Process for preparing a cross-linked hyaluronic acid product

Patent metadata

Field	Value
Publication number	US-10077320-B2
Application number	US-201414901462-A
Country	US
Kind code	B2
Filing date	Jun 5, 2014
Priority date	Jun 28, 2013
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

Efficient cross-linking of hyaluronic acid (HA) is provided by a manufacturing process. In the process, HA is activated by an initial cross-linking in an aqueous solution. Unreacted cross-linking agent is removed from the activated HA. Cross-linking of the activated HA is finalized, without addition of any additional cross-linking agent, in a suspension of a liquid precipitating medium and the activated HA in precipitated form. The resulting cross-linked HA products exhibit high effective cross-linker ratio and other favorable properties, making the products useful as implants and in medical and cosmetic surgery.

First claim

The invention claimed is:

1. A process for manufacturing a cross-linked hyaluronic acid (HA) product, comprising:
(a) initiating cross-linking of HA by reacting HA with one or more polyfunctional cross-linking agents in an aqueous solution to obtain an activated HA;
(b) removing unreacted cross-linking agent(s) from the activated HA; and
(c) finalizing the cross-linking of the activated HA by subjecting the activated HA to further cross-linking conditions without addition of any additional cross-linking agent to obtain a cross-linked HA product;
wherein the finalizing cross-linking step (c) is performed in a suspension of a liquid precipitating medium and the activated HA in precipitated form.

2. A process according to claim 1 , wherein the removing step (b) comprises:
(b1) precipitating the activated HA in a liquid precipitating medium to obtain a suspension comprising the liquid precipitating medium and the activated HA in precipitated form; and
(b2) removing unreacted cross-linking agent(s) from the suspension of precipitated, activated HA.

3. A process according to claim 2 , wherein the removing substep (b2) comprises washing the precipitated, activated HA with a liquid precipitating medium.

4. A process according to claim 1 , wherein the finalizing cross-linking step (c) comprises:
(c1) precipitating the activated HA in a liquid precipitating medium to obtain a suspension comprising the liquid precipitating medium and the activated HA in precipitated form; and
(c2) finalizing the cross-linking of the activated HA by subjecting the suspension of precipitated, activated HA to further cross-linking conditions without addition of any additional cross-linking agent to obtain a cross-linked HA product.

5. A process according to claim 1 , wherein the liquid precipitating medium contains more than 65 wt % of a water-soluble organic solvent.

6. A process according to claim 5 , wherein the water-soluble organic solvent is ethanol.

7. A process according to claim 1 , wherein the initial cross-linking step (a) provides an activated HA in gel form.

8. A process according to claim 1 , wherein the cross-linking agent is selected from the group consisting of divinyl sulfone, multiepoxides and diepoxides.

9. A process according to claim 1 , wherein the cross-linking agent is 1,4-butanediol diglycidyl ether (BDDE).

10. A process according to claim 1 , further comprising the steps of:
(d) subjecting the precipitated, cross-linked HA product from step (c) to non-precipitating conditions; and
(e) isolating the cross-linked HA product in non-precipitated form.

11. A process according to claim 1 , comprising a step of sterilizing the cross-linked HA product.

12. The process according to claim 1 , comprising the preparation of a desired shape of the activated HA obtained in step (a) prior to the final cross-linking in step (c).

13. The process according to claim 12 , wherein the preparation of a desired shape of the activated HA obtained in step (a) occurs prior to the removing of unreacted cross-linking agent(s) from the activated HA in step (b).

14. The process according to claim 12 , wherein the desired shape is particles having a size of 0.1 - 5.0 mm.

15. The process according to claim 12 , wherein the desired shape is a string, a net, or a film.

16. The process according to claim 12 , wherein the desired shape is a string, said string having a ratio between its length and its width of 5:1 or higher.

Assignees

• Galderma Sa

Inventors

• Karlsson Morgan
• Edsman Katarina

Classifications

• C08B37/0072 Primary

  Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates · CPC title

• C08J3/244

  Stepwise homogeneous crosslinking of one polymer with one crosslinking system, e.g. partial curing · CPC title

• A61K31/728

  Hyaluronic acid · CPC title

• A61K8/735

  Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof · CPC title

• A61K8/042

  Gels · CPC title