Resorbable implantable device based on crosslinked glycosaminoglycans, and process for the preparation thereof

Abstract

Disclosed is a process for the preparation of hydrogels consisting of crosslinked glycosaminoglycans, which comprises: a) reacting at least one hybrid cooperative complex obtained by heating aqueous solutions of low- and high-molecular-weight glycosaminoglycans at 80-160° C. with a diepoxide as crosslinker in a ratio with the complex ranging between 0.1 and 1 equivalents, preferably between 0.2 and 0.4 equivalents, the concentration by weight of the complex in the solution ranging between 1% and 15%, preferably between 2% and 10%; b) purifying by dialysis, ultrafiltration and diafiltration.

1 . Implantable devices comprising the hydrogels obtained by a process comprising:
 a) reacting an aqueous solution of at least one hybrid cooperative complex between a first component selected from low-molecular-weight hyaluronic acid, chondroitin and chondroitin sulphate and a second component consisting of high-molecular-weight hyaluronic acid with a diepoxide as crosslinker in an 0.1 to 1 equivalent ratio to the complex, the weight concentration of the complex in the solution ranging from 1% to 15%;   b) purifying by dialysis, ultrafiltration and diafiltration,   wherein:   the hybrid cooperative complex is prepared by subjecting the aqueous solution of a mixture of said first and second components to heat treatment at 80-160° C. for a time ranging between 10 and 30 minutes, followed by cooling to 20-25° C. in a time ranging between 5 and 15 minutes;   the concentration by weight of the first component with low molecular weight ranges between 0.1 and 50%, and the concentration by weight of the second component with high molecular weight ranges between 0.01 and 10%;   wherein the molecular weight of the low-molecular-weight hyaluronic acid ranges from 50·10 3  Da to 900·10 3  Da, the molecular weight of the chondroitin or chondroitin sulphate ranges from 5000 to 150,000 Da, and the molecular weight of the high-molecular-weight hyaluronic acid ranges from 1·10 6  Da to 3·10 6  Da (MW obtained by SEC and/or SEC-TDA).   
     
     
         2 . The implantable device according to  claim 1  formulated in phosphate buffer or saline solution. 
     
     
         3 . The implantable device according to  claim 1 , suitable in the medical, surgical, aesthetic, orthopaedic, dental, ophthalmic and dermocosmetic fields. 
     
     
         4 . The implantable device according to  claim 1  wherein the reaction is carried out at a temperature ranging from 10° C. to 50° C., for reaction times ranging from 2 h to 48 h. 
     
     
         5 . The implantable device according to  claim 1 , wherein the number of hybrid complexes is 1 to 4. 
     
     
         6 . The implantable device according to  claim 1 , wherein both the glycosaminoglycans are high- and low-molecular weight hyaluronic acid. 
     
     
         7 . The implantable device according to  claim 1 , wherein the low-molecular-weight glycosaminoglycan is chondroitin or chondroitin sulphate. 
     
     
         8 . The implantable device according to  claim 1 , wherein the diepoxide is 1,4-butanediol-diglycidyl-ether. 
     
     
         9 . The implantable device according to  claim 1  wherein the purification steps are carried out at temperature gradients ranging from 10° C. to 58° C. 
     
     
         10 . The implantable device according to  claim 9 , wherein the purification steps are carried out at a temperature gradients ranging from 20° C. to 50° C. 
     
     
         11 . The implantable device according to  claim 9  wherein ultrafiltration is carried out with 1 to 10 diafiltration volumes at a permeation rate ranging from 0.1 L/h to 10 L/h, with ΔP from 1 to 2 bars, using a hollow fibre membrane with cut-off from 250 to 750 KDa. 
     
     
         12 . Process according to  claim 9 , wherein dialysis is carried out with cellulose membranes with cut-off ranging from 10 KDa to 50 KDa and using purified water or phosphate buffer with osmolarity ranging from 200 mOsm/L to 400 mOsm/L as dialysis medium.