# US 11,896,737 B2 · Injectable gel product

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- Number: US 11,896,737 B2
- Document ID: US11896737B2
- Status: Granted
- Kind: B2
- Application number: 17/857,925
- Filed: 2022-07-05
- Published: 2022-12-22
- Granted: 2024-02-13
- Earliest claimed: 2017-12-22
- Assignees: Galderma Holding SA
- Applicants: Galderma Holding SA
- Inventors: Åke Öhrlund; Morgan Karlsson
- Web page: https://patentgrep.com/patent/US11896737B2

## CPC

- A61L 27/48: with macromolecular fillers
- A61L 27/20: Polysaccharides
- A61L 27/26: Mixtures of macromolecular compounds
- A61L 27/52: Hydrogels or hydrocolloids
- 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
- C08J 3/126: {Polymer particles coated by polymer, e.g. core shell structures}
- C08J 3/245: {Differential crosslinking of one polymer with one crosslinking type, e.g. surface crosslinking}
- C08L 5/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- A61L 2400/06: Flowable or injectable implant compositions
- A61L 2430/34: for soft tissue reconstruction
- A61L 2430/40: Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
- C08J 2305/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- C08J 2405/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- C08L 2203/02: for biomedical use
- C08L 2205/025: containing two or more polymers of the same hierarchy C08L, and differing only in parameters such as density, comonomer content, molecular weight, structure
- C08L 2207/53: Core-shell polymer
- C08L 2312/00: Crosslinking
- 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)
- 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

A method of producing an injectable gel product is provided, comprising (a) cross-linking a first glycosaminoglycan (GAG) with a first crosslinking agent to produce a gel, wherein the charging ratio of crosslinking agent to disaccharide unit is below 0.15; (b) preparing particles of the gel; (c) mixing the glycosaminoglycan (GAG) gel particles with a second GAG to provide a mixture; (d) cross-linking the mixture with a second crosslinking agent to obtain cross-linking between the GAGs of the second, outer phase, thereby providing a gel having a first, inner phase of the cross-linked GAG gel particles, embedded in a gel of the second GAG outer phase; and (e) preparing injectable particles, each such particle containing a plurality of the cross-linked GAG gel particles of the first, inner phase. An injectable gel product, an aqueous composition, and a pre-filled syringe as also provided.

## Claims

### Claim 1

A method of producing an injectable gel product, comprising:
(a) cross-linking a first glycosaminoglycan (GAG) with a first crosslinking agent at a first charging ratio of crosslinking agent to disaccharide unit below 0.15 to produce a gel;
(b) preparing particles of the gel;
(c) mixing the GAG gel particles with a second GAG to provide a mixture;
(d) cross-linking the second GAG with a second crosslinking agent to obtain a gel having a first, inner phase of the cross-linked GAG gel particles embedded in a second, outer phase comprising the second GAG, and
(e) preparing injectable particles of the gel from (d), each such particle containing a plurality of the cross-linked GAG gel particles of the first, inner phase;
wherein the inner phase, the outer phase, or both the inner phase and the outer phase are crosslinked via one or more polyfunctional cross-linking agent selected from 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the one or more polyfunctional cross-linking agent is BDDE.

### Claim 3 (depends on 1)

The method according to claim 1, wherein both the first GAG and the second GAG are covalently crosslinked via a polyfunctional cross-linking agent selected from 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the first GAG is covalently crosslinked via a polyfunctional cross-linking agent selected from 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.

### Claim 5 (depends on 4)

The method according to claim 4, wherein the second GAG is covalently crosslinked via crosslinks comprising a spacer group selected from the group consisting of di-, tri-, tetra-, and oligosaccharides.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the spacer group is a hyaluronic acid tetrasaccharide, hyaluronic acid hexasaccharide, trehalose, lactose, maltose, sucrose, cellobiose or raffinose residue.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the second GAG is covalently crosslinked via a polyfunctional cross-linking agent selected from 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the first GAG is covalently crosslinked via crosslinks comprising a spacer group selected from the group consisting of di-, tri-, tetra-, and oligosaccharides.

### Claim 9 (depends on 8)

The method according to claim 8, wherein the spacer group is a hyaluronic acid tetrasaccharide, hyaluronic acid hexasaccharide, trehalose, lactose, maltose, sucrose, cellobiose or raffinose residue.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the second GAG is cross-linked with the second crosslinking agent at a second charging ratio of crosslinking agent to disaccharide unit that is less than the first charging ratio.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the second charging ratio is less than 0.05.

### Claim 12 (depends on 1)

The method according to claim 1, wherein the cross-linking (d) further comprises cross-linking between the gels of the first, inner phase and the second, outer phase.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the GAG gel particles and the second GAG are both in a dry state when mixed.

### Claim 14 (depends on 1)

The method according to claim 1, wherein the preparation of particles comprise precipitating and drying.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the mixture (c) comprises at least 50% by dry weight of the GAG gel particles.

### Claim 16 (depends on 1)

The method according to claim 1, wherein the crosslinking (a) and/or (b) results in ether bonds.

### Claim 17 (depends on 1)

The method according to claim 1, wherein the GAG is hyaluronic acid.

### Claim 18

An injectable gel product comprising a first, inner phase of a plurality of cross-linked glycosaminoglycan (GAG) gel particles embedded in a second, outer phase of a cross-linked GAG gel,
wherein the second, outer phase is in the form of particles,
wherein the gel of the first, inner phase has a Degree of Modification (MoD) of 0.15 or lower,
wherein the gel of the second, outer phase has a MoD that is lower than the MoD of the gel of the first, inner phase, and
wherein the MoD is the molar amount of bound cross-linking agent(s) relative to the total molar amount of repeating GAG disaccharide units;
wherein the inner phase, the outer phase, or both the inner phase and the outer phase are crosslinked via one or more polyfunctional cross-linking agent selected from 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.

### Claim 19 (depends on 18)

The injectable gel product according to claim 18, wherein the one or more polyfunctional cross-linking agent is BDDE.

### Claim 20 (depends on 18)

The injectable gel product according to claim 18, wherein each of the plurality of crosslinked GAG gel particles in the first, inner phase and the plurality of crosslinked GAG gel particles in the second, outer phase are independently covalently crosslinked via a polyfunctional cross-linking agent selected from 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.

### Claim 21 (depends on 18)

The injectable gel product according to claim 18, wherein the plurality of crosslinked GAG gel particles in the first, inner phase are covalently crosslinked via a polyfunctional cross-linking agent selected from 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.

### Claim 22 (depends on 21)

The injectable gel product according to claim 21, wherein the plurality of crosslinked GAG gel particles in the second, outer phase are independently covalently crosslinked via crosslinks comprising a spacer group selected from the group consisting of di-, tri-, tetra-, and oligosaccharides.

### Claim 23 (depends on 22)

The injectable gel product according to claim 22, wherein the spacer group is a hyaluronic acid tetrasaccharide, hyaluronic acid hexasaccharide, trehalose, lactose, maltose, sucrose, cellobiose or raffinose residue.

### Claim 24 (depends on 18)

The injectable gel product according to claim 18, wherein the plurality of crosslinked GAG gel particles in the second, outer phase are covalently crosslinked via a polyfunctional cross-linking agent selected from 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.

### Claim 25 (depends on 24)

The injectable gel product according to claim 24, wherein the plurality of crosslinked GAG gel particles in the first, inner phase are independently covalently crosslinked via crosslinks comprising a spacer group selected from the group consisting of di-, tri-, tetra-, and oligosaccharides.

### Claim 26 (depends on 25)

The injectable gel product according to claim 25, wherein the spacer group is a hyaluronic acid tetrasaccharide, hyaluronic acid hexasaccharide, trehalose, lactose, maltose, sucrose, cellobiose or raffinose residue.

### Claim 27 (depends on 18)

The injectable gel product according to claim 18, wherein the MoD of the gel of the second, outer phase is 0.10 or lower.

### Claim 28 (depends on 18)

The injectable gel product according to claim 18, wherein the gel of the second, outer phase has a Swelling factor (SwF) above 3.0.

### Claim 29 (depends on 18)

The injectable gel product according to claim 18, wherein the gels of the first, inner phase and the second, outer phase are cross-linked to each other.

### Claim 30 (depends on 18)

The injectable gel product according to claim 18, wherein the particles of the second, outer phase have a particle size at least three times the size of an inner particle size.

### Claim 31 (depends on 18)

The injectable gel product according to claim 18, wherein the cross-linked GAG of the first, inner phase have a dry weight content of that is at least 50% of the total dry weight content of GAGs in the inner and outer phase.

### Claim 32 (depends on 18)

The injectable gel product according to claim 18, wherein the GAG is hyaluronic acid.

### Claim 33 (depends on 18)

The injectable gel product according to claim 18, wherein the cross-linking is with ether bonds.

### Claim 34 (depends on 18)

The injectable gel product according to claim 18, further comprising a buffering agent.

### Claim 35 (depends on 18)

A pre-filled syringe, comprising the injectable gel product according to claim 18.