Patent EA-001500-B1 (EA)
Title: Process for preparing cross-linked biopatible polysaccharide gel, compositions of said gel and use of said compositions
Inventor: AGERUP BENGT
IPC: C08B37/08
Filed: 1996-05-28
Abstract: 1. A process for preparing a cross-linked biocompatible polysaccharide gel composition, which comprises: forming an aqueous solution of a water soluble cross-linkable polysaccharide; initiating a cross-linking of said polysaccharide in the presence of a polyfunctional cross-linking agent therefor; sterically hindering the cross-linking reaction from being terminated before gelation occurs, an activated polysaccharide thereby being obtained; and reintroducing sterically unhindered conditions for said activated polysaccharide cross-linking reaction so as to terminate the cross-linking thereof up to a viscoelastic gel. 2. A process according to claim 1, wherein the polysaccharide is glucoseaminoglucan. 3. A process according to claim 2, wherein said glucoseaminoglucan is hyaluronic acid. 4. A process according to any one of claims 1-3, wherein the cross-linking agent is selected from the group consisting of epoxides, polyaziridyl compounds, glycidyl ethers. 5. A process according to claim 4, wherein said glycidyl ether is 1,4-butanediol diglycidyl ether. 6. A process according to any one of claims 1-5, wherein said sterically hindering of the cross-linking reaction comprises diluting the aqueous medium in which the cross-linking reaction is performed, to accomplish a lower concentration of the polysaccharide in said medium. 7. A process according to any one of claims 1-6, wherein said reintroduction of sterically unhindered conditions comprises evaporating the aqueous medium in which the cross-linking reaction is performed, to accomplish a higher concentration of the polysaccharide in said medium. 8. A process according to any one of claims 1-6, wherein said reintroduction of sterically unhindered conditions comprises dialysing the aqueous medium in which the cross-linking reaction is performed. 9. A process according to any one of claims 1-8, wherein the initial cross-linking reaction in the presence of a polyfunctional cross-linking agent is performed at an alkaline pH, preferably above pH 9, ether cross-linking reactions thereby being promoted. 10. A process according to any one of claims 1-8, wherein the initial cross-linking reaction in the presence of a polyfunctional cross-linking agent is performed at an acidic pH, preferably at pH 2-6, ester cross-linking reactions thereby being promoted. 11. A process according to any one of claims 1-10, wherein said sterical hindrance of the cross-linking reaction is accomplished before said cross-linking agent has been consumed. 12. A process according to any one of claims 1-11, wherein a biologically active substance is enclosed within the cross-linked polysaccharide gel composition during the preparation thereof, by dissolving or dispersing the same in said activated polysaccharide before subjecting last-mentioned polysaccharide to sterically unhindered conditions for continuation of cross-linking reaction, wherein introduction of the biologically active compound is preferably made in physiological conditions. 13. A process according to any of claims 1-11, wherein cells are enclosed within the cross-linking polysaccharide gel composition before providing sterically unhindered conditions for continuation of cross-linking reaction of said polysaccharide, wherein introduction of the cells is preferably made in physiological conditions. 14. A process according to claim 12 wherein said biologically active substance is selected from the group consisting of hormones, cytokines, vaccines and tissue augmenting substances. 15. A process according to claim 14, wherein said tissue augmenting substance comprises a polymer selected from collagen, starch, dextranomer, polylactide and copolymers thereof, and poly-hydroxybutyrate and copolymers thereof. 16. A process according to claim 14, wherein said hormone is selected from the group consisting of erytropoeitin and calcitonin. 17. A process according to any one of claims 12-16, wherein said biologically active substance contains functional groups reactive with the polysaccharide and is enclosed within the gel structure by chemical reaction therewith. 18. A process according to claim 17, wherein said biologically active substance containing functional groups which react with a cross-linking agent for said polysaccharide in the process of obtaining  of the composition of cross-linked biocompatible polysacharide gel. 19. A partially cross-linked biocompatible activated polysacharide gel composition whenever prepared by a process as claimed in any one of claims 1-18, which is terminated before the stage of continuation of cross-linking reaction of activated polysaccharide by reintroducing said sterically unhindered conditions for the cross-linking reaction as in is mentioned in claim 1. 20. A cross-linked biocompatible polysaccharide gel composition, which is obtained by a process according to any of claims 1-18. 21. A composition according to claim 20, which is obtained by a process according to any of claims 2-11. 22. A composition according to any of claims 20-21, which is obtained by a process according to any of claims 12-18, comprising biologically active substance. 23. Use of a composition according to any one of claims 20-22 as a medical or prophylactic composition. 24. Use of a composition according to claim 23 as a depot for medical or prophylactic composition. 25. Use of a composition according to any one of claims 23-24 for the manufacture of a medical or prophylactic composition for hormone treatment or tissue augmentation of a mammal, especially a human being.