Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J3/00—Processes of treating or compounding macromolecular substances
  • C08J3/12—Powdering or granulating
  • C08J3/16—Powdering or granulating by coagulating dispersions
• • 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
  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/04—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers only
  • C08G65/06—Cyclic ethers having no atoms other than carbon and hydrogen outside the ring
  • C08G65/14—Unsaturated oxiranes
• • 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
  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
  • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
  • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
  • C08G65/3324—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof cyclic
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
  • C08L71/02—Polyalkylene oxides
• • 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
  • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
  • C08G2650/34—Oligomeric, e.g. cyclic oligomeric
• • 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
  • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
  • C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers

Definitions

• the present invention relates to the synthesis of crosslinked polymers. More particularly, the present invention relates to biodegradable crosslinked hydrogel copolymers.
• degradable polymers In addition to use as suture material, degradable polymers have been used in other biomedical applications, such as polymer-based drug delivery systems. In such a system, degradable polymers are used as a matrix for the controlled or sustained delivery or release of biologically active agents, such as protein drugs, to the human body.
• biologically active agents such as protein drugs
• endoscopic surgical techniques has resulted in the need for developing such degradable drug delivery systems wherein the placement of the drug delivery device is targeted for specific anatomical locations. Examples of such polymer-based drug delivery systems are described in the following U.S. patents: U.S. Patent No. 6,183,781, entitled “Method for Fabricating Polymer-based Controlled-release Devices"; U.S. Patent No.
• Degradable polymers have also been used in other biomedical applications, including use as polymer scaffolds for tissue engineering, and are described in U.S. Patent No. 6,103,255, for example, incorporated herein by reference. Additional biomedical applications for synthetic biodegradable polymers include use with fracture fixation, for example, as absorbable orthopedic fixation devices, and are described in U.S. Patent Nos. 5,902,599 and 5,837,752, both of which are incorporated herein by reference. Synthetic biodegradable polymers are also used in dental applications, and are described, for example, in U.S. Patent No. 5,902,599.
• Synthetic degradable absorbable polymers already developed to date for use in biomedical applications include, for example, poly(p-dioxanone), which is an alternating ether-ester polymer, and its copolymers; polycaprolactone; polyhydroxyalkanoates; poly(propylene fiimarate); poly(ortho esters); other polyesters including poly(block-ether esters), poly(ester amides), poly(ester urethanes), polyphosphonate esters, and polyphosphoesters; polyanhydrides; polyphosphazenes; poly(alkylcyanoacrylates); and polyacrylic acids, polyacrylamides, and their hydrogels.
• poly(p-dioxanone) which is an alternating ether-ester polymer, and its copolymers
• polycaprolactone polyhydroxyalkanoates
• poly(ortho esters) other polyesters including poly(block-ether esters), poly(ester amide
• Caprolactone is the cyclic ester derivative of hydroxy caproic acid, HO(CH 2 ) 5 CO 2 H, and can be ring-opened to form the polyester poly(caprolactone), -[O(CH 2 ) 5 CO 2 ]-. It should be noted that caprolactone has two structural isomers, designated e- and ⁇ -caprolactone. Any discussion of caprolactone generally applies to both forms, unless specifically noted.
• Lactic acid- and glycolic acid-based polymers with high molecular weights are not obtained through direct condensation of the corresponding carboxylic acid due to reversibility of the condensation reaction, backbiting reactions, and the high degree of conversion required. Rather, lactic acid- and glycolic acid- based polymers are typically obtained by ring-opening polymerization of the corresponding diester dimers, lactide and glycolide, respectively, themselves. Alternatively, the reaction can be carried out as a condensation of lactic and glycolic acid.
• Copolymers incorporating both monomers are also available and are termed poly(lactide-co- glycolides) abbreviated PLGA and poly(glycolide-eo-lactides) abbreviated PGLA, or collectively PLGs.
• PLGA poly(lactide-co- glycolides)
• PGLA poly(glycolide-eo-lactides)
• U.S. Patent No. 5,650,173, incorporated herein by reference describes examples of these commercially available polymers and copolymers based on lactic acid and glycolic acid.
• lactide has two structural isomers, denoted D and L. Any discussion of lactide generally is referring to a racemic mixture of both isomers, i.e., D,L-lactide, abbrevi
• hydrogels are three-dimensional networks, composed of homopolymers or copolymers, that are capable of absorbing large amounts of water or biological fluids.
• a characteristic of hydrogels is that they swell in water without dissolving. Their high water content and soft consistency make hydrogels similar to natural living tissue more than any other class of synthetic biomaterials. Thus, hydrogels have found numerous applications especially in medical and pharmaceutical sectors. Hydrogels have been investigated widely as drug carriers due to their adjustable swelling capacities, which permit flexible control of drug release rates.
• hydrogel networks are generally insoluble due to the presence of chemical crosslinks (i.e., nodes or junctions) or of physical crosslinks (i.e., entanglements).
• chemical crosslinks i.e., nodes or junctions
• physical crosslinks i.e., entanglements
• hydrogels are not biodegradable, which limits their clinical use in the human body.
• nonbiodegradable hydrogels include poly(N-isopropyl acrylamide), poly(hydroxy ethylmethacrylate), poly(vinyl alcohol), poly(acrylic acid), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, and combinations thereof.
• Incorporation of chemically hydrolyzable or biochemically cleavable groups into the polymer network structure is one of the methods used to prepare biodegradable hydrogels.
• hydrogels are advantageously hydrophilic, they are disadvantageously difficult to biodegrade.
• polymers based on lactide and/or glycolide are advantageously biodegradable, they are disadvantageously hydrophobic.
• degradable polymers can be synthesized in which additional monomer units are incorporated into the backbone of poly(caprolactone), PLA, PGA, or PLGs.
• copolymerization with preformed polymers having a hydrophilic segment can be used.
• Such hydrophilic segments include any number of segments based on diol- or glycol- containing linkages, for example, polyethylene glycol (PEG), also known as polyethylene oxide (PEO), polypropylene oxide (PPO), and pluronics.
• the resulting copolymers thus include lactide and/or glycolide monomer units along with the polyether hydrophilic core initiating segment as a single block in the backbone of the polymer.
• a PEG with molecular weight of 600 would consist of a block of at least 13 monomer units.
• Other polymers have multiple large segments or blocks of PEG alternating with blocks of a polyester.
• Polyactive® is a copolymer that has large blocks of PEG alternating with blocks of poly(butylene terephthalate).
• U.S. Patent No. 5,702,717 to Cha et al. and U.S. Patent No. 6,117,949 to Ramesh et al. report thermogelling polymers of the same type with molecular weights of the hydrophilic segments (i.e., PEG) lower than 5000 Daltons.
• PCT/US00/32130 (WO 01/41735) to Shah et al. discloses the synthesis of polymers based on triblock copolymers of low molecular weight pluronics with PLGA. All of the foregoing patents and published patent applications are incorporated herein by reference. All of the polymers disclosed in these patents, while having improved hydrophilicity due to the presence of PEG or pluronics, are nevertheless linear polymers containing only physical, rather than chemical, crosslinks. Such, physical crosslinks are due to the interaction between chains of the polymer and the different parts of the polymer's building blocks. The lack of chemical crosslinks between polymer chains may limit the formation of a variety of three-dimensional networks that could advantageously be manipulated for use in drug delivery systems and other applications where control of water content is important.
• Crosslinking linear polymer chains is frequently accomplished through the introduction of an additional block in the copolymer backbone that has functionality capable of reacting chemically with functionality on another linear polymer chain.
• Epoxides i.e., molecules containing the oxirane functionality, i.e., a three-membered C - O - C ring, are known to undergo ring-opening polymerization reactions in the same manner and under the same conditions as the ring-opening polymerization of cyclic esters, i.e., lactide, glycolide, and caprolactone.
• the ring-opening polymerization of epoxides takes advantage of the fact that cyclic monomers inherently have associated ring strain, which is inversely proportional to the size of the ring. The greater the ring strain, the less energy required to open the ring, and the milder the reaction conditions necessary to achieve polymerization.
• copolymerizing a functionalized epoxide and a cyclic ester incorporates the ring- opened epoxide into the backbone of the linear copolymer.
• Choice of appropriate functionality on the epoxide may permit subsequent crosslinking of the linear copolymer chains.
• this patent involves the crosslinking of epoxide and lactide/glycolide copolymers
• this patent does not address the inco ⁇ oration of hydrophilic segments into the polymer network in order to affect the ability of that network to absorb water.
• none of the crosslinked polymers described therein are hydrogels.
• none of the crosslinked polymers described therein are used in drug delivery systems.
• This patent describes the inco ⁇ oration of unsaturated groups in the linear polymer chains by means of reaction of the hydroxyl groups at the chain ends with acrylic acids or chlorides. The result is the presence of ethylenic unsaturation only at the ends of the linear polymer chains. Any subsequent crosslinking reaction will only result in crosslinks at the ends of the linear polymer chains. This provides minimal control over the degree of crosslinking and thus minimal control over the properties of the resulting polymer network, in particular, the ability of the network to absorb water and the ability of the network to act as a drug delivery system.
• This patent describes neither the inco ⁇ oration of unsaturated groups into the polymer backbone by using a bifunctional ring-opening polymerizable monomer, such as an ethylenically unsaturated epoxide, nor that that inco ⁇ oration is random inside the copolymer backbone, thereby creating multiple sites for potential future crosslinking reactions.
• biodegradable polymer systems based on ring- opened cyclic esters, that not only contain hydrophilic segments capable of absorbing significant amounts of water, but also contain sufficient functionality to facilitate crosslinking reactions in order to form three-dimensional networks.
• the present invention solves the need in the art for development of such biodegradable crosslinked hydrogel networks.
• the present invention provides for the synthesis of various biodegradable copolymers.
• the copolymers are synthesized through the process of ring-opening polymerization.
• the copolymers synthesized through the process of ring-opening polymerization are comprised of a ring-opened cyclic ester, a ring-opened ethylenically unsaturated epoxide, and a hydrophilic segment.
• the ring-opened cyclic ester units contain the requisite ester functionality in the backbone of the polymer to readily permit degradation, in particular biodegradation.
• the ring-opened ethylenically unsaturated epoxide units are randomly distributed in the polyester backbone and contain unsaturated functionality to permit crosslinking and the formation of three-dimensional networks.
• the hydrophilic segment is also inco ⁇ orated in the backbone of the polymer to enhance the hydrophilicity of the copolymer, resulting in a hydrogel network upon crosslinking.
• the copolymers comprising a ring-opened cyclic ester, a ring-opened ethylenically unsaturated epoxide, and a hydrophilic segment are subsequently crosslinked, through the unsaturated functionality of the ring-opened epoxide, to form a three-dimensional network.
• the crosslinking can be accomplished by any known means, e.g., through photocuring, radiation, or by chemical means.
• the present invention provides for a method of synthesizing biodegradable crosslinked polymer networks by means of a two-step synthesis: the first step is the ring-opening copolymerization of a cyclic ester and an ethylenically unsaturated epoxide in the presence of a hydrophilic segment, such that the ring-opened epoxide is randomly distributed in the polyester backbone; the second step is the crosslinking of the resulting copolymer linear chains.
• Polymerization in this way permits the inco ⁇ oration of hydrophilic units into the polyester backbone, in order to impart desirable hydrogel characteristics to the copolymer, and then permits the crosslinking of copolymer chains to form a three-dimensional network.
• This synthetic procedure results in the synthesis of ⁇ -hydroxy, e.g., lactide- and/or glycolide-based, biodegradable hydrogels.
• the present invention provides for the synthesis of biodegradable crosslinked hydrogels that can be used for the controlled delivery of drugs, or any other biologically active agents, i.e., proteins, in a sustained manner.
• the presenf invention also provides for the use of such biodegradable crosslinked hydrogels as scaffolds in tissue engineering, tissue replacement, and tissue regeneration, as surgical sealants and tissue sealants for wound repair, as adhesives, and as coatings.
• the present invention contemplates in vivo as well as ex vivo applications.
• the present invention provides for mixing the copolymers with active agents before the copolymers are crosslinked.
• the copolymers are first mixed with active agents and then injected subcutaneously into a human patient. After injection, the copolymers are crosslinked in situ.
• One method of in situ crosslinking involves curing with ultraviolet radiation.
• the present invention provides for the preparation of crosslinked microparticles or implantable hydrogels that encapsulate the inco ⁇ orated active agents.
• the present invention advantageously can be used for the synthesis of biodegradable crosslinked hydrogel polymers heretofore unavailable.
• the synthetic methods of the present invention are easily adaptable to existing polymer synthesis protocols.
• the present invention avoids the hydrophobicity of previous lactide- and/or glycolide-based polymers, while at the same time provides for the biodegradability of the resulting crosslinked hydrogel three-dimensional networks, which networks previously lacked acceptable degradation characteristics.
• the present invention also provides for the random inco ⁇ oration of unsaturated functionality into the polyester backbone of linear polymer chains, rather than merely at the ends of the polymer chains. As the amount of unsaturated functionality directly relates to the amount of subsequent crosslinking, controlling the inco ⁇ oration of this unsaturation permits greater control over the physical properties of the resulting hydrogel, in particular, the consistency of the gel itself as well as the amount of gel obtained from the crosslinking of the original copolymers.
• crosslinked hydrogels of the present invention can be processed to form particulates for delivery of active agents in pharmaceutical applications, and can be used as scaffolds in tissue engineering, tissue replacement, and tissue regeneration, as surgical sealants and tissue sealants for wound repair, as adhesives, and as coatings, involving both in vivo as well as ex vivo applications.
• FIGS. l(a)-l(d) are the ⁇ NMR spectra of poly(D,L-lactide-c ⁇ -glycidyl methacrylate)-b/->c£-poly(ethylene glycol)-b/oc£-poly(D,L-lactide-c ⁇ -glycidyl methacrylate) copolymers according to the present invention.
• the ⁇ NMR spectrum of the copolymer of Sample 1 is shown in Fig. 1(a), wherein the ratio of PEG:DLLA:GMA is 66.5/16.4/17.1 wt. %;
• the ⁇ NMR spectrum of the copolymer of Sample 2A is shown in Fig.
• FIG. 2 shows the relevant gas chromatograms of samples of the reaction mixture during the synthesis of poly(D,L-lactide-c ⁇ -glycidyl methacrylate)-b/oc£-poly(ethylene glycol)-b/oc&-poly(D,L-lactide-c ⁇ -glycidyl methacrylate) copolymers according to Example 8 after 1.0, 2.0, 4.5, and 8.5 hours of reaction.
• FIG. 3 shows the results of the in vivo ⁇ -IFN release study for both the crosslinked copolymers of Sample 1 and Sample 6, wherein the serum concentration of ⁇ -IFN is plotted as a function of time (data normalized to 1 mg/kg).
• the polymers of the present invention are preferably degradable.
• degradable is meant that the material should be susceptible to degradation or destruction under certain conditions.
• the polymers are preferably biodegradable and biocompatible.
• biodegradable is meant a material that should degrade by bodily processes or under conditions present in the body to products readily disposable by the body and should not accumulate in the body.
• the products of the biodegradation should also be biocompatible with the body.
• biocompatible is meant not toxic to the body, is pharmaceutically acceptable, is not carcinogenic, and does not significantly induce inflammation in body tissues.
• body preferably refers to the human body, but it should be understood that body can also refer to a non-human animal body.
• Polymerization according to the methods of the present invention involves the combination of "monomers” or discrete chemical units. Monomers react with each other or with one or more other, different monomers to form a higher molecular weight compound called a "polymer.” Polymerization of a single type of monomer generates a "homopolymer,” that is, a polymer having only one type of building block unit in the polymer backbone. Polymerization of more than one type of monomer generates a "copolymer,” that is, a polymer having more than one type of building block unit in the polymer backbone. Copolymerization requires the presence of at least two different monomers.
• the present invention relates to the synthesis of copolymers comprising a randomly distributed ring-opened ethylenically unsaturated epoxide, a ring-opened cyclic ester, and a hydrophilic segment.
• the copolymers of the present invention comprise a copolymer of a cyclic ester (e.g., an ⁇ -hydroxy acid such as lactide and/or glycolide) randomly copolymerized with an ethylenically unsaturated epoxide (e.g., glycidyl methacrylate) by means of ring opening polymerization using ionic initiation with a macroinitiator (e.g., poly(ethylene glycol) or pluronics), thereby inco ⁇ orating a hydrophilic segment into the copolymer, in the presence of a catalyst (e.g., stannous octoate).
• a cyclic ester e.g., an ⁇ -hydroxy acid such as lactide and/or glycolide
• an ethylenically unsaturated epoxide e.g., glycidyl methacrylate
• a macroinitiator e.g., poly(
• the resulting copolymer can be described generally as an ethylenically unsaturated poly( ⁇ - hydroxy acid-co-vinyl epoxide)-b/oc£-(hydrophilic segmenf)-b oc£-poly( ⁇ -hydroxy acid-co- vinyl epoxide) copolymer. More particularly, when the cyclic ester is D,L.
• the ethylenically unsaturated epoxide is glycidyl methacrylate (GJMA)
• the hydrophilic segment is poly(ethylene glycol) (PEG)
• the copolymer formed according to the present invention is poly(D,L-lactide-c ⁇ -glycidyl methacrylate)-b/oc£-poly(ethylene glycol)-b/ocA:- poly(D,L-lactide-co-glycidyl methacrylate).
• the materials used for the synthesis of the copolymers of the present invention are as follows: D,L-lactide (99.9+%, Purac) was used as received. The amount of D,L-lactide used ranged from about 1 to about 50 wt. %. Glycolide (99.9+%, Purac) was used as received. The amount of glycolide used ranged from about 1 to about 50 wt. %. Poly(ethylene glycols) (Aldrich) were dried under vacuum at 110°C before use. The amount of poly(ethylene glycol) used ranged from about 40 to about 95 wt. %. Pluronics (VWR) was used as received.
• the amount of pluronics used ranged from about 40 to about 95 wt. %.
• Glycidyl methacrylate (97%, Aldrich) was used as received.
• the amount of glycidyl methacrylate used ranged from about 1 to about 50 wt. %.
• Stannous octoate (Sigma) was used as the catalyst and was used as received.
• the amount of stannous octoate catalyst used ranged from about 0.001 to about 2 wt. %.
• Various chemical radical inhibitors were used to prevent premature and undesired polymerization.
• An example of a chemical radical inhibitor is 1 ,4-benzoquinone (Aldrich) and was used as received.
• the amount of chemical radical inhibitor used was about 10 '3 to about 10 '2 mol/L.
• a typical procedure for the synthesis of the copolymers of the present invention is described as follows: Appropriate amounts of lactide and/or glycolide and poly(ethylene glycol) were weighed into a necked tube. The tube's contents were stirred and melted at 150°C in an oil bath under nitrogen flow. After addition of the radical inhibitor solution in ether or dibutyl phthalate, the glycidyl methacrylate was added to the reaction tube. Then, the stannous octoate solution in ether or dibutyl phthalate was added to the tube, and the tube was evacuated using an oil pump and sealed under vacuum. The reaction proceeded at 175°C for one hour, after which the tube was opened. The resulting copolymer was dissolved in THF, precipitated in ether, and recovered by filtration.
• cyclic esters of the present invention are lactide and glycolide
• the cyclic ester monomer can be any cyclic ester susceptible to cationic ring- opening polymerization.
• examples of cyclic esters containing a single ester moiety, also called lactones include propiolactone (four-membered ring), valerolactone (six-membered ring), caprolactone (seven-membered ring), and pentadecalactone (fifteen-membered ring).
• cyclic esters containing a single ester moiety, but also other nonaliphatic functionality in the ring include, for example, l,4-dioxan-2-one, wherein the other ring functionality is an ether linkage.
• Cyclic esters that contain two ester moieties in a single six- membered-ringed structure and have been used as monomers in ring-opening polymerization include lactide and glycolide.
• the cyclic ester used in the present invention is either lactide, glycolide, caprolactone, l,4-dioxan-2-one, a cyclic carbonate, or mixtures thereof. It should be appreciated that the present invention contemplates using a single ring- opened cyclic ester in the copolymer backbone as well as multiple different ring-opened cyclic esters in the copolymer backbone.
• lactic acid- and glycolic acid-based polymers are typically obtained by ring-opening polymerization of the corresponding diester dimers, lactide and glycolide, respectively, themselves.
• the resulting polymers of these ring-opening polymerization reactions are poly(lactic acid), also known as poly(lactide), abbreviated PLA and poly(glycolic acid), also known as poly(glycolide), abbreviated PGA.
• Copolymers inco ⁇ orating both monomers are also available and are termed poly(lactide-co-glycolides) abbreviated PLGA and poly(glycolide-c ⁇ -lactides) abbreviated PGLA, collectively PLGs.
• U.S. Patent No. 5,650,173, previously inco ⁇ orated herein by reference describes examples of these commercially available polymers and copolymers based on lactic acid and glycolic acid.
• the present invention contemplates using as the cyclic ester monomer caprolactams, in particular, N-vinylcaprolactam.
• glycidyl methacrylate is the preferred ethylenically unsaturated epoxide
• the present invention contemplates the use of any epoxide containing a vinyl group, i.e., the ethylenical unsaturation, whether the vinyl group is further substituted or not. This includes epoxides with any additional functional groups as well. While not intended to limit the scope of the ethylenically unsaturated epoxides of the present invention, it is noted that U.S. Patent No.
• hydrophilic segments of the copolymers of the present invention are derived from the macroinitiator used for ring opening polymerization and generally include one or more hydroxy, i.e., -OH, groups.
• hydrophilic segment herein includes hydroxy-containing species, whether specifically termed hydrophilic (such as PEG) or not, and includes hydroxy-containing species also termed amphiphilic (such as pluronics).
• Suitable macroinitiators which become the hydrophilic segments in the copolymers of the present invention, include those hydroxy-containing materials capable of imparting the requisite hydrophilicity to the copolymer, such that a hydrogel will be formed upon subsequent crosslinking of the copolymers.
• suitable macroinitiators include, but are not limited to, alkane diols (e.g., butanediol, hexanediol, tetraethylene glycol (TEG), and the like), alcohols with unsaturation (e.g., alkenols), long chain alcohols (e.g., hydroxy end-capped polymers, alcohols based on polyethylene glycol (PEG), also known as polyethylene oxide (PEO), polypropylene oxide (PPO), and the like), pluronics, fatty alcohols, cholesterol, and polyols (dendrimers, glycerol, polyvinylalcohol, and the like).
• alkane diols e.g., butanediol, hexanediol, tetraethylene glycol (TEG), and the like
• alcohols with unsaturation e.g., alkenols
• long chain alcohols e.g., hydroxy end
• the hydrophilic segment of the present invention is either PEG or pluronics.
• the present invention also contemplates the situation where the macroinitiator comprises alcohol-containing photopolymerizable groups.
• An example of such a photopolymerizable group is one that contains unsaturation as well as a hydroxy group, for example, hydroxyethylmethacrylate (HEMA).
• HEMA hydroxyethylmethacrylate
• the present invention contemplates the inco ⁇ oration of multiple hydrophilic segments in the copolymer, including the situation where the multiple hydrophilic segments are the same (i.e., derived from the same macroinitiator) as well as the situation where the multiple hydrophilic segments are different (i.e., derived from different macroinitiators).
• the inco ⁇ oration of multiple hydrophilic segments may result when either an excess of the macroinitiator is added at the beginning of the polymerization reaction, beyond that required to initiate ring-opening polymerization, or when additional macroinitiators (either the same or different) are added during the polymerization reaction subsequent to the initial initiation.
• organometallic compounds are the preferred catalysts of the present invention.
• organometallic compounds include, but are not limited to, tin-, iron-, platinum-, titanium-, copper-, and zinc-containing compounds, and cationic photoinitiation salts, including sulfonium salts, phosphonium salts, and iodinium salts.
• organometallic compounds used as the catalyst of the present invention include titanium alkoxides, copper or iron phthalocyanines, zinc acetate, organoplatinum compounds, and organotin compounds, e.g., alkyltin ester compounds such as dibutyl tin diacetate, dibutyl tin dilaurate, dibutyl tin dioctoate and the like, halogen- containing organic tin compounds such as acetylacetonanto complex of tin dibromide, and tin orthoester compounds and the like.
• the catalyst comprises a stannous, i.e., +2 oxidation state, organotin compound.
• the organotin compound is stannous (2-ethyl-hexanoate), also known as stannous octoate, and abbreviated SnOct 2 .
• the present invention further relates to the crosslinking of the copolymers comprising a randomly distributed ring-opened ethylenically unsaturated epoxide, a ring- opened cyclic ester, and a hydrophilic segment by means of radical polymerization to form a chemically crosslinked hydrogel.
• the ethylenically unsaturated poly( ⁇ -hydroxy acid-co-vinyl epoxide)-b/ ⁇ c£-(hydrophilic segment)-b/ ⁇ c&-poly( ⁇ -hydroxy acid-co-vinyl epoxide) copolymers are crosslinked using a UV source in the presence of a UV initiator such as 2,2-dimethoxy-2-phenyl-acetophenone at room temperature or a heat sensitive initiator such as azoisobutyronitrile (AIBN) or benzoyl peroxide at moderate temperatures of about 60°C to 80°C.
• a UV initiator such as 2,2-dimethoxy-2-phenyl-acetophenone at room temperature
• a heat sensitive initiator such as azoisobutyronitrile (AIBN) or benzoyl peroxide at moderate temperatures of about 60°C to 80°C.
• the crosslinking can be carried out in an aqueous or organic solution as well as an emulsion or suspension of these unsaturated copolymers.
• the crosslinking of the copolymers of the present invention in particular when the cyclic ester is D,L.
• lactide DLLA
• GMA glycidyl methacrylate
• PEG polyethylene glycol
• the materials used for the crosslinking of the copolymers are as follows: AIBN (Aldrich), a heat-sensitive initiator, was purified by recrystallization from methanol. The amount of heat-sensitive initiator used ranged from about 10 " to about 10 " mol/L. 2,2- dimethoxy-2-phenyl-acetophe ⁇ one (Aldrich), a UV initiator, was used as received. The amount of UV initiator used ranged from about 10 "3 to about 10 '2 mol/L.
• Other crosslinking materials, activated by heat, UV irradiation, or otherwise, known to those of skill in the art are also comtemplated in the present invention.
• a typical procedure for the crosslinking of the unsaturated copolymer is described as follows: A desired concentration of the unsaturated copolymer was prepared in phosphate buffer saline (PBS) solution or an organic solvent like tetrahydrofuran (THF) or chloroform. To this solution was added a chemical initiator, e.g., AIBN or benzoyl peroxide, and a crosslinking agent, e.g., ethylene glycol dimethacrylate (EGDMA). The final solution was heated at 60°C to 80°C. The hydrogels were formed in about one to about two hours.
• PBS phosphate buffer saline
• THF tetrahydrofuran
• EGDMA ethylene glycol dimethacrylate
• the unsaturated copolymer solution was added a UV sensitive initiator solution, e.g , 2,2-dimethoxy-2-phenyl-acetophenone in N-vinylpyrrolidone (NVP).
• a UV sensitive initiator solution e.g , 2,2-dimethoxy-2-phenyl-acetophenone in N-vinylpyrrolidone (NVP).
• N-vinylpyrrolidone N-vinylpyrrolidone
• the crosslinking solution comprises about 20 to about 25 wt. % of the unsaturated copolymer solution dissolved in water and about 10 wt. % of the UV sensitive initiator solution, based on the polymer content.
• the final solution was irradiated with long wavelength UV light at 365 ran.
• the hydrogels were formed generally in less than 15 minutes.
• Example 1 The copolymer that was obtained (Sample 1) was isolated by filtration, washed with ether and dried at room temperature under vacuum. The presence of methacrylate groups inside the polymer backbone was confirmed by ⁇ NMR.
• M n The number average molecular weight of this copolymer as measured by gel permeation chromatograph (GPC) was 9,400 g mol.
• the catalyst used was SnOct 2 at 1.0 wt. % based on the weight of DLLA and GJMA.
• the presence of methacrylate groups inside the polymer backbone was confirmed by ⁇ NMR and is shown in Figures 1(a), 1(b), and 1(c), for Samples 1, 2A, and 2B, respectively, by the peaks at approximately 5.6 ppm and 6.2 ppm.
• Example 3 Synthesis of Poly(D,L-Lactide-co-Glycidyl Methacrylate)-b/oc&- Poly(Ethylene Glycol)-b/oc£-Poly(D,L-Lactide-co-Glycidyl Methacrylate) Block Copolymers Containing PEG with Different Molecular Weights.
• the catalyst used was SnOct 2 at 1.0 wt. % based on the weight of DLLA and GMA.
• the presence of methacrylate groups inside the polymer backbone of the copolymers was confirmed by ⁇ NMR (data not shown), similar to Samples 1, 2A, and 2B shown in Fig. 1.
• Solubility data for the various copolymers as described in Table 2 were based on a visual analysis using a 20 wt. % solution of the copolymer in water.
• Example 4 Photocrosslinking of Aqueous Solutions of Poly(D,L-Lactide-co- Glycidyl Methacrylate)-b/oc£-Poly(Ethylene Glycol)-b/oc£-Poly(D,L-Lactide-co-Glycidyl Methacrylate) Block Copolymers Using Long Wavelength UV Irradiation.
• a 20 wt. % solution of the copolymer of Example 1 (Sample 1) was prepared by solubilizing 250 mg of the copolymer in 1 mL of PBS with pH of 7.4. Into a 4 mL vial was added 250 mg of this solution, followed by addition of 25 mg of a 300 mg/mL solution of 2,2-dimethoxy-2-phenyl-acetophenone in N-vinyl pyrrolidone (J VP) as a UV initiator. Using a portable UV lamp, the solution was irradiated with long wavelength UV radiation at 365 nm. The hydrogel was formed in about ten minutes.
• copolymers of poly(D,L-lactide-c ⁇ -glycidyl methacrylate)-b/oc£-poly(ethylene glycol)-b/oc / fc-poly(D,L-lactide-co-glycidyl methacrylate) prepared in Examples 2 and 3, and described in Tables 1 and 2, were also submitted to the photocrosslinking conditions in PBS solution just described. The same gelation effect was observed for the PBS solutions of Samples 2A, 2B, 3 A, and 3C.
• Example 5 Gel Content and Water Content of Photocrosslinked Hydrogels of Poly(D,L-Lactide-co-Glycidyl Methacrylate)-b/ocA:-Poly(Ethylene Glycol)-b/o :-(D,L- Lactide-co-Glycidyl Methacrylate) Block Copolymers.
• Wi dried weight of the copolymer after reaction
• W 2 dried weight of the copolymer after extraction with CHC1 3 .
• Sample 2A four data points were obtained to determine gel content: 57.8, 57.6, 57.1, 58.2%, for an average of 57.7%.
• Sample 2B four data points were obtained to determine gel content: 47.1, 46.3, 46.1, and 45.6%, for an average of 46.3%.
• Sample 2A four data points were obtained to determine water content of the gel: 90.6, 90.7, 90.2, 90.4%, for an average of 90.5%.
• Sample 2B four data points were obtained to determine water content of the gel: 87.8, 85.1, 85.7, and 85.5%, for an average of 86.0%.
• Example 6 One Step Synthesis of Poly(D,L-Lactide-co-Glycidyl Methacrylate)- b/oc :-Poly(Ethylene Glycol)-b/oc ⁇ -Poly(D,L-Lactide-co-Glycidyl Methacrylate) Block Copolymers Without a Precipitation Purification Step; Subsequent Photocrosslinking of Their Aqueous Solutions Using Long Wavelength UV Irradiation.
• a UV initiator 300 mg of 2,2-dimethoxy-2-phenyl-acetophenone in NVP
• a copolymer was prepared according to the synthetic procedure of Example 6 using only PEG and D,L-lactide in the amounts as described in Example 6, but not glycidyl methacrylate. Rather, a suspension of glycidyl methacrylate was physically mixed with the PEG-b/ ⁇ c£-poly(D,L-lactide) copolymer just described. Then, a PBS solution of the copolymer (23 wt. %) and the suspension of glycidyl methacrylate containing 10 wt. % of a UV initiator (300 mg of 2,2-dimethoxy-2-phenyl-acetophenone in NVP) was exposed to long wavelength UV irradiation.
• a UV initiator 300 mg of 2,2-dimethoxy-2-phenyl-acetophenone in NVP
• Example 7 In vitro Degradation Studies of (D,L-Lactide-co-Glycidyl Methacrylate)-b/ ⁇ c :-Poly(Ethylene Glycol)-b/ ⁇ c£-(D,L-Lactide-co-Glycidyl Methacrylate) Block Copolymers Photocrosslinked Hydrogels.
• Figure 2 shows the relevant gas chromatograms of the samples of the reaction mixture analyzed after 1.0, 2.0, 4.5, and 8.5 hours of reaction. As can be seen from the data in Table 3 and the gas chromatograms, the small amount of residual GMA after approximately 2 hours of reaction time indicates that essentially complete reaction has occurred.
• Example 9 Effect of Catalyst Concentration on the Synthesis of Poly(D,L-Lactide- co-Glycidyl Methacrylate)-b/oc&-Poly(Ethylene Glycol)-b/ocA-Poly(D,L-Lactide-co-Glycidyl Methacrylate) Block Copolymers.
• the present invention also involves the synthesis of copolymers derived from multiple functionalized epoxides, one or more cyclic esters, and one or more hydrophilic segments (either the same or different).
• Analogous ring-opening polymerization catalyst systems as well as analogous crosslinking initiating systems as described above can be used for these copolymerization and crosslinking reactions, respectively.
• the present invention describes a copolymer that, when crosslinked to form a hydrogel, improves the release profile and bioavailability of an encapsulated active agent, such as a protein.
• An improved bioavailability indicates that more of the dose of the active agent is having a therapeutic effect, which could allow less drug to be used (at lower cost).
• the following example shows the use of the crosslinked hydrogel copolymers of the present invention to improve the bioavailability of active agents.
• Example 10 In Vivo Release Studies of ⁇ -IFN from Crosslinked Poly(D,L-Lactide- co-Glycidyl Methacrylate)-b/oc£-Poly(Ethylene Glycol)-W ⁇ c >Poly(D,L-Lactide-c ⁇ -Glycidyl Methacrylate) Hydrogel Copolymers.
• the copolymers synthesized according to the methods of the present invention are used in the preparation of particulates and capsules.
• the present invention relates to improved methods of preparing a pharmaceutical composition in particulate or capsule form.
• the pharmaceutical composition may be designed for the controlled release of an effective amount of an active agent over an extended period of time.
• the pharmaceutical compositions as described herein may additionally comprise a second polymer, e.g., as an additive or a blend, depending on the desired properties of the pharmaceutical compositions.
• the methods of the present invention may be carried out using pre-formed particulates, or may additionally comprise the production of the particulates. It should be readily apparent to one skilled in the art, that the present invention is not limited to any particular method of preparing a finished particulate or capsule product. Particulate formation may be effected by methods known to one skilled in the art and include any means of mechanical disruption. Those methods include, but are not limited to, spray drying, sonication, ultrasound, mutual dielectrophoresis, coacervation, and phase separation processes such as those described in U.S. Patent No. 5,718,921, issued to Mathiowitz et al, entitled "Microspheres Comprising Polymer and Drug Dispersed There Within,” and U.S. Patent No.
• Suitable emulsion-based methods include phase separation methods that use a coacervating agent.
• Other suitable emulsion-based methods include non- phase separation methods that use other means for extracting solvent to form hardened particulates.
• the method includes preparing an emulsion that comprises a first phase and a second phase.
• the first phase preferably comprises an active agent, a polymer, and a solvent for the polymer.
• the second phase is a continuous phase, preferably an aqueous phase.
• the solvent is extracted from the emulsion to form particulates containing the active agent.
• suitable methods of preparing a finished particulate product are accomplished by using Prolease® technology, developed by Alkermes Controlled Therapeutics, Inc. I of Cambridge, MA, and as described in U.S. Patent No. 5,019,400, issued to Gombotz et al., entitled “Very Low Temperature Casting of Controlled Release Microspheres," and U.S. Patent No. 5,922,253, issued to Herbert et al., entitled “Production Scale Method of Forming Microprarticles,” both inco ⁇ orated herein by reference.
• the Prolease® technology generally involves the preparation of particulates using very cold temperatures to freeze mixtures of a polymer and an active agent forming polymeric particulates.
• a polymer is dissolved in a solvent together with an active agent forming a mixture.
• This mixture is atomized into a vessel containing a liquid non-solvent, alone or frozen and overlayed with a liquefied gas, at a temperature below the freezing point of the polymer/active agent solution.
• the combination with the liquefied gas is used, the atomized droplets freeze into particulates upon contacting the cold liquefied gas, then sink onto the frozen non-solvent layer. If frozen, the non-solvent is then thawed. As the non-solvent thaws, the particulates which are still frozen sink into the liquid non- solvent.
• the solvent in the particulates then thaws and is extracted into the non-solvent, resulting in a hardened particulate containing active agent either as a homogeneous mixture of the polymer and the active agent or as a heterogeneous two phase system of discrete zones of polymer and active agent. If a cold non-solvent is used alone, the atomized droplets freeze upon contacting the solvent, and sink to the bottom of the vessel. As the non-solvent for the polymer is warmed, the solvent in the particulates thaws and is extracted into the non-solvent, resulting in hardened particulates. Excipients that modify, release or stabilize the encapsulated active agent can also be inco ⁇ orated (e.g., U.S.
• Patent No. 6,156,508 issued to Tracy et al., entitled “Controlled Release of Metal Cation-Stabilized Interferon,” inco ⁇ orated herein by reference).
• suitable methods of preparing a finished particulate product can be accomplished by using the AIRTM inhalation delivery technology, developed by Advanced Inhalation Research, Inc. of Cambridge, MA, and as described in U.S. Patent Nos. 5,874,064 and 6,136,295, both issued to Edwards et al., and both entitled “Aerodynamically Light Particles for Pulmonary Drug Delivery,” and both inco ⁇ orated herein by reference.
• the AIRTM inhalation delivery technology is a pulmonary delivery system whereby active agents are delivered to the respiratory tract.
• the formation of aerodynamically light particles for use in the AIRTM inhalation delivery technology can be accomplished by various methods known to those of ordinary skill in the art, including single , and double emulsion solvent evaporation, spray drying, and solvent extraction.
• the polymers of the present invention may also be used to prepare pharmaceutical compositions in particulate or capsule form for oral administration.
• the pharmaceutical composition may be designed for the controlled release of an effective amount of an active agent over an extended period of time.
• the formulation prepared by the process of the present invention may contain an active agent dispersed in the particulate polymeric matrix material.
• the amount of such agent inco ⁇ orated in the particulates can range from very small to very large amounts, i.e., from about 0.1 wt. % to about 90 wt. %, preferably 0.5 wt. % to 30 wt. %.
• active agents that can be encapsulated by the particulate or capsule formulation methods of the present invention are legion and include generally, for example, such molecules as peptides, proteins, biopolymers, small molecules, and macromolecules. Preferred active agents are proteins.
• active agents include the following: local anesthetics; non-steroidal antifertility agents; parasympathomimetic agents; psychotherapeutic agents; tranquilizers; decongestants; sedative hypnotics; steroids; sulfonamides; sympathomimetic agents; vaccines; vitamins; antimalarials; anti-migraine agents; anti-Parkinson agents such as L-dopa; anti-spasmodics; anticholinergic agents (e.g.
• oxybutynin antitussives
• bronchodilators cardiovascular agents such as coronary vasodilators and nitroglycerin
• alkaloids analgesics
• narcotics such as codeine, dihydrocodienone, meperidine, mo ⁇ hine and the like
• non-narcotics such as salicylates, aspirin, acetaminophen, d-propoxyphene and the like
• opioid receptor antagonists such as naltrexone and naloxone
• antibiotics such as gentamycin, tetracycline and penicillins
• anti-cancer agents anti-convulsants
• anti-emetics antihistamines
• anti-inflammatory agents such as hormonal agents, hydrocortisone, prednisolone, prednisone, non-hormonal agents, allopurinol, indomethacin, phenylbutazone and the like
• prostaglandins and cytotoxic drugs
• Suitable biologically active agents include viruses and cells, peptides (e.g., luteinizing-hormone-releasing-hormone analogues, such as goserelin and exendin) and proteins, analogs, muteins, and active fragments thereof, such as immunoglobulins, antibodies, cytokines (e.g.
• lymphokines monokines, chemokines
• blood clotting factors hemopoietic factors, interleukins (IL-2, IL-3, IL-4, IL-6), interferons ( ⁇ -IFN, ⁇ -IFN and ⁇ -IFN), erythropoietm, nucleases, tumor necrosis factor, colony stimulating factors (e.g., GCSF, GM-CSF, MCSF), insulin, enzymes (e.g., superoxide dismutase, tissue plasminogen activator), tumor suppressors, blood proteins, gonadotropins (e.g., FSH, LH, CG, etc.), hormones and hormone analogs (e.g., growth hormone, adrenocorticotropic hormone and luteinizing hormone releasing hormone (LHRH)), vaccines (e.g., tumoral, bacterial and viral antigens); somatostatin; antigens; blood coagulation factors; growth factors (e.g., nerve
• Small molecular weight agents suitable for use in the invention include, antitumor agents such as bleomycin hydrochloride, carboplatin, methotrexate and adriamycin; antipyretic and analgesic agents; antitussives and expectorants such as ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride and codeine phosphate; sedatives such as chlo ⁇ romazine hydrochloride, prochlo ⁇ erazine hydrochloride and atropine sulfate; muscle relaxants such as tubocurarine chloride; antiepileptics such as sodium phenytoin and ethosuximide; antiulcer agents such as metoclopramide; antidepressants such as clomipramine; antiallergic agents such as diphenhydramine; cardiotonics such as theophillol; antiarrhythmic agents such as propranolol hydrochloride; vasodil
• Other preferred active agents include 1 ,2-benzazoles, more particularly, 3- piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles, including 3-[2-[4-(6- fluoro- 1 ,2-benzisoxazol-3-yl)- 1 -piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido- [l,2-a]pyrimidin-4-one ("risperidone”) and 3-[2-[4-(6-fluro-l,2-benzisoxazol-3-yl)-l- piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H ⁇ pyrido[l,2-a]pyrimidin-4-one ("9-hydroxyrisperidone”) and the pharmaceutically acceptable salts thereof.
• Risperidone (which term, as used herein, is intended to include its pharmaceutically acceptable salts) is also preferred. Risperidone can be prepared in accordance with the teachings of U.S. Patent No. 4,804,663, which is inco ⁇ orated herein by reference. 9-hydroxyrisperidone can be prepared in accordance with the teachings of U.S. Patent No. 5,158,952, which is inco ⁇ orated herein by reference.
• such delivery systems can also be formulated, using microchips.
• An example of such systems is described in U.S. Patent No. 5,797,898, which is inco ⁇ orated herein by reference.
• active agent delivery systems involve etching of reservoirs into a substrate, such as silicon, using any etching technique commonly used in the field of microfabrication, such as chemical (wet) etching or ion (dry) etching techniques.
• the active agents to be released in a controlled manner are placed in the reservoirs.
• the reservoirs are capped with a material that degrades at a known rate or has a known permeability for the active agents.
• the degradable polymers of the present invention can be used to make the substrates into which the reservoirs are etched and/or the caps for the reservoirs. Similar approaches can be used to develop ingestible, injectible or implantable delivery systems that comprise multiple reservoirs containing one or more biologically active agents.
• the preferred polymer of the present invention is one that can be chemically or photochemically cured.
• the polymers of the present invention when used as active agent delivery systems could also be used in applications where it is desirable for the polymer to undergo a phase transition when coming in contact with physiological conditions.
• Thermoresponsive polymers were described previously, as in U.S. Patent No. 5,702,717, issued to Cha, et al., entitled "Thermosensitive Biodegradable Polymers Based on Poly(Ether-Ester) Block Copolymers," and U.S. Patent No.
• the degradable crosslinked hydrogel copolymers of the present invention can also be used in other medical applications not involving active agent delivery systems.
• any medical application that uses a biocompatible and/or degradable polymer would find the copolymers of the present invention relevant. Examples of such applications include use as sutures, use as polymer scaffolds for tissue engineering, tissue regeneration, and tissue replacement, use in orthopedic applications, such as fracture fixation and bone replacement/healing, use in dental applications, use as prosthetic devices, use as tissue sealants and surgical sealants for wound healing, use as adhesives, and use as coatings.
• the present invention contemplates in vivo as well as ex vivo applications.
• the applications for active agent delivery systems discussed above wherein it is desirable for the polymers of the present invention to undergo a phase transition when coming in contact with physiological conditions are equally relevant to medical applications wherein the primary pu ⁇ ose is not active agent delivery, but rather those just described, in particular, orthopedic applications, dental applications, and prosthetic devices.
• the degradable crosslinked hydrogel copolymers of the present invention can be used to produce polymeric networks with the desirable physical characteristic of having high mechanical strength. Potential uses of such high strength materials include orthopedic and dental applications, such as those disclosed in U.S. Patent No.

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