# US 9,872,827 B2 · Cross-linked sodium hyaluronate gel for tissue filler for plastic surgery and preparation method thereof

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- Number: US 9,872,827 B2
- Document ID: US9872827B2
- Status: Granted
- Kind: B2
- Application number: 14/432,405
- Filed: 2013-07-26
- Published: 2015-11-19
- Granted: 2018-01-23
- Earliest claimed: 2012-09-29
- Assignees: Hangzhou Gallop Biological Products Co., Ltd.
- Applicants: Hangzhou Gallop Biological Products Co., Ltd.
- Inventors: Xuejun Chen; Xiaobin Zhao; Yitao Zou
- Web page: https://patentgrep.com/patent/US9872827B2

## CPC

- A61K 8/735: {Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof}
- A61K 8/042: {Gels}
- A61L 27/20: Polysaccharides
- A61L 27/52: Hydrogels or hydrocolloids
- A61Q 19/00: Preparations for care of the skin
- A61Q 19/08: Anti-ageing preparations
- C08B 37/0072: {Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates}
- C08J 3/075: Macromolecular gels
- C08L 63/00: Compositions of epoxy resins; Compositions of derivatives of epoxy resins
- C08L 71/08: Polyethers derived from hydroxy compounds or from their metallic derivatives (C08L71/02 takes precedence)
- A61K 2800/91: Injection
- A61L 2400/06: Flowable or injectable implant compositions
- A61L 2430/02: for reconstruction of bones; weight-bearing implants
- A61L 2430/06: for cartilage reconstruction, e.g. meniscus
- A61L 2430/24: for joint reconstruction
- C08J 2305/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- C08B: POLYSACCHARIDES; DERIVATIVES THEREOF (polysaccharides containing less than six saccharide radicals attached to each other by glycosidic linkages C07H; fermentation or enzyme-using processes C12P19/00; sugar industry C13; production of cellulose D21)
- C08J: WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H (working, e.g. shaping, of plastics B29)
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

The present invention relates to a cross-linked sodium hyaluronate gel for tissue filler for plastic surgery and the preparation method thereof. The alkaline solution of sodium hyaluronate reacts with the long chain alkane containing epoxy group and the cross-linking agent containing epoxy group for 2˜5 hours at 35° C.˜50° C. to produce cross-linked sodium hyaluronate, then washed, gelled and sterilized, to prepare the gel. Among which, the molar ratio of sodium hyaluronate:cross-linking agent containing epoxy group:long chain alkane containing epoxy group is 10:4˜1:1˜4; the number of carbon atoms of the said long chain alkane containing epoxy group is 6 to 18. The gel prepared in the present invention can, on one hand, effectively enhance the resistance to enzymolysis to become more stable, and on the other hand, maintain the excellent biocompatibility of sodium hyaluronate without affecting its injectability.

## Claims

### Claim 1

A method for preparing a cross-linked sodium hyaluronate gel for tissue filler suitable for plastic surgery, consisting of:
{circle around (1)} dissolving a dry powder of sodium hyaluronate in a mixture of 0.2˜0.5M aqueous sodium hydroxide solution and dimethyl sulfoxide to produce an alkaline solution of sodium hyaluronate, and then adding a long-chain alkane containing a single epoxy group and a cross-linking agent containing an epoxy group, heating the alkaline solution of sodium hyaluronate to 35° C.˜50° C. with stirring for 2˜5 hours to produce a product solution, cooling the product solution down to room temperature; then adding acetone dropwise while stirring to form a solid-liquid mixture, adding hydrochloric acid to adjust the pH value of the solid-liquid mixture to 6.5˜7.4, filtering the solid-liquid mixture and collecting a solid material, which is washed 3˜5 times using isopropanol and acetone, respectively, and then drying the solid material under vacuum until a content of a volatile matter is lower than 2 ppm to produce a cross-linked sodium hyaluronate powder; wherein a weight ratio of sodium hyaluronate:the cross-linking agent containing an epoxy group:the long-chain alkane containing a single epoxy group is 10:4˜1:1˜4; a number of carbon atoms in the long-chain alkane containing the epoxy group is 6˜18; a volume ratio of 0.2-0.5M sodium hydroxide solution to dimethyl sulfoxide is 10:7˜1; a concentration of sodium hyaluronate is 4 wt % to 8 wt % in the sodium hyaluronate alkaline solution; a volume ratio of the sodium hydroxide solution to acetone added dropwise is 1:4˜2:3; an average molecular weight of sodium hyaluronate is 500,000˜2,000,000 Da; the cross-linking agent containing an epoxy group is one of the following: 1,4-butanediol diglycidyl ether, polyethylene glycol diglycidyl ether with a molecular weight of 500˜6,000, 1,2,7,8-diepoxyoctane, or 1,2,3,4-diepoxybutane;
{circle around (2)} adding water to the cross-linked sodium hyaluronate powder obtained in step {circle around (1)} to form a cross-linked sodium hyaluronate gel; collecting gel particles, which are washed with water while stirring for 2˜5 hours at 15° C.˜35° C., followed by filtration to collect the gel particles, and repeating water washing 4˜5 times, and then collecting the gel particles;
{circle around (3)} adding isotonic saline to the gel particles collected in step {circle around (2)}; after stirring for 2˜5 hours at 15° C.˜35° C. collecting the gel particles by filtration, followed by washing with isotonic saline, repeating isotonic saline washing 4˜5 times, and then collecting gel particles with an average particle size of 150 μm-350 μm by screen sieving; and
{circle around (4)} filling a pre-sterilized disposable syringe with the gel particles collected in step {circle around (3)}, and sterilizing the filled syringe by steam at 121° C.˜125° C. for 15˜25 min to produce the cross-linked sodium hyaluronate gel for tissue filler suitable for plastic surgery.

### Claim 2 (depends on 1)

The method for preparing the cross-linked sodium hyaluronate gel according to claim 1, wherein the cross-linked sodium hyaluronate gel contains chemically bonded hydrophobic groups having a self-adhesive self-aggregating property.