Hyaluronic acid anti-adhesion barrier

Abstract

Methods of forming crosslinked hyaluronic acid anti-adhesion barriers, crosslinked hyaluronic acid anti-adhesions barriers, methods for preventing or inhibiting adhesions, and methods of promoting healing of a wound are provided. The method of forming the crosslinked hyaluronic acid anti-adhesion barrier includes freeze-drying a solution including hyaluronic acid to form a hyaluronic acid foam, which is then reacted with a crosslinking agent to form a crosslinked hyaluronic acid foam. The crosslinked hyaluronic acid foam is mixed with a solution containing hyaluronic acid to form an anti-adhesion barrier.

What is claimed is:  
     
         1 . A method of forming an anti-adhesion barrier comprising: 
 freeze-drying a solution including hyaluronic acid to form a foam;    reacting the foam with a crosslinking agent to form a crosslinked foam; and    mixing the crosslinked foam with an aqueous solution containing hyaluronic acid to form an anti-adhesion barrier.    
     
     
         2 . The method according to  claim 1  wherein the concentration of the solution including hyaluronic acid is from about 0.5 to about 4.0% by weight hyaluronic acid.  
     
     
         3 . The method according to  claim 1  wherein during the freeze-drying step the solution including hyaluronic acid is frozen at a temperature of about −94 to about −130° C.  
     
     
         4 . The method according to  claim 1  wherein the solution including hyaluronic acid is freeze-dried at less than about 50×10 −3  torr and about −10° C.  
     
     
         5 . The method according to  claim 1  wherein the crosslinking agent is selected from the group consisting of di-epoxides, polyfunctional epoxides, diisocyanates, polyisocyanates, polyhydric alcohols, water-soluble carbodiimides, diaminoalkanes, diamines, polycarboxylic acids, diacid halides and dimethylol urea.  
     
     
         6 . The method according to  claim 5  wherein the crosslinking agent is a diacid halide.  
     
     
         7 . The method according to  claim 6  wherein the diacid halide is diglycolyl chloride.  
     
     
         8 . The method according to  claim 1  wherein a solution of crosslinking agent contains from about  10  to about  80  % by weight crosslinking agent.  
     
     
         9 . The method according to  claim 1  wherein the proportion of foam to crosslinking agent is from about 3.0 to about 100 grams foam/gram of crosslinking agent.  
     
     
         10 . The method according to  claim 1  wherein the aqueous solution containing hyaluronic acid solution contains from about 0.5 to about 4.0% by weight hyaluronic acid.  
     
     
         11 . The method according to  claim 1  wherein the proportion of the crosslinked foam to the aqueous solution containing hyaluronic acid is from about 0.2 to about 1.0 grams crosslinked foam/ml aqueous solution containing hyaluronic acid.  
     
     
         12 . An anti-adhesion barrier which is a gel produced by combining a freeze-dried crosslinked hyaluronic acid foam with an aqueous solution comprising hyaluronic acid.  
     
     
         13 . The anti-adhesion barrier according to  claim 12  wherein the crosslinked foam is crosslinked with a diacid halide.  
     
     
         14 . The anti-adhesion barrier according to  claim 13  wherein the diacid halide is diglycolyl chloride.  
     
     
         15 . A composition comprising an antiadhesion barrier according to  claim 12 , and a pharmaceutically acceptable carrier.  
     
     
         16 . The composition according to  claim 15  further including a medicinal agent.  
     
     
         17 . An anti-adhesion barrier produced according to the method of  claim 1 .  
     
     
         18 . The anti-adhesion barrier according to  claim 17  wherein the solution including hyaluronic acid contains from about 0.5 to about 4.0% by weight hyaluronic acid.  
     
     
         19 . The anti-adhesion barrier according to  claim 17  wherein the crosslinking agent is a diacid halide.  
     
     
         20 . The anti-adhesion barrier according to  claim 19  wherein the diacid halide is diglycolyl chloride.  
     
     
         21 . A composition comprising an antiadhesion barrier according to  claim 17 , and a pharmaceutically acceptable carrier.  
     
     
         22 . The composition according to  claim 21  further including a medicinal agent.  
     
     
         23 . A method of preventing or inhibiting the formation of adhesions comprising applying an effective amount of the anti-adhesion barrier according to  claim 12  to a wound site.  
     
     
         24 . The method according to  claim 23  wherein the crosslinked foam is crosslinked with diglycolyl chloride.  
     
     
         25 . A method of promoting healing of a wound comprising applying an effective amount of the anti-adhesion barrier according to  claim 12  to the wound.  
     
     
         26 . A two-part kit comprising 
 a first part including a freeze-dried crosslinked hyaluronic acid foam; and a second part including a solution including hyaluronic acid.    
     
     
         27 . The kit according to  claim 26  wherein the crosslinked hyaluronic acid foam is crosslinked with a diacid halide.  
     
     
         28 . The kit according to  claim 27  wherein the diacid halide is diglycolyl chloride.  
     
     
         29 . The kit according to  claim 26  further including means for combining the crosslinked hyaluronic acid foam and the solution including hyaluronic acid.  
     
     
         30 . The kit according to  claim 26  further including a medicinal agent.  
     
     
         31 . An anti-adhesion barrier comprising a hyaluronic acid foam, a crosslinking agent and an aqueous solution containing hyaluronic acid.  
     
     
         32 . The anti-adhesion barrier according to  claim 31  wherein the crosslinking agent is selected from the group consisting of di-epoxides, polyfunctional epoxides, diisocyanates, polyisocyanates, polyhydric alcohols, water-soluble carbodiimides, diaminoalkanes, diamines, polycarboxylic acids, diacid halides and dimethylol urea.  
     
     
         33 . The anti-adhesion barrier according to  claim 32  wherein the crosslinking agent is a diacid halide.  
     
     
         34 . The anti-adhesion barrier according to  claim 33  wherein the diacid halide is diglycolyl chloride.  
     
     
         35 . The anti-adhesion barrier according to  claim 31  wherein the solution containing hyaluronic acid contains from about 0.5 to about 4.0% by weight hyaluronic acid.  
     
     
         36 . A composition comprising an anti-adhesion barrier according to  claim 31 , and a pharmaceutically acceptable carrier.  
     
     
         37 . The composition according to  claim 36  further including a medicinal agent.