Sawhney, Amarpreet S. (Lexington, MA, US)
Jarrett, Peter K. (Sudbury, MA, US)
Coury, Arthur J. (Boston, MA, US)
Rudowsky, Ronald S. (Sudbury, MA, US)
Lyman, Michelle D. (Peabody, MA, US)
Avila, Luis Z. (Arlington, MA, US)
Enscore, David J. (Sudbury, MA, US)
Goodrich, Stephen D. (Tucson, AZ, US)
Nason, William C. (Groton, MA, US)
Yao, Fei (N. Andover, MA, US)
Weaver, Douglas (Bedford, MA, US)
Barman, Shikha P. (Bedford, MA, US)

10/351930

07/03/2007

01/23/2003

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Genzyme Corporation (Cambridge, MA, US)

424/426

514/772.100, 514/772.300, 525/415, 525/413, 528/354, 514/777, 525/408, 528/361, 424/490, 525/54.200, 514/773, 128/898, 424/489, 525/54.100

A61F2/02

525/413-415, 128/898, 528/354, 424/490, 514/772.3, 514/772.1, 525/54.1, 514/777, 528/361, 525/54.2, 525/408, 424/426, 514/773, 424/489

2703316	Polymers of high melting lactide	March, 1955	Schneider
2789968	Polycarbonates from polymethylene glycol-bis	April, 1957	Reynolds et al.
2917410	Polyglycol-polyacid ester treatment of textiles	December, 1959	Vitalis
2962524		November, 1960	Hostettier et al.
3021310	Polymerization of cyclic esters	February, 1962	Cox et al.
3030331	Process for preparing copolyesters comprising reacting a carbonyl halide with a dicarboxylic acid and a dihydroxy compound in the presence of a tertiary amine	April, 1962	Goldberg
3046255	Process for preparing polycarbonates	July, 1962	Strain et al.
3063988	Steroid-21-amino acid esters and process of preparing them	November, 1962	Schultz
3157622	Resinous compositions	November, 1964	Goldberg
3161615	Resinous copolymeric polycarbonate of a mixture of dihydric phenols	December, 1964	Goldberg
3169121	Carbonate-carboxylate copolyesters of dihydric phenols and difunctional carboxylic acids	February, 1965	Goldberg
3223083	Method for adhesively securing together skin and other soft tissue and bone	December, 1965	Cobey
3268486	Process for preparing polyesters	August, 1966	Klootwijk
3268487	Process for polymerization of lactides	August, 1966	Klootwijk
3297033	Surgical sutures	January, 1967	Schmitt et al.
3301824	Polymers of cyclic carbonates	January, 1967	Hostettier et al.
3301825	Polyester polycarbonate polymers	January, 1967	Hostettier et al.
3305605	Compositions containing polycarbonate plasticizers	February, 1967	Hostettier et al.
3312753	Preparation of block copolymers of a caprolactone and oxirane compound	April, 1967	Bailey, Jr. et al.
3379693	Carbonate compositions	April, 1968	Hostettler et al.
3438374	METHOD OF BONDING TISSUE SURFACES AND CONTROLLING HEMORRHAGING THEREOF USING A TISSUE ADHESIVE AND HEMOSTATIC COMPOSITION	April, 1969	Falb et al.
3442871	PROCESS FOR POLYMERIZING A GLYCOLIDE	May, 1969	Schmitt et al.
3463158	POLYGLYCOLIC ACID PROSTHETIC DEVICES	August, 1969	Schmitt et al.
3531561	SUTURE PREPARATION	September, 1970	Trehu
3552986		January, 1971	Bassemir et al.
3620118		November, 1971	Kolshikawa
3626948	ABSORBABLE POLYGLYCOLIC ACID SUTURE OF ENHANCED IN-VIVO STRENGTH RETENTION	December, 1971	Glik et al.
3629374		December, 1971	Lundberg et al.
3639503		February, 1972	Matzner
3641200		February, 1972	Matzner
3739773	POLYGLYCOLIC ACID PROSTHETIC DEVICES	June, 1973	Schmitt et al.
3784585		January, 1974	Schmitt et al.
3795701		March, 1974	Jenkins et al.
3839297	USE OF STANNOUS OCTOATE CATALYST IN THE MANUFACTURE OF L(-)LACTIDE-GLYCOLIDE COPOLYMER SUTURES	October, 1974	Wasserman et al.
3865723	METHOD TO FORM STABLE COMPLEXES OF POLYANIONS OCCURRING IN BIOLOGICAL LIQUIDS	February, 1975	Marchisio et al.
3867190	REDUCING CAPILLARITY OF POLYGLYCOLIC ACID SUTURES	February, 1975	Schmitt et al.
3875937	Surgical dressings of absorbable polymers	April, 1975	Schmitt et al.
3882192	Polycarbonate-polyvinyl chloride moulding compositions	May, 1975	Elghani et al.
3896802	Flexible flocked dressing	July, 1975	Williams
3937223	Compacted surgical hemostatic felt	February, 1976	Roth
3939049	Process for radiation grafting hydrogels onto organic polymeric substrates	February, 1976	Ratner et al.
3960152	Surgical sutures of unsymmetrically substituted 1,4-dioxane-2,5-diones	June, 1976	Augurt et al.
3966788	Process for the preparation of aliphatic diol polycarbonates	June, 1976	Senet et al.
3982543	Reducing capillarity of polyglycolic acid sutures	September, 1976	Schmitt et al.
3991766	Controlled release of medicaments using polymers from glycolic acid	November, 1976	Schmitt et al.
4033938	Polymers of unsymmetrically substituted 1,4-dioxane-2,5-diones	July, 1977	Augurt et al.
4045418	Copolymers of D,L-lactide and epsilon caprolactone	August, 1977	Sinclair
4057537	Copolymers of L-(-)-lactide and epsilon caprolactone	November, 1977	Sinclair
4066630	End capped polyalkylene carbonates having improved thermal stability	January, 1978	Dixon et al.
4067876	High polymers containing nicotinic acid, process for their preparation and their use	January, 1978	Ferruti et al.
4072704	Multi-block coupled polyoxyalkylene copolymer surfactants	February, 1978	Langdon
4079038	Poly(carbonates)	March, 1978	Choi et al.
4093677	Macromolecular materials suitable for forming antithrombogenic prosthesis and artificial organs and process for preparing same	June, 1978	Ferruti et al.
4104264	End capped polyalkylene carbonates having improved thermal stablity	August, 1978	Dixon et al.
4137280	Polyalkylene carbonates as processing aids for polyvinyl chloride	January, 1979	Dixon et al.
4137921	Addition copolymers of lactide and glycolide and method of preparation	February, 1979	Okuzumi et al.
4143017	Process of producing soft contact lenses	March, 1979	Tarumi et al.
4145320	Polymers containing polyunsaturated acid radicals, process for their preparation and use thereof	March, 1979	Ferruti et al.
4145525	End capped polyalkylene carbonates	March, 1979	Dixon et al.
4157437	Addition copolymers of lactide and glycolide and method of preparation	June, 1979	Okuzumi et al.
4166902	High polymers containing nicotinic acid, process for their preparation and their use	September, 1979	Ferruti et al.
4169923	High polymers containing nicotinic acid, process for their preparation and their use	October, 1979	Ferruti et al.
4179304	Finger nail lacquer	December, 1979	Rossomando
4189609	Multi-block coupled polyoxyalkylene copolymer surfactants	February, 1980	Langdon
4211865	Novel prostaglandin precursors in polymeric form	July, 1980	Ferruti et al.
4223011	Therapeutic compositions containing polymers having polyunsaturated acid radicals	September, 1980	Ferruti et al.
4239861	Polyvinyl chloride-polycarbonate alloys	December, 1980	Braese et al.
4243775	Synthetic polyester surgical articles	January, 1981	Rosensaft et al.
4264752	Radiation-curable acrylated urethane polycarbonate compositions	April, 1981	Watson, Jr.
4297455	Process for the preparation of carbonic acid aryl esters of polyester-diols lengthened via carbonate groups and their use for the preparation of polyester-diol bis-diphenol carbonates and polyester/polycarbonates	October, 1981	Lindner et al.
4300565	Synthetic polyester surgical articles	November, 1981	Rosensaft et al.
4303066	Burn dressing	December, 1981	D'Andrea
4316001	Anionic polymerization of heterocyclic monomers with alkali metal amide hydroxylated compound initiator	February, 1982	Boileau et al.
4330481	Process for preparing polycarbonates	May, 1982	Timberlake et al.
4354487	Fiber/absorbent polymer composites and method of forming same	October, 1982	Oczkowski et al.
4415502	Polycarbonate type nonionic surfactants	November, 1983	Timberlake et al.
4429080	Synthetic copolymer surgical articles and method of manufacturing the same	January, 1984	Casey et al.
4436839	Process for preparing polycarbonate-polyether-blockcopolymers	March, 1984	Behnke et al.
4452973	Poly(glycolic acid)/poly(oxyethylene) triblock copolymers and method of manufacturing the same	June, 1984	Casey et al.
4503216	Hydroxyl-terminated polyether-esters	March, 1985	Fagerburg et al.
4511478	Polymerizable compounds and methods for preparing synthetic polymers that integrally contain polypeptides	April, 1985	Nowinski et al.
4526938	Continuous release formulations	July, 1985	Churchill et al.
4532929	Dry coating of surgical filaments	August, 1985	Mattei et al.
4559945	Absorbable crystalline alkylene malonate copolyesters and surgical devices therefrom	December, 1985	Koelmel et al.
4643191	Crystalline copolymers of p-dioxanone and lactide and surgical devices made therefrom	February, 1987	Bezwada et al.
4653497	Crystalline p-dioxanone/glycolide copolymers and surgical devices made therefrom	March, 1987	Bezwada et al.
4699974	Method of preparing copolyester carbonate from cyclic aromatic polycarbonate oligomer and lactone	October, 1987	Evans
4705820	Surgical suture coating	November, 1987	Wang et al.
4716203	Diblock and triblock copolymers	December, 1987	Casey et al.
4727134	Method for preparing cyclic polycarbonate oligomer mixtures	February, 1988	Brunelle et al.
4741872	Preparation of biodegradable microspheres useful as carriers for macromolecules	May, 1988	De Luca et al.
4745160	Biodegradable amphipathic copolymers	May, 1988	Churchill et al.
4760117	Method for preparing copolycarbonates from cyclic polycarbonate oligomers	July, 1988	Evans et al.
4768523	Hydrogel adhesive	September, 1988	Cahalan et al.
4769388	Polycondensation products between 1,10-bis(2-hydroxyethylthio)decane, poly(oxyethylene glycol)s or poly(oxypropyleneglycol)s, and bis(carboxylic acid)s	September, 1988	Ferruti et al.
4781183	Surgical prosthesis	November, 1988	Casey et al.
4788979	Bioabsorbable coating for a surgical article	December, 1988	Jarrett et al.
4791929	Bioabsorbable coating for a surgical article	December, 1988	Jarrett et al.
4804691	Method for making a biodegradable adhesive for soft living tissue	February, 1989	English et al.
4826945	Biodegradable polymeric materials based on polyether glycols, processes for the preparation thereof and surgical articles made therefrom	May, 1989	Cohn et al.
4846165	Wound dressing membrane	July, 1989	Hare et al.
4857602	Bioabsorbable surgical suture coating	August, 1989	Casey et al.
4882168	Polyesters containing alkylene oxide blocks as drug delivery systems	November, 1989	Casey et al.
4891263	Polycarbonate random copolymer-based fiber compositions and method of melt-spinning same and device	January, 1990	Kotliar et al.
4900797	Thermoplastic polycarbonate mixtures containing aliphatic	February, 1990	Leitz et al.
4916193	Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides	April, 1990	Tang et al.
4920203	Medical devices fabricated from homopolymers and copolymers having recurring carbonate units	April, 1990	Tang et al.
4929750	Compounds having hypolipemizing activity	May, 1990	Ferruti et al.
4938763	Biodegradable in-situ forming implants and methods of producing the same	July, 1990	Dunn et al.
4942035	Continuous release formulations	July, 1990	Churchill et al.
4944767	Synthetic material apt to stably adsorb high quantities of heparin, and process for the production thereof	July, 1990	Barbucci et al.
4960866	Catalyst-free resorbable homopolymers and copolymers	October, 1990	Bendix et al.
4961890	Method of preparing comtrolled release fenofibrate	October, 1990	Boyer
4965300	Sequential copolymers based on cyclic carbonates and esters	October, 1990	Eichenauer et al.
4997722	Composition and method for improving adherence of copper foil to resinous substrates	March, 1991	Adler
5009224	Method for attaching a pressure-sensitive film article having high moisture vapor transmission rate	April, 1991	Cole
5019094	Crystalline copolymers of p-dioxanone and poly(alkylene oxides)	May, 1991	Bezwada et al.
5019100	Use of a polymer network, method for preparing a prepolymer and also preparation which yields a polymer network after curing	May, 1991	Hennink et al.
5043398	Grafting of functional compounds onto functional oxymethylene polymer backbones, with diisocyanate coupling agents, and the graft polymers thereof	August, 1991	Auerbach et al.
5051272	Method for improving the storage stability of a polymeric article susceptible to hydrolytic degradation and resulting article	September, 1991	Hermes et al.
5061281	Bioresorbable polymers and implantation devices thereof	October, 1991	Mares et al.
5066772	Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides	November, 1991	Tang et al.
5067961	Non-biodegradable two phase corneal implant and method for preparing same	November, 1991	Kelman et al.
5076807	Random copolymers of p-dioxanone, lactide and/or glycolide as coating polymers for surgical filaments	December, 1991	Bezwada et al.
5081224	Process for production of olefin-terminated polyesters	January, 1992	Ando et al.
5100992	Polyurethane-based polymeric materials and biomedical articles and pharmaceutical compositions utilizing the same	March, 1992	Cohn et al.
5104957	Biologically compatible collagenous reaction product and articles useful as medical implants produced therefrom	April, 1992	Kelman et al.
5116929	Copolyester-diol polycarbonates, process for producing them and their use	May, 1992	Greco et al.
5120802	Polycarbonate-based block copolymers and devices	June, 1992	Mares et al.
5137800	Production of three dimensional bodies by photopolymerization	August, 1992	Neckers et al.
5145945	Homopolymers and copolymers having recurring carbonate units	September, 1992	Tang et al.
5147698	Pressure sensitive adhesive film article having high moisture vapor transmission rate	September, 1992	Cole
5152781	Medical devices fabricated from homopolymers and copolymers having recurring carbonate units	October, 1992	Tang et al.
5156613	Collagen welding rod material for use in tissue welding	October, 1992	Sawyer
5160745	Biodegradable microspheres as a carrier for macromolecules	November, 1992	De Luca et al.
5173301	Surgical adhesive	December, 1992	Itoh et al.
5177120	Chain extended urethane diacrylate and dental impression formation	January, 1993	Hare et al.
5201764	Biologically compatible collagenous reaction product and articles useful as medical implants produced therefrom	April, 1993	Kelman et al.
5209776	Tissue bonding and sealing composition and method of using the same	May, 1993	Bass et al.
5225129	Method for the manufacture of polymer products from cyclic esters	July, 1993	van den Berg
5226877	Method and apparatus for preparing fibrinogen adhesive from whole blood	July, 1993	Epstein
5252701	Segmented absorbable copolymer	October, 1993	Jarrett et al.
5256764	Medical devices fabricated from homopolymers and copolymers having recurring carbonate units	October, 1993	Tang et al.
5264425	Glycosaminoglycan salts and pharmaceutical compositions containing them	November, 1993	Dal Pozzo et al.
5274074	Medical devices fabricated from homopolymers and copolymers having recurring carbonate units	December, 1993	Tang et al.
5278200	Thromboresistant material and articles	January, 1994	Coury et al.
5296627	Ethylenically unsaturated poly(alkyleneoxy) surfactants	March, 1994	Tang et al.
5308887	Pressure-sensitive adhesives	May, 1994	Ko et al.
5310599	Method for making polymers of alpha-hydroxy acids	May, 1994	Ford
5324307	Polymeric surgical staple	June, 1994	Jarrett et al.
5332475	Cross-linking collagenous product	July, 1994	Mechanic
5332802	Human collagen processing and autoimplant use	July, 1994	Kelman et al.
5354336	Method for bonding soft tissue with collagen-based adhesives and sealants	October, 1994	Kelman et al.
5359026	Poly(lactide) copolymer and process for manufacture thereof	October, 1994	Gruber
5360892	Water and UV degradable lactic acid polymers	November, 1994	Bonsignore et al.
5364700	Prepregable resin composition and composite	November, 1994	Domeier
5366756	Method for treating bioabsorbable implant material	November, 1994	Chesterfield et al.
5372585	Instrument and associated method for applying biologically effective composition during laparoscopic operation	December, 1994	Tiefenbrun et al.
5378801	Continuous process for the preparation of resorable polyesters and the use thereof	January, 1995	Reichert et al.
5385606	Adhesive composition and method	January, 1995	Kowanko
5391707	Process for the production of dioxanone	February, 1995	Jiang
5397816	Reinforced absorbable polymers	March, 1995	Reilly et al.
5403347	Absorbable block copolymers and surgical articles fabricated therefrom	April, 1995	Roby et al.
5403626	Process for preparing hydrophilic polymer films and apparatus thereof	April, 1995	Kim et al.
5410016	Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers	April, 1995	Hubbell et al.
5412067	Preparation process of polyester	May, 1995	Shinoda et al.
5412068	Medical devices fabricated from homopolymers and copolymers having recurring carbonate units	May, 1995	Tang et al.
5425984	Bioabsorbable melt spun fiber based on glycolide-containing copolymer	June, 1995	Kennedy et al.
5447966	Treating bioabsorbable surgical articles by coating with glycerine, polalkyleneoxide block copolymer and gelatin	September, 1995	Hermes et al.
5449743	Method for ring opening polymerization using a hydrolase catalyst	September, 1995	Kobayashi et al.
5459177	Adhesive for soft tissue and kit thereof	October, 1995	Miyakoshi et al.
5463012	Polycarbonates and the use thereof for the preparation of bioerosible matrices	October, 1995	Ferruti et al.
5468253	Elastomeric medical device	November, 1995	Bezwada et al.
5476515	Method of making intraocular lenses with injectable collagen-based compositions	December, 1995	Kelman et al.
5478921	Method of purifying bioabsorable polymer	December, 1995	Roby et al.
5480427	Biologically compatible collagenous reaction product and articles useful as medical implants produced therefrom	January, 1996	Kelman et al.
5484913	Calcium-modified oxidized cellulose hemostat	January, 1996	Stilwell et al.
5486593	Medical devices fabricated from copolymers having recurring carbonate units	January, 1996	Tang et al.
5496872	Adhesive compositions for surgical use	March, 1996	Constancis et al.
5502158	Degradable polymer composition	March, 1996	Sinclair et al.
5508317	Photocrosslinked polymers	April, 1996	Müller
5512091	Associative polymer hydrogels	April, 1996	Steiner
5516825	Biodegradable polymer compositions	May, 1996	Montador et al.
5521280	Reinforced absorbable polymers	May, 1996	Reilly et al.
5522841	Absorbable block copolymers and surgical articles fabricated therefrom	June, 1996	Roby et al.
5525646	Bioresorbable material and an article of manufacture made of such material for medical use	June, 1996	Lundgren et al.
5525647	Method and device for controllably affecting the reaction of dental adhesives	June, 1996	Eichmiller
5527864	Poly(propylene fumarate-co-ethylene oxide)	June, 1996	Suggs et al.
5529914	Gels for encapsulation of biological materials	June, 1996	Hubbell et al.
5530038	Primer composition and curable composition	June, 1996	Yamamoto et al.
5531707	Device for introducing a substance into a body cavity of a patient	July, 1996	Kers et al.
5531709	Syringe for the controlled discharge of viscous materials	July, 1996	Eykmann et al.
5540677	Endoscopic systems for photoreactive suturing of biological materials	July, 1996	Sinofsky
5550209	Monodispersed polymer or copolymer and a preparation process thereof	August, 1996	Inoue et al.
5552452	Organic tissue glue for closure of wounds	September, 1996	Khadem et al.
5554665	Method and dispenser for making dental products	September, 1996	Tateosign et al.
5561157	Method for enhancing the therapeutic effect of a composition comprising hydroquinone and comprising same	October, 1996	Yu et al.
5563238	Water and UV degradable lactic acid polymers	October, 1996	Bonsignore et al.
5567435	Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers	October, 1996	Hubbell et al.
5573934	Gels for encapsulation of biological materials	November, 1996	Hubbell et al.
5589563	Surface-modifying endgroups for biomedical polymers	December, 1996	Ward et al.
5594095	Viscosity-modified lactide polymer composition and process for manufacture thereof	January, 1997	Gruber et al.
5607686	Polymeric composition	March, 1997	Totakura et al.
5621050	Coating for tissue drag reduction	April, 1997	Jarrett et al.
5621119	Di(meth)acrylates having cyclic carbonate groups	April, 1997	Podszun et al.
5629384	Polymers of N-acryloylmorpholine activated at one end and conjugates with bioactive materials and surfaces	May, 1997	Veronese et al.
5631322	Polymers of N-acryloylmorpholine activated at one end and conjugates with bioactive materials and surfaces	May, 1997	Veronese et al.
5631336	Chain-terminated N-vinyl lactam polymers and graft-copolymers and methods for making same	May, 1997	Ferruti et al.
5633342	Method for the synthesis of environmentally degradable block copolymers	May, 1997	Verser et al.
5650234	Electrophilic polyethylene oxides for the modification of polysaccharides, polypeptides (proteins) and surfaces	July, 1997	Dolence et al.
5658995	Copolymers of tyrosine-based polycarbonate and poly(alkylene oxide)	August, 1997	Kohn et al.
5665428	Preparation of peptide containing biodegradable microspheres by melt process	September, 1997	Cha et al.
5665474	Paper having a melt-stable lactide polymer coating and process for manufacture thereof	September, 1997	Gruber et al.
5698213	Hydrogels of absorbable polyoxaesters	December, 1997	Jamiolkowski et al.
5698661	High molecular weight polyesterpolycarbonates and the use thereof for the preparation of bioerosible matrices	December, 1997	Ferruti et al.
5837752	Semi-interpenetrating polymer networks	November, 1998	Shastri et al.

CA1080740	January, 1980
DE2206144	February, 1972
DE2850824	May, 1980
DE4402590	August, 1994
EP0152833	August, 1985
EP0258749	March, 1988			Surgical filament coating.
EP0370646	May, 1990			Apparatus and method for the manufacture of absorbent materials.
EP0587357	March, 1994			New chain-terminated N-vinyl lactam polymers and graft-copolymers and methods for making same.
EP0588853	March, 1994			POLYCARBONATES AND THE USE THEREOF FOR THE PREPARATION OF BIOEROSIBLE MATRICES.
EP0610731	August, 1994			Post-surgical anti-adhesion device.
EP0635276	January, 1995			Adhesive compositions for surgical use.
EP0390860	April, 1995			MEDICAL DEVICES FABRICATED FROM HOMOPOLYMERS AND COPOLYMERS HAVING RECURRING CARBONATE UNITS.
EP0737703	April, 1995			Hydrogel-forming , self-solvating absorbable polyester copolymers, and methods for use therefor
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JP62267762	May, 1986			PRODUCTION OF POLYMERIZED TONER
JP5310808	May, 1992
WO/1992/015340	September, 1992			BIORESORBABLE MATERIAL AND AN ARTICLE OF MANUFACTURE MADE OF SUCH MATERIAL FOR MEDICAL USE
WO/1992/022600	December, 1992			POLYCARBONATES AND THE USE THEREOF FOR THE PREPARATION OF BIOEROSIBLE MATRICES
WO/1993/016687	September, 1993			GELS FOR ENCAPSULATION OF BIOLOGICAL MATERIALS
WO/1993/017669	September, 1993			PHOTOPOLYMERIZABLE BIODEGRADABLE HYDROGELS AS TISSUE CONTACTING MATERIALS AND CONTROLLED-RELEASE CARRIERS
WO/1995/012629	May, 1995			HIGH MOLECULAR WEIGHT POLYESTERPOLYCARBONATES AND THE USE THEREOF FOR THE PREPARATION OF BIOEROSIBLE MATRICES
WO/1996/011671	April, 1996			TARGETED DELIVERY VIA BIODEGRADABLE POLYMERS
WO/1996/029370	September, 1996			REDOX AND PHOTOINITIATOR SYSTEMS FOR PRIMING FOR IMPROVED ADHERENCE OF GELS TO SUBSTRATES
WO/1997/025067	July, 1997			POLYMERS
WO/1997/025366	July, 1997			POLYMERS WITH CONTROLLED PHYSICAL STATE AND BIOERODIBILITY
WO/1997/029145	August, 1997			COPOLYMERS WITH POLYESTER POLYCARBONATE BLOCKS CONTAINING POLY(CAPROLACTONE) SEGMENTS, AND USE THEREOF FOR THE PREPARATION OF BIODEGRADABLE MATRICES

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Azpuru, Carlos A.

Blundell, Isabelle A. S.

This application is a divisional of application Ser. No. 08/944,739, filed Oct. 6, 1997, now U.S. Pat. No. 6,083,524 which is a continuation-in-part of application Ser. No. 08/710,689 filed Sep. 23, 1996, now U.S. Pat. No. 5,900,245.

We claim:

1. A method for forming a polymeric, biocompatible coating on tissue comprising: a) applying to the tissue surface a polymerization initiator capable of initiating polymerization via free radical or cationic polymerization; b) applying to the initiator-coated surface a solution of a biodegradable, polymerizable macromer with a solubility of at least one gram/liter in aqueous solutions at a temperature in the range between about 0 and 50° C. comprising at least one water soluble region, at least one degradable region, and at least one functional group capable of being polymerized via free radical or cationic polymerization, wherein the polymerizable regions are separated from each other by at least one degradable region and wherein at least one degradable region is a carbonate or dioxanone region; and c) polymerizing the macromer.

2. The method of claim 1, wherein the macromer solution further comprises a polymerization initiator capable of initiating polymerization via free radical or cationic polymerization.

3. The method of claim 1, wherein the tissue is coated to prevent leakage of gases or bodily fluids from the tissue.

4. The method of claim 1, wherein the tissue is coated to prevent adhesion of the tissue to other tissue.

5. The method of claim 1, wherein the tissue is coated and adhered to other tissue during polymerization.

6. The method of claim 1 wherein the macromer solution further comprises a prophylactic, therapeutic or diagnostic agent.

7. The method of claim 1 wherein the initiator binds to the tissue, further comprising removing unbound initiator prior to application of the macromer solution.

8. A method for making a device for controlled release of a prophylactic, therapeutic or diagnostic agent comprising: a) mixing a prophylactic, therapeutic or diagnostic agent with a solution of a biodegradable, polymerizable macromer with a solubility of at least one gram/liter in aqueous solutions at a temperature between about 0 and 50° C. comprising at least one water soluble region, at least one degradable region, and at least one functional group capable of being polymerized via free radical or cationic polymerization, wherein the polymerizable regions are separated from each other by at least one degradable region and wherein at least one degradable region is a carbonate or dioxanone region; and b) polymerizing the macromer to incorporate the agent within the resulting polymer.

9. The method of claim 8 wherein the polymer is formed into a shape selected from the group consisting of particles, sheets, rods, and nano or microcapsules.

10. The method of claim 8 wherein the macromer is polymerized in situ in or on a living tissue.

11. The method of claim 8 wherein the controlled release device is formed on the surface of a medical device.

12. The method of claim 11 wherein the device is coated after implantation into the body.

13. The method of claim 11 wherein the device is coated prior to implantation.

14. A method for increasing the elasticity of a hydrophilic polymer gel comprising incorporating one or more carbonate linkages into a reactive polymer before gelation by reaction of the reactive groups, wherein the resulting polymer has a solubility in water of at least one gram/liter of an aqueous solution at a temperature in the range between about 0 and 50° C., is biodegradable, and wherein each reactive group is separated from each other reactive group by at least one degradable linkage.

15. The method of claim 14 wherein the carbonate linkage is prepared from trimethylene carbonate.

16. The method of claim 14, wherein two or more polymer blocks are linked by linkages comprising carbonate groups to obtain a higher molecular weight of reactive macromer without compromise of biodegradability.

17. A method for improving the biodegradability of a carbonate-comprising chemically-reactive macromer, the method comprising: a) reacting a carbonate with a biocompatible compound which has a solubility of at least one gram/liter in aqueous solutions at a temperature in the range between about 0 and 50° C., wherein the biocompatible compound comprises at least two hydroxyl groups to form a carbonate-comprising precursor, the reaction continuing for a sufficient time to ensure completion of the reaction and attainment of equilibrium among reacting species, and the carbonate providing a first biodegradable linkage; b) adding to the carbonate-comprising precursor an excess of a first reagent to form a second biodegradable linkage, wherein the first reagent comprises a biodegradable moiety other than a carbonate; and then c) adding to the carbonate-comprising precursor a second reagent which forms at least one chemically-reactive group, thereby forming the chemically-reactive macromer, wherein the chemically reactive group of step c) is attached to the macromer via the biodegradable moiety of step b).

18. The method of claim 17, wherein the carbonate is a cyclic aliphatic carbonate.

19. The method of claim 17 in which the polymer is a polyalkylene glycol.

20. The method of claim 17 in which the first reagent comprises a residue of a hydroxycarboxylic acid.

21. The method of claim 20 which the hydroxycarboxylic acid residue is an alpha-hydroxy acid.

22. The method of claim 21 in which the acid is selected from lactic acid, lactide, and lactoyl chloride.

23. The method of claim 17 wherein the chemically-reactive group of step c) comprises at least one component selected from the group consisting of ethylenically unsaturated groups, acetylenically unsaturated groups, isocyanates, oxiranes, sulfhydryls, succinimides, maleimides, amines, imines, carboxylic acids, sulfonic acids, and phosphoric acids.

24. A polymer comprising a biodegradable macromer comprising at least one water soluble region, at least one degradable region, and at least one functional, polymerizable group, wherein the polymerizable groups are separated from each other by at least one degradable region, and wherein at least one degradable region is a carbonate or dioxanone region.

25. The polymer of claim 24, further comprising a prophylactic, therapeutic, or diagnostic agent.

26. The polymer of claim 24, wherein the polymer is a hydrogel.

27. The polymer of claim 24, wherein the polymer is formed into a shape selected from the group consisting of particles, sheets, rods, and nano or microcapsules.

28. The polymer of claim 24, wherein the polymer is a tissue sealant.

29. The polymer of claim 24, wherein the water soluble region is selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, polysaccharides, carbohydrates, proteins, and combinations thereof.

30. The polymer of claim 29, wherein the water soluble region is poly(ethylene glycol).

31. The polymer of claim 24, wherein at least one biodegradable region is selected from the group consisting of poly(hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), and poly(phosphoesters).

32. The polymer of claim 31, wherein the biodegradable region is a poly(hydroxy acid) selected from the group consisting of poly(glycolic acid), poly(D,L-lactic acid) and poly(L-lactic acid).

33. The polymer of claim 31, wherein the biodegradable region is a poly(lactone) selected from the group consisting of poly(epsilon-caprolactone), poly(delta-valcrolactone) and poly(gamma-butyrolactone).

34. The polymer of claim 24, wherein the carbonate linkage is prepared from a cyclic aliphatic carbonate.

35. The polymer of claim 24, wherein the carbonate linkage is prepared from trimethylene carbonate.

36. The polymer of claim 24, wherein the one or more reactive polymerizable group(s) are selected from the group consisting of ethylenically or acetylenically unsaturated groups, isocyanates, epoxides (oxiranes), sulfhydryls, succinimides, maleimides, amines, imines, amides, carboxylic acids, sulfonic acids, and phosphate groups.

37. The polymer of claim 36, wherein the one or more reactive polymerizable group(s) are ethylenically-unsaturated groups.

38. The polymer of claim 37, wherein the ethylenically-unsaturated group is selected from the group consisting of vinyl groups, allyl groups, unsaturated monocarboxylic acids, diacrylates, oligoacrylates, unsaturated dicarboxylic acids, and unsaturated tricarboxylic acids.

39. The polymer of claim 24, wherein the macromer comprises carbonate or dioxanone residues in range from about 0.3% to 20% (by weight).

40. The polymer of claim 24, wherein the water soluble region forms the core of the macromer.

FIELD OF THE INVENTION

The present invention relates to improved photopolymerizable biodegradable hydrogels for use as tissue adhesives, coatings, sealants and in controlled drug delivery devices. The improved materials incorporate carbonate and/or dioxanone linkages. These biodegradable linkages allow improved control of various properties of the macromers, particular increasing viscosity while preserving biodegradability.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,410,016 to Hubbell et al. discloses biocompatible, biodegradable macromers which can be polymerized to form hydrogels. The macromers are block copolymers that include a biodegradable block, a water-soluble block with sufficient hydrophilic character to make the macromer water-soluble, and one or more polymerizable groups. The polymerizable groups are separated from each other by at least one degradable group, Hubbell specifically discloses using polyhydroxy acids, such as polylactide, polyglycolide and polycaprolactone as the biodegradable polymeric blocks. One of the disclosed uses for the macromers is to plug or seal leaks in tissue.

Other hydrogels have been described, for example, in U.S. Pat. No. 4,938,763 to Dunn et al., U.S. Pat. Nos. 5,100,992 and 4,826,945 to Cohn et al., U.S. Pat. Nos. 4,741,872 and 5,160,745 to De Luca et al., U.S. Pat. No. 5,527,864 to Suggs et al., and U.S. Pat. No. 4,511,478 to Nowinski et al. Methods of using such polymers are described in U.S. Pat. No. 5,573,934 to Hubbell et al. and PCT WO 96/29370 by Focal.

While numerous references disclose using homopolymers and copolymers including carbonate linkages to form solid medical devices, such as sutures, suture coatings and drug delivery devices (see, for example, U.S. Pat. No. 3,301,824 to Hostettler et al., U.S. Pat. No. 4,243,775 to Rosensaft et al., U.S. Pat. No. 4,429,080 to Casey et al., U.S. Pat. No. 4,716,20 to Casey et al., U.S. Pat. No. 4,857,602 to Casey et al., U.S. Pat. No. 4,882,168 to Casey, EP 0 390 860 B1 by Boyle et al., U.S. Pat. No. 5,066,772 to Tang et al., U.S. Pat. No. 5,366,756 to Chesterfield et al., U.S. Pat. No. 5,403,347 to Roby et al. and U.S. Pat. No. 5,522,841 to Roby et al.), none of these publications discloses incorporating polymerizable groups on the polymers so that the polymers can be further polymerized. Accordingly, none of these polymers can be used in the same manner as the macromers in U.S. Pat. No. 5,410,016 to Hubbell et al.

Sealing or plugging holes in lung tissue is inherently more difficult than sealing other types of tissue because the tissue is constantly expanded and contracted during normal respiration. It would be advantageous to provide macromers which can be rapidly polymerized in vivo to form hydrogels which are more elastic than conventional hydrogels, for example, for use in sealing lung tissue.

It is therefore an object of the present invention to provide biodegradable, biocompatible macromers that can be rapidly polymerized in vivo to form hydrogels which are more elastic than conventional hydrogels.

It is a further object of the present invention to provide a macromer solution which can be administered during surgery or outpatient procedures and polymerized as a tissue adhesive, cell encapsulating medium, tissue sealant, wound dressing or drug delivery device.

It is a still further object of the present invention to provide a macromer solution which can be polymerized in vivo on a surface to be coated in a very short time frame to form conformal coating layers.

SUMMARY OF THE INVENTION

Biocompatible, biodegradable, polymerizable and at least substantially water-soluble macromers and methods of preparation and use thereof are disclosed. The macromers are block copolymers that include at least one water-soluble block, at least one biodegradable block, and at least one polymerizable group. At least one of the biodegradable blocks comprises a linkage based on a carbonate or dioxanone group, and the macromers can contain other degradable linkages or groups in addition to carbonate or dioxanone.

The carbonate and dioxanone linkages impart more elasticity to the polymer and degrade at a different rate than hydroxy acid linkages. Carbonate linkages can also increase macromer viscosity, at a given concentration, without requiring increased molecular weight of the nondegradable components of the macromer. The macromers can also include poly(hydroxy acid) linkages which degrade by hydrolysis into relatively non-toxic hydroxy acid residues, or other biodegradable blocks such as polycaprolactones, polyorthoesters, polyanhydrides, and polypeptides. The degradation time of the polymers can be controlled, for example, by selecting the types and proportion of the biodegradable blocks.

The polymerizable groups can be polymerized by either free radical (homolytic) processes or by heterolytic processes (such as cationic polymerization). Preferably, the groups are polymerized photochemically. The macromer can be polymerized in the presence of prophylactic, therapeutic or diagnostic agents, for delivery of the incorporated agents in a controlled manner as the resulting polymer degrades. The macromers are useful for delivering hydrophobic, hydrophilic and/or labile materials. They can be particularly useful for delivery of hydrophobic materials.

The macromers can be polymerized in an interfacial manner to form ultrathin coatings which are intimately adhered to the coated surface, or in a bulk manner to form relatively thick coatings which may or may not be intimately adhered to the coated surface. Alternatively, the two methods can be combined to provide a relatively thick coating which is intimately adhered to the surface. Each of these methods is advantageous for certain applications.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the elastic strength (seal pressure, mm Hg) over time (hr) of five different sealant materials: 10% 35K T, 20% 35K T, 10% 20K TL, 10% 20 K TL, and 20% 35K TL K is defined as 100 Daltons (weight average molecular weight, T is trimethylene carbonate (TMC), L is lactide, and TL is a copolymer of TMC and lactide.

FIGS. 2A and 2B are graphs of the degradation (% mass loss) over time (days) for 20K T (FIG. 2A) and 35K T (FIG. 2B) for subcutaneous polymeric implants in rats.

DETAILED DESCRIPTION OF THE INVENTION

Polymers

Water-soluble, biocompatible, biodegradable macromers and methods of preparation and use thereof, are disclosed. The macromers include at least one water-soluble block, at least one biodegradable block, and at least one polymerizable group. At least one biodegradable block contains a carbonate or dioxanone group. To obtain a biodegradable material after polymerization, each polymerizable group must be separated from any other polymerizable group on the macromer by at least one biodegradable linkage or group.

At least a portion of the macromers will contain more than one reactive group and thereby be effective as crosslinkers, so that the macromers can be crosslinked to form a gel. The minimal proportion required will vary with the nature of the macromer and its concentration in solution, and the proportion of crosslinker in the macromer solution can be as high as 100% of the macromer solution.

For example, the macromers include at least 1.02 polymerizable groups on average, and, more preferably, the macromers each include two or more polymerizable groups on average.

Since in the preferred homolytic (free radical) polymerization reactions each polymerizable group will polymerize into a chain, crosslinked hydrogels can be produced using only slightly more than one reactive group per macromer (i.e., about 1.02 polymerizable groups on average). However, higher percentages are preferable, and excellent gels can be obtained in polymer mixtures in which most or all of the molecules have two or more reactive double bonds. Poloxamines, an example of a water-soluble block, have four arms and thus may readily be modified to include four polymerizable groups.

As used herein, a “biocompatible” material is one which stimulates only a mild, often transient, implantation response, as opposed to a severe or escalating response.

As used herein, a “biodegradable” material is one which decomposes under normal in vivo physiological conditions into components which can be metabolized or excreted.

As used herein, a “block” is a region of a copolymer differing in subunit composition from neighboring regions. Blocks will generally contain multiple subunits, up to about one thousand subunits or less for non-degradable materials, and without an upper limit for degradable materials. In the lower limit, the size of a block depends on its function; the minimum size is that which is sufficient to allow the function to be performed. In the case of a block conferring water-solubility on the macromer, this will by typically 400 daltons or more, preferably 600 daltons or more, more preferably at least 1000 daltons, and most preferably in the range of 2000 to 40,000 daltons. For degradable linkages, the minimum block size is a single linkage of the appropriate degradability for the function. More preferably, the block size is two to forty groups; most preferably, three to twenty. The reactive groups may be considered as a block for some purposes; the typical number of units in such a block is one, but may be two to five.

As used herein, a carbonate is a functional group with the structure —O—C(O)—O—. The carbonate starting material can be cyclic, such as trimethylene carbonate (TMC), or can be linear, such as dimethylcarbonate (CH ₃ O—C(O)—OCH ₃ ). After incorporation into the polymerizable macromer, the carbonate will be present at least in part as R—O—C(═O)—O—R′, where R and R′ are other components of the macromer.

As used herein, a dioxanone is a repeating unit with the structure —O—C(O)—R—O—, where R is a straight, branched or cyclic alkyl group. An example of a cyclic dioxanone is 1,4-dioxan-2-one, 1,4-dioxan-2-one is a preferred dioxanone.

As used herein, a hydrogel is a substance formed when an organic polymer (natural or synthetic) is cross-linked via covalent, ionic, or hydrogen bonds to create a three-dimensional open-lattice structure which entraps water molecules to form a gel.

As used herein, “water-soluble” is defined as a solubility of at least one gram/liter in an aqueous solution at a temperature in the range of about 0° C. and 50° C. Aqueous solutions can include small amounts of water-soluble organic solvents, such as dimethylsulfoxide, dimethylformamide, alcohols, acetone, and/or glymes.

Types of Block Copolymers

In general terms, the macromers are block co-polymers that comprise a biodegradable block, a water-soluble block, and at least one polymerizable group. Preferably, the macromers comprise at least 1.02 polymerizable groups on average, and, more preferably, include at least two polymerizable groups per macromer, on average. Average numbers of polymerizable groups can be obtained, for example, by blending macromers with different amounts of polymerizable groups.

The individual polymeric blocks can be arranged to form different types of block copolymers, including di-block, tri-block, and multi-block copolymers. The polymerizable blocks can be attached directly to biodegradable blocks or indirectly via water-soluble nondegradable blocks, and are preferably attached so that the polymerizable groups are separated from each other by a biodegradable block. For example, if the macromer contains a water-soluble block coupled to a biodegradable block, one polymerizable group may be attached to the water-soluble block and another attached to the biodegradable block. Preferably, both polymerizable groups would be linked to the water-soluble block by at least one degradable linkage.

The di-block copolymers include a water-soluble block linked to a biodegradable block, with one or both ends capped with a polymerizable group. The tri-block copolymers can include a central water-soluble block and outside biodegradable blocks, with one or both ends capped with a polymerizable group. Alternatively, the central block can be a biodegradable block, and the outer blocks can be water-soluble. The multiblock copolymers can include one or more of the water-soluble blocks and biocompatible blocks coupled together in a linear fashion. Alternatively, the multiblock copolymers can be brush, comb, dendritic or star copolymers. If the backbone is formed of a water-soluble block, at least one of the branches or grafts attached to the backbone is a biodegradable block. Alternatively, if the backbone is formed of a biodegradable block, at least one of the branches or grafts attached to the backbone is a water-soluble block, unless the biodegradable block is also water-soluble. In another embodiment, a multifunctional compound, such as a polyol, can be coupled to multiple polymeric blocks, at least one of which is water-soluble and at least one of which is biodegradable.

In general, any formulation of the macromer which is intended to be biodegradable must be constructed so that each polymerizable group is separated from each other polymerizable group by one or more linkages which are biodegradable. Non-biodegradable materials are not subject to this constraint.

Those skilled in the art will recognize that the individual polymeric blocks may have uniform compositions, or may have a range of molecular weights, and may be combinations of relatively short chains or individual species which confer specifically desired properties on the final hydrogel, while retaining the required characteristics of the macromer. The lengths of oligomers referred to herein may vary from single units (in the biodegradable portions) to many, subject to the constraint of preserving the overall water-solubility of the macromer.

In the discussion below and the examples, macromers are often designated by a code of the form xxKZn. xxK represents the molecular weight of the backbone polymer, which is polyethylene glycol (“PEG”) unless otherwise stated, in thousands of Daltons. Z designates the biodegradable linkage, using a code wherein where L is for lactic acid, G is for glycolic acid, D is for dioxanone, C is for caprolactone, T is for trimethylene carbonate, and n is the average number of degradable groups in the block. The molecules are terminated with acrylic ester groups, unless otherwise stated. This is sometimes also indicated by the suffix A2.

While the preferred biodegradable groups (in addition to carbonate or dioxanone) are hydroxy acids, orthoesters, anhydrides, or other synthetic or semisynthetic degradable linkages, natural materials may be used in the biodegradable sections when their degree of degradability is sufficient for the intended use of the macromer. Such biodegradable groups may comprise natural or unnatural amino acids, carbohydrate residues, and other natural linkages. Biodegradation time will be controlled by the local availability of enzymes hydrolyzing such linkages. The availability of such enzymes may be ascertained from the art or by routine experimentations.

Water soluble regions

Suitable water-soluble polymeric blocks include those prepared from poly(ethylene glycol), poly(ethylene oxide), partially or fully hydrolyzed poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers (poloxamers and meroxapols), poloxamines, carboxymethyl cellulose, hydroxyalkylated celluloses such as hydroxyethyl cellulose and methylhydroxypropyl cellulose, polypeptides, polynucleotides, polysaccharides or carbohydrates such as Ficoll® polysucrose, hyaluronic acid, dextran, heparan sulfate, chondroitin sulfate, heparin, or alginate, and proteins such as gelatin, collagen, albumin, or ovalbumin. Preferably, the water-soluble polymeric blocks are made from poly (ethylene glycol) or poly(ethylene oxide).

The soluble polymer blocks may be intrinsically biodegradable or may be poorly biodegradable or effectively non-biodegradable in the body. In the latter two cases, the soluble blocks should be of sufficiently low molecular weight to allow excretion. The maximum molecular weight to allow excretion in human beings (or other species in which use is intended) will vary with polymer type, but will often be about 40,000 daltons or below. Water-soluble natural polymers and synthetic equivalents or derivatives, including polypeptides, polynucleotides, and degradable polysaccharides, can be used.

The water-soluble blocks can be a single block with a molecular weight of at least 600, preferably 2000 or more, and more preferably at least 3000 Daltons. Alternatively, the water-soluble blocks can be two or more water-soluble blocks which are joined by other groups. Such joining groups can include biodegradable linkages, polymerizable linkages, or both. For example, an unsaturated dicarboxylic acid, such as maleic, fumaric, or aconitic acid, can be esterified with degradable groups as described below, and such linking groups can be conjugated at one or both ends with hydrophilic groups such as polyethylene glycols. In another embodiment, two or more PEG molecules can be joined by biodegradable linkages including carbonate linkages, and subsequently be end-capped with polymerizable groups.

Biodegradable Blocks.

The biodegradable blocks are preferably hydrolyzable under in vivo conditions. At least one biodegradable region is a carbonate or dioxanone linkage. Additional biodegradable polymeric blocks can include polymers and oligomers of hydroxy acids or 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), and poly(phosphoesters). Polylactones such as poly(epsilon-caprolactone), poly(delta-valerolactone), poly(gamma-butyrolactone) and poly(beta-hydroxybutyrate), for example, are also useful.

Biodegradable regions can be constructed from monomers, oligomers or polymers using linkages susceptible to biodegradation, such as ester, peptide, anhydride, orthoester, and phosphoester bonds.

By varying the total amount of biodegradable groups, and selecting the ratio between the number of carbonate or dioxanone linkages (which are relatively slow to hydrolyze) and of lower hydroxy acid linkages (especially glycolide or lactide, which hydrolyze relatively rapidly), the degradation time of hydrogels formed from the macromers can be controlled.

Carbonates and Dioxanones

Any carbonate can be used to make the macromers. Preferred carbonates are aliphatic carbonates, for maximum biocompatibility. For example, trimethylene carbonate and dimethyl carbonate are examples of aliphatic carbonates. Lower dialkyl carbonates are joined to backbone polymers by removal by distillation of alcohols formed by equilibration of dialkyl carbonates with hydroxyl groups of the polymer.

More preferred carbonates are the cyclic carbonates, which can react with hydroxy-terminated polymers without release of water. Suitable cyclic carbonates include ethylene carbonate (1,3-dioxolan-2-one), propylene carbonate (4-methyl-1,3-dioxolan-2-one), trimethylene carbonate (1,3-dioxan-2-one) and tetramethylene carbonate (1,3-dioxepan-2-one). Under some reaction conditions, it is possible that orthocarbonates may react to give carbonates, or that carbonates may react with polyols via orthocarbonate intermediates, as described in Timberlake et al, U.S. Pat. No. 4,330,481. Thus, certain orthocarbonates, particularly dicyclic orthocarbonates, can be suitable starting materials for forming the carbonate-linked macromers.

Alternatively, suitable diols or polyols, including backbone polymers, can be activated with phosgene to form chloroformates, as is described in the art, and these active compounds can be mixed with backbone polymers containing suitable groups, such as hydroxyl groups, to form macromers containing carbonate linkages.

All of these materials are “carbonates” as used herein.

Suitable dioxanones include dioxanone (p-dioxanone; 1,4-dioxan-2-one; 2-keto-1,4-dioxane), and the closely related materials 1,4-dioxolan-2-one, 1,4-dioxepan-2-one and 1,5-dioxepan-2-one. Lower alkyl, for example C1-C4 alkyl, derivatives of these compounds are also contemplated, such as 2-methyl p-dioxanone (cyclic O-hydroxyethyl ether of lactic acid).

Polymerizable Groups.

The term “polymerizable group” is defined as a reactive functional group that has the capacity to form additional covalent bonds resulting in macromer interlinking. Polymerizable groups specifically include groups capable of polymerizing via free radical polymerization and groups capable of polymerizing via cationic or heterolytic polymerization. Suitable groups include, but are not limited to, ethylenically or acetylenically unsaturated groups, isocyanates, epoxides (oxiranes), sulfhydryls, succinimides, maleimides, amines, imines, amides, carboxylic acids, sulfonic acids and phosphate groups. (Aliphatic hydroxy groups are not considered to be reactive groups for the chemistry disclosed herein, except in formulations which also contain groups capable of covalent crosslinking with such hydroxyls.) Ethylenically unsaturated groups include vinyl groups such as vinyl ethers, N-vinyl amides, allyl groups, unsaturated monocarboxylic acids, unsaturated dicarboxylic acids, and unsaturated tricarboxylic acids. Unsaturated monocarboxylic acids include acrylic acid, methacrylic acid and crotonic acid. Unsaturated dicarboxylic acids include maleic, fumaric, itaconic, mesaconic or citraconic acid. Unsaturated tricarboxylic acids include aconitic acid. Polymerizable groups may also be derivatives of such materials, such as acrylamide, N-isopropylacrylamide, hydroxyethylacrylate, hydroxyethylmethacrylate, and analogous vinyl and allyl compounds. Reactive group forming compounds will preferably be available in a stable activated form, to allow simple incorporation into the macromer. Examples of such materials are (meth)acrylyl chloride, acrylic anhydride, and allyl glycidyl ether. The polymerizable groups are preferably located at one or more ends of the macromer. In a less preferred embodiment, the polymerizable groups can be located within the macromer.

Polymerization is initiated by any convenient reaction, including photopolymerization, chemical or thermal free-radical polymerization, redox reactions, cationic polymerization, and chemical reaction of active groups (such as isocyanates, for example.) Polymerization is preferably initiated using photoinitiators. Photoinitiators that generate a free radical or a cation on exposure to UV light are well known to those of skill in the art. Free-radicals can also be formed in a relatively mild manner from photon absorption of certain dyes and chemical compounds. The polymerizable groups are preferably polymerizable by free radical polymerization. The preferred polymerizable groups are acrylates, diacrylates, oligoacrylates, methacrylates, dimethacrylates, oligomethacrylates, cinnamates, dicinnamates, oligocinnamates, and other biologically acceptable photopolymerizable groups.

These groups can be polymerized using photoinitiators that generate free radicals upon exposure to light, including UV (ultraviolet) and IR (infrared) light, preferably long-wavelength ultraviolet light (LWUV) or visible light. LWUV and visible light are preferred because they cause less damage to tissue and other biological materials than short-wave UV light. Useful photoinitiators are those which can be used to initiate polymerization of the macromers without cytotoxicity and within a short time frame, minutes at most and most preferably seconds.

Exposure of dyes, preferably in combination with co-catalysts such as amine, to light, preferably visible or LWUV light, can generate free radicals. Light absorption by the dye causes the dye to assume a triplet state, and the triplet state subsequently reacts with the amine to form a free radical which initiates polymerization, either directly or via a suitable electron transfer reagent or co-catalyst, such as an amine. Polymerization can be initiated by irradiation with light at a wavelength of between about 200-1200 nm, most preferably in the long wavelength ultraviolet range or visible range, 320 nm or higher, and most preferably between about 365 and 550 nm.

Numerous dyes can be used for photopolymerization. Suitable dyes are well known to those of skill in the art. Preferred dyes include erythrosin, phloxime, rose bengal, thionine, camphorquinone, ethyl eosin, eosin, methylene blue, riboflavin, 2,2-dimethyl-2-phenylacetophenone, 2-methoxy-2-phenylacetophenone, 2,2-dimethoxy-2-phenyl acetophenone, other acetophenone derivatives, and camphorquinone. Suitable cocatalysts includes amines such as N-methyl diethanolamine, N,N-dimethyl benzylamine, tri-ethanol amine, triethylamine, dibenzyl amine, N-benzylethanolamine, N-isopropyl benzylamine. Triethanolamine is a preferred cocatalyst.

Suitable chemical, thermal and redox systems may initiate the polymerization of unsaturated groups by generation of free radicals in the initiator molecules, followed by transfer of these free radicals to the unsaturated groups to initiate a chain reaction. Peroxides and other peroxygen compounds are well-known in this regard, and may be considered as chemical or thermal initiators. Azobisbutyronitrile is a chemical initiator. A combination of a transition metal, especially iron, with a peroxygen and preferably a stabilizing agent such as glucuronic acid allows generation of free radicals to initiate polymerization by a cycling redox reaction.

Combinations of chemical or redox systems with photo-initiated systems have been demonstrated to be effective in WO 96/29370, and are a preferred initiation system for many applications of the macromers of the present invention.

It is also possible to use the macromers with other types of linking reactions. For example, a macromer could be constructed with amine termination, with the amine considered as an active group; and another macromer could be constructed with isocyanate termination, with the isocyanate as the active group. On mixing, the materials will spontaneously react to form a gel. Alternatively, an isocyanate-terminated macromer could be polymerized and crosslinked with a mixture of diamines and triamines. Such a reaction is more difficult to control than a photoinitiated reaction, but could be preferred for high volume extracorporeal production of gels for implantation, perhaps as drug delivery systems. Other pairs of reactants include maleimides with amines or sulfhydryls, or axiranes with amines, sulfhydryls or hydroxyls.

Preferred Macromers

Preferably, the macromers contain between about 0.3% and 20% by weight of carbonate residues or dioxanone residues, more preferably, between about 0.5% and 15% carbonate or dioxanone residues, and most preferably, about 1% to 5% carbonate or dioxanone residues. In those embodiments where hydroxy acid residues are desired, the macromer contains between about 0.1 and 10 residues per residue of carbonate or dioxanone, more preferably between about 0.2 and 5, and most preferably one or more such residue per macromer.

In a preferred embodiment, the macromer includes a core, an extension on each end of the core, and an end cap on each extension. The core is a hydrophilic polymer or oligomer; each extension is a biodegradable oligomer comprising one or more carbonate or dioxanone linkage; and each end cap comprises one or more functional groups capable of cross-linking the macromers. In a particularly preferred embodiment, the core includes hydrophilic poly(ethylene glycol) oligomers with a molecular weight between about 400 and 40,000 Da; each extension includes 1 to 10 residues selected from carbonate and dioxanone, and optionally further included between one and five hydroxyacid residues, preferably alpha-hydroxy acid residues; wherein the total of all residues in the extension is sufficiently small to preserve water-solubility of the macromer, being typically less than about 20% of the weight of the macromer, more preferably 10% or less.

Preferably, each end cap includes a polymerizable group. The preferred groups are free-radical (homolytically) polymerizable. More preferably, they are ethylenically-unsaturated (i.e., containing carbon-carbon double bonds), with a preferred molecular weight between about 50 and 300 Da, which are capable of cross-linking and/or polymerizing the macromers. A preferred embodiment incorporates a core consisting of poly(ethylene glycol) oligomers of molecular weight about 25,000 Da; extensions including polycarbonate or poly(dioxanone) oligomers with a molecular weight of about 200 to 1000 D, alone or in combination with extensions formed of hydroxy acid oligomers; and end caps consisting of acrylate moieties (which are about 55 Da molecular weight).

Macromer Synthesis

The macromers can be synthesized using means well known to those of skill in the art. General synthetic methods are found in the literature, for example in U.S. Pat. No. 5,410,016 to Hubbell et al., U.S. Pat. No. 4,243,775 to Rosensaft et al., and U.S. Pat. No. 4,526,938 to Churchill et al.

For example, a polyethylene glycol backbone can be reacted with trimethylene carbonate (TMC) or a similar carbonate in the presence of a Lewis acid catalyst, such as stannous octoate, to form a TMC-polyethylene glycol terpolymer. The TMC-PEG polymer may optionally be further derivatized with additional degradable groups, such as lactate groups. The terminal hydroxyl groups can then be reacted with acryloyl chloride in the presence of a tertiary amine to end-cap the polymer with acrylate end-groups. Similar coupling chemistry can be employed for macromers containing other water-soluble blocks, biodegradable blocks, and polymerizable groups, particularly those containing hydroxyl groups.

When polyethylene glycol is reacted with TMC and a hydroxy acid in the presence of an acidic catalyst, the reaction can be either simultaneous or sequential. As shown in the examples below, the simultaneous reaction will produce an at least partially random copolymer of the three components. Sequential addition of a hydroxy acid after reaction of the PEG with the TMC will tend to produce an inner copolymer of TMC and one or more PEGs, which will statistically contain more than one PEG residue linked by linkages derived from TMC, with hydroxy acid largely at the ends of the (TMC, PEG) region. There is a tendency for TM and other carbonate groups to re-arrange by “back-biting” during synthesis, which is why multiple PEG molecules can become incorporated in the same macromer. When the hydroxy acid contains a secondary hydroxyl, as in lactic acid, then the tendency towards rearrangement is reduced.

In principle, the degradable blocks or regions could be separately synthesized and then coupled to the backbone regions. In practice, this more complex reaction does not appear to be required to obtain useful materials.

Sequential Addition

In a preferred embodiment, sequential addition of biodegradable groups to a carbonate-containing macromer can be used to enhance biodegradability of the macromer after capping with reactive end groups.

Upon reaction of, for example, trimethylene carbonate (TMC) with polyethylene glycol (PEG), the TMC linkages in the resulting copolymers have been shown to form end linked species of PEG, resulting in segmented copolymers, i.e. PEG units coupled by one or more adjacent TMC linkages. The length of the TMC segments can vary, and is believed to exhibit a statistical distribution. Coupling may also be accomplished via the carbonate subunit of TMC. These segmented PEG/TMC copolymers form as a result of transesterification reactions involving the carbonate linkages of the TMC segments during the TMC polymerization process when a PEG diol is used as an initiator. Similar behavior is expected if other polyalkylene glycol initiators were used. The end-linking may begin during the reaction of the TMC with the PEG, and completion of the end linking and attainment of equilibrium is observable by a cessation of increase of the viscosity of the solution.

If the product of this first reaction step is then reacted with a reactive end-capping material, such as acryloyl chloride, a significant percentage of the macromer end groups can be PEG hydroxyls, resulting in the attachment of the reactive groups directly to one end of a non-biodegradable PEG molecule. Such a reaction of the PEG/TMC segmented copolymers can be prevented by adding additional segments of other hydrolyzable co-monomers (e.g. lactate, glycolate, 1,4-dioxanone, dioxepanone, caprolactone) on either end of the PEG/TMC segmented copolymer. Some scrambling of the comonomer segments with the PEG/TMC prepolymer is expected, but this can be minimized by using proper reaction conditions. The basic PEG/TMC segmented copolymer or the further reacted PEG/TMC/comonomer segmented terpolymer is then further reacted to form crosslinkable macromers by affixing reactive end groups (such as acrylates) to provide a macromer with reactive functionality. Subsequent reaction of the end groups in an aqueous environment results in a bioabsorbable hydrogel. Similar segmented structures would be expected if another polyalkylene glycol (PAG) were used, for example a poloxamer.

The copolymers and macromers can have tailorable solubility and solution viscosity properties. The hydrogels can have tailorable modulus and degradation rate. For a given solution concentration in water, the viscosity is affected by the degree of end linking, the length of the TMC (and other hydrophobic species) segments, and the molecular weight of the starting PAG. The modulus of the hydrogel is affected by the molecular weight between crosslinks. The hydrogel degradation rate can be modified by adding a second, more easily hydrolyzed comonomer (e.g. lactate, glycolate, 1,4-dioxanone) as a segment on the ends of the basic PAG/TMC copolymer prior to adding the crosslinkable end group to form the macromer.

Some of these structures described herein are depicted below. PEG, lactate and acrylate units are used solely for purposes of illustration.

SOME BASIC STRUCTURES:

(CH ₂ —CH ₂ —O) _x ═PEG repeat unit═(PEG) _x

(CO—(CH ₂ ) ₃ —O) _y ═TMC repeat unit═(TMC) _y

(CO—CH(CH ₃ )—O) _z ═Lactate repeat unit═(LA) _z

—CO—CH═CH _2═ Acrylate end group═AA

SEGMENTED PEG/TMC COPOLYMER:

HO—(CO—(CH ₂ ) ₃ —O) _y —[(CH ₂ —CH ₂ —O) _x —(CO—(CH ₂ ) ₃ —O) _y ] _n —H

or HO—(TMC)y—[(PEG)x—(TMC)y]n—H

SEGMENTED PEG/TMC/Lactate TERPOLYMER:

HO—(CH(CH ₃ )—CO) _z —O—(CO—(CH ₂ ) ₃ —O) _y —[(CH ₂ —CH ₂ —O) _x —(CO—(CH ₂ ) ₃ —O) _y ] _n —(CO—C H(CH ₃ )—O) _z —H

or HO—(LA) _z —(TMC) _y —[(PEG) _x —(TMC) _y ] _n —(LA) _z —H

SEGMENTED PEG/TMC MACROMER (acrylated):

CH ₂ ═CH—CO—O—(CO—(CH ₂ ) ₃ O) _y —[(CH ₂ —CH ₂ —O) _x —(CO—(CH ₂ ) ₃ —O) _y ] _n —CO—CH═CH ₂

or AA—(TMC) _y —[(PEG) _x —(TMC) _y ] _n —AA

SEGMENTED PEG/TMC/Lactate TERPOLYMER MACROMER (acrylated):

AA—(LA) _z —(TMC) _y —[(PEG) _x —(TMC) _y ] _n —(LA) _z —AA

Applications for the Macromers.

Sealing Leaks in Tissue

A preferred application of the polymers is in a method of sealing leaks, for example, leaks of gases and/or bodily fluids (such as blood, cerebrospinal fluid, urine and bile), in tissue such as lung, urethra, ureter, gastrointestinal tract, reproductive tract, liver, spleen, dura, and the spinal cord. The method involves priming the surface of the tissue with a polymerization initiator, applying a macromer solution that also contains one or more polymerization initiators to the surface of the tissue to be coated, and then polymerizing the macromer. Preferably, the polymerization initiator comprises a photoinitiator.

Applying the initiator to surface of the tissue before adding the macromer solution polymerizes the macromer at the interface between the solution and the tissue surface. This “interfacial polymerization” provides excellent adherence of the resulting polymer to the tissue surface. Providing an initiator in the macromer solution allows a relatively thick, for example 1 mm to 10 mm, layer of polymer to be formed on the tissue surface. Relatively thick polymer layers may be required to effectively seal some types of tissue, for example, lung tissue or dura, depending on the size of the leak.

An advantage of the macromers when prepared with at least one carbonate group is that during the synthesis of the macromer, short blocks of non-biodegradable but excretable polymer, such as polyethylene oxide chains of up to about 40,000 D, can become linked by carbonate groups so give higher molecular weights to the macromers while preserving the biodegradability to secretable products of the macromer. It is believed that the higher molecular weights increase the elasticity of the final hydrogel. This is an important and useful property when the polymer must be readily and repeatedly stretched, as in a sealant layer applied to lung tissue. High elasticity can also be provided by linking nondegradable blocks with other polyfunctional linkers, such as dicarboxylic acids. However, since the synthetic chemistry required to make such macromers can be more complex than the simple reactions required for carbonate-based linking, this method is less preferred.

Prevention of Surgical Adhesions

Another preferred application is a method of reducing formation of adhesions after a surgical procedure in a patient. The method involves coating damaged tissue surfaces in a patient with an aqueous solution of a light-sensitive free-radical polymerization initiator and a macromer solution as described above. The coated tissue surfaces are exposed to light sufficient to polymerize the macromer. The light-sensitive free-radical polymerization initiator may be a single compound (e.g., 2,2-dimethoxy-2-phenyl acetophenone) or a combination of a dye and a cocatalyst (e.g., ethyl eosin or eosin Y, and triethanolamine).

Controlled delivery of incorporated agents.

Another preferred application involves locally applying an incorporated agent, such as a prophylactic, therapeutic or diagnostic agent, to tissue surfaces of a patient. The method includes the steps of mixing an agent to be incorporated with an aqueous solution including a suitable polymerization initiator, such as a light-sensitive free-radical polymerization initiator, and a macromer, to form a coating mixture. Tissue surfaces are coated with the coating mixture and the macromer is polymerized, for example, by exposure of the coating mixture to an effective amount of light of an appropriate wavelength.

Any of a variety of therapeutic, prophylactic or diagnostic agents can be delivered using these methods. Examples include synthetic and natural inorganic and organic compounds such as proteins (100 amino acid residues or more), peptides (less than 100 amino acid residues), carbohydrates, lipids, nucleic acid molecules, and small synthetic materials such as ethical drugs, having therapeutic, prophylactic or diagnostic activities. Nucleic acid molecules include genes, antisense molecules which bind to complementary DNA to inhibit transcription, aptamers, triple helix forming oligomers and ribozymes. The agents to be delivered can have a variety of biological activities. Diagnostic agents such as radiolabelled compounds, enzymatically labeled compounds, fluorescently labeled compounds, and other detectable agents can also be incorporated. Compounds with a wide range of molecular weights can be incorporated, for example, between 100 and 500,000 grams or more per mole.

Therapeutic or prophylactic compounds (“drugs”) of particular interest are those whose efficacy in treatment of a localized medical condition is increased by local delivery of the compound at or near the site of the localized medical condition. Examples of classes of such drugs are those which inhibit the formation or re-formation of scars or adhesions; those which prevent unwanted proliferation of vascular tissue or other luminal tissue; and growth factors, cytokines, etc. which only needs to be effective locally.

Imaging agents which may be utilized include commercially available agents used in positron emission tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI).

Examples of suitable materials for use as contrast agents in MRI include the gadolinium chelates currently available, such as diethylene triamine pentacetic acid (DTPA) and gadopentotate dimeglumine, as well as iron, magnesium, manganese, copper and chromium.

Examples of materials useful for CAT and x-rays include iodine based materials for intravenous administration, such as ionic monomers typified by diatrizoate and iothalamate, non-ionic monomers such as ioparnidol, isohexol, and ioversol, non-ionic dimers, such as iotrol and iodixanol, and ionic dimers, for example, ioxagalte.

Hydrogels incorporating these agents can be detected using standard techniques available in the art and commercially available equipment.

The macromers are particularly useful for delivering hydrophilic and/or labile materials. Because the macromer is water-soluble, water can penetrate the polymer and dissolve or extract incorporated hydrophilic materials. Labile materials can be incorporated without exposure of the material to organic solvents which would destroy biological activity. Hydrophobic materials may also be incorporated, if the rate of dissolution of the hydrophobic material and/or the gel matrix is sufficiently rapid to release the material at a therapeutically-effective rate. In all cases, the polymerized hydrogel will tend to protect the therapeutic material from attack by biological activities of the subject, such as enzyme activity.

In a variation of the method for controlled drug delivery, the macromers are polymerized with incorporated agent on the surface of tissue or a medical device.

The macromers may be polymerized to form devices in the shape of particles, sheets, rods, or nano or microcapsules.

Preferred Macromers

Preferably, the macromers contain between about 0.3% and 20% by weight of carbonate residues or dioxanone residues, more preferably, between about 0.5% and 15% carbonate or dioxanone residues, and most preferably, about 1% to 5% carbonate or dioxanone residues. In those embodiments where hydroxy acid residues are desired, the macromer contains between about 0.1 and 10 residues per residue of carbonate or dioxanone, more preferably between about 0.2 and 5, and most preferably one or more such residue per macromer.

In a preferred embodiment, the macromer includes a core, an extension on each end of the core, and an end cap on each extension. The core is a hydrophilic polymer or oligomer; each extension is a biodegradable oligomer comprising one or more carbonate or dioxanone linkage; and each end cap comprises one or more functional groups capable of crosslinking the macromers. In a particularly preferred embodiment, the core includes hydrophilic poly(ethylene glycol) oligomers with a molecular weight between about 400 and 40,000 Da; each extension includes 1 to 10 residues selected from carbonate and dioxanone, and optionally further includeds between one and five hydroxyacid residues, preferably alpha-hydroxy acid residues; wherein the total of all residues in the extensions is sufficiently small to preserve water-solubility of the macromer, being typically less than about 20% of the weight of the macromer, more preferably 10% or less.

Preferably, each end cap includes a polymerizable group. The preferred groups are free-radical (homolytically) polymerizable. More preferably, they are ethylenically-unsaturated (i.e., containing carbon-carbon double bonds), with a preferred molecular weight between about 50 and 300 Da, which are capable of cross-linking and/or polymerizing the macromers. A preferred embodiment incorporates a core consisting of poly(ethylene glycol) oligomers of molecular weight about 25,000 Da; extensions including polycarbonate or poly(dioxanone) oligomers with a molecular weight of about 200 to 1000 D, alone or in combination with extensions formed of hydroxy acid oligomers; and end caps consisting of acrylate moieties (which are about 55 Da molecular weight).

Tissue Adhesives.

The macromers, and hydrogels formed therefrom, can also be used to adhere tissue surfaces in a patient. The macromer is mixed with a suitable polymerization initiator system, such as a photoinitiator or photoinitiator/amine mixture, to form an aqueous mixture. The mixture is applied to a tissue surface to which tissue adhesion is desired. The tissue surface is contacted with the tissue with which adhesion is desired, forming a tissue junction. The macromers are then polymerized at the tissue junction.

Such a technique can be used to hold surgically severed tissue in apposition during the healing process, thereby replacing or supplementing the use of sutures, staples, etc. In addition, such a gel may also be used to form a protective barrier.

Tissue Coatings.

In a particularly preferred application of these macromers, an ultra thin coating is applied to the surface of a tissue, most preferably the inside surface of a blood vessel. Such coatings can be used to treat or prevent stenosis or restenosis of blood vessels. A polymerization initiator, preferably a photoinitiator, is applied to the surface of the tissue, allowed to stain the tissue, and, optionally, the excess photoinitiator is removed by dilution or rinsing. After the initiator has been applied to the tissue, the macromer solution is applied and the macromer is polymerized. As demonstrated below, this method is capable of creating a uniform polymeric coating of between about one and 300 microns in thickness, more preferably about ten to 200 microns, most preferably 20 to 80 microns, which does not evoke thrombosis during its residence at the site.

Coating Medical Devices

The surface of medical devices can be coated with the macromers using interfacial polymerization, bulk polymerization, or both, as discussed above. Coating layers applied using interfacial polymerization or a combination of interfacial and bulk polymerization typically adhere more strongly to the medical devices than those prepared using only bulk polymerization.

The present invention will be more fully understood by reference to the following non-limiting examples.

Example 1: General Synthesis of Macromers: Melt Method.

Methods analogous to those described in U.S. Pat. No. 4,526,938 to Churchill et al. were used to form derivatized PEG by the melt method. Polyethylene glycol (PEG) was obtained commercially. The molecular weight listed on the label was assumed to be the molecular weight of the material. The PEG was optionally dissolved in methanol and purified by passage over an ion exchange resin, and dried.

Purified or as-supplied PEG was charged to a reactor, optionally with a small amount of xylene, and heated for five to six hours at about 110° C. (note: all temperatures herein are in degrees Celsius) under vacuum to complete removal of water. After cooling under vacuum, the flask was placed in a glove bag, the materials for forming the biodegradable linkages (including T (trimethylene carbonate) and L (lactide)) were added to the PEG, and the temperature was raised to about 160-165° C. under an argon blanket.

After dissolution of the reactants in the melted PEG, a catalyst, typically stannous octoate, was added, the temperature was raised to 185° C., and ring-opening addition was allowed to proceed for about 3 hours, with stirring under argon. The PEG—(T,L) intermediate could be further reacted at this stage, but typically was freed of unreacted monomers by precipitation in hexane, recovery and drying.

The purified intermediate, for example, PEG—(TnLm), where “n” is the number of T groups and “m” is the number of L groups, or the original reaction mixture without purification, was taken up in toluene, and an agent capable of adding unsaturated linkages, such as acryloyl chloride, was added, typically in excess, under mild heating (e.g., about 50° C.) and in the presence of an acid-neutralizing agent such as triethylamine. Suitable reactant ratios were found to be 1 ml acryloyl chloride and 1.8 ml triethylamine per 30 grams of PEG. The endcapped macromer, PEG-(T, L)-A2, was purified by precipitation in hexane, recovered and dried. Stabilizer was optionally added at this stage. The extent of incorporation of monomers was determined by NMR.

A similar procedure was used to prepare other macromers. PEG—(Tn)—A2, PEG—(Dn, Gm)—A2, where D is dioxanone and G is glycolide, and like materials were formed by similar procedures. Synthesis of macromers based on other starting hydrophilic blocks follows similar procedures, with adjustment in precipitation conditions as required. In a synthesis with multi-hydroxy compounds, such as polyvinyl alcohol, the water would be removed azeotropically under mild reflux in, e.g., toluene; and the degradable linkages are preferably synthesized by polymerization onto the hydroxy compound as described above, although such blocks could be added as preformed activated acrylated blocks, for example, using a carbodiimide derivative of the acylated poly(degradable linkage), if greater control were required.

Example 2: Synthesis of PEG-TMC and PEG-TMC-Lactide Macromers.

35K(T8)A2 (“35KT” in the examples below) was made from purified PEG of nominal molecular weight 35,000 by the melt procedure as described above. T was charged into the reactor at a nominal molar ratio of 13:1 to the PEG to obtain this result. The final actual acrylate incorporation averaged 1.6 per PEG molecule, or about 2 acrylates per macromer.

35K(T7L2)A2 (“35KTL”) contained about 7 T units (6.88 measured) and 2 lactate units (1.86 measured) as synthesized. (Note that there are 2 lactate units per lactide molecule.) T and L were charged at nominal molar ratios of 10:1 and 3:1 relative to PEG.

20K(T30L15)A2 contained about 30 T units and 15 lactide units per 20,000 D PEG molecule. The actual acrylate to PEG ratio was 1.42.

Example 3: Seal pressure text on latex to measure strength and elasticity

Poly(ethylene glycol)-lactide-trimethylene carbonate terpolymers endcapped with acrylate esters were evaluated using a seal pressure test apparatus to determine the failure pressure for coatings prepared using the macromers.

One of the materials tested had a poly(ethylene glycol) molecular weight of 20,000 Daltons (“20 kD”), a lactate incorporation of 13.8 and a trimethylene carbonate incorporation of 16.0, with nominal acrylation of 2 per macromer (“20KTL”). Also tested were 35 kD PEG esterified with about 8 TMC linkages and then endcapped with acrylates (“35KT”), and 35 kD PEG esterified with about 8 TMC and about 8 lactate groups (“35KTL”), both also acrylated. The reagents applied were “primer” and “sealant”. The complete system contained both a photoinitiation system (Eosin Y/triethanolamine) and a redox initiation system (ferrous gluconate/fructose, plus t-butylhydroperoxide after mixing) which did not cause significant polymerization of the macromer until both mixed (primer and sealant) and activated by light.

Primer solution contained Eosin Y (2000 ppm, w/w), 5000 ppm ferrous gluconate, 10,000 ppm (1%) fructose, 30,000 ppm NaCl, and 30% w/w of 3.5KL5 macromer (made according to U.S. Pat. No. 5,410,016). Primer was applied to a 2 cm×2 cm piece of latex film (from a latex examination glove; about 1 mm thick) with a 6 mm diameter hole created in the center. A toroidal Teflon® fluoropolymer template with a 1 cm. diameter central hole was placed on the latex film to control the area of application of the sealant, by limiting its spread.

Sealant solution contained macromer (in this example, 10% or 20% w/w of one of the macromers described above) dissolved in an aqueous solution containing isotonic saline, 90 mM triethanolamine as buffer and electron transfer component, Eosin Y (20 ppm) as a photoinitiator, 4000 ppm vinylcaprolactam as comonomer, and 125 ppm t-butylhydroperoxide as part of the light-sensitized redox initiation system. Two drops of sealant were dispensed inside the template above the hole and then carefully mixed in with the primer, using a brush. Three more drops of sealant were dispensed, and then the area was illuminated with visible light from a xenon arc lamp (450-550 nm) at an intensity of 100 mW/cm ² for 40 seconds. Samples were laced in phosphate buffered saline (pH 7.4) at 37° C. for different times (t=0, 4 hours, 1 days, 3 days, 6 days and 10 days).

Samples were evaluated at each time point using a seal pressure test apparatus to determine the failure pressure. The test apparatus was a modified membrane holder, in which the latex sample was clamped at the edges between gaskets. Pressure was then applied to the side of the latex away from the polymer seal, and the pressure required to rupture the seal was measured.

FIG. 1 shows the results obtained with five different sealant materials. The seal pressure decreases over the course of time, presumably due to a combination of swelling of the hydrogel due to hydration and programmed degradation of the hydrogel.

Example 4: Bioabsorption in-vivo

Poly(ethylene glycol)-trimethylene carbonate copolymers, optionally containing lactate, and endcapped with acrylate esters, were evaluated. Two of the materials described with Example 3 were used (20KTL and 35KT). The macromers were polymerized using visible light illumination from a xenon arc lamp (450-550 nm) at an intensity of 100 mW/cm ² in a sealant solution containing macromer, eosin, triethanolamine, vinylcaprolactam, t-butylhydroperoxide and saline as in Example 3. Macromer concentration was 10% for 20KTL and 20% for 35KT.

The absorption of the sealant was determined by subcutaneous implants in rats. Five female Sprague Dawley rats (250-300 g) were used in this study. The animals were anesthetized by intramuscular (“IM”) injection of 3.2 ml/kg mixture of Ketamine (52.4 mg/kg), Xylazine (2.8 mg/kg), Acepromazine (0.7 mg/kg). Four 1 cm longitudinal incisions were made through the skin on the back. Two incisions were made on each side of the spinal column, spaced 1 cm off the midline and 2 cm apart. A 2×2 cm pocket was created at each incision site by blunt dissection. Preformed hydrogel disks were prepared using sterile technique. One hundred microliters of sealant solution was placed in the bottom of one well of a standard 24-well tissue culture plate, and was illuminated for 40 sec at 100 mW/cm ² , producing a thin disc about 18 mm. in diameter. One disk was placed in each subcutaneous pocket. Incisions were then closed with surgical staples. Animals were euthanized at intervals by CO ₂ inhalation. Incisions were opened and gross observations were recorded. Each site was harvested and analyzed by gel permeation chromatography for mass loss.

FIGS. 2A and 2B show that the 20KTL based hydrogels were completely absorbed in 20 days in vivo (FIG. 2 A), whereas the 35KT based hydrogels were partially absorbed (60% weight loss) in 154 days (FIG. 2 B). This illustrates the significant effect of rapidly-degrading linkages such as lactate groups.

Example 5: Sealing of Dural Leak in Canine Craniotomy

A poly(ethylene glycol)-trimethylene carbonate-lactate copolymer endcapped with acrylate ester (20KTL, from Example 2) was evaluated for its ability to seal fluid leaks in membranes in vivo. The poly(ethylene glycol) molecular weight used was 20,000 Da. The lactate incorporation was 13.8 and the trimethylene carbonate incorporation was 16.0. The macromer was fully acrylated.

The performance of the sealant was evaluated in a dural incision injury model in three mongrel canines. The animals were pre-anesthetized, intubated and maintained on isoflurane gas anesthesia. With the head elevated, a bilateral craniotomy was created. Two dural incisions, each 2 cm. long, were made, one on the left side and one on the right side. Incisions were closed using 3 simple interrupted 4 - 0 to 6 - 0 silk sutures spaced approximately 5 mm apart. Cerebrospinal fluid (CSF) pressure was raised by inflating the lungs to 20 cm H ₂ O and the leak was assessed. All incisions were found to leak, as expected from the closure.

The control side (left) received no additional closure of the incision. For the treatment side (right), the primer (a low-viscosity solution; described in example 4) was applied and mixed with the fluid on the tissue interface. The sealant (10% w/w solution of 20KTL (described above) with other materials as in Example 4) was layered over the primer, and the primer and sealant were mixed with a brush. Illumination for 40 sec. with a visible xenon arc lamp (450-550 nm) at an intensity of 100 mW/cm ² was then performed to complete the polymerization.

The leaks were re-verified by raising the CSF pressure by inflating the lungs to 20 cm H ₂ O. Leakage was observed on the control side, but not on the experimental side. The bone flaps were replaced and the incision was repaired.

All animals were euthanized at 21 days and the craniotomy was re-opened. Adhesions between the dura and the bone flap were recorded, and the dura repair sites were inspected for evidence of CSF fluid leaks. Dural repair sites were dissected free from underlying cortical tissue and the presence of adhesions noted. The tissues were harvested, rinsed in saline, and fixed in 10% neutral buffered formalin. Hematoxylin and eosin stained histological sections were taken.

At the time of explant, the control sites showed a slight fibrosis present between the dura mater and calvarium. No inflammation was detected. The sealant was not apparent in two out of three animals and only small amounts were present in the third animal. The dural edges were approximated. Defects in the bone (resulting from the surgery) were filled with fibro-osseous tissue at 21 days, in both control and treated sites. Normal healing appeared to be taking place, both visually and histologically.

EXAMPLE 6. Solution Synthesis

Macromers can also be made by synthesis in solution. While requiring additional waste disposal, the solution synthesis is more easily controlled (compared to the melt synthesis of Example 1 or 2), and is preferred for most applications. This example also illustrates the practice of sequential addition of monomers; the method is also useful for simultaneous addition of monomers.

35KTLA was made by dissolving 75 g of 35kD (nominal) PEG in toluene to 20% w/w concentration, and was dried by nitrogen purge for 3 hours at 108° C. 3.06 G TMC (14 mole equivalents per PEG) and 0.024 g stannous octoate catalyst were added, and the solution was held at 108° C. for 4 hours with stirring. Then 0.46 g (1.5 equiv.) lactide was added, and stirring continued for 2 hrs. Then 300 ml toluene was added to give about a 10% wt/vol solution of polymer. After cooling the solution to about 50°, 4.6 g of triethylamine and 2.5 ml of acryloyl chloride were added. The solution was stirred for 20 min. at about 50. Acrylated macromer was recovered by precipitation and optionally filtration as described in Ex. 1 and 2. The resulting polymer contained 5 TMC residues and 1.2 lactate residues per PEG molecule, and ratios of lactate:acrylate of 0.6.

EXAMPLE 7. In Vitro Degradation

35KTLA2 was synthesized as described in Example 6. The completed macromer had a TMC:PEG molar ratio of 3.57; an acrylate: PEG ratio of 1.52; a lactate: PEG ratio of 1.39; and contained 766 ppm TMC. On gel permeation chromatography, the macromer was 48.1% “monomer” (one PEG unit per macromer molecule), 46.3% “dimer” two PEG units per macromer molecule), 5.4% “trimer” and 0.1% higher oligomer.

Discs of the macromer were made as described in example 4 and were incubated in phosphate-buffered saline, pH 7.4, at 37° and 57°. At 57°, half of the mass was lost at about 140 hrs, while at 37°, half the mass was lost at about 42 days. Mass loss was determined by rinsing the specimen, drying to constant weight, and correcting for the amount of buffer and salt present.

EXAMPLE 8. Dioxanone-containing Macromers

Dioxanone (1,4-dioxan-2-one; p-dioxanone) was synthesized from DEG (diethylene glycol) essentially according to U.S. Pat. No. 2,807,629, Example 1. Two kilograms of DEG were mixed with 40 g. copper chromite (Aldrich) and heated at about 230° for 4 hours under nitrogen purge, which displaced generated hydrogen. Dioxanone and DEG were distilled from the mixture under vacuum at about 50° pot temperature. DEG was partially removed by extraction in cold (4°) diethyl ether. The partially purified material was dissolved in chloroform and applied to a silica column equilibrated in chloroform. Dioxanone was recovered in the initial fractions.

Macromer 35KDA was made by drying overnight (vacuum, 110°) 15 g of 35K PEG, 1.7 g dioxanone, and 0.01 g of catalyst (stannous octoate). This is a ratio of 21:1 D:PEG. Samples were also made at other amounts of D (1.0 g, 18:1, 0.84 g, 15:1, 1.34 g, 24:1). Vials were sealed and heated at 150 for 5 hrs. Samples were dissolved in chloroform; optionally precipitated in ether; and acrylated as described in previous examples. NMR showed final molar ratios in the synthesized polymer of D/PEG, 1.82; Ac/PEG, 1.64.

Macromer 35KDLA: To a mixture of 15 g PEG, 0.84 g Dioxanone and 0.01 g catalyst was also added 0.39 g d,l-lactide. A mixture was dried, then incubated at 185° overnight; dissolved in chloroform and precipitated in ether, filtered and vacuum-dried; and acrylated with excess acryloyl chloride and triethylamine.