COMBINATION OF CROSS-LINKED HYALURONIC ACIDS AND METHOD OF PREPARING THE SAME

• US 20190315887A1
• Filed: 06/21/2019
• Published: 10/17/2019
• Est. Priority Date: 01/29/2016
• Status: Active Grant

• Current Assignee: Hanmi Pharmaceutical Company Limited
• Original Assignee: Hanmi Pharmaceutical Company Limited
• Inventors: CHOI, Sung Chul, KIM, Hyun Il, YANG, Ki Young, PARK, Hyo Seung, LEE, Back Ho
• Granted Patent: US 11,180,576 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/08 containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 8/0241 Containing particulates characterized by their shape and/or structure see also A61K8/04, A61K8/11, and A61K8/14, further aspects are classified in A61K2800/40 and subcodes
• CPC Class Codes: A61K 8/735 Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 2430/34 for soft tissue reconstruction
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61Q 19/08 Anti-ageing preparations
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• CPC Class Codes: C08J 2305/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08J 3/24 Crosslinking, e.g. vulcanising, of macromolecules mechanical aspects B29C35/00; crosslinking agents C08K
• CPC Class Codes: 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
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

Provided are a combination of cross-linked hyaluronic acids comprising: a cross-linked hyaluronic acid having an elasticity of about 50 to about 200 Pa and a viscosity of about 20 to about 100 Pa, and a cross-linked hyaluronic acid having an elasticity of about 400 to about 800 Pa and a viscosity of about 40 to about 100 Pa, and a method for preparing the same.

Claims

1. A combination of cross-linked hyaluronic acids comprising:

a cross-linked hyaluronic acid having an elasticity of about 50 to about 200 Pa and a viscosity of about 20 to about 100 Pa, and

a cross-linked hyaluronic acid having an elasticity of about 400 to about 800 Pa and a viscosity of about 40 to about 100 Pa.

2. The combination of cross-linked hyaluronic acids of claim 1 having an elasticity of about 100 to about 150 Pa and a viscosity of about 20 to about 60 Pa.

3. The combination of cross-linked hyaluronic acids of claim 2, wherein the cross-linked hyaluronic acid having an elasticity of about 50 to about 200 Pa and a viscosity of about 20 to about 100 Pa and the cross-linked hyaluronic acid having an elasticity of about 400 to about 800 Pa and a viscosity of about 40 to about 100 Pa are combined in a weight ratio of about 8:

2 to about 9;

1.

4. A combination of cross-linked hyaluronic acids comprising:

a cross-linked hyaluronic acid having an elasticity of about 50 to about 200 Pa and a viscosity of about 20 to about 100 Pa, and prepared by a method comprising cross-linking hyaluronic acid with an epoxy-based cross-linking agent having at least two epoxy functional groups in an ethanol-containing aqueous alkaline solution; and

a cross-linked hyaluronic acid having an elasticity of about 400 to about 800 Pa and a viscosity of about 40 to about 100 Pa, and prepared by a method comprising cross-linking the cross-linked hyaluronic acid having an elasticity of about 50 to about 200 Pa and a viscosity of about 20 to about 100 Pa with an epoxy-based cross-linking agent having at least two epoxy functional groups in an aqueous alkaline solution.

5. The combination of cross-linked hyaluronic acids of claim 4 having an elasticity of about 100 to about 150 Pa and a viscosity of about 20 to about 60 Pa.

6. The combination of cross-linked hyaluronic acids of claim 5, wherein the cross-linked hyaluronic acid having an elasticity of about 50 to about 200 Pa and a viscosity of about 20 to about 100 Pa and the cross-linked hyaluronic acid having an elasticity of about 400 to about 800 Pa and a viscosity of about 40 to about 100 Pa are combined in a weight ratio of about 8:

2 to about 9;

1.

7. The combination of cross-linked hyaluronic acids of claim 5, wherein the combination of cross-linked hyaluronic acids is in the form of particles having an average particle size of about 500 to about 750 μ

m.

8. A biocompatible material comprising the combination of cross-linked hyaluronic acids of claim 4.

9. The biocompatible material of claim 8, wherein the biocompatible material is selected from the group consisting of arthritis treatment implants, wrinkle fillers, cosmetic fillers, and drug carriers.

10. A method of preparing a combination of cross-linked hyaluronic acids comprising:

combining (a) a cross-linked hyaluronic acid having an elasticity of about 50 to about 200 Pa and a viscosity of about 20 to about 100 Pa with (b) a cross-linked hyaluronic acid having an elasticity of about 400 to about 800 Pa and a viscosity of about 40 to about 100 Pa;

wherein the (a) cross-linked hyaluronic acid is prepared by a method comprising cross-linking hyaluronic acid with an epoxy-based cross-linking agent having at least two epoxy functional groups in an ethanol-containing aqueous alkaline solution;

wherein the (b) cross-linked hyaluronic acid is prepared by a method comprising cross-linking the cross-linked hyaluronic acid having an elasticity of about 50 to about 200 Pa and a viscosity of about 20 to about 100 Pa with an epoxy-based cross-linking agent having at least two epoxy functional groups in an aqueous alkaline solution; and

wherein the combining ratio is adjusted to meet a target viscoelasticity of the combination of cross-linked hyaluronic acids to be prepared.

11. The method of claim 10, wherein the combining ratio of the (a) cross-linked hyaluronic acid to the (b) cross-linked hyaluronic acid is about 9:

1 to about 8;

2 by weight.

12. The method of claim 10, wherein the hyaluronic acid is obtained by fermentation with a microorganism.

13. The method of claim 10, wherein the hyaluronic acid includes hyaluronic acid, a salt of hyaluronic acid, or a mixture thereof.

14. The method of claim 10, wherein the salt of hyaluronic acid is selected from the group consisting of sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, tetrabutylammonium hyaluronate, and a combination thereof.

15. The method of claim 10, wherein the hyaluronic acid comprises sodium hyaluronate having a molecular weight of about 100,000 to about 6,000,000.

16. The method of claim 10, wherein the epoxy-based cross-linking agent having at least two epoxy functional groups is selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), ethylene glycol diglycidyl ether (EGDGE), 1,6-hexanediol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, trimethylpropane polyglycidyl ether, 1,2-(bis(2,3-epoxypropoxy)ethylene, pentaerythritol polyglycidyl ether, sorbitol polyglycidyl ether, and a combination thereof.

17. The method of claim 10, wherein the ethanol-containing aqueous alkaline solution contains about 5 to about 13% w/w of ethanol.

18. The method of claim 10, wherein the ethanol-containing aqueous alkaline solution is an aqueous sodium hydroxide solution of about 0.7 to 1.3% w/w containing about 5 to about 13% w/w of ethanol.