New hyaluronic acid derivatives as innovative fillers

Claims

1. Hyaluronic acids cross-linked with activated derivatives of plant polyphenols selected from polydatin, gallic acid, chlorogenic acid, ellagic acid and phloridzin.

2. Cross-linked hyaluronic acids according to claim 1, wherein the activated derivatives of plant polyphenols are glycidyl ethers (oxiran-2-yl-methyl ethers) or 2-chloroacetyl esters.

3. Cross-linked hyaluronic acids according to claim 2, wherein the activated derivative is selected from diglycidylated polydatin, hexa-chloroacetylpolydatin, a mixture of mono-, di-, tri- and tetra-2-chloroacetyl esters of polydatin, 3,4,5-tris(2-chloroacetyl) esters of gallic acid, oxiran-2-ylmethyl-3,4,5-tris(oxiran-2-ylmethoxy)benzoate, hepta-2-chloroacetyl derivative of phlorizin, penta-chloroacetyl derivative of chlorogenic acid, oxiran-2-ylmethyl-3,4,5-tris(oxiran-2-ylmethoxy)benzoate, 3,4,5-tris(2-chloroacetoxy)benzoic acid.

4. Cross-linked hyaluronic acids according to claim 3, wherein the activated derivatives are glycidyl esters or 2-chloroacetyl esters of polydatin or gallic acid.

5. Cross-linked hyaluronic acids according to claim 3, wherein the relative molar ratio of mono-, di-, tri- and tetra-2-chloroacetyl esters of polydatin is 17±3.4% / 44.3±8.8% / 17.7±3.6% / 1.9±0.4%.

6. Cross-linked hyaluronic acids according to any one of claims 1-5, obtained from hyaluronic acid having an average molecular weight Mn of 80-110 kDa.

7. Cross-linked hyaluronic acids according to any one of claims 1-5, obtained from hyaluronic acid having an average molecular weight Mn of 250-450 kDa.

8. Cross-linked hyaluronic acids according to any one of claims 1-5, obtained from hyaluronic acid having an average molecular weight Mn of 1.5-3.0 MDa.

9. Cross-linked hyaluronic acids according to one or more claims 1-8, having a degree of cross-linking such that the ratio of the viscosity modulus (G'') to the elastic modulus (G') is less than 1.

0.

10. A method for producing cross-linked hyaluronic acids according to any one of claims 1 to 9, comprising reacting cross-linked hyaluronic acid in an aqueous solution with activated derivatives of plant polyphenols in a dimethyl sulfoxide solution at a temperature in the range from 30 to 80°C, preferably from 50 to 80°C.

11. The method according to claim 10, wherein the molar ratio of the activated polyphenol derivative to hyaluronic acid is in the range from 1:1 to 1:

10.

12. Intradermal or intra-articular injection compositions in the form of sterile gels containing cross-linked hyaluronic acids according to any one of claims 1 to 9.

13. Injectable compositions according to claim 12, containing a mixture of cross-linked hyaluronic acids of different molecular weights.

14. Injectable compositions according to claim 13, containing cross-linked hyaluronic acids according to any one of claims 6, 7 and 8.

15. Injectable compositions according to any one of claims 12 to 14, containing from 1 mg / ml to 50 mg / ml of cross-linked hyaluronic acids, optionally in the presence of an anesthetic, preferably lidocaine, at a concentration of 0.1 to 0.4% w / v.

16. The compound (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(3-(oxiran-2-ylmethoxy)-5-((E)-4-(oxiran-2-ylmethoxy)styryl)phenoxy)tetrahydro-2H-pyran-3,4,5-triol of the formula:

17. Hexa-2-chloroacetyl-polydatin of the formula:

18. Hepta-2-chloroacetyl-phlorizin formula:

19. Penta-2-chloroacetyl-chlorogenic acid formula: