Method for producing cross-linked hyaluronic acid

摘要

A method for producing a cross-linked hyaluronic acid in accordance with the present invention comprises: (a) cross-linking at least one polymer at a temperature, from about 35° C. to about 60° C., for a reaction time of from about 0.1 hour to about 72 hours with a cross-linking agent; and (b) lowering the temperature in step (a) to form about 10° C. to about 30° C. for a reaction time of from about 48 hours to about 28 days to obtain the cross-linked hyaluronic acid, whereby, a cross-linking agent content in a product of the method can be decreased so the product does not require purification.

主权项

1. A method for producing a cross-linked hyaluronic acid gel composition suitable to be applied directly to an animal comprising a cross-linking step, wherein the cross-linking step consists of:
(a) cross-linking at least one polymer at a first constant temperature, from about 35° C. to about 50° C., for a reaction time of from about 3 hours to about 12 hours with a cross-linking agent, wherein the cross-linking agent is at a concentration of from about 0.6 w/v % to about 1.0 w/v %; and (b) continuing cross-linking the at least one polymer with the cross-linking agent after step (a) by cooling the first constant temperature to a second constant temperature from about 10° C. to about 30° C. for a reaction time of from about 3 days to about 28 days to obtain the cross-linked hyaluronic acid, wherein the steps (a) and (b) are conducted under a basic condition of about 0.2 N to about 1.0 N; the at least one polymer comprises hyaluronic acid, or hyaluronate or a mixture thereof; the method is absent a step of purifying the cross-linked hyaluronic acid; the content of the cross-linking agent with free-state functional group is below about 2 ppm in the cross-linked hyaluronic acid gel composition; and the cross-linking agent is 1,4-butanediol diglycidyl ether.