# US 2019/0169375 A1 · Method of crosslinking glycosaminoglycans

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- Number: US 2019/0169375 A1
- Document ID: US20190169375A1
- Status: Published application
- Kind: A1
- Application number: 16/322,615
- Filed: 2017-08-02
- Published: 2019-06-06
- Earliest claimed: 2016-08-03
- Assignees: Galderma Research & Development; Centre National De La Recherche Scientifique
- Applicants: Galderma Research & Development; Centre National de la Recherche Scientifique
- Inventors: Rachel AUZELY-VELTY; Tamiris FIGUEIREDO; Laura JING JING; Craig Steven HARRIS; Jean-Guy BOITEAU; Thibaut GERFAUD; Loic TOMAS
- Web page: https://patentgrep.com/patent/US20190169375A1

## CPC

- C08J 3/075: Macromolecular gels
- A61K 31/728: Hyaluronic acid
- 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 3/24: Crosslinking, e.g. vulcanising, of macromolecules (mechanical aspects B29C35/00; crosslinking agents C08K)
- C08K 5/1545: Six-membered rings
- C08K 5/55: Boron-containing compounds {(C08K5/0091 takes precedence)}
- C08L 5/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- C08J 2305/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- C08L 2203/02: for biomedical use
- C08L 2312/00: Crosslinking
- 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)
- 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)
- 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)
- C08K: Use of inorganic or non-macromolecular organic substances as compounding ingredients (paints, inks, varnishes, dyes, polishes, adhesives C09)
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

A new hydrogel made of crosslinked glycosaminoglycans, particularly crosslinked hyaluronic acid, chondroitin or chondroitin sulfate, having reversible linkages using boronic acid or boroxole derivatives leading to new benefits. Glycosaminoglycans that are crosslinked via an alkoxyboronate ester anion formed between a diol portion of a diol-functional moiety grafted to a first glycosaminoglycan and a boronate hemiester grafted to a second glycosaminoglycan.

## Claims

### Claim 1

Crosslinked glycosaminoglycans, wherein said glycosaminoglycans are crosslinked via an alkoxyboronate ester anion formed between a diol portion of a diol-functional moiety grafted to a first glycosaminoglycan and a boronate hemiester grafted to a second glycosaminoglycan.

### Claim 2 (depends on 1)

Crosslinked glycosaminoglycans according to claim 1, wherein said crosslinked glycosaminoglycans has a structure of Formula (I)
wherein
R1 is selected from H, F, Cl, NO2, C1-C3alkyl, C1-C3haloalkyl and C1-C3alkoxy;
R2, R3 and R4 are independently selected from H, F, Cl, C1-C3haloalkyl, NO2, C1-C3alkoxy, C1-C3alkyl and a linker, said linker binding covalently to said second glycosaminoglycan;
X is selected from CHR7 and a bond;
R5, R6 and R7 are independently selected from H, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, and a five- to six-membered heteroaromatic ring comprising 1 to 3 heteroatoms selected from O, N and S; and
wherein one of R2, R3 and R4 is a linker.

### Claim 3 (depends on 1)

Crosslinked glycosaminoglycans according to claim 1, wherein said glycosaminoglycans are hyaluronic acid.

### Claim 4 (depends on 2)

Crosslinked glycosaminoglycans according to claim 2, wherein
said linker is —NR9-Y or —O—Y— and forms an amide bond or an ether bond with said second glycosaminoglycan, wherein R9 is selected from hydrogen, C1-C3alkyl and C1-C3fluoroalkyl;
Y is selected from a bond and C1-C6alkylene in which one or two CH2 are optionally replaced by a group selected from O, NH and phenylene, said C1-C6alkylene being optionally substituted with 1 to 12 R8; and
R8 is selected from F, Cl, C1-C3alkyl, C1-C3haloalkyl, phenyl, OH, C1-C3hydroxyalkyl, C1-C3alkoxy, NH2, N—C1-C3alkylamino, N,N—C1-C4dialkylamino.

### Claim 5 (depends on 2)

Crosslinked glycosaminoglycans according to claim 2, wherein R2 is a linker.

### Claim 6 (depends on 2)

Crosslinked glycosaminoglycans according to claim 2, wherein said linker is —NR9—Y— and forms an amide bond with said second glycosaminoglycans, wherein R9 is selected from hydrogen, C1-C3alkyl and C1-C3fluoroalkyl; and
Y is a bond or an unsubstituted C1-C6alkylene.

### Claim 7 (depends on 2)

Crosslinked glycosaminoglycans according to claim 2, wherein
R1, R3 and R4 are independently selected from H, F, OCH3, CF3 and CH3;
R2 is a linker;
said linker is —HN—Y— and forms an amide bond with said second glycosaminoglycan;
Y is a bond or an unsubstituted C1-C3alkylene;
X is a bond or CH2; and
R5 and R6 are independently selected from H and C1-C3alkyl.

### Claim 8 (depends on 1)

Crosslinked glycosaminoglycans according to claim 1, wherein said boronate hemiester is selected from
wherein the boronate hemiester is grafted to said second glycosaminoglycan by that the —NH2 group of the boronate hemiester forms an amide with a backbone carboxylate group of said second glycosaminoglycan.

### Claim 9 (depends on 1)

Crosslinked glycosaminoglycans according to claim 1, said crosslinked glycosaminoglycans having a structure of Formula (II)

### Claim 10 (depends on 1)

Crosslinked glycosaminoglycans according to claim 1, wherein said diol portion is selected from a monosaccharide, a disaccharide and an alditol or a derivative thereof, or selected from maltose, fructose, lactose and sorbitol or a derivative thereof.

### Claim 11

(canceled)

### Claim 12

(canceled)

### Claim 13

(canceled)

### Claim 14

A method of crosslinking a first glycosaminoglycan grafted with a diol-functional moiety having a diol portion and a second glycosaminoglycan grafted with a boronate hemiester, comprising
crosslinking said first glycosaminoglycan with said second glycosaminoglycan by forming an alkoxyboronate ester anion linkage between the boronate hemiester of said second glycosaminoglycan and the diol portion of said diol-functional moiety of said first glycosaminoglycan.

### Claim 15 (depends on 14)

A method according to claim 14, further comprising prior to the crosslinking step:
grafting said second glycosaminoglycan with said boronate hemiester, said boronate hemiester being a compound of Formula (III),
wherein
R1 is selected from H, F, Cl, NO2, C1-C3alkyl, C1-C3haloalkyl and C1-C3alkoxy;
R2, R3 and R4 are independently selected from H, F, Cl, C1-C3haloalkyl, NO2, C1-C3alkoxy, C1-C3alkyl and a linker binding covalently to said second glycosaminoglycan;
X is selected from CHR7 and a bond; and
R5, R6 and R7 are independently selected from H, C1-C4alkyl, C3-C6cycloalkyl, phenyl, and a five- to six-membered heteroaromatic ring comprising 1 to 3 heteroatoms selected from O, N and S,
wherein one of R2, R3 and R4 is a linker.

### Claim 16 (depends on 14)

A method according to claim 14, wherein said first and said second glycosaminoglycans are hyaluronic acid.

### Claim 17 (depends on 15)

A method according to claim 15, wherein said linker is H2N—Y— or
and forms an amide bond or an ether bond to said second glycosaminoglycan;
Y is selected from a bond and C1-C6alkylene in which one or two CH2 are optionally replaced by a group selected from O, NH and phenylene, said C1-C6alkylene being optionally substituted with 1 to 12 R8; and
R8 is selected from F, Cl, C1-C3alkyl, C1-C3haloalkyl, phenyl, OH, C1-C3hydroxyalkyl, C1-C3alkoxy, NH2, N—C1-C3alkylamino, N,N—C1-C4dialkylamino.

### Claim 18 (depends on 15)

A method according to claim 15, wherein
R2 is a linker.

### Claim 19 (depends on 15)

A method according to claim 15, wherein
said linker is HR9N—Y— and forms an amide bond with said second glycosaminoglycan, wherein R9 is selected from hydrogen, C1-C3alkyl and C1-C3fluoroalkyl; and
Y is a bond or an unsubstituted C1-C6alkylene.

### Claim 20 (depends on 15)

A method according to claim 15, wherein
R1, R3 and R4 are independently selected from H, F, OCH3, CF3 and CH3;
R2 is a linker;
said linker is H2N—Y— and forms an amide bond with said second glycosaminoglycan;
Y is a bond or an unsubstituted C1-C3alkylene;
X is a bond or CH2; and
R5 and R6 are independently selected from H and C1-C3alkyl.

### Claim 21 (depends on 14)

A method according to claim 14, wherein said boronate hemiester is selected from
wherein the boronate hemiester is grafted to said second glycosaminoglycan by that the —NH2 group of the boronate hemiester forms an amide with a backbone carboxylate group of said second glycosaminoglycan.

### Claim 22

(canceled)

### Claim 23 (depends on 14)

A method according to claim 14, wherein said diol portion is selected from a monosaccharide, a disaccharide and an alditol or a derivative thereof, or selected from maltose, fructose, lactose and sorbitol or a derivative thereof.

### Claim 24

(canceled)

### Claim 25

(canceled)

### Claim 26

(canceled)

### Claim 27

(canceled)

### Claim 28

(canceled)

### Claim 29

(canceled)

### Claim 30

(canceled)

### Claim 31

(canceled)

### Claim 32

(canceled)

### Claim 33

(canceled)

### Claim 34

(canceled)

### Claim 35

(canceled)

### Claim 36

(canceled)

### Claim 37

(canceled)

### Claim 38

(canceled)

### Claim 39

(canceled)

### Claim 40 (depends on 1)

Polymer composition comprising crosslinked glycosaminoglycans according to claim 1 and an aqueous buffer.

### Claim 41

(canceled)