Hydrogels and Hyaluronic Acid and Alpha, Beta-Polyaspartyl-Hydrazide and Their Biomedical and Pharmaceutical Uses

• US 20080292664A1
• Filed: 06/23/2005
• Published: 11/27/2008
• Est. Priority Date: 06/28/2004
• Status: Abandoned Application

• Current Assignee: Universita' Degli Studi Di Palermo (Repubblica Italiana)
• Original Assignee: Universita' Degli Studi Di Palermo (Repubblica Italiana)
• Inventors: Giammona, Gaetano, Pitarresi, Giovanna, Palumbo, Fabio Salvatore
• Application Number:
  US11/630,985
• Publication Number:
  US 20080292664A1
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

Compositions and products based on the chemical crosslinking of hyaluronic acid with a polyfunctional polymer having a protein-like structure, bearing hydrazido pendent groups along the polymeric chain. The polymer is preferably, alpha-beta-polyaspartylhydrazide, a biocompatible macromolecule. The materials obtained after crosslinking, specifically hydrogels, undergo a reduced chemical and enzymatic degradation, unlike the starting hyaluronic acid, and they can be used to prepare systems for applications in the biomedical and pharmaceutical field.

Claims

1. A composition comprising hyaluronic acid chemically crosslinked with a polyhydrazide polymer, wherein one or more carboxy groups of the disaccharide units of hyaluronic acid are chemically linked, respectively, to one or more hydrazido groups of the polyhydrazide polymer.

2. A composition according to claim 1, wherein said polyhydrazide polymer is alpha,beta-polyaspartylhydrazide.

3. A composition according to claim 1, wherein the hyaluronic acid has a molecular weight from 50,000 to 1,500,000 dalton.

4. A composition according to claim 2, wherein the alpha,beta-polyaspartylhydrazide has a molecular weight from 2,000 to 40,000 dalton.

21. Compositions and hydrogels according to any one of the previous claims, in the form of nanoparticles, microparticles, film, membranes, rods, sponges or gels.

5. A hydrogel composed of hyaluronic acid chemically crosslinked with a polyhydrazide polymer, wherein one or more carboxy groups of the disaccharide units of hyaluronic acid are chemically linked, respectively, to one or more hydrazido groups of the polyhydrazide polymer.

6. A hydrogel claimed in claim 5, wherein said polyhydrazido polymer is alpha, beta-polyaspartylhydrazide.

7. A hydrogel according to claim 6, wherein the hyaluronic acid has a molecular weight from 50,000 to 1,500,000 dalton and the alpha,beta-polyaspartylhydrazide has a molecular weight from 2,000 to 40,000 dalton.

8. hydrogel according to claim 6, wherein the ratio between moles of repeating unit of alpha, beta-polyaspartylhydrazide and moles of repeating unit of hyaluronic acid is from 0.01 to 5.

9. A hydrogel according to claim 5, obtainable by reacting hyaluronic acid and a polyhydrazide polymer in the presence of a carbodiimide as an activating agent.

10. A hydrogel according to claim 9, wherein said carbodiimide is Nethyl-N′

-(3-dimethylaminopropyl)-carbodiimide.

11. A hydrogel according to claim 10, wherein the ratio between moles of N-ethyl-N′

-(3-dimethylaminopropyl)-carbodiimide and moles of repeating unit of hyaluronic acid is from 0.01 to 10.

12. A hydrogel according to claim 9, further obtainable in the presence of a N-hydroxysuccinimide as a further activating agent.

13. A hydrogel according to claim 12, wherein said N-hydroxysuccinimide is N-hydroxysulfosuccinimide.

14. A hydrogel according to claim 13, wherein said N-hydroxysulfosuccinimide is present in the same molar amount as the said N-ethyl-N′

-(3-dimethylaminopropyl)-carbodiimide.

15. A manufacturing process for producing a hydrogel as defined in claim 5, wherein said hyaluronic acid and said polyhydrazide polymer are dissolved in double-distilled water in a prefixed molar ratio and a fixed amount of carbodiimide is added thereto, the resulting reaction mixture is kept at a temperature from 0°

C. to 60°

C. for a period of time from 1 hour to 5 days, and subsequently the product is recovered in hydrogel form.

16. A process according to claim 15, wherein said polyhydrazide polymer is alpha,beta-polyaspartylhydrazide and said carbodiimide is N-ethyl-N′

-(3-dimethylaminopropyl)-carbodiimide.

17. A process according to claim 15, wherein during the reaction the pH is maintained in the range from 3 to 8.

18. A process according to claim 15, wherein in addition to said carbodiimide, a prefixed in advance amount of a N-hydroxysuccinimide is added.

19. A process according to claim 18, wherein said N-hydroxysuccinimide is N-hydroxysulfosuccinimide.

20. A process according to claim 18 wherein during the reaction the pH is maintained in a range from 4 to 10.

22. A kit for the in situ preparation of a hydrogel composed of hyaluronic acid chemically crosslinked with a polyhydrazide polymer, comprising a container with a first hyaluronic acid-based component and a container with a second polyhydrazido polymer-based component, the said two components being able to form the hydrogel after their mutual contact, directly on the application site.

23. A kit according to claim 22, wherein said polyhydrazide polymer is alpha, beta-polyaspartylhydrazide.