Cross-linked fatty acid-based biomaterials

• US 9,000,040 B2
• Filed: 02/03/2009
• Issued: 04/07/2015
• Est. Priority Date: 09/28/2004
• Status: Expired due to Fees

• Current Assignee: Atrium Medical Corporation (Getinge AB)
• Original Assignee: Atrium Medical Corporation (Getinge AB)
• Inventors: Faucher, Keith M., Tang, Hui, Martakos, Paul, Herweck, Steve A., Karwoski, Theodore, Corbeil, Scott E., Sullivan, Allison, Melville, Greg
• Primary Examiner(s): Basquill, Sean
• Assistant Examiner(s): Rosenthal, Andrew S
• Application Number:
  US12/364,763
• Publication Number:
  US 20090208552A1
• Time in Patent Office: 2,254 Days
• Field of Search: 514/558
• US Class Current: 514/558
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61K 31/4353 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2420/06 Coatings containing a mixture of two or more compounds
• CPC Class Codes: A61L 2430/00 Materials or treatment for tissue regeneration
• CPC Class Codes: A61L 31/08 Materials for coatings
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Fatty acid-based, pre-cure-derived biomaterials, methods of making the biomaterials, and methods of using them as drug delivery carriers are described. The fatty acid-derived biomaterials can be utilized alone or in combination with a medical device for the release and local delivery of one or more therapeutic agents. Methods of forming and tailoring the properties of said biomaterials and methods of using said biomaterials for treating injury in a mammal are also provided.

Claims

1. A coating for a medical device, comprising:

fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds, and a therapeutic agent, wherein the fatty acids are partially cross-linked to each other by one or more of ester bonds or lactone bonds before association with the therapeutic agent, and wherein the coating hydrolyzes in vivo.

2. The coating of claim 1, wherein the therapeutic agent is contained within the coating in such a manner that the therapeutic agent has an enhanced release profile.

3. The coating of claim 1, further comprising pre-cured glyceride.

5. The coating of claim 1, wherein the oil comprises 5-25% C₁₄ fatty acids.

6. The coating of claim 1, wherein the oil comprises 5-30% C₁₆ fatty acids.

20. The coating of claim 1, wherein the coating comprises approximately 30-90% saturated fatty acids.

21. The coating of claim 1, wherein the coating comprises approximately 30-80% unsaturated fatty acids.

22. The coating of claim 1, wherein the coating further comprises a glyceride.

23. The coating of claim 1, wherein the coating further comprises one or more of the group consisting of a glyceride, a glycerol, and a fatty alcohol, any of which can be partially cross-linked.

24. The coating of claim 1, further comprising vitamin E.

25. The coating of claim 1, wherein the coating is associated with an implantable device.

26. The coating of claim 1, wherein the coating is associated with a medical device, and the medical device is a stent, a catheter, a surgical mesh, or a balloon.

27. The coating of claim 1, wherein the therapeutic agent is an anti-proliferative drug, an anti-inflammatory agent, an antimicrobial agent or antibiotic agent.

28. The coating of claim 1, wherein the therapeutic agent is Compound A, Compound B, Compound C, Compound D, Compound E, a cyclosporine derivative or rapamycin derivative.

29. The coating of claim 1, wherein the coating has a release profile of the therapeutic agent in 0.01 M phosphate buffered saline (PBS) out to about 5-20 days.

30. The coating of claim 1, wherein the coating releases the therapeutic agent at a desired release rate in vivo.

31. The coating of claim 1, wherein the coating has a release profile of the therapeutic agent in 0.01 M phosphate buffered saline (PBS) out to more than 20 days.

32. The coating of claim 1, wherein the coating comprises approximately 10-20% C₁₄ saturated fatty acids and approximately 25-50% C₁₆ saturated fatty acids.

33. The coating of claim 1, wherein the coating comprises lactone cross links and ester cross links.

34. The coating of claim 1, wherein the coating contains disordered hydrocarbon chains as determined by infrared absorption and X-ray diffraction.

35. The coating of claim 1, wherein the coating does not contain a cross-linking agent.

36. The coating of claim 1, wherein the coating hydrolyzes in vivo into fatty acids, glycerols, and glycerides.

37. The coating of claim 1, wherein the coating hydrolyzes in vivo into non-inflammatory components.

38. The coating of claim 1, wherein the coating contains an amount of carboxylic acid groups sufficient to facilitate hydrolysis in vivo.

39. The coating of claim 1, wherein the coating comprises approximately 50-90% saturated fatty acids.

40. The coating of claim 1, wherein the coating comprises approximately 10-50% unsaturated fatty acids.

41. The coating of claim 1, wherein the coating further comprises a glyceride.

42. The coating of claim 1, wherein the coating further comprises one or more of the group consisting of a glyceride, a glycerol, and a fatty alcohol, any of which can be partially cross-linked.

43. The coating of claim 1, wherein the source of the fatty acids is an oil.

44. The coating of claim 43, wherein the oil is a fish oil, olive oil, grape oil, palm oil, or flaxseed oil.

45. The coating of claim 43, wherein the oil is a fish oil.

88. The coating of claim 1, wherein the coating is formed from one or more of eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), or alpha-linolenic acid (ALA).

4. A fatty-acid based, pre-cure-derived coating for a medical device, comprising:

one or more therapeutic agents and fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds, wherein the fatty acids are partially cross-linked to each other by one or more of ester bonds or lactone bonds before association with the therapeutic agent, wherein the fatty acids comprise approximately 5-50% C₁₆ fatty acids, and wherein the coating hydrolyzes in vivo.

19. The coating of claim 4, wherein the coating hydrolyzes in vivo substantially into one or more of free fatty acids, glycerides, or glycerols.

7. A fatty-acid based, pre-cure-derived coating for a medical device comprising a therapeutic agent and fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds, wherein the fatty acids comprise approximately 5-25% C₁₄ fatty acids and 5-50% C₁₆ fatty acids, and wherein the coating hydrolyzes in vivo.

8. A fatty-acid based, pre-cure-derived coating for a medical device comprising fatty acids and glycerides, wherein the fatty acids are cross-linked to each other by one or more of ester bonds or lactone bonds, wherein the fatty acids and glycerides have disordered alkyl groups, which cause the coating to be flexible and hydratable, and wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerols, or glycerides.

9. A fatty-acid based, pre-cure-derived coating for a medical device comprising a fatty acid-derived biomaterial, wherein the fatty acid-derived biomaterial comprises fatty acids and glycerides, wherein the fatty acids are cross-linked to each other by one or more of ester bonds or lactone bonds, and wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerols, or glycerides.

10. A fatty-acid based, pre-cure-derived coating for a medical device, wherein the coating comprises fatty acids and glycerides, wherein the fatty acids are cross-linked to each other by one or more of lactone bonds or ester bonds, as indicated by an infrared absorption spectrum having a peak from approximately 1740-1850cm⁻

1, and wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerols, or glycerides.

11. A fatty-acid based, pre-cure-derived coating for a medical device, comprising a cross-linked, fatty acid-derived biomaterial, wherein approximately 60-90% of the biomaterial is constituted by fatty acids with molecular weights below 500, wherein the coating comprises fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds, and wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerols, or glycerides.

12. A fatty-acid based, pre-cure-derived biomaterial suitable for achieving modulated healing in a tissue region in need thereof, wherein the biomaterial is administered in an amount sufficient to achieve the modulated healing, wherein the modulated healing comprises a modulation of platelet or fibrin deposition in or near the tissue region, wherein the biomaterial comprises one or more fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds, and wherein the biomaterial hydrolyzes in vivo into one or more of free fatty acids, glycerols, or glycerides.

13. The biomaterial of claim 12, wherein the tissue region is the vasculature of a subject.

18. The fatty-acid based, pre-cure-derived biomaterial of claim 12 or 14, wherein the biomaterial is administered to the region in need thereof via a catheter, balloon, stent, surgical mesh, surgical dressing, or graft.

14. A fatty-acid based, pre-cure-derived biomaterial suitable for achieving modulated healing at a site of vascular injury in need thereof, wherein the biomaterial is formed from one or more of eicosapentaenoic acid (EPA), docosahexanoic acid (DHA) or alpha-linolenic acid (ALA), wherein the biomaterial comprises fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds, wherein the biomaterial is administered in an amount sufficient to achieve the modulated healing, wherein the modulated healing comprises a modulation of at least one metric of organized tissue repair and wherein the biomaterial hydrolyzes in vivo into one or more of fatty acids, glycerols, or glycerides.

15. The fatty-acid based, pre-cure-derived biomaterial of claim 14, wherein the vascular healing is the inflammatory stage of vascular healing.

16. The fatty-acid based, pre-cure-derived biomaterial of claim 14, wherein the organized tissue repair comprises platelet or fibrin deposition at the site of vascular injury.

17. The fatty-acid based, pre-cure-derived biomaterial of claim 14, wherein the modulation of at least one metric of organized tissue repair is a delay in the healing process at a site of vascular injury.

46. A preparation for deriving a coating for a medical device, the preparation comprising:

fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds, wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerides, or glycerols, and wherein a portion of the preparation comprises a pre-cured natural oil.

47. The preparation of claim 46, further comprising a therapeutic agent.

48. The preparation of claim 46, wherein the preparation has a viscosity of about 1.0×

10⁵ to about 1.0×

10⁷ cps.

49. The preparation of claim 46, wherein the preparation is further dissolved in an organic solvent.

50. A method for producing a fatty-acid based, pre-cure-derived coating for a medical device, wherein the method comprises:

curing an oil-containing starting material according to a first curing condition to form a second material comprising partially cross-linked fatty acids and glycerides, wherein the fatty acids and glycerides are cross-linked to each other by one or more of ester bonds or lactone bonds;

combining a therapeutic agent with the second material to form a third material; and

curing the third material such that a coating is produced;

wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerides, or glycerols.

51. The method of claim 50, wherein the therapeutic agent is combined with an oil-containing material or organic solvent before combining with the second material.

52. The method of claim 50, wherein the curing temperature of the first curing condition and/or total curing duration exceed the degradation temperature of the therapeutic agent.

53. The method of claim 50, wherein the first curing condition results in appreciable formation of esters and lactones in the oil such that substantial cross linking of fatty acids occurs during the second curing condition.

54. The method of claim 50, wherein the curing temperature and duration is adjusted to tailor the release profile of the therapeutic agent.

55. The method of claim 50, wherein vitamin E is added to the second material.

56. The method of claim 50, wherein the third material is combined with an organic solvent, and applied to a medical device before curing to form a conformal coating.

57. The method of claim 50, wherein the third material is sprayed on a medical device before curing to form a coating.

58. The method of claim 50, wherein the oil-containing starting material is fish oil.

59. The method of claim 50, wherein the medical device is a stent, a catheter, a surgical mesh or a balloon.

60. The second material for use in a fatty-acid based, pre-cure derived coating produced by the method of claim 50.

61. The second material of claim 60, wherein the second material has a viscosity of about 1.0×

10⁵ to about 1.0×

10⁷ cps.

62. The non-polymeric coating produced by the method of claim 50.

63. The method of claim 50, wherein the therapeutic agent is an anti-proliferative drug.

64. The method of claim 50, wherein the therapeutic agent is an anti-inflammatory agent.

65. The method of claim 56, wherein:

the first curing condition is tailored such that the second material, when applied to a medical device, provides a non-conformal coating on the medical device; and

wherein the second curing condition is tailored such that the third material, when applied to a coating, provides a conformal coating.

66. The method of claim 50 wherein the curing time for the first curing condition can be substantially increased in order to reduce the curing time required for the second curing condition to obtain desired mechanical properties of the final coating.

67. The method of claim 50 wherein the curing time for the first curing condition can be substantially increased in order to reduce the curing time required for the second curing condition to obtain desired mechanical properties and preserve a thermally sensitive drug to the final coating.

68. A fatty-acid based, pre-cure-derived coating for a medical device, the coating comprising:

a hydrophobic, non-polymeric cross-linked fish oil comprising fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds; and

a therapeutic agent;

wherein the coating can coating can withstand 16-22 psi of compressive force; and

wherein the coating hydrolyzes in vivo.

69. The fatty-acid based, pre-cure-derived coating of claim 68, wherein the coating hydrolyzes in vivo into one or more of fatty acids, glycerols, or glycerides.

70. A fatty-acid based, pre-cure-derived coating for a medical device, comprising:

fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds; and

a therapeutic agent;

wherein the therapeutic agent is contained within the coating in such a way that the therapeutic agent has an enhanced release profile; and

wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerides, or glycerols.

71. A preparation for deriving a coating for a medical device, the preparation comprising:

fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds; and

a therapeutic agent;

wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerides, or glycerols.

72. A fatty-acid based, pre-cure-derived coating for a medical device, comprising:

fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds; and

a therapeutic agent;

wherein the coating is prepared by;

curing a natural oil-containing starting material to induce cross-linking of a portion of the fatty acids contained therein;

adding a therapeutic agent to the partially-cross linked fatty acid oil to form a therapeutic agent-oil composition; and

curing the therapeutic agent-oil composition to induce additional cross links of the fatty acids contained therein, such that the coating is formed;

wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerides, or glycerols.

73. The coating of claim 72, wherein the therapeutic agent is combined with a natural oil-containing material, organic solvent and/or vitamin E before combining with the partially-cross linked fatty acid oil.

74. The coating of claim 72, wherein the therapeutic agent is combined with vitamin E before combining with the partially-cross linked fatty acid oil, such that the therapeutic agent has an enhanced release profile.

75. A stand-alone film comprising a pre-cured fatty acid;

wherein the pre-cured fatty acid comprises fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds; and

wherein the stand-alone film hydrolyzes in vivo.

76. The stand-alone film of claim 75, wherein the stand-alone film comprises approximately 5-50% C₁₆ fatty acids.

77. The stand-alone film of claim 75, wherein the stand-alone film comprises 5-25% C₁₄ fatty acids.

78. The stand-alone film of claim 75, wherein the stand-alone film comprises 5-40% C₁₆ fatty acids.

79. The stand-alone film of claim 75, further comprising vitamin E.

80. The stand-alone film of claim 75, wherein the film is bioabsorbable.

81. The stand-alone film of claim 75, wherein the film maintains anti-adhesive properties.

82. The stand-alone film of claim 75, further comprising a therapeutic agent.

83. The stand-alone film of claim 82, wherein the therapeutic agent is Compound A, Compound B, Compound C, Compound D, Compound E, a cyclosporine derivative or rapamycin derivative.

84. The stand-alone film of claim 75, wherein a therapeutic agent is combined with pre-cured fatty acid prior to formation of the film, resulting in the therapeutic agent being interspersed throughout the film.

85. A stand-alone film, comprising:

a cross-linked fatty acid oil, and a therapeutic agent;

wherein the stand-alone film is prepared by curing a natural oil-containing starting material to induce cross-linking of a portion of the fatty acids to each other by one or more of ester bonds or lactone bonds;

adding a therapeutic agent to the partially-cross linked fatty acid oil to form a therapeutic agent-oil composition; and

curing the therapeutic agent-oil composition to induce additional cross links in the fatty acids, such that the stand-alone film is formed;

wherein the stand-alone film hydrolyzes in vivo.

86. A fatty-acid based, pre-cure-derived biomaterial comprising:

fatty acids cross-linked to each other by one or more of ester bonds or lactone bonds; and

a therapeutic agent;

wherein the biomaterial comprises at least 40%, by weight, of the therapeutic agent;

and

wherein the coating hydrolyzes in vivo into one or more of free fatty acids, glycerides, or glycerols.

87. The fatty-acid based, pre-cure-derived biomaterial of claim 86, wherein the biomaterial comprises at least 50%, by weight, of the therapeutic agent.