Tunably crosslinked polysaccharide compositions

Abstract

The present invention generally relates to novel biocompatible crosslinked polysaccharide gel compositions, methods of their manufacture and use, and the novel crosslinkers used to make them. In one aspect of the invention, a novel polyethylene glycol crosslinking agent is described for crosslinking hyaluronic acid. In another aspect of the invention, novel crosslinking agents comprising more than two functional groups are described. These multifunctional crosslinking agents can be used on their own to crosslink hyaluronic acid, or they may be combined with bifunctional crosslinking agents in varying ratios to make hyaluronic acid of tunable mechanical strength and hardness. The present invention also discloses novel hyaluronic acid compositions that have been coated with polyethylene glycol and methods of their use.

1 . A process for the preparation of crosslinked hyaluronic acid, said process comprising:
 contacting hyaluronic acid with a polyethylene glycol based crosslinking agent; and   contacting the hyaluronic acid with a non-polyethylene glycol based crosslinking agent.   
     
     
         2 . The process of  claim 1 , wherein the polyethylene glycol based crosslinking agent is bifunctional. 
     
     
         3 . The process of  claim 1 , wherein the polyethylene glycol based crosslinking agent is multifunctional. 
     
     
         4 . The process of  claim 1 , wherein the non-polyethylene glycol based crosslinking agent is BDDE. 
     
     
         5 . The process of  claim 1 , wherein the polyethylene glycol based crosslinking agent is tetrafunctional and the non-polyethylene glycol based crosslinking agent is BDDE. 
     
     
         6 . The process of  claim 1 , wherein the polyethylene glycol based crosslinking agent is 4-Arm Star PEG epoxide. 
     
     
         7 . A composition for soft tissue augmentation obtained by a process according to  claim 1 . 
     
     
         8 . A composition for soft tissue augmentation obtained by a process according to  claim 5 . 
     
     
         9 . A composition for soft tissue augmentation, said composition comprising hyaluronic acid that has been crosslinked with at least two types of polyethylene glycol based crosslinking agents, wherein at least one of the at least two types of polyethylene glycol based crosslinking agents is bifunctional. 
     
     
         10 . The composition of  claim 9 , wherein said at least one type of polyethylene glycol based crosslinking agent is multifunctional. 
     
     
         11 . The composition of  claim 9 , wherein said at least one type of polyethylene glycol based crosslinking agent is a 4-Arm Star PEG epoxide. 
     
     
         12 . The composition of  claim 9  for use as a dermal filler. 
     
     
         13 . The composition of  claim 11  for use as a dermal filler.