# US 10,767,037 B2 · Hyaluronic acid conjugates and uses thereof

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- Number: US 10,767,037 B2
- Document ID: US10767037B2
- Status: Granted
- Kind: B2
- Application number: 16/094,559
- Filed: 2017-04-18
- Published: 2019-04-25
- Granted: 2020-09-08
- Earliest claimed: 2016-04-19
- Assignees: Universite De Geneve
- Applicants: Universite De Geneve
- Inventors: Pierre Maudens; Eric Allemann; Olivier Jordan
- Web page: https://patentgrep.com/patent/US10767037B2

## CPC

- C08L 51/02: grafted on to polysaccharides
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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
- C08K 5/20: Carboxylic acid amides
- C08K 5/3472: Five-membered rings
- A61K 47/6939: {the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin}
- A61L 27/20: Polysaccharides
- C08L 2203/02: for biomedical use
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- 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
- 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)
- C08K: Use of inorganic or non-macromolecular organic substances as compounding ingredients (paints, inks, varnishes, dyes, polishes, adhesives C09)
- 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)

## Abstract

The present invention is directed to new graft polymer of a hyaluronic acid polymer and N-isopropylacrylamide based polymer, preparations, compositions and uses thereof. In particular, the invention relates to pH and/or thermo-sensitive compositions able to form spontaneously nanoparticles useful as active and agents and delivery systems for at least one bioactive agent.

## Claims

### Claim 1

A graft polymer of a hyaluronic acid polymer and a N-isopropylacrylamide based polymer wherein the hyaluronic acid polymer and the N-isopropylacrylamide based are conjugated through at least one linker L of Formula (II):
wherein one of Ra and Rb is covalently linked to the N-isopropylacrylamide based polymer and one of Ra and Rb is covalently linked to the hyaluronic acid polymer and when Ra or Rb is covalently linked to the N-isopropylacrylamide based polymer, it is equal to R1 and when Ra or Rb is covalently linked to the hyaluronic acid polymer, it is equal to R3, wherein R1 is a group selected from (CH2)x—NH(CH2)y—S—, —(CH2)x—NH—O—C(O)—(CH2)y—S—, —(CH2)x—NH—(CH2)y—C(O)—NH—(CH2)z—S—, —(CH2)x—O—C(O)—CR7R8—, —C(O)—(CH2)x—C(O)—NH—(CH2)z—S and an optionally substituted polyethylene chain wherein R7 and R8 are optionally substituted C1-C6 alkyl; R3 is a group -E-G-L1- wherein E is either absent or selected from —C(O)—NR9—, —C(O)—O— and —C(O)—, G is linker group selected from optionally substituted C1-C20 alkyl, optionally substituted polyethylene glycol (PEG) chain, optionally substituted acylamino C1-C6 alkyl, optionally substituted acyl C1-C6 alkyl, optionally substituted aminocarbonyl C1-C6 alkyl and optionally substituted C1-C6 alkoxy and L1 is selected from —NR10C(O)—, —C(O)—NR10—, —C(O)—O— and —C(O)— wherein R9 and R10 are independently selected from H and optionally substituted C1-C6 alkyl; A is an optionally substituted C5-C10-cycloalkyl, or optionally substituted heterocycloalkyl ring wherein R5 represents one or more substituent(s) independently selected from H, optionally substituted alkoxy and optionally substituted C1-C6 alkyl; x, y and z are integers independently selected from 1 to 20 or any pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

The graft polymer according to claim 1 of Formula (I):
wherein M is a group selected from a moiety of Formula (M1) and of Formula (M2):
R2 is a group —B—(CH2)i-D, wherein B is either absent or selected from —S—C(S)—S— and —S—; D is a group selected from optionally substituted C1-C15 alkyl, optionally substituted alkoxycarbonyl C1-C4 alkyl, optionally substituted amino C1-C4 alkyl, optionally substituted aminocarbonyl C1-C6 alkyl, —COOH and —NH2; p is an integer independently selected from 1 to 500; i is an integer independently selected from 0 to 500; R6 is a group selected from —COOH and R3, depending on the degree of substitution; L is a linker of Formula (II) as defined in claim 1 and n is an integer selected from 1 to 7,000 or any pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 1)

The graft polymer according to claim 1, having a Formula (Ia):
or any pharmaceutically acceptable salts thereof wherein L is a linker as defined in claim 1; R2 is a group —B—(CH2)i-D, wherein B is either absent or selected from —S—C(S)—S— and —S—; R6 is a group selected from —COOH and R3, depending on the degree of substitution and p is an integer independently selected from 1 to 500.

### Claim 4 (depends on 1)

The graft polymer according to claim 1, wherein the linker L is linked to the HA polymer of the graft polymer through its Rb substituent.

### Claim 5 (depends on 1)

The graft polymer according to claim 1, wherein the linker L is linked to the HA polymer of the graft polymer through its Ra substituent.

### Claim 6 (depends on 1)

The graft polymer according to claim 1, wherein x is from 2 to 10.

### Claim 7 (depends on 1)

The graft polymer according to claim 1, wherein B is absent or —S—C(S)—S—.

### Claim 8 (depends on 1)

The graft polymer according to claim 1, wherein L is a group according to Formula (II′):
wherein R11 and R12 represent one or more substituent independently selected from H, optionally substituted alkoxy and optionally substituted C1-C4 alkyl; Ra and Rb are as described in claim 1.

### Claim 9 (depends on 1)

The graft polymer according to claim 1, wherein L is a group according to Formulae (II) having a formula selected from Formula (II″) and (II′″):
wherein Q is absent or a group of the following formula: —NH—C(O)—(CH2—CH2—O)1-4—CH2—CH2—; G1 is a PEG, in particular (CH2—CH2—O)1-4— and R11 and R12 represent one or more substituent independently selected from H, optionally substituted alkoxy and optionally substituted C1-C4 alkyl.

### Claim 10 (depends on 1)

The graft polymer according to claim 1, wherein said graft polymer is selected from the following group:
having a substitution degree between about 0.5 and 50 or any pharmaceutically acceptable salts thereof.

### Claim 11 (depends on 1)

A method for the preparation of a graft polymer of a hyaluronic acid polymer and N-isopropylacrylamide based polymer wherein the hyaluronic acid polymer and the N-isopropylacrylamide based are conjugated by at least one linker L of Formula (II)
wherein A, Ra, Rb and R5 are as defined in claim 1,
comprising the steps of:
(a) providing an HA polymer having at least one carboxylic acid group which is conjugated to at least one first functional group capable of participating in a “click chemistry” reaction;
(b) providing a N-isopropylacrylamide based polymer having at least one-second complementary functional group capable of participating in a “click chemistry” reaction with the first functional group wherein said one of the functional groups is an azide moiety and the other functional group is an alkyne-bearing precursor of the said linker L;
(c) reacting the at least one first functional group of the HA polysaccharide with the at least one-second complementary functional group of the N-isopropylacrylamide based polymer via a “click chemistry” reaction to obtain a graft polymer composition of the invention; and
(d) isolating the graft polymer composition.

### Claim 12 (depends on 1)

A composition comprising at least one graft polymer according to claim 1 and at least one carrier.

### Claim 13 (depends on 12)

The composition according to claim 12, wherein said composition is a hydrogel or nanoparticle composition.

### Claim 14 (depends on 12)

The composition according to claim 12, wherein said composition is a cell or tissue culture medium further comprising cell or tissue nutrients.

### Claim 15 (depends on 12)

The composition according to claim 12, wherein said composition is a reconstruction tissue.

### Claim 16 (depends on 12)

The composition according to claim 12, wherein said composition is a cosmetic composition and the said carrier is a cosmetically acceptable carrier.

### Claim 17 (depends on 1)

A soft tissue filler comprising at least one graft polymer according to a graft polymer according to claim 1.

### Claim 18 (depends on 1)

A method for the preparation of a delivery system of an active principle, said method comprising the steps of:
a) Providing a graft polymer or hydrogel according to claim 1 in gel state;
b) Providing an active principle to be delivered;
c) Mixing the said graft polymer composition or hydrogel with the said active principle;
d) Optionally inducing formation of nanoparticles by increasing the temperature to the mixture; and
e) Collecting the obtained composition, hydrogel or nanoparticles loaded with the active principle.

### Claim 19 (depends on 1)

A method of preventing, treating or ameliorating a medical disorder selected from joint pathologies, articular diseases, eye pathologies, skin defects or injuries, urological tissue bulking and any tissue degeneration, a tumor or a vascular malformation in a subject, said method comprising administering to a subject in need thereof an effective amount of at least one HA graft polymer according to claim 1 or a pharmaceutical formulation thereof.

### Claim 20 (depends on 12)

The composition according to claim 12, wherein the carrier is a pharmaceutically acceptable carrier.

### Claim 21 (depends on 1)

A method of preparing a cell or tissue culture medium comprising mixing at least one HA graft polymer according to claim 1 with cell or tissue culture medium.

### Claim 22 (depends on 1)

A method of preparing a material for tissue engineering comprising mixing at least one HA graft polymer according to claim 1 with a tissue engineering material.

### Claim 23 (depends on 22)

The method according to claim 22, wherein the tissue engineering material is bone, cartilage, epidermal material or cells.

### Claim 24 (depends on 1)

A method of preparing a composition comprising mixing at least one HA graft polymer according to claim 1 with a carrier.