# US 2014/0193360 A1 · Hydrogel comprising catechol group-coupled chitosan or polyamine and poloxamer comprising thiol group coupled to end thereof, preparation method thereof, and hemostat using same

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- Number: US 2014/0193360 A1
- Document ID: US20140193360A1
- Status: Published application
- Kind: A1
- Application number: 14/239,538
- Filed: 2011-11-21
- Published: 2014-07-10
- Earliest claimed: 2011-11-21
- Assignees: Innotherapy Inc.
- Inventors: Haeshin Lee; Moon Sue Lee; Ji Hyun Ryu
- Web page: https://patentgrep.com/patent/US20140193360A1

## CPC

- A61L 24/08: Polysaccharides {(A61L24/043 takes precedence)}
- A61L 24/0015: {Medicaments; Biocides}
- A61L 24/0031: {Hydrogels or hydrocolloids}
- A61L 24/0042: {Materials resorbable by the body}
- A61L 24/043: {Mixtures of macromolecular materials}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 51/1213: {Semi-solid forms, gels, hydrogels, ointments, fats and waxes that are solid at room temperature}
- A61L 2400/04: Materials for stopping bleeding
- 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)

## Abstract

The present invention relates to an adhesive hydrogel composition containing catechol group-coupled chitosan and Pluronic comprising a thiol group coupled to the end thereof, and more specifically, to an adhesive composition which is safe in vivo and in vitro, is temperature sensitive, and has an excellent hemostatic effect and thus can be used as a bioadhesive, and a medical adhesive, an adhesion barrier and a surface adsorption inhibitor comprising the same.

## Claims

### Claim 1

A hydrogel composition comprising: (i) a catechol group-coupled chitosan or polyamine; and (ii) a polaxamer thiol group-coupled to the end thereof.

### Claim 2 (depends on 1)

The hydrogel composition of claim 1, wherein said catechol group-coupled chitosan or polyamine has a molecular weight of 10,000 Da˜1,000,000 Da.

### Claim 3 (depends on 1)

The hydrogel composition of claim 1, wherein said catechol group-coupled chitosan or polyamine has a molecular weight of 50,000 Da˜200,000 Da.

### Claim 4 (depends on 1)

The hydrogel composition of claim 1,
wherein said polaxamer comprises a block copolymer represented by the following formula 2 or an amphiphilic triblock copolymer structurally similar thereto, or a block copolymer represented by the following formula 3:
wherein a is an integer in a range of from 2 to 200; b is an integer in a range of from 10 to 100; and the ratio of a:b is in a range of from 1:9 to 8:2; and
wherein a is an integer in a range of from 2 to 600; b is an integer in a range of from 10 to 150; and the ratio of a:b is in a range of from 1:9 to 9:1.

### Claim 5 (depends on 1)

The hydrogel composition of claim 1, wherein said catechol group-coupled polyamine is any one or more selected from the group consisting of ethylene diamine, 1,3-diaminopropane, hexamethylenediamine, tetraethylmethylenediamine, putrescine, cadaverine, spermidine, spermine, linear polyethyleneimine, branched polyethyleneimine, and ε-poly-L-lysine.

### Claim 6 (depends on 1)

The hydrogel composition of claim 1, wherein said catechol group-coupled chitosan or polyamine has a 1-20 mole % of catechol group content to the chitosan or polyamine.

### Claim 7 (depends on 1)

The hydrogel composition of claim 1, wherein said polaxamer thiol group-coupled to the end thereof has a 50-100 mole % of thiol group content to the polaxamer.

### Claim 8 (depends on 1)

The hydrogel composition of claim 1, wherein the hydrogel composition further comprises a therapeutic drug.

### Claim 9 (depends on 8)

The hydrogel composition of claim 8, wherein the therapeutic drug is any one or more selected from the group consisting of human growth hormones, erythropoietin, interferon, insulin, interleukin, calcitonin, G-CSF, Angiopoietin, VEGF-Trap, monoclonal antibodies, antibody fragments, hemostatic proteins, antibiotics, analgesics, angina therapeutic agents, allergen extract, anti-histamines, and anti-allergic agents.

### Claim 10 (depends on 1)

A hemostat comprising the hydrogel composition of claim 1.

### Claim 11

A method for preparing a hydrogel, the method comprising:
(A) preparing a catechol group-coupled chitosan or polyamine;
(B) preparing a polaxamer thiol group-coupled to the end thereof;
(C) preparing a catechol-chitosan or catechol-polyamine solution by dissolving the catechol group-coupled chitosan or polyamine in a buffer;
(D) preparing a thiol-polaxamer solution by dissolving the polaxamer thiol group-coupled in a buffer;
(E) preparing an adhesive hydrogel solution by mixing the catechol-chitosan or catechol-polyamine solution of step (C) with the thiol-polaxamer solution of step (D); and
(F) gelating the adhesive hydrogel solution of step (E).

### Claim 12 (depends on 11)

The method of claim 11, wherein step (A) of preparing the catechol group-coupled chitosan or polyamine comprises the steps of:
(a) preparing a chitosan or polyamine solution by adding 0.2-5 parts by weight of chitosan or polyamine to 100 parts by weight of distilled water;
(b) preparing a hydrocaffeic acid solution by adding 1-5 parts by weight of hydrocaffeic acid and 2-10 parts by weight of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) to 100 parts by weight of distilled water;
(c) preparing a catechol group-coupled chitosan or polyamine mixture by mixing the chitosan or polyamine solution of step (a) with the hydrocaffeic acid solution of step (b) at a volume ratio of 1:1 to 3:1 and stirring the mixture; and
(d) purifying the catechol group-coupled chitosan or polyamine by dialyzing the catechol group-coupled chitosan or polyamine mixture of step (c) through a dialysis membrane in a buffer for 6-48 hours, and then drying purified catechol group-coupled chitosan or polyamine.

### Claim 13 (depends on 11)

The method of claim 11, wherein step (B) of preparing the polaxamer thiol group-coupled to the end thereof comprises the steps of:
(1) preparing a polaxamer solution by adding 5-15 parts by weight of polaxamer to 100 parts by weight of a non-polar organic solvent and 0.1-1 part by volume of triethylamine to 100 parts by volume of the non-polar organic solvent;
(2) preparing a nitrophenyl chloroformate solution by adding 5-20 parts by weight of nitrophenyl chloroformate to 100 parts by weight of a non-polar organic solvent;
(3) preparing a polaxamer mixture solution by mixing the polaxamer solution of step (1) with the nitrophenyl chloroformate solution of step (2) at a volume ratio of 5:1 to 10:1, and stiffing the mixture;
(4) preparing a polaxamer mixture by precipitating and drying the polaxamer mixture solution of step (3);
(5) preparing a thiol group-coupled polaxamer mixture by adding 5-20 parts by weight of the polaxamer mixture of step (4) and 0.2-5 parts by weight of cysteamine to 100 parts by weight of a mixture of a non-polar organic solvent and a polar solvent, and stirring the mixture;
(6) preparing a thiol group-coupled block copolymer mixture by precipitating and drying the thiol group-coupled polaxamer mixture of step (5); and
(7) purifying the thiol group-coupled block copolymer by dialyzing the thiol group-coupled block copolymer mixture of step (6) through a dialysis membrane in distilled water for 12-120 hours, and then drying purified thiol group-coupled block copolymer.

### Claim 14 (depends on 11)

The method of claim 11, wherein the catechol-chitosan or catechol-polyamine solution of step (C) is prepared by adding 0.1-10 wt % of the catechol group-coupled chitosan or polyamine to 100 wt % of the buffer.

### Claim 15 (depends on 11)

The method of claim 11, wherein the thiol-polaxamer solution of step (D) is prepared by 3-50 wt % of the thiol group-coupled polaxamer to 100 wt % of the buffer.

### Claim 16 (depends on 11)

The method of claim 11, wherein the adhesive hydrogel solution of step (E) is prepared by mixing the catechol-chitosan or catechol-polyamine solution with the thiol-polaxamer solution at a volume ratio of 1:3 to 3:1.

### Claim 17 (depends on 11)

The method of claim 11, wherein step (F) is carried out at a temperature of 4 to 37° C.

### Claim 18 (depends on 12)

The method of claim 12, wherein the catechol group in step (A) is represented by the following formula 1:
wherein the catechol group-coupled chitosan or polyamine has a molecular weight of 10 kDa-1,000 kDa; and the catechol group-coupled chitosan or polyamine is any one or more selected from the group consisting of ethylene diamine, 1,3-diaminopropane, hexamethylenediamine, tetraethylmethylenediamine, putrescine, cadaverine, spermidine, spermine, linear polyethyleneimine, branched polyethyleneimine, ε-poly-L-lysine, and poly(allylamine hydrochloride).

### Claim 19 (depends on 13)

The method of claim 13, wherein the polaxamer of step (B) is comprises a block copolymer represented by the following formula 2 or a block copolymer represented by the following formula 3:
wherein a is an integer in a range of from 2 to 200; b is an integer in a range of from 10 to 100; and the ratio of a:b is in a range of from 1:9 to 8:2; and
wherein a is an integer in a range of from 2 to 600; b is an integer in a range of from 10 to 150; and the ratio of a:b is in a range of from 1:9 to 9:1.