Method of Cross-Linking Hyaluronic Acid with Divinylsulfone

Abstract

The present invention relates to methods of producing a homogenous hydrogel comprising hyaluronic acid, or salt thereof, crosslinked with divinylsulfone (DVS), said method comprising the steps of (a) providing an alkaline solution of hyaluronic acid, or salt thereof; (b) adding DVS to the solution of step (a), whereby the hyaluronic acid, or salt thereof, is crosslinked with the DVS to form a gel; (c) treating the gel of step (b) with a buffer, wherein the gel swells and forms a hydrogel comprising hyaluronic acid, or salt thereof, crosslinked with DVS.

1 . A hydrogel comprising hyaluronic acid, or a salt thereof, crosslinked with divinylsulfone (DVS), wherein the hydrogel is sufficiently homogenous that when injected from a 1 ml syringe through a 27G½ needle over a distance of 55 mm at a speed of 12.5 mm/min, the injection force varies no more than about 5 Newton (N) when measured from 40 seconds after the initial injection until the syringe is empty. 
     
     
         2 . The hydrogel according to  claim 1 , wherein the injection force varies no more than about 3 Newton (N) when measured from 40 seconds after the initial injection until the syringe is empty. 
     
     
         3 . The hydrogel according to  claim 1 , wherein the injection force varies no more than about 2 Newton (N) when measured from 40 seconds after the initial injection until the syringe is empty. 
     
     
         4 . The hydrogel according to  claim 1 , wherein the injection force varies no more than about 1 Newton (N) when measured from 40 seconds after the initial injection until the syringe is empty. 
     
     
         5 . The hydrogel according to  claim 1 , wherein the hyaluronic acid or salt thereof has a molecular weight in the range of between 300,000 and 3,000,000. 
     
     
         6 . The hydrogel according to  claim 1 , wherein the hyaluronic acid or salt thereof has a molecular weight in the range of between 600,000 and 1,800,000. 
     
     
         7 . The hydrogel according to  claim 1 , wherein the hyaluronic acid or salt thereof has a low average molecular weight in the range of between 10,000 and 800,000 Da. 
     
     
         8 . The hydrogel according to  claim 1 , wherein the hyaluronic acid or salt thereof has a low average molecular weight in the range of between 50,000 and 300,000 Da. 
     
     
         9 . The hydrogel according to  claim 1 , which comprises an inorganic salt of hyaluronic acid. 
     
     
         10 . The hydrogel according to  claim 9 , wherein the inorganic salt of hyaluronic acid is selected from sodium hyaluronate, potassium hyaluronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, and cobalt hyaluronate. 
     
     
         11 . A composition comprising the hydrogel of  claim 1  and an active ingredient. 
     
     
         12 . A composition comprising the hydrogel of  claim 1  and a pharmacologically active agent. 
     
     
         13 . The composition according to  claim 12 , further comprising a water-soluble excipient. 
     
     
         14 . The composition according to  claim 13 , wherein the water-soluble excipient is lactose. 
     
     
         15 . The composition according to  claim 12 , further comprising a preservative. 
     
     
         16 . A pharmaceutical composition comprising an effective amount of the hydrogel of  claim 1 , together with a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         17 . A pharmaceutical composition comprising an effective amount of the hydrogel of  claim 1  as a vehicle, together with a pharmacologically active agent. 
     
     
         18 . A cosmetic article or composition comprising the hydrogel of  claim 1 . 
     
     
         19 . A sanitary, medical or surgical article comprising the hydrogel of  claim 1 . 
     
     
         20 . A medicament capsule or microcapsule comprising the hydrogel of  claim 1 .