Bioactive thermogelling polymer systems and methods of their use

• US 8,110,212 B2
• Filed: 04/07/2006
• Issued: 02/07/2012
• Est. Priority Date: 04/07/2005
• Status: Expired due to Fees

• Current Assignee: Drexel University
• Original Assignee: Drexel University
• Inventors: Marcolongo, Michele Staud, Lowman, Anthony M., Ho, Emily Y.
• Primary Examiner(s): Harlan, Robert D.
• Application Number:
  US11/910,494
• Publication Number:
  US 20090269384A1
• Time in Patent Office: 2,132 Days
• Field of Search: 424/423, 523/116, 514/772.4
• US Class Current: 424/423
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• CPC Class Codes: A61F 2/44 for the spine, e.g. vertebrae, spinal discs
• CPC Class Codes: A61F 2002/30075 swellable, e.g. when wetted
• CPC Class Codes: A61F 2002/444 for replacing the nucleus pulposus
• CPC Class Codes: A61F 2210/0061 swellable
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: C04B 2111/00836 for medical or dental applications
• CPC Class Codes: C04B 22/124 Chlorides of ammonium or of the alkali or alkaline earth metals, e.g. calcium chloride
• CPC Class Codes: C04B 22/16 containing phosphorus in the anion, e.g. phosphates
• CPC Class Codes: C04B 2201/10 for the viscosity
• CPC Class Codes: C04B 24/2623 Polyvinylalcohols; Polyvinylacetates
• CPC Class Codes: C04B 24/2641 Polyacrylates; Polymethacrylates
• CPC Class Codes: C04B 24/2647 containing polyether side chains
• CPC Class Codes: C04B 24/2652 Nitrogen containing polymers, e.g. polyacrylamides, polyacrylonitriles
• CPC Class Codes: C04B 24/32 Polyethers, e.g. alkylphenol polyglycolether
• CPC Class Codes: C04B 24/42 Organo-silicon compounds
• CPC Class Codes: C04B 26/04 obtained by reactions only involving carbon-to-carbon unsaturated bonds

Abstract

Hydrogels comprising poly(N-alkylacrylamide), poly(alkyleneglyco)di-acrylate or methacrylate, cross-linking agent, a source of calcium ions, and water are described, as well as methods of their preparation and use.

Claims

1. A hydrogel comprising:

poly(N-alkylacrylamide),

poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate,

cross-linking agent,

a source of calcium ions, and

water.

2. A hydrogel according to claim 1 wherein the poly(N-alkylacrylamide) is poly(N-isopropylacrylamide).

3. A hydrogel according to claim 1 wherein the poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate is poly(ethyleneglycol)dimethacrylate or poly(propyleneglycol)dimethacrylate.

4. A hydrogel according to claim 1 wherein the cross-linking agent is an acrylo-siloxane.

5. A hydrogel according to claim 1 wherein the cross-linking agent is an acryloxy- or methacryloxyalkylpolyalkoxysilane.

6. A hydrogel according to claim 1 wherein the cross-linking agent is 3-methacryloxypropyltrimethoxysilane.

7. A hydrogel according to claim 1 wherein the source of calcium ions is calcium chloride, calcium bromide, or calcium phosphate.

8. A hydrogel according to claim 1 wherein the source of calcium ions and cross-linking agent are present in a molar ratio of between about 1:

1 to about 3;

1.

9. A hydrogel according to claim 1 wherein the source of calcium ions and cross-linking agent are present in a molar ratio of about 2:

1.

10. A hydrogel according to claim 1 further comprising at least one calcium-binding component.

11. A hydrogel according to claim 10 wherein the calcium-binding component is poly(acrylic acid), acrylic acid, poly(methacrylic acid), methacrylic acid, or mixtures thereof, an amount of up to about 10% by weight.

12. A hydrogel according to claim 1 further comprising methyl methacrylate, poly(methyl methacrylate), vinyl acetate, poly(vinyl acetate), or mixtures thereof.

13. A hydrogel according to claim 12 wherein the methyl methacrylate, poly(methyl methacrylate), vinyl acetate, poly(vinyl acetate), or mixtures thereof are present in an amount of up to about 25% by weight.

14. A hydrogel according to claim 1 further comprising a medicament, an osteoclastic inhibitor, a pain reliever, or a chemotherapeutic agent, or mixtures thereof.

15. A hydrogel according to claim 1 further comprising radiopacifiers, radiomarkers, or radiopaque material.

16. A hydrogel according to claim 1 further comprising about 65-85 weight percent of water.

17. A hydrogel according to claim 1 further comprising about 75 weight percent of water.

18. A hydrogel according to claim 1 having an equilibrium viscosity of about 75-125 Poise.

19. A hydrogel according to claim 1 having an equilibrium viscosity of about 115-125 Poise.

20. A hydrogel according to claim 1 having an equilibrium viscosity of about 118 Poise.

21. A hydrogel according to claim 1 having an equilibrium viscosity of about 75-90 Poise.

22. A hydrogel according to claim 1 having an equilibrium viscosity of about 83 Poise.

23. A hydrogel according to claim 1 having an elastic modulus of about 0.5-0.9 MPa.

24. A hydrogel according to claim 1 having an elastic modulus of about 0.7 MPa.

25. A hydrogel according to claim 1, said hydrogel being prepared using N-alkylacrylamide.

26. A hydrogel according to claim 25 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of from about 250:

1 to about 150;

1 by weight.

27. A hydrogel according to claim 25 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of about 200:

1 by weight.

28. A hydrogel according to claim 25 wherein the cross-linking agent and N-alkylacrylamide are present in a molar ratio of up to about 0.01.

29. A hydrogel according to claim 25 wherein the molar ratio of cross-linking agent:

N-alkylacrylamide is between about 0.0005 and 0.01.

30. A hydrogel according to claim 25 wherein the molar ratio of cross-linking agent:

N-alkylacrylamide is about 0.0005.

31. A hydrogel according to claim 25 wherein the molar ratio of cross-linking agent:

N-alkylacrylamide is about 0.0075.

32. A hydrogel according to claim 25 wherein the molar ratio of cross-linking agent:

N-alkylacrylamide is about 0.005.

33. A hydrogel according to claim 25 wherein the molar ratio of cross-linking agent:

N-alkylacrylamide is about 0.003.

34. A hydrogel according to claim 25 wherein the molar ratio of cross-linking agent:

N-alkylacrylamide is about 0.001.

35. A hydrogel according to claim 25 wherein the molar ratio of cross-linking agent:

N-alkylacrylamide is about 0.01 fracture a hydrogel according to claim 1.

36. A method of reinforcing a vertebral bone structure comprising injecting into the vicinity of the bone structure a hydrogel according to claim 1.

37. A method of resurfacing an articulating joint comprising providing to the joint a hydrogel according to claim 1.

38. A method of preparing a hydrogel comprising:

(a) providing a mixture of N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate in a solvent to form a first mixture;

(b) adding a cross-linking agent, a source of calcium ions, and an initiator to the first mixture to form a second mixture;

(c) polymerizing the second mixture for a time and at a temperature sufficient to cause polymerization to form a polymer;

(d) drying the polymer;

(e) pulverizing the polymer to form a powder; and

(f) adding water to the powder.

39. The method of claim 38 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of from about 250:

1 to about 150;

1 by weight.

40. The method of claim 38 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of about 200:

1 by weight.

41. The method of claim 38 wherein the N-alkylacrylamide is N-isopropylacrylamide.

42. The method of claim 38 wherein the poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate is poly(ethyleneglycol)dimethacrylate or poly(propyleneglycol)dimethacrylate.

43. The method of claim 38 wherein the source of calcium ions is calcium chloride, calcium bromide, or calcium phosphate present in a molar ratio of about 2:

1.

44. The method of claim 38 wherein the cross-linking agent is an acrylo-siloxane.

45. The method of claim 38 wherein the cross-linking agent is an acryloxy- or methacryloxyalkylpolyalkoxysilane.

46. The method of claim 38 wherein the cross-lining agent is 3-methacryloxypropyltrimethoxysilane.

47. A method of repairing a vertebral fracture comprising injecting into the vicinity of the fracture a hydrogel comprising:

poly(N-alkylacrylamide),

poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate,

cross-linking agent,

a source of calcium ions, and

water.

48. The method of claim 47 wherein the poly(N-alkylacrylamide) is poly(N-isopropylacrylamide).

49. The method of claim 47 wherein the poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate is poly(ethyleneglycol)dimethacrylate.

50. The method of claim 47 wherein the poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate is poly(propyleneglycol)dimethacrylate.

51. The method of claim 47 wherein the source of calcium ions is calcium chloride, calcium bromide, or calcium phosphate.

52. The method of claim 47 wherein the source of calcium ions and cross-linking agent are present in a molar ratio of about 2:

1.

53. The method of claim 47 wherein the cross-linking agent is an acrylo-siloxane.

54. The method of claim 47 wherein the cross-linking agent is an acryloxy- or methacryloxyalkylpolyalkoxysilane, methacryloxypropyltrimethoxysilane.

55. The method of claim 47, said hydrogel being prepared using N-alkylacrylamide.

56. The method of claim 55 wherein the N-alkylacrylamide is N-isopropylacrylamide.

57. The method of claim 55 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of from about 250:

1 to about 150;

1 by weight.

58. The method of claim 55 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of about 200:

1 by weight.

59. The method of claim 55 wherein the cross-linking agent and N-alkylacrylamide are present in a molar ratio of up to about 0.01.

60. A method of reinforcing a vertebral bone structure comprising injecting into the vicinity of the bone structure a hydrogel comprising:

poly(N-alkylacrylamide),

poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate,

cross-linking agent,

a source of calcium ions, and

water.

61. The method of claim 60 wherein the poly(N-alkylacrylamide) is poly(N-isopropylacrylamide).

62. The method of claim 60 wherein the poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate is poly(ethyleneglycol)dimethacrylate.

63. The method of claim 60 wherein the poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate is poly(propyleneglycol)dimethacrylate.

64. The method of claim 60 wherein the source of calcium ions is calcium chloride, calcium bromide, or calcium phosphate.

65. The method of claim 60 wherein the source of calcium ions and cross-linking agent are present in a molar ratio of about 2:

1.

66. The method of claim 60 wherein the cross-linking agent is an acryloxy- or methacryloxyalkylpolyalkoxysilane.

67. The method of claim 60 wherein the cross-linking agent is 3-methacryloxypropyltrimethoxysilane.

68. The method of claim 60, said hydrogel being prepared using N-alkylacrylamide.

69. The method of claim 68 wherein the N-alkylacrylamide is N-isopropylacrylamide.

70. The method of claim 68 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of from about 250:

1 to about 150;

1 by weight.

71. The method of claim 68 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of about 200:

1 by weight.

72. The method of claim 68 wherein the cross-linking agent and N-alkylacrylamide are present in a molar ratio of up to about 0.01.

73. A method of resurfacing an articulating joint comprising providing to the joint a hydrogel comprising:

poly(N-alkylacrylamide),

poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate,

cross-linking agent,

a source of calcium ions, and

water.

74. The method of claim 73 wherein the poly(N-alkylacrylamide) is poly(N-isopropylacrylamide).

75. The method of claim 73 wherein the poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate is poly(ethyleneglycol)dimethacrylate.

76. The method of claim 73 wherein the poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate is poly(propyleneglycol)dimethacrylate.

77. The method of claim 73 wherein the source of calcium ions and cross-linking agent are present in a molar ratio of about 2:

1.

78. The method of claim 73 wherein the cross-linking agent is an acrylo-siloxane.

79. The method of claim 73 wherein the cross-linking agent is an acryloxy- or methacryloxyalkylpolyalkoxysilane.

80. The method of claim 73 wherein the cross-linking agent is 3-methacryloxypropyltrimethoxysilane.

81. The method of claim 73, said hydrogel being prepared using N-alkylacrylamide.

82. The method of claim 81 wherein the N-alkylacrylamide is N-isopropylacrylamide.

83. The method of claim 81 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of from about 250:

1 to about 150;

1 by weight.

84. The method of claim 81 wherein the N-alkylacrylamide and poly(alkyleneglycol)di-acrylate or poly(alkyleneglycol)di-methacrylate are present in a ratio of about 200:

1 by weight.

85. The method of claim 81 wherein the cross-linking agent and N-alkylacrylamide are present in a molar ratio of up to about 0.01.