is intermediate formation of solid particles that are relatively small and are eliminated from the body by phagocytosis. The size of the water-insoluble particles is reduced through the incorporation of the diglycolide or glycolide units, thus facilitating and expediting the phagocytosis of the particles.
  • Applications in the non-medical sector are, for example, packaging materials and building material.
  • incorporation of the diol into the block copolymers of the invention makes it possible to influence the rate of degradation of the crystalline component.
  • the degradability in the body is controlled only through the incorporation of the glycolide or diglycolide units. It is therefore possible to control the degradability of such block copolymers via the crystalline component alone, the amorphous component alone or both components together.
  • the block copolymer of exemplary embodiments of the invention can be obtained by linear polycondensation of a diol with a further component selected from the group of the same diol, an ⁇ , ⁇ -dihydroxypolyester or an ⁇ , ⁇ -dihydroxypolyether in the presence of diisocyanate, diacid halide or phosgene. Linkage of these components results in polyurethanes with diisocyanate, polyesters with diacid halide and polycarbonates with phosgene.
  • the diol (1) can be obtained by transesterification of ⁇ , ⁇ -dihydroxy[oligo(3-(R)-hydroxybutyrate)ethylene-oligo(3-(R)-hydroxybutyrate)] (2), which is referred to hereinafter as PHB diol, with diglycolide (3) dilactide or caprolactone or mixtures thereof, the transesterification preferably being carried out in the presence of a catalyst.
  • m is 1 to 50
  • n is 1 to 50
  • x+y is 1 to 50.
  • the resulting polymers When diglycolide is incorporated, the resulting polymers have a high rate of degradability in the body, whereas dilactide and caprolactone units have no influence thereon.
  • Preferred catalysts are transesterification catalysts in particular based on tin, e.g. dibutyltin dilaurate.
  • the diol preferably has a molecular weight of from 500 to 10 000 daltons.
  • the diol (1) preferably has a total glycolide content of up to 40 mol %, particularly preferably up to 30 mol %.
  • a preferred diol of exemplary embodiments of the invention is ⁇ , ⁇ -dihydroxy[oligo(3-(R)-hydroxybutyrate)-stat-glycolide)ethyleneoligo(3-(R)-hydroxybutyrate-stat-glycolide) or the corresponding stat-lactide or stat-caprolactate compounds if dilactide or caprolactone is used instead of diglycolide.
  • An ⁇ , ⁇ -dihydroxypolyester can be obtained for example by transesterification of poly[(R)-(3)-hydroxybutyric acid] or its copolymers with 3-hydroxy-valeric acid with ethylene glycol.
  • ⁇ , ⁇ -dihydroxypolyesters are oligomers of ⁇ -, ⁇ -, ⁇ - and ⁇ -hydroxy carboxylic acids and their cooligomers which are obtained by ring-opening polymerization of cyclic esters or lactones.
  • Preferred cyclic esters of this type are (L,L)-dilactide, (D,D)-dilactide, (D,L)-dilactide, diglycolide or the preferred lactones such as ⁇ -(R)-butyrolactone, ⁇ -(S)-butyrolactone, ⁇ -rac-butyrolactone and ⁇ -caprolactone or mixtures thereof.
  • the ring opening takes place with aliphatic diols such as ethylene glycol or longer-chain diols.
  • the molecular weight of the resulting macrodiol is determined by the stoichiometrically employed amount of these diols.
  • the ring-opening polymerization of the cyclic esters or lactones preferably takes place without diluent in the presence of a catalyst, for example SnO(Bu) 2 at 100° C. to 160° C.
  • a catalyst for example SnO(Bu) 2 at 100° C. to 160° C.
  • the resulting macrodiols have molecular weights of about 300-10 000 daltons.
  • the macrodiols prepared from mixtures of cyclic esters or lactones have a microstructure which depends on the amount of catalyst and which is statistical or alternating in the distribution of the monomeric components between block form. The distributions statistics have an influence on the physical properties.
  • esters which are obtained by ring-opening polymerization of cyclic esters and lactones in the presence of a catalyst and which can be used to prepare the block copolymers are ⁇ , ⁇ -dihydroxy-[poly(L-lactide)-ethylene-poly(L-lactide)]; ⁇ , ⁇ -dihydroxy-[oligo(3-(R)-hydroxybutyrate-ran-3-(S)-hydroxybutyrate)-ethylene-oligo(3-(R)-hydroxybutyrate-ran-3-(S)-hydroxybutyrate)]; ⁇ , ⁇ -dihydroxy-[oligo(glycolide-ran- ⁇ -caprolactone)-ethylene-oligo(glycolide-ran- ⁇ -caprolactone)]; ⁇ , ⁇ -dihydroxy-[oligo(L)-lactide-ran- ⁇ -caprolactone)-ethylene-oligo(L)-lactide-ran- ⁇ -caprolactone)]; ⁇ , ⁇ -di
  • Diisocyanates suitable for preparing the polyurethane variant of the block copolymers are in particular hexamethylene diisocyanate, 2,2,4-trimethylhexamethylene diisocyanate, cyclohexyl 1,4-diisocyanate, cyclohexyl 1,2-diisocyanate, isophorone diisocyanate, methylenedicyclohexyl diisocyanate and L-lysine diisocyanate methyl ester.
  • Diacid halides particularly suitable for preparing the polyester variant of the block copolymers are those of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, trimethyladipic acid, sebacic acid, dodecanediacid, tetradecanedioic acid and hexadecanedioic acid.
  • a particularly preferred block copolymer is poly[poly[ ⁇ , ⁇ -dihydroxy-[oligo(3-(R)-hydroxybutyrate)-stat-glycolide)-ethylene-oligo-(3-(R)-hydroxybutyrate-stat-glycolide)]alt-2,2,4-trimethylhexamethylene 1,6-diisocyanate]]-co-poly[dihydroxy[oligo-glycolide-ran- ⁇ -caprolactone)-ethylene-(oligo-glycolide-ran- ⁇ -caprolactone)]alt-2,2,4-trimethylhexamethylene 1,6-diisocyanate] of the formula
  • the block copolymers and diols comprising glycolide units which are particularly preferred are those degradable in five to six days within the human or animal body. Further preferred block copolymers and diols are those whose degradation takes place over months or years. The rate of degradation depends primarily on the number of diglycolide or glycolide units. On storage in a neutral buffer solution at 37° C., the molecular weight decreases with time as a function of the glycolide content. The use of dilactide or caprolactone units does not change the rate of degradability of the polymers of exemplary embodiments of the invention in the body.
  • the block copolymer of exemplary embodiments of the invention forms phase-segregated crystalline domains in the solid polymer, which decisively determine the mechanical properties of the block copolymer of exemplary embodiments of the invention, such as, for example, the good strength, the brittleness, and the increased ultimate elongation and ultimate tensile stress.
  • the physical properties of such block copolymers are decisively controlled by the mass ratio of crystalline and amorphous polymer contents.
  • a crystalline content of from 5 to 50% is preferred in this connection.
  • the amount of crystalline component which has a decisive influence on the mechanical properties, can be chosen relatively freely due to the diol, because the rate of degradation can also be controlled by the diol.
  • the block copolymers and diols of the invention have exceptionally good solubility in organic solvents such as dioxane, chlorinated solvents, DMSO etc. and have the special advantage that their physical, chemical and biological properties can be adjusted within a wide range through the number of diglycolide/dilactide/caprolactone units.
  • the block copolymers and diols of exemplary embodiments of the invention can thus be adapted for specific uses in each case.
  • the block copolymers can be modified by copolymerization with further low molecular weight compounds. These copolymerized compounds have one or more functional groups. These functional groups may be protected or unprotected reactive groups, or groups which confer particular use properties on the diols. For example, these low molecular weight compounds may make it possible to use the block copolymers as X-ray contrast agents or in other diagnostic methods such as CT and MRI as agents for increasing contrast. If the functional groups are reactive groups, they make it possible for active substances to be covalently bonded to the block copolymer of exemplary embodiments of the invention. Examples of such active substances are diagnostics such as contrast agents, pharmaceutical active substances, peptides, proteins, etc.
  • Particularly suitable low molecular weight comonomers are diatrizoic acid monoglyceryl ester; 10,11-dihydroxyundecanoic acid; phenacyl 10,11-dihydroxyundecanoate; 2,2-bis(hydroxymethyl)propionic acid; phenacyl bis(hydroxymethyl)propionate.
  • diatrizoic acid monoglyceryl ester 10,11-dihydroxyundecanoic acid
  • phenacyl 10,11-dihydroxyundecanoate 2,2-bis(hydroxymethyl)propionic acid
  • phenacyl bis(hydroxymethyl)propionate phenacyl bis(hydroxymethyl)propionate.
  • a further important property of the diol of exemplary embodiments of the invention or of the block copolymers is their melt-processibility. They can generally be processed at temperatures between 80° to 200°, preferably between 100° and 150°. Processing can take place correspondingly by known methods by means of extrusion and blow or injection molding. Sheets can also be produced by compression. This melt-processibility entails the advantage for medical implants that the shape and size of the implant can be adapted. A further possibility is for surgical suture material made thereof to be welded appropriately, making it possible to dispense with complicated knotting.
  • the implants may also be in the form of a tube.
  • the tube may be rigid or flexible.
  • the tubes may have circular, elliptical and polygonal cross sections, it also being possible to dispose a plurality of channels within one tube. It is possible with the implants of the invention to regenerate a functional vessel wall or a nerve. It is possible by a coating with functional vessel cells to avoid a thrombotic occlusion on long-term use, i.e. the biocompatible polymer can in time be replaced by new endogenous cells.
  • the implant material may have a porous structure for particular uses. It may also have a capsule shape to receive pharmaceutical active substances or diagnostics also in the form of particles.
  • Tubular structures (vessel substitute, trachea substitute, substitute for other biological tubular structures) in firm, coiled, flexible, expandable, self-expanding, braided and knitted form, which may in accordance with the biological and functional requirement have a physically and pharmacologically appropriate texture or coating on the inside or outside.
  • the pharmacological substances are retained either by absorption or covalent chemical bonding to the diol or to the block copolymer.
  • the implant materials are likewise suitable for producing stents (rigid, expandable, self-expanding) for vessels or other biological tubular structures (esophagus, biliary tract, urinary tract).
  • Sheet-like structures (wound covering, membrane oxygenators, corneal substitute bases etc.) can likewise be produced with the diol of exemplary embodiments of the invention or the block copolymer.
  • Thread-like structures as surgical suture material and for processing to woven, braided or knitted structures.
  • Preconditioned place holders for skin substitute, adipose tissue, tendons, cartilage and bone, nerves etc.).
  • Polymeric structures which, owing to the physical or biological loading properties and physical structures (foams, gel, micro- and nanospheres) and the surface structure, make it possible to deliver therapeutic (hormones, medicaments) or cosmetic (liposomes, proteins, vitamins) substances via internal anatomical structures or via the skin.
  • Shaped articles which, in a suitable shape and loading with bioactive substances, make reversible or irreversible contraception possible through blockage (oviduct, spermatic duct).
  • the diol or block copolymer of exemplary embodiments of the invention can additionally be used as base for culturing corneal cells on sheets for transplantation as corneal substitute.
  • further possible uses in appropriate physical and or biological form are in medical dental, micro- or nanotechnologies.
  • the diols of exemplary embodiments of the invention are extremely biocompatible in in vitro cell cultures with macrophages and fibroblasts owing to the observation of cell adhesion, cell growth, cell vitality and cell activation, and of the production of extracellular proteins and cytokines.
  • the polymers of exemplary embodiments of the invention are, apart from in the medical sector, suitable as packaging materials and as building material.
  • the degraded oligomer is filtered off and suspended in about 6 to 7 L of distilled water a total of 5 times, and filtered off again after 20 hours. After the last washing, the granular oligomer is sucked dry for one hour and then dried in 2 large crystallizing dishes firstly in a drying oven at 50° C. in vacuo. Then, the oligomer is further dried under high vacuum (10 ⁇ 2 bar) in a drying oven at 60° C. for 30 hours.
  • the dry oligomer is subsequently dissolved in methylene chloride to result in a 30-35% solution.
  • the slightly warmed solution is then filtered through a quartz sand bed on a glass filter funnel.
  • the filtrate is purified by chromatography on a silica gel 60 column.
  • the precipitate is filtered off and dried.
  • the transesterification of ⁇ , ⁇ -dihydroxy[oligo-3-(R)-hydroxybutyrate)-ethylene-oligo-(3-(R)-hydroxybutyrate)] with diglycolide was carried out in an oil-heated jacketed 350 ml reactor, which was equipped with a temperature sensor, capillary for nitrogen as protective gas and a reflux condenser on a dropping funnel with pressure equalization.
  • the dropping funnel was packed with A4 molecular sieves.
  • Diglyme or xylenes or other high-boiling inert solvents were used as solvents. The mixture was heated until the required reaction temperature of 140° C. in the reactor was reached.
  • the desired amount of diglycolide was dissolved in dry diglyme and slowly added in the desired amount per unit time by means of a metering pump to the contents of the reactor.
  • the catalyst dibutyltin dilaurate was put into the reactor at the start of the addition of glycolide.
  • the amount of added catalyst was between 0-10% by weight based on the diglycolide.
  • the total reaction time was increased by comparison with the glycolide addition time in some experiments in order to obtain more quantitative glycolide incorporation.
  • the reaction temperature was 140° C., but 130° C. for E7 and 120° C. for E8. After the reaction, the polymer was precipitated in 5 times the amount of n-hexane, filtered off and dried.
  • 25 g of crude polymer are extracted with methanol in a SOXHLET with cooling jacket cooling to 18° C. for 6 hours and then dried in vacuo.
  • the polymer is then extracted with dry methylene chloride in the same cooled SOXHLET and precipitated with five times the amount of dry methanol and dried in vacuo.
  • the polymerization was carried out in an oil-heated jacketed 1000 mL reactor, which was equipped with a temperature sensor, capillary for nitrogen as protective gas and a reflux condenser on a dropping funnel with pressure equalization.
  • the dropping funnel was packed with A4 molecular sieves.
  • Glycolide/ ⁇ -caprolactone 1/1 molar; PHB/glycolide diol from Example 1.
  • the influence of the glycolide-modified PHB diol on the rate of degradation was determined in relation to a structurally analogous polymer with unmodified PHB diol.
  • the degradation experiments were carried out on the crude polymer in powder form and on polymer samples, which were previously processed to films and open-cell foams (pore size about 50-300 ⁇ m).

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  • Chemical Kinetics & Catalysis (AREA)
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  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Materials For Medical Uses (AREA)
  • Polyesters Or Polycarbonates (AREA)
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US10/564,360 2003-07-16 2004-07-06 Degradable biocompatible block copolymer Abandoned US20060178477A1 (en)

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US12/940,786 US8362159B2 (en) 2003-07-16 2010-11-05 Degradable biocompatible block copolymer

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EP03016148.3A EP1498147B1 (de) 2003-07-16 2003-07-16 Abbaubares biokompatibles Blockcopolymer
EP03016148.3 2003-07-16
PCT/EP2004/007344 WO2005007210A1 (de) 2003-07-16 2004-07-06 Abbaubares biokompatibles blockcopolymer

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US8674032B2 (en) 2004-01-15 2014-03-18 Innocore Technologies B.V. Biodegradable multi-block co-polymers
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US20100168832A1 (en) * 2006-06-09 2010-07-01 Peter Neuenschwander Scaffolds for artificial heart valves and vascular structures
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US9173973B2 (en) 2006-07-20 2015-11-03 G. Lawrence Thatcher Bioabsorbable polymeric composition for a medical device
US9724864B2 (en) 2006-10-20 2017-08-08 Orbusneich Medical, Inc. Bioabsorbable polymeric composition and medical device
US9211205B2 (en) 2006-10-20 2015-12-15 Orbusneich Medical, Inc. Bioabsorbable medical device with coating
US9649412B2 (en) 2008-01-15 2017-05-16 Abbott Cardiovasculary Systems Inc. Implantable medical devices fabricated from polyurethanes with biodegradable hard and soft blocks and blends thereof
US9006382B2 (en) 2008-05-19 2015-04-14 Molecon, Inc. Synthesis polyesters with precisely sequenced two or more structural units
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US8765161B2 (en) 2009-07-31 2014-07-01 Rutgers, The State University Of New Jersey Monomers and phase-separated biocompatible polymer compositions prepared therefrom for medical uses
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US11124603B2 (en) 2012-02-03 2021-09-21 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
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US12030983B2 (en) 2012-02-03 2024-07-09 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
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US10266647B2 (en) 2014-12-23 2019-04-23 Rutgers, The State University Of New Jersey Biocompatible iodinated diphenol monomers and polymers
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JP2009513747A (ja) 2009-04-02
US20110093066A1 (en) 2011-04-21
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US8362159B2 (en) 2013-01-29

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