EP1250361A2 - Hydrogels d'alcool polyvinylique degradable - Google Patents

Hydrogels d'alcool polyvinylique degradable

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Publication number
EP1250361A2
EP1250361A2 EP00993007A EP00993007A EP1250361A2 EP 1250361 A2 EP1250361 A2 EP 1250361A2 EP 00993007 A EP00993007 A EP 00993007A EP 00993007 A EP00993007 A EP 00993007A EP 1250361 A2 EP1250361 A2 EP 1250361A2
Authority
EP
European Patent Office
Prior art keywords
hydrogel
crosslinking
group
groups
modifiers
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00993007A
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German (de)
English (en)
Inventor
Thomas Hirt
Troy Holland
Vimala Francis
Hassan Chaouk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biocure Inc
Original Assignee
Biocure Inc
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Filing date
Publication date
Application filed by Biocure Inc filed Critical Biocure Inc
Publication of EP1250361A2 publication Critical patent/EP1250361A2/fr
Withdrawn legal-status Critical Current

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    • 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
    • C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/24—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/64—Use of materials characterised by their function or physical properties specially adapted to be resorbable inside the body
    • 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
    • A61L27/16—Macromolecular materials obtained 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61L31/048—Macromolecular materials obtained 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • 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
    • C08F261/00—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00
    • C08F261/02—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00 on to polymers of unsaturated alcohols
    • C08F261/04—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00 on to polymers of unsaturated alcohols on to polymers of vinyl alcohol
    • 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
    • C08F8/00—Chemical modification by after-treatment
    • 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
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/12—Hydrolysis
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/003—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds

Definitions

  • the present invention relates generally to degradable hydrogels and more specifically to degradable poly(vinyl alcohol) (PVA) hydrogels that are suitable for use as biomaterials.
  • PVA poly(vinyl alcohol)
  • Biocompatible hydrogels have become a favored material for many biomedical applications. In many cases, it is preferable to employ a hydrogel that is biodegradable so that the body can rid itself of the foreign material over a period of time.
  • a biodegradable hydrogel is disclosed in U.S. Patent No. 5,410,016 to Hubbell et al. This material is made from biodegradable, polymerizable macromers having a water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and free radical polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer interlinking, wherein the polymerizable end groups are separated from each other by at least one degradable region.
  • the macromers include a central backbone of polyethylene glycol flanked by degradable regions of polycaprolactone or polylactide, which are in turn flanked by polymerizable vinyl groups.
  • a primary disadvantage of the macromers and hydrogels disclosed by Hubbell is that they are inflexible in design. PEG has only two groups which are easily modified, the terminal hydroxyl groups, and those groups are modified with the biodegradable and polymerizable groups.
  • Hubbell does not disclose any ways in which the macromers can be modified or in which the hydrogel can be modified after its formation.
  • the degradable PEG material developed by Hubbell et al. exhibits a large degree of swelling in aqueous solutions, which is disadvantageous in many applications.
  • PVA based hydrogels are disclosed in U.S. Patent Nos. 5,508,317 and 5,932,674 to Muller. However, these hydrogels are not degradable.
  • PVA hydrogels offer many advantages over PEG based hydrogels.
  • the availability of pendant OH groups along a PVA backbone adds versatility in terms of the various modifications that could be made to the macromer (e.g. attachment of degradable segments, active agents, hydrophobic groups, etc).
  • a PVA system with its pendant OH groups allows for variations in loading (density) of the attached groups, and this is an important feature to have in a macromer.
  • PEG hydrogels are noted for their superior swelling in aqueous environments. This swelling property could be undesirable for certain applications.
  • the choice of a suitable PVA (with appropriate attached groups if desired) can yield a non- swellable, minimally swellable. or even shrinkable system.
  • PVA possesses greater adhesive properties than PEG. This might be desirable for certain applications. Furthermore, PVA due to its hydrocarbon backbone has greater oxidative stability than PEG and it can be stored as aqueous solutions as opposed to PEG that has to be stored as a freeze-dried powder.
  • PVA macromer can be done in aqueous medium with a final ultrafiltration step for purification.
  • PEG-based acrylates/ methacrylates are prepared in organic solvents, and if not purified well can have toxic residuals such as triethylamine hydrochloride.
  • PVA hydrogels that have been developed are not degradable. Accordingly, it would be advantageous to have a PVA hydrogel that is degradable and methods for making such hydrogels. Moreover, it would be advantageous to have a degradable hydrogel having multiple pendant groups that allow for the attachment of various modifiers.
  • the invention is directed to biodegradable biocompatible hydrogels based on poly(vinyl alcohol) and methods for their preparation.
  • the degradable hydrogels can be formed in vivo or ex vivo.
  • the hydrogels can be used for a number of biomedical applications, including, but not limited to, implants, embolic agents, wound healing dressings, adhesion prevention, sealants, bulking agents, coatings for biomaterials, and delivery of biologically active compounds such as drugs, genes, proteins, and enzymes.
  • the hydrogels are advantageous in that the PVA backbone can be easily modified and can provide hydrogels having very different properties.
  • the methods for preparation of the hydrogels involve the use of prepolymers.
  • the prepolymers have a PVA backbone and pendant chains that include a polymerizable group.
  • the pendant chains also include a biodegradable region.
  • biodegradable regions are incorporated into the hydrogel during its formation.
  • a PVA prepolymer having crosslinkable groups and a second component having a degradable region flanked by crosslinkable groups are combined under conditions suitable for crosslinking the groups.
  • the resulting hydrogel that is formed contains PVA chains linked by degradable regions.
  • PVA prepolymers are formed having pendant crosslinkable groups separated from the PVA backbone by a biodegradable region.
  • Hydrogels are formed by exposing the prepolymers to conditions that initiate crosslinking of the crosslinkable groups.
  • the many pendant hydroxyl groups of PVA allow great versatility in design of hydrogels with desired characteristics. Suitable hydrogels can be formed without having to employ each of the hydroxyl groups for attaching crosslinkable groups. Certain hydroxyl groups can be modified before the prepolymer is formed, after the prepolymer is formed, or even after the hydrogel is formed.
  • Figure 1 illustrates the mass loss over time in pH 7.4 buffer for a hydrogel made from a 3 -ester acrylate modified PVA at 1 meq/g crosslinker density. ⁇ indicates the degradation at 37C; ⁇ indicates the degradation at 50C.
  • Figure 2 illustrates the mass loss for a hydrogel made from 3-ester acrylate modified
  • ⁇ indicates the degradation at 0.5 meq/g crosslinker density and 50C; ⁇ indicates the degradation at 0.5 meq/g crosslinker density and 70C; x indicates the degradation at 1.0 meq/g crosslinker density and 50C: • indicates the degradation at 1 .0 meq/g crosslinker density and 70C: • indicates the degradation at 1 .8 meq/g crosslinker density and 50C: and I indicates the degradation at 1.8 meq/g crosslinker density and 70C.
  • Figure 3 illustrates the mass loss for a hydrogel made from 3-ester methacrylate modified PVA at 1 meq/g crosslinker density in pH 7.4 buffer.
  • ⁇ indicates an average wet weight of four samples at 37C (wet); ⁇ indicates the degradation at 50C (wet); ⁇ indicates the degradation at 37C (dry); and x indicates the degradation at 50C (dry).
  • Figure 4 illustrates the mass loss for a hydrogel made from 5-ester acrylate modified
  • ⁇ indicates the degradation at 70C and pH 7.4; and x indicates the degradation at 70C and pH 9.0.
  • Biodegradable hydrogels based on poly(vinyl alcohol) have been developed which can be rapidly formed in an aqueous surrounding, e.g., in vivo.
  • the PVA based hydrogels can be designed to degrade as fast as a few hours to more than 1 year. Degradation rates are determined in one respect by selection of an appropriate degradable region. For example, use of hydroxyethyl methacrylate (HEMA)-lactate as the biodegradable/ crosslinkable groups will likely provide faster degradation than the use of a 3-ester methacrylate such as mono-2- (methacryoyloxy)ethyl succinate. Other factors that will affect the degradation rate are the density of the pendant chain bearing the degradable region, the length of the degradable region, the hydrophobicity of the network, and the crosslinking density.
  • HEMA hydroxyethyl methacrylate
  • Other factors that will affect the degradation rate are the density of the pendant chain bearing the degradable region, the length of the
  • the hydrogels are formed by crosslinking two components.
  • Component A is a prepolymer having a PVA backbone having pendant chains with crosslinkable groups
  • component B is a molecule having a degradable region flanked by crosslinkable groups.
  • Component A Prepolymer Backbone with Polymerizable Groups PVA
  • the prepolymers have a backbone of a polyhydroxy polymer, such as PVA or copolymers of vinyl alcohol that contain, for example, a 1,3-diol skeleton.
  • the backbone can also contain hydroxyl groups in the form of 1.2-glycols. such as copolymer units of 1.2- dihydroxyethylene. These can be obtained, for example, by alkaline hydrolysis of vinyl acetate-vinylene carbonate copolymers.
  • Other polymeric diols can be used, such as saccharides.
  • the prepolymers can also contain small proportions, for example of up to 20%. preferably of up to 5%, of comonomer units of ethylene, propylene.
  • Mowiol ® products from Hoechst. in particular those of the 3-83, 4-88, 4-98, 6-88. 6-98. 8-88, 8-98. 10-98, 20-98, 26-88, and 40-88 types.
  • copolymers of hydrolyzed or partially hydrolyzed vinyl acetate which are obtainable, for example, as hydrolyzed ethylene-vinyl acetate (EVA), or vinyl chloride-vinyl acetate. N-vinylpyrrolidone-vinyl acetate, and maleic anhydride-vinyl acetate.
  • EVA hydrolyzed ethylene-vinyl acetate
  • vinyl chloride-vinyl acetate vinyl chloride-vinyl acetate
  • N-vinylpyrrolidone-vinyl acetate N-vinylpyrrolidone-vinyl acetate, and maleic anhydride-vinyl acetate.
  • the prepolymer backbones are, for example, copolymers of vinyl acetate and vinylpyrrolidone, it is again possible to use commercially available copolymers. for example the commercial products available under the name Luviskol ® from BASF. Particular examples are Luviskol VA 37 HM.
  • Polyvinyl alcohols that can be derivatized in accordance with the invention preferably have a molecular weight of at least 10.000.
  • the polyvinyl alcohols may have a molecular weight of up to 1 ,000,000.
  • the polyvinyl alcohols have a molecular weight of up to 300.000. especially up to approximately 100,000 and especially preferably up to approximately 30.000.
  • the polyvinyl alcohols usually have a poly(2-hydroxy)ethylene structure.
  • the polyvinyl alcohols derivatized in accordance with the disclosure may, however, also comprise hydroxy groups in the form of 1 ,2-glycols.
  • the PVA system can be a fully hydrolyzed PVA, with all repeating groups being - CH 2 -CH(OH), or a partially hydrolyzed PVA with varying proportions (25% to 1 %) of pendant ester groups.
  • PVA with pendant ester groups have repeating groups of the structure CH 2 -CH(OR) where R is COCH 3 group or longer alkyls, as long as the water solubility of the PVA is preserved.
  • the ester groups can also be substituted by acetaldehyde or butyraldehyde acetals that impart a certain degree of hydrophobicity and strength to the PVA.
  • the commercially available PVA can be broken down by NaI0 -KMn0 oxidation to yield a small molecular weight (3-4K) PVA.
  • the PVAs are prepared by basic or acidic, partial or virtually complete hydrolysis of polyvinyl acetate.
  • the polyvinyl alcohol derivatized in accordance with the invention comprises less than 50% of vinyl acetate units, especially less than about 25% of vinyl acetate units.
  • Preferred amounts of residual acetate units in the polyvinyl alcohol derivatized in accordance with the invention, based on the sum of vinyl alcohol units and acetate units, are approximately from 3 to 25%.
  • the prepolymers contain pendant groups that can be crosslinked to one end of the component B molecules.
  • Various crosslinkable groups can be used.
  • Crosslinkable Groups Crosslinking of components may be via any of a number of means, such as physical crosslinking or chemical crosslinking. Physical crosslinking includes, but is not limited to, complexation. hydrogen bonding, desolvation, Van der wals interactions, and ionic bonding.
  • Chemical crosslinking can be accomplished by a number of means including, but not limited to, chain reaction (addition) polymerization, step reaction (condensation) polymerization and other methods of increasing the molecular weight of polymers/oligomers to very high molecular weights.
  • Chain reaction polymerization includes but is not exclusive to free radical polymerization (thermal, photo, redox, atom transfer polymerization, etc.), cationic polymerization (including onium). anionic polymerization (including group transfer polymerization), certain types of coordination polymerization, certain types of ring opening and metathesis polymerizations, etc.
  • Step reaction polymerizations include all polymerizations which follow step growth kinetics including but not limited to reactions of nucleophiles with electrophiles. certain types of coordination polymerization, certain types of ring opening and metathesis polymerizations, etc.
  • Other methods of increasing molecular weight of polymers/oligomers include but are not limited to polyelectrolyte. formation, grafting, ionic crosslinking, etc.
  • a two part redox system is employed.
  • One part of the system contains a reducing agent such as ferrous salt.
  • a reducing agent such as ferrous salt.
  • ferrous salts can be used, such as ferrous gluconate dihydrate, ferrous lactate dihydrate, or ferrous acetate.
  • the other half of the solution contains an oxidizing agent such as hydrogen peroxide.
  • Either or both of the redox solutions can contain macromer, or it may be in a third solution. The two solutions are combined and the agents react to initiate the crosslinking.
  • reducing agents can be used, such as, but not limited to cuprous salts, cerous salts, cobaltous salts, permanganate, and manganous salts.
  • oxidizing agents include, but are not limited to. t-butyl hydroperoxide. t-butyl peroxide, benzoyl peroxide, cumyl peroxide, etc.
  • crosslinkable groups consist preferably of the following groups: (meth)acrylamide, (meth)acrylate. styryl, vinyl ester, vinyl ketone, vinyl ethers, etc. Specific Prepolymers
  • units containing a crosslinkable group conform, in particular, to the formula I
  • R is a linear or branched C ⁇ -C 8 alkylene or a linear or branched C j -C 12 alkane.
  • Suitable alkylene examples include octylene, hexylene, pentyiene, butylene, propylene, ethylene, methylene, 2-propylene, 2-butylene and 3-pentylene.
  • Preferably lower alkylene R has up to 6 and especially preferably up to 4 carbon atoms.
  • the groups ethylene and butylene are especially preferred.
  • Alkanes include, in particular, methane, ethane, n- or isopropane, n-. sec- or tert-butane. n- or isopentane. hexane, heptane, or octane.
  • Preferred groups contain one to four carbon atoms, in particular one carbon atom.
  • R- is hydrogen, a CpC ⁇ alkyl. or a cycloalkyl, for example, methyl, ethyl, propyl or butyl and R 2 is hydrogen or a C]-C ⁇ alkyl, for example, methyl, ethyl, propyl or butyl.
  • Ri and R 2 aie preferably each hydrogen.
  • R 3 is an olefinically unsaturated electron attracting copolymerizable radical having up to 25 carbon atoms. In one embodiment. R 3 has the structure
  • R 5 is hydrogen or C 1 -C 4 alkyl, for example, n-butyl. n- or isopropyl, ethyl, or methyl; n is zero or 1. preferably zero: and
  • R and R7 independently of one another, are hydrogen, a linear or branched CpCs alkyl, aryl or cyclohexyl. for example one of the following: octyl, hexyl, pentyl, butyl, propyl, ethyl, methyl, 2-propyl, 2-butyl or 3-pentyl.
  • Re is preferably hydrogen or the CH 3 group
  • R 7 is preferably a C
  • R 6 and R 7 as aryl are preferably phenyl.
  • R 3 is an olefinically unsaturated acyl group of formula R -
  • Rg is an olefinically unsaturated copolymerizable group having from 2 to 24 carbon atoms, preferably from 2 to 8 carbon atoms, especially preferably from 2 to 4 carbon atoms.
  • the olefinically unsaturated copolymerizable radical Rg having from 2 to 24 carbon atoms is preferably alkenyl having from 2 to 24 carbon atoms, especially alkenyl having from 2 to 8 carbon atoms and especially preferably alkenyl having from 2 to 4 carbon atoms, for example ethenyl, 2-propenyl. 3-propenyl, 2-butenyl. hexenyl. octenyl or dodecenyl.
  • the groups ethenyl and 2-propenyl are preferred, so that the group -CO-Rg is the acyl radical of acrylic or methacrylic acid.
  • the group R 3 is a radical of formula
  • R 9 and Rio are each independently lower alkylene having from 2 to 8 carbon atoms, arylene having from 6 to 12 carbon atoms, a saturated divalent cycloaliphatic group having from 6 to 10 carbon atoms, arylenealkylene or alkylenearylene having from 7 to 14 carbon atoms or arylenealkylenearylene having from 13 to 16 carbon atoms, and R 8 is as defined above.
  • Lower alkylene R 9 or R* 0 preferably has from 2 to 6 carbon atoms and is especially straight-chained. Suitable examples include propylene, butylene. hexylene. dimethylethylene and. especially preferably, ethylene.
  • Arylene R 9 or Rio is preferably phenylene that is unsubstituted or is substituted by lower alkyl or lower alkoxy, especially 1.3-phenylene or 1 ,4-phenylene or methyl- 1.4- phenylene.
  • a saturated divalent cycloaliphatic group R 9 or Rio is preferably cyclohexylene or cyclohexylene-lower alkylene, for example cyclohexylenemethylene. that is unsubstituted or is substituted by one or more methyl groups, such as, for example, trimethylcyclohexylenemethylene, for example the divalent isophorone radical.
  • the arylene unit of alkylenearylene or arylenealkylene R 9 or R is preferably phenylene, unsubstituted or substituted by lower alkyl or lower alkoxy. and the alkylene unit thereof is preferably lower alkylene. such as methylene or ethylene, especially methylene.
  • Such radicals R 9 or Rio are therefore preferably phenylenemethylene or methyienephenylene.
  • Arylenealkylenearylene R 9 or Rio is preferably phenylene-lower alkylene-phenylene having up to 4 carbon atoms in the alkylene unit, for example phenyleneethylenephenylene.
  • the radicals R 9 and R ] 0 are each independently preferably lower alkylene having from 2 to 6 carbon atoms, phenylene, unsubstituted or substituted by lower alkyl, cyclohexylene or cyclohexylene-lower alkylene, unsubstituted or substituted by lower alkyl, phenylene-lower alkylene, lower alkylene-phenylene or phenylene-lower alkylene-phenylene.
  • the divalent group -R 9 -NH-CO-O- is present when q is one and absent when q is zero. Prepolymers in which q is zero are preferred.
  • the divalent group -CO-NH-(R 9 -NH-CO-O) q -R ⁇ 0 -O ⁇ is present when p is one and absent when p is zero.
  • Prepolymers in which p is zero are preferred. In prepolymers in which p is one. q is preferably zero. Prepolymers in which p is one, q is zero, and Rio is lower alkylene are especially preferred.
  • All of the above groups can be monosubstituted or polysubstituted, examples of suitable substituents being the following: C
  • -C 4 alkyl a 5- or 6-membered heterocyclic ring, such as, in particular, indole or imidazole.
  • -NH-C(NH)- NH a phenoxyphenyl (unsubstituted or substituted by, for example. -OH or halogen, such as Cl. Br or especially I), an olefinic group, such as ethylene or vinyl, and CO-NH-C(NH)-NH 2 .
  • Preferred substituents are lower alkyl, which here, as elsewhere in this description, is preferably C,-C 4 allyl, C r C 4 alkoxy. COOH, SH, -NH 2 . -NH(C,-C 4 alkyl), -N(C, -C 4 alkyl) 2 or halogen. Particular preference is given to -C 4 alkyl. C 1 -C 4 alkoxy, COOH and SH.
  • cycloalkyl is. in particular, cycloalkyl
  • aryl is. in particular, phenyl, unsubstituted or substituted as described above.
  • the prepolymers can include further modifier groups and crosslinkable groups such as those described in U.S. Patent No. 5,932,674.
  • Crosslinkable groups and the optional further modifier groups can be bonded to the prepolymer skeleton in various ways, for example through a certain percentage of the 1 ,3-diol units being modified to give a 1.3-dioxane, which contains a crosslinkable radical, or a further modifier, in the 2-position.
  • Modifiers that might be attached to the hydroxyls include those to modify the hydrophobicity, active agents or groups to allow attachment of active agents, photoinitiators. modifiers such as polymers or molecules to enhance or reduce adhesiveness, polymers to impart thermoresponsiveness. polymers to impart other types of responsiveness, and additional crosslinking groups.
  • Component B Component B is a molecule having a degradable region flanked by crosslinkable groups. Component B contains at least 1 group capable of crosslinking with the crosslinkable groups of component A. Component B also includes at least one group capable of crosslinking with other components B after they have been attached to component A.
  • component A crosslinks with component B
  • component B includes a group capable of crosslinking with the olefinically unsaturated group of component A.
  • Component B can include other copolymers in addition to the degradable region and crosslinkable group.
  • Crosslinkable Groups Any of the crosslinkable groups described above with respect to component A can also be used on component B. Different types of crosslinking may be employed for crosslinking of A to one end of B and of B with other B's. Degradable Regions
  • the degradable region is preferably degradable under in vivo conditions by hydrolysis.
  • the degradable region can be enzymatically degradable.
  • the degradable region may be polymers and oligomers of glycolide, lactide, ⁇ -caprolactone. other hydroxy acids, and other biologically degradable polymers that yield materials that are non- toxic or present as normal metabolites in the body.
  • Preferred poly( ⁇ -hydroxy acid)s are poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid).
  • Other useful materials include poly(amino acids), poly(anhydrides), poly(orthoesters), poly(phosphazines), and poly(phosphoesters).
  • Polylactones such as poly( ⁇ -caprolactone), poly( ⁇ -caprolactone). poly( ⁇ -valerolactone) and poly( ⁇ -butyrolactone), for example, are also useful.
  • Enzymatically degradable linkages include poly(amino acids), gelatin, chitosan, and carbohydrates.
  • the biodegradable regions may have a degree of polymerization ranging from one up to values that would yield a product that was not substantially water soluble. Thus, monomeric, dimeric, trimeric, oligomeric, and polymeric regions may be used.
  • the biodegradable region could, for example, be a single methacrylate group.
  • Biodegradable regions can be constructed from polymers or monomers using linkages susceptible to biodegradation, such as ester, acetal, carbonate, peptide. anhydride, orthoester, phosphazine, and phosphoester bonds.
  • the prepolymers of formulae I are extraordinarily stable. Spontaneous crosslinking by homopolymerization does not typically occur.
  • the prepolymers of formula I can furthermore be purified in a manner known per se, for example by precipitation with acetone, dialysis, or ultrafiltration. Ultrafiltration is especially preferred. By means of that purification process the prepolymers of formula I can be obtained in extremely pure form, for example in the form of concentrated aqueous solutions that are free, or at least substantially free, from reaction products, such as salts, and from starting materials.
  • the preferred purification process for the prepolymers of the invention can be carried out in a manner known per se. It is possible for the ultrafiltration to be carried out repeatedly, for example from two to ten times. Alternatively, the ultrafiltration can be carried out continuously until the selected degree of purity is attained.
  • the selected degree of purity can in principle be as high as desired.
  • a suitable measure for the degree of purity is, for example, the sodium chloride content of the solution, which can be determined simply in known manner.
  • the prepolymers of formulae I are crosslinkable in an extremely effective and controlled manner.
  • the methods of making a hydrogel from components A and B involves combining the components under conditions suitable for crosslinking of components A and B and, optionally in a second step, crosslinking of components B after they have been attached to components A.
  • a suitable solvent is in principle any solvent that dissolves components A and B.
  • a suitable solvent for example water, alcohols, such as lower alkanols, for example ethanol or methanol. also carboxylic acid amides, such as dimethylforrnamide. or dimethyl sulfoxide, and also a mixture of suitable solvents, such as, for example, a mixture of water with an alcohol, such as, for example, a water/ethanol or a water/methanol mixture.
  • the combination of A and B is preferably carried out in a substantially aqueous solution.
  • the criterion that the prepolymer is soluble in water denotes in particular that the prepolymer is soluble in a concentration of approximately from 3 to 90%) by weight, preferably approximately from 5 to 60%) by weight, in a substantially aqueous solution.
  • prepolymer concentrations of more than 90% are also included in accordance with the invention.
  • substantially aqueous solutions of the prepolymer comprise especially solutions of the prepolymer in water, in aqueous salt solutions, especially in aqueous same solutions that have an osmolarity of approximately from 200 to 450 milliosmol per 1000 ml (unit: mOsm/1), preferably an osmolarity of approximately from 250 to 350 mOsm/I, especially approximately 300 mOsm/1, or in mixtures of water or aqueous salt solutions with physiologically tolerable polar organic solvents, such as, for example, glycerol. Solutions of the prepolymer in water or in aqueous salt solutions are preferred.
  • the viscosity of the solution of the prepolymer in the substantially aqueous solution is, within wide limits, not critical, but the solution should preferably be a flowable solution that can be deformed strain-free.
  • the molecular weight of the prepolymer is also, within wide limits, not critical. Preferably, however, the prepolymer has a molecular weight of from approximately 3,000 to approximately 200.000. most preferably from about 3,000 to 30,000.
  • Components A and B are preferably combined such that a hydrogel is formed having crosslinking in an amount of from approximately 0.25 to 10 milliequivalents of crosslinker per gram of PVA (meq/g), more desirably about 0.25 to 1.5 meq/g.
  • a large excess of B can be used, such as a ten fold increase. It is possible that a partially degradable hydrogel will result from this system. Such a partially degradable hydrogel may be desirable for some applications.
  • the prepolymers used in the process according to the invention can be purified in a manner known per se, for example by precipitation with organic solvents, such as acetone, filtration and washing, extraction in a suitable solvent, dialysis or ultrafiltration, ultrafiltration being especially preferred.
  • organic solvents such as acetone, filtration and washing
  • the prepolymers can be obtained in extremely pure form, for example in the form of concentrated aqueous solutions that are free, or at least substantially free, from reaction products, such as salts, and from starting materials, such as, for example, non-polymeric constituents.
  • the preferred purification process for the prepolymers used in the process according to the invention, ultrafiltration can be carried out in a manner known per se.
  • the ultrafiltration can be carried out repeatedly, for example from two to ten times.
  • the ultrafiltration can be carried out continuously until the selected degree of purity is attained.
  • the selected degree of purity can in principle be as high as desired.
  • a suitable measure for the degree of purity is, for example, the sodium chloride content of the solution, which can be determined simply in a known manner, such as by conductivity measurements.
  • One additive that is added, where appropriate, to the solution of the prepolymer is an initiator for the crosslinking, should an initiator be required for crosslinking the crosslinkable groups.
  • an initiator be required for crosslinking the crosslinkable groups.
  • a prepolymer is used to produce the hydrogel.
  • the prepolymer includes a PVA backbone having pendant chains having a degradable region and crosslinkable group.
  • the biodegradable regions are attached to the PVA backbone to form a prepolymer prior to crosslinking of the prepolymer into a hydrogel. It is desired that at least a majority of the crosslinkable groups are attached to the polymer via the degradable region.
  • the prepolymer when polymerized results in a crosslinked network that is permeable to water but water insoluble. This crosslinked PVA network has degradable segments in between the crosslinked moieties.
  • the degradable segment may be attached to the backbone in two ways.
  • One method involves the preparation of a degradable crosslinker containing both the polymerizable segment and the degradable segment, followed by its attachment to the PVA backbone.
  • the attachment of the degradable crosslinker to the backbone can be done by suitable functional ization of pendant hydroxyl groups on the PVA backbone and/or the degradable crosslinker.
  • a second method involves the attachment of the degradable segment first to the PVA backbone, following which the crosslinkable moiety is attached to the degradable segment.
  • the ease of synthesis as well as the type of degradable segment and crosslinker used determines the type of method used.
  • the choice of a suitable degradable segment, its length and loading dictate the final degradation profile achieved, although this is also a function of certain environmental factors such as pH. temperature and buffer concentrations.
  • Wacker Polyviol ®
  • Mowiol ® products from Hoechst, in particular those of the 3-83.
  • 4-88 4-98, 6-88, 6-98, 8-88, 8-98, 10-98, 20-98, 26-88, and 40-88 types.
  • copolymers of hydrolyzed or partially hydrolyzed vinyl acetate which are obtainable, for example, as hydrolyzed ethylene-vinyl acetate (EVA), or vinyl chloride-vinyl acetate, N-vinylpyrrolidone-vinyl acetate, and maleic anhydride-vinyl acetate.
  • EVA hydrolyzed ethylene-vinyl acetate
  • vinyl chloride-vinyl acetate vinyl chloride-vinyl acetate
  • N-vinylpyrrolidone-vinyl acetate N-vinylpyrrolidone-vinyl acetate
  • maleic anhydride-vinyl acetate maleic anhydride-vinyl acetate.
  • copolymer backbones are, for example, copolymers of vinyl acetate and vinylpyrrolidone.
  • commercially available copolymers for example the commercial products available under the name Luviskol ® from BASF. Particular examples are Luvis
  • the prepolymer backbones are polyvinyl acetates, Mowilith 30 from Hoechst is particularly suitable.
  • the PVA should preferably have a molecular weight of at least 10,000.
  • the polyvinyl alcohols may have a molecular weight of up to 1 ,000,000.
  • the polyvinyl alcohols have a molecular weight of up to 300.000. especially up to approximately 100,000 and especially preferably up to approximately 30,000.
  • PVAs usually have a poly(2-hydroxy)ethylene structure.
  • the PVA may, however, also comprise hydroxy groups in the form of 1 ,2-glycols.
  • the PVA system can be a fully hydrolyzed PVA, with all repeating groups being -
  • PVA with pendant ester groups have repeating groups of the structure CH -CH(OR) where R is COCH 3 group or longer alkyls, as long as the water solubility of the PVA is preserved.
  • the ester groups can also be substituted by acetaldehyde or butyraldehyde acetals that impart a certain degree of hydrophobicity and strength to the PVA.
  • the commercially available PVA can be broken down by NaI0 4 -KMn0 4 oxidation to yield a small molecular weight (3-4K) PVA.
  • the PVA is prepared by basic or acidic, partial or virtually complete hydrolysis of polyvinyl acetate.
  • the polyvinyl alcohol derivatized in accordance with the invention comprises less than 50%> of vinyl acetate units, especially less than 20% of vinyl acetate units.
  • Preferred amounts of residual acetate units in the polyvinyl alcohol derivatized in accordance with the invention, based on the sum of vinyl alcohol units and acetate units, are approximately from 3 to 20%, preferably approximately from 5 to 16%).
  • Degradable Region Generally the same degradable regions can be used as are described above for the two component embodiment.
  • the PVA based hydrogels can be designed to degrade as fast as an hour to a day (with cross linkers containing rapidly degradable segments such as HEMA- glycolate and HEA-glycolate), to a few days or more than 1 year, with degradable segments such as 3-ester or 5-ester methacrylates or acrylates (for example, using mono-2- (methacryloyloxy)ethyl succinate (a 3-ester methacrylate), or mono-2-(Acryloyloxy)ethyl succinate (AOES, a 3-ester acrylate).
  • the desired degradability can be achieved using an appropriate degradable region, an appropriate region length, by varying the hydrophobicity of the network with pendant groups, and by varying the density or loading of the degradable/ crosslinking chains.
  • crosslinkable groups that can be used in the single component embodiment are the same as those described above with respect to the two component embodiment. Modifiers
  • the prepolymers can include further modifier groups and crosslinkable groups such as those described in U.S. Patent No. 5,932,674.
  • Crosslinkable groups and the optional further modifier groups can be bonded to the prepolymer skeleton in various ways, for example through a certain percentage of the 1.3-diol units being modified to give a 1 ,3-dioxane. which contains a crosslinkable radical, or a further modifier, in the 2-position.
  • Modifiers that might be attached to the hydroxyls include those to modify the hydrophobicity, active agents or groups to allow attachment of active agents, photoinitiators, modifiers such as polymers or molecules to enhance or reduce adhesiveness, polymers to impart thermoresponsiveness. polymers to impart other types of responsiveness, and additional crosslinking groups.
  • the prepolymers can be made in at least two ways.
  • a degradable crosslinker containing both the polymerizable group and the degradable region is prepared, followed by its attachment to the PVA backbone.
  • the attachment of the degradable cross linker to the backbone can be done by suitable functionalization of pendant hydroxyl groups on the PVA backbone and/or groups on the degradable cross linker.
  • the degradable segment is first attached to the PVA backbone, following which the cross linkable moiety is attached to the degradable segment.
  • the methods for attaching the crosslinkable group to the degradable region and for attaching the degradable region to the PVA will vary according to the type of crosslinkable group and degradable region used. One skilled in the art will be capable of designing a synthetic scheme.
  • Degradable glycolide or lactide based crosslinkers can be prepared according to the reference Furch, M. et al., Polymer, 39(10): 1977- 1982 (1998). It should be noted that this experimental procedure offers several advantages. First, a variety of degradable segments derived from glycolide. lactide. caprolactone. cyclic anhydrides, etc. can be prepared each of which provides a specific degradation profile. Second, this technique also allows for a " 1 - step " synthesis of a degradable cross linker by simple control of the initial "feed ratio" of monomer to initiator. Third, by supplying a feed of different monomer types and monomer ratios, one could prepare a variety of random or block copolymers to achieve a specific degradation pattern. Fourth, one could incorporate end cappers such as succinic anhydride in the initial monomer feed to prepare acid-terminated segments, thereby eliminating an additional synthetic step. Methods for Using the Prepolymers and Hydrogels
  • the hydrogels can be used for a number of biomedical applications, including, but not limited to, implants, embolic agents, wound healing dressings, adhesion prevention, sealants, bulking agents, coatings for biomaterials, and delivery of biologically active compounds such as drugs, genes, proteins, and enzymes.
  • a hydrogel is formed from the prepolymers prior to implantation in or application or administration to a patient.
  • a hydrogel is formed in situ at the intended site of use.
  • a soft tissue implant can be formed by injecting a solution of prepolymers into the site where the implant is to be formed, along with the second component if the two component embodiment is used. Crosslinking of the prepolymers is initiated to form the hydrogel.
  • compositions can also be used to create tissue supports by forming shaped articles within the body to serve a mechanical function.
  • Such supports include, for example, sealants for bleeding organs, sealants for bone defects and space-fillers for vascular aneurysms. Further, such supports include strictures to hold organs, vessels or tubes in a particular position for a controlled period of time.
  • the compositions can be applied in a number of ways, such as injection, via catheter, by spray, by pouring or spreading on a surface.
  • the composition can be used for encapsulation of various agents, such as therapeutic, diagnostic and prophylactic agents.
  • the compositions can be used to deliver an active agent which can be any of a variety of materials, including proteins, carbohydrates, nucleic acids, and inorganic and organic biologically active molecules. Specific examples include enzymes, antibiotics, antineoplastic agents, local anesthetics, hormones, antiangiogenic agents, antibodies, neurotransmitters, psychoactive drugs, drugs affecting reproductive organs, and oligonucleotides such as antisense oligonucleotides. Cells, tissues, and organelles can also be encapsulated.
  • the prepolymers are polymerized with the biologically active materials to form microspheres or nanoparticles containing the biologically active material.
  • the macromer, photoinitiator, and agent to be encapsulated are mixed in an aqueous mixture. Particles of the mixture are formed using standard techniques, for example, by mixing in oil to form an emulsion, forming droplets in oil using a nozzle, or forming droplets in air using a nozzle.
  • the suspension or droplets are irradiated with a light suitable for photopolymerization of the macromer.
  • Hydrogels having moderate to slow degradation times, ranging from a few days, to months, to a year were prepared. Degradation profiles are shown in Tables 1 and 2.
  • Example 1 Preparation of Degradable PVA containing 3-ester acrylate cross linker.
  • 3-ester acrylate modified PVA was prepared having 0.5 to 1.8 milliequivalents of the side chain per gram of PVA (meq/g). The following recipe is for 1.0 meq/g. The proportion of crosslinker chain to PVA was adjusted to prepare prepolymers with other meq/g.
  • Dried mono-2-(acryloyloxy)ethyl succinate (AOES, 2.3 g, 10.6 mmoles) in dichloromethane (DCM, 35 mL) was maintained under nitrogen at about 5°C. One glass stopper was removed and replaced with a rubber septum.
  • DCM dichloromethane
  • DCC Dicyclohexylcarbodiimide
  • the dicyclohexylurea (DCU) byproduct was removed by filtration through a glass frit.
  • the precipitate was rinsed with a little DCM and the DCM was removed from the filtrate using the rotary evaporator.
  • About 5 mL or more of DMSO was added as needed in order to dissolve the anhydride.
  • 29.4 g of an 18% PVA solution in DMSO was added.
  • the PVA used was Mowiol 3-83.
  • some polymer may precipitate. If this does occur, stir the solution until the solution is homogenous. Heating the solution to 60°C may be required. When the solution was homogeneous. 5 drops of triethylamine was added. The solution was stirred at room temperature overnight. The following day, the solution was heated to 60°C for 1 hour. The solution was precipitated into a 10-fold excess of acetone (vs. volume of DMSO).
  • Additional DMSO may be needed to dilute the solution so the polymer is able to precipitate adequately. About 12-15% solids is appropriate.
  • the gels Prior to the degradation experiment, the gels were stored in USP water at 4°C. A gel sample was removed from solution using small forceps. The excess water was removed from the gel by touching the sample to the side of the beaker. The sample was then placed in a vial, the lid placed on the vial and weighed on a 4-place balance. Determination of the initial dry weight
  • the lid was removed and the samples were exposed in order for it to start to dry.
  • a few pieces of dry ice were placed in a small Dewar flask. Ethanol was slowly added to the dry ice. Wait until the evolution of C0 2 has slowed before beginning.
  • the vial was held without the lid using crucible tongs and about 1 cm of the bottom of the vial was submerged into the cold ethanol for 1 minute. At this time the vial was removed from the cold ethanol, the excess ethanol was dried from the bottom of the vial using a paper towel and the vial was placed in the freezer and kept there for at least 1 hour. The samples were placed into the freeze-drier overnight. The next day, the dried samples were weighed with the lids on.
  • the vial was removed from the oven and allowed to cool for a few minutes, then a small plastic pipet was used to remove the excess water without touching the sample. After all the excess water was removed, all the excess water from the lid and inside the vial was removed without touching the sample. The lid was replaced and the weight of the sample was determined as described above for the wet weight determination. After this was done, either some fresh HEPES solution was added to the vial or the sample was freeze-dried and the dry weight of the sample was determined.
  • Figure 1 illustrates the mass loss over time in pH 7.4 buffer for a hydrogel made from a 3-ester acrylate modified PVA at 1 meq/g crosslinker density. ⁇ indicates the degradation at 37C; ⁇ indicates the degradation at 50C.
  • Figure 2 illustrates the mass loss for a hydrogel made from 3-ester acrylate modified PVA in pH 9.0 buffer.
  • ⁇ indicates the degradation at 0.5 meq/g crosslinker density and 50C;
  • ⁇ indicates the degradation at 0.5 meq/g crosslinker density and 70C;
  • x indicates the degradation at 1.0 meq/g crosslinker density and 50C;
  • * indicates the degradation at 1.0 meq/g crosslinker density and 70C;
  • • indicates the degradation at 1.8 meq/g crosslinker density and 50C: and I indicates the degradation at 1.8 meq/g crosslinker density and 70C.
  • Example 2 Preparation of Degradable PVA containing 3-ester methacrylate cross linker.
  • Figure 3 illustrates the mass loss for a hydrogel made from 3-ester methacrylate modified PVA at 1 meq/g crosslinker density in pH 7.4 buffer.
  • ⁇ indicates an average wet weight of four samples at 37C (wet); A indicates the degradation at 50C (wet); ⁇ indicates the degradation at 37C (dry); and x indicates the degradation at 50C (dry).
  • Example 3 Preparation of Degradable PVA containing 5-ester acrylate cross linker.
  • AOES g, 13.88 mmoles
  • ethylene glycol 4.308g, 69.4 mmoles
  • DMAP dimethylaminopyridine
  • the solution was cooled to 4°C, and 1 M DCC solution (13.88 mL, 13.88 mmoles) was added over 25 minutes. At this time the solution was removed from the ice bath and stirred at room temperature for 4 hours.
  • the DCU precipitate was removed by filtration and the filtrate was extracted with 5% HC1 (2 x 75 mL), 1 M NaHC0 3 (2 x 75 mL) and deionized water (2 x 5 mL).
  • the organic phase was dried with MgS0 4 , the MgS0 4 was filtered, and the filtrate concentrated under reduced pressure. The product was dried overnight in a vacuum oven at room temperature.
  • the product of the above reaction (0.915 g, 3.52 mmoles) was dissolved in 10 mL of dichloroethane (DCE). Succinic anhydride (0.352 g, 3.52 mmoles) and 1 -methylimidazole (72 ⁇ L) was added to the solution. The solution was heated to 60 C for 3 hours, then cooled to room temperature, and extracted with 10% HC1 (2 x 50 mL) and deionized water (2 x 50 mL). The organic layer was dried using MgS0 4 , the MgS0 4 was filtered, and the filtrate concentrated under reduced pressure. The product was dried in a vacuum oven overnight at room temperature.
  • DCE dichloroethane
  • FIG. 4 illustrates the mass loss for a hydrogel made from 5-ester acrylate modified PVA at 1 meq/g crosslinker density in 10 mM HEPES buffer at pH 7.4 and pH 9.0.
  • ⁇ indicates the degradation at 37C and pH 7.4;
  • ⁇ indicates the degradation at 37C and pH 9.0:
  • A indicates the degradation at 70C and pH 7.4;
  • x indicates the degradation at 70C and pH 9.0.
  • Figure 5 illustrates the mass loss for a hydrogel made from 5-ester acrylate modified PVA at 1 meq/g crosslinker density in 0.1 M phosphate buffer at pH 7.4 and pH 9.0.
  • ⁇ indicates the degradation at 37C and pH 7.4;
  • ⁇ indicates the degradation at 37C and pH 9.0;
  • A indicates the degradation at 70C and pH 7.4:
  • x indicates the degradation at 70C and pH 9.0.
  • Example 4 Preparation of Degradable PVA containing carboxyethylacrylate cross linker. The same procedure as Example 1 was followed using carboxyethylacrylate and 3-83
  • Example 5 Preparation of Degradable PVA containing vinyl azlactone cross linker.
  • Example 2 The same procedure as Example 1 was followed using vinylazlactone and 4-88 PVA at 1.0 meq/g. Azlactone-modified PVA was prepared according to the literature reference Muhlebach. A. et. al, J. Polym. Sci., Polym. Chem. Ed. 1997. 35, 3603-361 1.
  • Example 6 Preparation of Degradable PVA containing I OK PEG diazlactone cross linker.
  • PEG 10K diol (10 g) was dissolved in 52 mL DCM. The material was dried by reflux of DCM through molecular sieves for an hour. Vinyl azlactone (0.5105 g, 0.0037 moles) was added to the PEG solution, followed by 20 ⁇ l of 1.8-diazabicyclo ⁇ 5,4,0 ⁇ undec-7-ene (DBU). The solution was heated under reflux for 24 hours. After the solution cooled, it was poured into 500 mL of hexane. The precipitate was filtered and dried in a vacuum oven at room temperature overnight.
  • DBU 1.8-diazabicyclo ⁇ 5,4,0 ⁇ undec-7-ene
  • Degradable glycolide cross linkers were prepared according to the reference Furch. M. et al., Polymer, 39( 10): 1977-1982 ( 1998). Materials: Glycolide obtained from PolySciences was used as received. Hydroxyethyl acrylate (HEA) and Hydroxyethyl methacrylate (HEMA) were dried over molecular sieves (4 A) and distilled under reduced pressure before use. Triethyl aluminum (Et 3 Al. 1 M solution in hexane) was obtained from Aldrich and used as received. Triethyl aluminum (Et 3 Al, 2M solution in toluene) was obtained from Aldrich and used as received.
  • Anhydrous methylene chloride (DCM, >99.9%, Aldrich), anhydrous DMSO (Aldrich), and diethyl ether were used as received. All glassware was dried in the oven, and flame dried under nitrogen flow before use. All transfers were done under strictly anhydrous conditions via syringe or cannula.
  • Example 7 Preparation of Degradable PVA containing HEMA Glycolate-COOH cross linker.
  • HEMA-Glvcolate-COOH cross linker HEMA-glycolate-OH (F.W. 246g/mol, 5g, 20 mmol) was taken in a 3-necked flask fitted with a water condenser. Succinic anhydride (3.15 g, 30.5 mmol). a pinch of 4- methoxyphenol. and 200 mL of anhydrous dichloroethane (DCE) were added to the above reaction flask and the contents were stirred. 1 -methyl imidazole(3.5 mL. 44 mmol) was added to the above reaction flask and the contents were stirred overnight ( ⁇ 18h) at 70 C using an oil bath.
  • DCE dichloroethane
  • the mixture was cooled to room temperature and transferred to a separator funnel. The contents were washed with 10%> HC1 (2x100 mL), followed by DI water (2x100 mL). Saturated NaCl was used to break up any emulsions in the course of the work up.
  • the organic layer (DCE) was separated, dried over MgS0 4 . and the MgS ⁇ 4 filtered off. The filtrate was concentrated on a rotary evaporator to yield the HEMA-glycolide- COOH product as yellow oil.
  • the product was characterized by IR. Proton NMR and Carbon NMR spectroscopy.
  • the HEMA-glycolate-COOH cross linker was attached to PVA by the following procedure. 60 mL of DCM was taken in a flame dried 3-necked flask fitted with a Soxhlet and a condenser (attached to the Soxhlet). The Soxhlet was pre-filled with dry molecular sieves. The contents were refluxed for 2.5h.
  • the HEMA-glycolate-COOH (F.W. 346 g/mol, 2.0 g, 5.8 mmol) in 20 mL of anhydrous DCM was added to the reaction flask by syringe and the contents were gently refluxed for an additional 0.5h.
  • Poly(vinyl alcohol) [PVA 4-88, 14.2g, 20% solution in anhydrous DMSO] was taken in a dry flask and 80 mL of DMSO was added to the flask by cannula. Triethyl amine (2 mL) was added to the PVA solution and the contents were stirred for ⁇ 5 minutes. Following this, the anhydride product in DMSO (prepared above) was cannulated in drops to the PVA solution with rapid stirring. The contents were stirred overnight at room temperature, and then for 2h at 60 °C using an oil bath. The contents were cooled to room temperature and the DMSO solution of PVA was precipitated into acetone (DMSO:acetone was 1 : 10, v/v) in drops with rapid stirring.
  • a fine white precipitate was obtained that was isolated by filtration or centrifuging process (dependent on the type of precipitate obtained). The precipitate was then dried under vacuum to yield a dry white fibrous solid which is the degradable PVA containing the HEMA-glycolate cross linker (loading of degradable segment on PVA is 1 meq/g).
  • a 30% solution of the degradable PVA prepolymer in water was prepared with 1 % Irgacure. The mixture was warmed to 60°C for about 15-30 minutes until the polymer completely dissolved. The polymer solution was then transferred into polypropylene molds and UV irradiated for 30 seconds (2.0-2.5 mW/cm 2 at 310 nm, and intensity of 65-75 mW/c ⁇ r at 365 nm) to yield a cross linked gel that was analyzed for degradation profiles.
  • the degradation profiles were determined as described below. After UV irradiation, the flats were placed in a suitable buffer at a specific temperature and the time to dissolution was determined. A static set up was used.
  • the degradation times of this hydrogel in various buffers at various temperatures is shown in Table 3.
  • the phosphate buffer used was a 100 mM solution at pH 9.0 (with 0.2%
  • the HEPES buffer used was a 10 mM solution at pH 9.0 (without 0.2% NaN3).
  • Example 8 Preparation of Degradable PVA containing HEA-Glycolate cross linker.
  • the flask was then transferred to an oil bath and stirred at 40 C for an additional 30 minutes.
  • Glycolide (3.5g, 30 mmol) was quickly weighed out into a clean dry flask with a stir bar and the flask was sealed with a rubber septum.
  • About 90 mL of DCM was cannulated into the flask containing the glycolide and the contents were stirred to effect dissolution.
  • the glycolide solution was then cannulated into the flask containing the HEA- Et 3 Al solution at 40 ° C.
  • the contents of the flask remained clear during this addition but became turbid with progress of the reaction.
  • the contents were allowed to stir for 20 h at room temperature.
  • trifluoroacetic acid in this case, 120 mL was added to the reaction mixture with vigorous stirring until most of the prepolymer dissolved (external cooling may be employed at this stage of the reaction if necessary).
  • the turbid mixture became increasingly translucent.
  • the mixture was then filtered through a coarse frit funnel and precipitation of the filtrate was checked in diethyl ether.
  • the entire filtrate about 230 mL was added in drops to diethyl ether (800 mL) with rapid stirring to yield a white precipitate.
  • the precipitate was filtered using a frit funnel under aspirator pressure and the product was dried in a vacuum oven overnight at room temperature.
  • This degradable cross linker could be attached to the PVA backbone by isocyanate coupling reaction between the hydroxyl groups.
  • a suitable diiisocyanate such as HMDI (hexamethylene diisocyanate) or IPDI (isophorone diisocyanate) can be employed for this reaction.
  • Example 9 Preparation of Degradable PVA containing HEMA-Glycolate cross linker.
  • the flask was then transferred to an oil bath and stirred at 40 C for an additional 30 minutes.
  • Glycolide (3.4 g, 29 mmol) was quickly weighed out into a clean dry flask with a stir bar and the flask was sealed with a rubber septum.
  • About 120 mL of DCM was cannulated into the flask containing the glycolide and the contents were stirred to effect dissolution.
  • the glycolide solution was then cannulated into the flask containing the HEMA- Et 3 Al solution at 40 ° C.
  • the contents of the flask remained clear during this addition but became turbid with progress of the reaction.
  • the contents were allowed to stir for 20 h at room temperature.
  • HEMA attached to 2 glycolate units (from 1 glycolide unit).
  • H NMR (CDC1 3 / CF 3 COOD mixture) 6.3 ppm (d, I H) of vinyl, 5.8 ppm (d, I H) of vinyl, 5.0 ppm (m, 2H) of CH 2 of glycolate unit.
  • 4.4-4.6 ppm (m, broad, 6H) includes CH 2 groups of HEMA and CH 2 OH of last glycolate segment of oligomer, 2.0 ppm (s, 3H) of CH 3 group of HEMA.
  • Example 10 Insitu synthesis of HEMA-glycolate-COOH 70 mL of DCM and Et 3 Al solution in hexane ( 1 M solution, 14.5 mL, 14.5 mmol) were placed in a flask that had been flame dried and purged with nitrogen, and equipped with a rubber septum. The contents in the flask were cooled to 0 C for about 15 minutes. Under vigorous stirring, freshly distilled HEMA ( 1 .75 mL, 14.4 mmol) in 30 mL of DCM was added by cannula to the flask containing the Et 3 Al solution. The color of the solution turned yellow on addition of the HEA and stayed yellow for a few seconds.
  • the contents were stirred at 0 C for 15 minutes and then at room temperature for lh.
  • the flask was then transferred to an oil bath and stirred at 40 ° C for an additional 30 minutes.
  • Glycolide (5.1 g, 43.2 mmol) was quickly weighed out into a clean dry flask with a stir bar and the flask was sealed with a rubber septum.
  • About 125 mL of DCM was cannulated into the flask containing the glycolide and the contents were stirred to effect dissolution.
  • the glycolide solution was then cannulated into the flask containing the HEMA- Et 3 Al solution at 40 C.
  • This degradable cross linker could be attached to the PVA polymer as described above in Example 8.

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Abstract

L'invention concerne des hydrogels biocompatibles biodégradables à base d'alcool polyvinylique et des procédés de préparations associés. Les procédés de préparation des hydrogels impliquent l'utilisation de prépolymères. Les prépolymères possèdent un squelette polyvinylique et des chaînes greffées comprenant un groupe polymérisable. Dans l'un des modes de réalisation, les chaînes greffées comprennent également une zone biodégradable. Dans un autre mode de réalisation, les zones biodégradables sont introduites dans l'hydrogel au cours de sa formation.
EP00993007A 1999-11-15 2000-11-15 Hydrogels d'alcool polyvinylique degradable Withdrawn EP1250361A2 (fr)

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JP2004504887A (ja) * 2000-08-02 2004-02-19 アエスクラップ　アーゲー　ウント　コー　カーゲー 医療技術製品、その製造方法、およびその外科用用途
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JP4655505B2 (ja) * 2004-04-28 2011-03-23 東レ株式会社 架橋生分解性粒子およびその製造方法
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