Cross-linked esters of hyaluronic acid

• US 4,957,744 A
• Filed: 10/13/1987
• Issued: 09/18/1990
• Est. Priority Date: 10/13/1986
• Status: Expired due to Term

• Current Assignee: Fidia S.P.A.
• Original Assignee: Fidia S.P.A.
• Inventors: Romeo, Aurelio, della Valle, Francesco
• Primary Examiner(s): Rollins, John W.
• Assistant Examiner(s): Peselev, Elli
• Application Number:
  US07/106,658
• Time in Patent Office: 1,071 Days
• Field of Search: 536/55.1, 514/54, 424/423, 424/443, 424/489, 424/401
• US Class Current: 424/401
• CPC Class Codes: A61F 13/00 Bandages or dressings radioactive dressings A61N5/1029; Absorbent pads
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• 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 8/735 Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• CPC Class Codes: A61L 15/28 Polysaccharides or their derivatives A61L15/225 takes precedence
• CPC Class Codes: A61L 17/10 containing macromolecular materials
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• 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: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

Cross-linked esters of hyaluronic acid are provided which result from the esterification of polyhydric alcohols with two or more carboxy groups of the hyaluronic acid polysaccharide. These cross-linked esters are useful in the field of biodegradable plastics for sanitary and surgical articles and in the pharmaceutical and cosmetic fields for the preparation of useful compositions and articles.

Claims

1. Total or partial cross-linked esters of hyaluronic acid with an aliphatic polyhydric alcohol, and salts of such partial esters with inorganic or organic bases, with the proviso that said cross-linked ester is not the cross-linked ester of hyaluronic acid with an alomethyloxirane or a bisepoxy compound

2. Cross-linked esters according to claim 1, wherein said aliphatic polyhydric alcohol is a dihydric alcohol.

3. Cross-linked esters according to claim 1, wherein said aliphatic polyhydric alcohol has between 2 and 16 carbon atoms.

4. Cross-linked esters according to claim 2, wherein said dihydric alcohol is a member selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, glycols derived from pentane, hexane, heptane and octane, and positional isomers thereof.

5. Cross-linked esters according to claim 1, wherein said aliphatic polyhydric alcohol is a member selected from the group consisting of glycerine, erythrite and pentaer/thrite.

6. Cross-linked esters according to claim 1, wherein at least one non-cross-linked carboxy group in said hyaluronic acid is esterified with an aliphatic alcohol having a maximum of 34 carbon atoms and wherein said aliphatic alcohol may be unsubstituted or substituted by one or two functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehyde, keto, carboxy, hydrocarbyl and dihydrocarbylamino groups, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy, carbamidic and substituted carbamidic groups substituted by one or two alkyl groups, the hydrocarbyl radicals in these functionally modified groups having a maximum of 6 carbon atoms, and in which such aliphatic alcohols may be interrupted in the carbon atom chain by heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen.

7. Cross-linked esters according to claim 6, wherein said aliphatic alcohol is ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl alcohols, an amyl, pentyl, hexyl or octyl alcohol.

8. Cross-linked esters according to claim 1, wherein at least one non-cross-linked carboxy group in said hyaluronic acid is esterified with an araliphatic alcohol having only be benzene residue and in which the aliphatic chain has a maximum of 4 carbon atoms and in which the benzene residue may be substituted with between 1 and 3 methyl or hydroxy groups or with halogen atoms, and in which the aliphatic chain may be substituted with one or two functional groups selected from the group consisting of free- or mono- or diethyl amino groups, pyrrolidine and piperidine groups.

9. Cross-linked esters according to claim 1, wherein at least one non-cross-linked carboxy group in said hyaluronic acid is esterified with a cycloaliphatic alcohol or aliphatic-cycloaliphatic alcohol or heterocyclic alcohol which derives from a mono- or polycyclic carbohydrate with a maximum of 34 carbon atoms and is unsubstituted or substituted by one or more functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehyde, keto, carboxy, hydrocarbyl- and dihydrocarbylamino groups, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy, carbamidic and substituted carbamidic groups, by one or two alkyl groups, the hydrocarbyl radicals in these functionally modified groups having a maximum of 6 carbon atoms, and may be int errupted in the carbon atom chain by heteroatoms chosen from the group formed by oxygen, nitrogen and sulfur, and may have one or more aromatic bonds.

10. Cross-linked esters according to claim 9, wherein at least one of said non-cross-linked carboxy groups is esterified with an alcohol selected from the group consisting of cortisone, hydrocortisone, prednisone, prednisolone, fluorocortisone, dexamethasone, betamethasone, corticosterone, deoxysicorticosterone, paramethasone, flumethasone, flucinolone and its acetonide, fluprednylidene, clobetasol and beclomethasone.

11. Salts of partial esters according to claim 1, wherein said salt is a salt of said cross-linked ester with an alkaline or alkaline earth metal, magnesium or aluminum.

12. A sodium or ammonium salt of a cross-linked ester according to claim 11.

13. Salts of partial esters according to claim 1, wherein said salt is a salt of said partial cross-linked ester with ammonium, or with an aliphatic, araliphatic, cycloaliphatic or heterocyclic amine.

14. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 1 together with a pharmaceutically acceptable carrier, excipient or diluent.

15. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 1 as a vehicle, in admixture with a pharmacologically active agent.

16. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 8, wherein said alcohol esterified with said non-cross-linked carboxy group is a pharmacologically active alcohol.

17. A cosmetic article comprising as an active ingredient an effective amount of a cross-linked ester or a salt thereof according to claim 1.

18. A cosmetic article comprising as a cosmetic vehicle a cross-linked ester or a salt thereof according to claim 1.

19. A sanitary, medical or surgical article comprising a cross-linked ester or a salt thereof according to claim 1.

20. A sanitary, medical or surgical article according to claim 19, comprising a film of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

21. A sanitary, medical or surgical article according to claim 19 comprising threads of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

22. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 1.

23. A cross-linked ester of hyaluronic acid according to claim 1, wherein said ester is a total cross-linked ester.

24. A cross-linked ester of hyaluronic acid according to claim 2, wherein said ester is a total cross-linked ester.

25. A cross-linked ester of hyaluronic acid according to claim 4, wherein said ester is a total cross-linked ester.

26. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 2, together with a pharmaceutically acceptable carrier, excipient or diluent.

27. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 4, together with a pharmaceutically acceptable carrier, excipient or diluent.

28. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 5, together with a pharmaceutically acceptable carrier, excipient or diluent.

29. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 6, together with a pharmaceutically acceptable carrier, excipient or diluent.

30. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 7, together with a pharmaceutically acceptable carrier, excipient or diluent.

31. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 8, together with a pharmaceutically acceptable carrier, excipient or diluent.

32. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 9, together with a pharmaceutically acceptable carrier, excipient or diluent.

33. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 10, together with a pharmaceutically acceptable carrier, excipient or diluent.

34. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 11, together with a pharmaceutically acceptable carrier, excipient or diluent.

35. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 12, together with a pharmaceutically acceptable carrier, excipient or diluent.

36. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 13, together with a pharmaceutically acceptable carrier, excipient or diluent.

37. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 23, together with a pharmaceutically acceptable carrier, excipient or diluent.

38. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 24, together with a pharmaceutically acceptable carrier, excipient or diluent.

39. A pharmaceutical composition comprising an effective amount of a cross-linked ester according to claim 25, together with a pharmaceutically acceptable carrier, excipient or diluent.

40. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 1, together with a pharmaceutically acceptable carrier, excipient, or diluent.

41. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 2, together with a pharmaceutically acceptable carrier, excipient, or diluent.

42. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 4, together with a pharmaceutically acceptable carrier, excipient, or diluent.

43. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 5, together with a pharmaceutically acceptable carrier, excipient, or diluent.

44. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 6, together with a pharmaceutically acceptable carrier, excipient, or diluent.

45. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 7, together with a pharmaceutically acceptable carrier, excipient, or diluent.

46. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 8, together with a pharmaceutically acceptable carrier, excipient, or diluent.

47. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 9, together with a pharmaceutically acceptable carrier, excipient, or diluent.

48. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 10, together with a pharmaceutically acceptable carrier, excipient, or diluent.

49. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 11, together with a pharmaceutically acceptable carrier, excipient, or diluent.

50. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 12, together with a pharmaceutically acceptable carrier, excipient, or diluent.

51. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 13, together with a pharmaceutically acceptable carrier, excipient, or diluent.

52. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 23, together with a pharmaceutically acceptable carrier, excipient, or diluent.

53. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 24, together with a pharmaceutically acceptable carrier, excipient, or diluent.

54. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 25, together with a pharmaceutically acceptable carrier, excipient, or diluent.

55. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to claim 1 as a vehicle, in admixture with a pharmacologically active agent.

56. A pharmaceutical composition which comprises from 10 to 90% of a cross-linked ester according to any one of claim 2, 4-10, 11-13 and 23, 25, in admixture with a pharmacologically active agent.

57. A pharmaceutical composition which comprises from 10-90% by weight of a cross-linked ester according to claim 8, wherein said alcohol esterified with said non-cross-linked carboxy group is a pharmacologically active alcohol.

58. A cosmetic article which comprises as an active ingredient from 5-50% by weight of a cross-linked ester or a salt thereof according to claim 1.

59. A cosmetic article which comprises as an active ingredient from 5-50% by weight of a cross-linked ester or a salt thereof according to claim 2.

60. A cosmetic article which comprises as an active ingredient from 5-50% by weight of a cross-linked ester or a salt thereof according to claim 4.

61. A cosmetic article which comprises as an active ingredient from 5-50% by weight of a cross-linked ester or a salt thereof according to claim 5.

62. A cosmetic article which comprises as an active ingredient from 5-50% by weight of a cross-linked ester or a salt thereof according to claim 7.

63. A cosmetic article which comprises as an active ingredient from 5-50% by weight of a cross-linked ester or a salt thereof according to claim 10.

64. A cosmetic article which comprises as an active ingredient from 5-50% by weight of a cross-linked ester or a salt thereof according to claim 23.

65. A cosmetic article which comprises as an active ingredient from 5-50% by weight of a cross-linked ester or a salt thereof according to claim 24.

66. A cosmetic article which comprises as an active ingredient from 5-50% by weight of a cross-linked ester or a salt thereof according to claim 25.

67. A cosmetic article comprising as a cosmetic vehicle a cross-linked ester or a salt thereof according to claim 2.

68. A cosmetic article comprising as a cosmetic vehicle a cross-linked ester or a salt thereof according to claim 4.

69. A cosmetic article comprising as a cosmetic vehicle a cross-linked ester or a salt thereof according to claim 23.

70. A cosmetic article comprising as a cosmetic vehicle a cross-linked ester or a salt thereof according to claim 24.

71. A sanitary, medical or surgical article comprising a cross-linked ester or a salt thereof according to claim 2.

72. A sanitary, medical or surgical article comprising a cross-linked ester or a salt thereof according to claim 4.

73. A sanitary, medical or surgical article comprising a cross-linked ester or a salt thereof according to claim 23.

74. A sanitary, medical or surgical article comprising a cross-linked ester or a salt thereof according to claim 24.

75. A sanitary, medical or surgical article according to claim 2, comprising a film of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

76. A sanitary, medical or surgical article according to claim 4, comprising a film of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

77. A sanitary, medical or surgical article according to claim 23, comprising a film of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

78. A sanitary, medical or surgical article according to claim 24, comprising a film of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

79. A sanitary, medical or surgical article according to claim 2 comprising threads of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

80. A sanitary, medical or surgical article according to claim 4 comprising threads of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

81. A sanitary, medical or surgical article according to claim 23 comprising threads of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

82. A sanitary, medical or surgical article according to claim 24 comprising threads of a cross-linked ester wherein said aliphatic polyhydric alcohol is a therapeutically inert alcohol.

83. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 2.

84. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 4.

85. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 7.

86. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 8.

87. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 9.

88. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 10.

89. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 23.

90. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 24.

91. A capsule or microcapsule for medicaments comprising a cross-linked ester or a salt thereof according to claim 25.