# US 10,307,512 B2 · Process for preparing hydrogels

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- Number: US 10,307,512 B2
- Document ID: US10307512B2
- Status: Granted
- Kind: B2
- Application number: 15/536,039
- Filed: 2015-12-15
- Published: 2017-12-14
- Granted: 2019-06-04
- Earliest claimed: 2014-12-15
- Assignees: Teoxane
- Applicants: Teoxane
- Inventors: Francois Bourdon; Stephane Meunier
- Web page: https://patentgrep.com/patent/US10307512B2

## CPC

- A61L 27/52: Hydrogels or hydrocolloids
- A61K 8/042: {Gels}
- A61K 8/24: Phosphorous; Compounds thereof
- A61K 8/735: {Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 31/728: Hyaluronic acid
- A61L 27/20: Polysaccharides
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 27/02: Ophthalmic agents
- A61P 27/12: for cataracts
- A61Q 11/00: Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
- A61Q 19/08: Anti-ageing preparations
- C08B 37/0063: {Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan}
- 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 5/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- A61K 2800/91: Injection
- A61L 2400/06: Flowable or injectable implant compositions
- A61L 2430/16: for reconstruction of eye parts, e.g. intraocular lens, cornea
- A61L 2430/24: for joint reconstruction
- C08J 2305/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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 process for preparing a crosslinked gel of at least one polysaccharide or a salt thereof, comprising at least the steps consisting in: a) providing a solution formed from an aqueous medium comprising at least said polysaccharide(s) or a salt thereof in a non-crosslinked form, at least one difunctional or multifunctional epoxide crosslinking agent chosen from butanediol diglycidyl ether, diepoxyoctane, 1,2-bis(2,3-epoxypropyl)-2,3-ethylene, and mixtures thereof, and at least one phosphate salt; b) crosslinking the solution from step a) and, where appropriate; c) recovering said crosslinked gel formed.

## Claims

### Claim 1

A process for preparing a crosslinked gel of at least one polysaccharide or a salt thereof, comprising:
a) providing a solution formed from an aqueous medium comprising at least one polysaccharide or a salt thereof in a non-crosslinked form, at least one difunctional or multifunctional epoxide crosslinking agent chosen from butanediol diglycidyl ether, diepoxyoctane, 1,2-bis(2,3-epoxypropyl)-2,3-ethylene, and mixtures thereof, and at least one phosphate salt, the at least one phosphate salt being sodium trimetaphosphate;
b) crosslinking the solution from step a) to form a crosslinked gel, and
c) recovering said crosslinked gel.

### Claim 2 (depends on 1)

The process according to claim 1, further comprising homogenizing the solution from step a), prior to and/or simultaneously with the crosslinking step b).

### Claim 3 (depends on 1)

The process according to claim 1, wherein the crosslinking step b) is performed at a temperature from 15 to 35° C.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the crosslinking step b) is performed over a period of between 5 hours and 336 hours.

### Claim 5 (depends on 1)

The process according to claim 1, wherein the difunctional or multifunctional epoxide crosslinking agent is butanediol diglycidyl ether.

### Claim 6 (depends on 1)

The process according to claim 1, wherein the polysaccharide is hyaluronic acid or a salt thereof.

### Claim 7 (depends on 6)

The process according to claim 6, wherein the hyaluronic acid salt is chosen from a sodium salt, a potassium salt, a zinc salt, a silver salt, and mixtures thereof.

### Claim 8 (depends on 1)

The process according to claim 1, wherein the solution from step a) comprises a number of moles of phosphate salt(s)/total number of moles of polysaccharide units molar ratio of between 0.005 and 1.

### Claim 9 (depends on 1)

The process according to claim 1, wherein the solution from step a) comprises a number of moles of difunctional or multifunctional epoxide crosslinking agent(s)/total number of moles of polysaccharide units molar ratio of between 0.005 and 1.

### Claim 10 (depends on 1)

The process according to claim 1, further comprising adding at least one non-crosslinked polysaccharide after step b) but prior to, simultaneously with or subsequent to the recovery of step c).

### Claim 11 (depends on 1)

The process according to claim 1, wherein the crosslinked polysaccharide(s) included in the crosslinked gel have a degree of modification of between 0.1% and 10%.

### Claim 12 (depends on 1)

The process according to claim 1, wherein the crosslinked gel has an elastic modulus (G′) of between 20 and 1000 Pa associated with a phase angle (δ) of less than 45°.

### Claim 13

An injectable and sterile dermatological composition comprising, in a physiologically acceptable medium, at least one crosslinked gel having at least one polysaccharide or a salt thereof, at least one difunctional or multifunctional epoxide crosslinking agent chosen from butanediol diglycidyl ether, diepoxyoctane, 1,2-bis(2,3-epoxypropyl)-2,3-ethylene, and mixtures thereof, and at least one phosphate salt, the at least one phosphate salt being sodium trimetaphosphate.

### Claim 14

A cosmetic or dermatological composition comprising at least one crosslinked gel having at least one polysaccharide or a salt thereof, at least one difunctional or multifunctional epoxide crosslinking agent chosen from butanediol diglycidyl ether, diepoxyoctane, 1,2-bis(2,3-epoxypropyl)-2,3-ethylene, and mixtures thereof, and at least one phosphate salt, the at least one phosphate salt being sodium trimetaphosphate.

### Claim 15

A kit comprising:
packaging containing at least one dose of a crosslinked gel, the crosslinked gel having at least one polysaccharide or a salt thereof, at least one difunctional or multifunctional epoxide crosslinking agent chosen from butanediol diglycidyl ether, diepoxyoctane, 1,2-bis(2,3-epoxypropyl)-2,3-ethylene, and mixtures thereof, and at least one phosphate salt, the at least one phosphate salt being sodium trimetaphosphate; and
a device for injection into or through the skin or a skin microperforation device for administration of the one dose of the crosslinked gel.

### Claim 16

A method for filling skin volume defects by administering a crosslinked gel having at least one polysaccharide or a salt thereof, at least one difunctional or multifunctional epoxide crosslinking agent chosen from butanediol diglycidyl ether, diepoxyoctane, 1,2-bis(2,3-epoxypropyl)-2,3-ethylene, and mixtures thereof, and at least one phosphate salt, the at least one phosphate salt being sodium trimetaphosphate.

### Claim 17

A crosslinked gel for treating gingival deficiencies comprising at least one polysaccharide or a salt thereof, at least one difunctional or multifunctional epoxide crosslinking agent chosen from butanediol diglycidyl ether, diepoxyoctane, 1,2-bis(2,3-epoxypropyl)-2,3-ethylene, and mixtures thereof, and at least one phosphate salt, the at least one phosphate salt being sodium trimetaphosphate.

### Claim 18

A crosslinked gel for articular viscosupplementation comprising at least one polysaccharide or a salt thereof, at least one difunctional or multifunctional epoxide crosslinking agent chosen from butanediol diglycidyl ether, diepoxyoctane, 1,2-bis(2,3-epoxypropyl)-2,3-ethylene, and mixtures thereof, and at least one phosphate salt, the at least one phosphate salt being sodium trimetaphosphate.

### Claim 19

A crosslinked gel for treating ophthalmic disorders comprising at least one polysaccharide or a salt thereof, at least one difunctional or multifunctional epoxide crosslinking agent chosen from butanediol diglycidyl ether, diepoxyoctane, 1,2-bis(2,3-epoxypropyl)-2,3-ethylene, and mixtures thereof, and at least one phosphate salt, the at least one phosphate salt being sodium trimetaphosphate.