Biodegradable drug-polymer delivery system

• US 20050276841A1
• Filed: 06/07/2005
• Published: 12/15/2005
• Est. Priority Date: 06/07/2004
• Status: Active Grant

• Current Assignee: California Institute of Technology
• Original Assignee: California Institute of Technology
• Inventors: Mack, Brendan, Davis, Mark E., Wright, Kenneth W.
• Granted Patent: US 8,128,954 B2
• Time in Patent Office: Days
• US Class Current: 424/443
• CPC Class Codes: A61K 31/724 Cyclodextrins
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 47/6953 the form being a fibre, a textile, a slab or a sheet
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/0063 Periodont
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

A sustained-release biodegradable polymeric drug-eluting fiber is disclosed. In some embodiments, the therapeutic drug is complexed with cyclodextrin. In certain embodiments, the polymeric component of the fiber comprises cyclodextrin. The fiber may be fabricated to provide a thread and/or suture. The fiber may be used for treatment of ocular diseases or disorders.

Claims

1. A fiber comprising:

a) one or more polymers;

b) one or more cyclodextrins; and

c) one or more therapeutic agents.

2. The fiber of claim 1, wherein the therapeutic agent is present throughout the width of one or more sections of the fiber.

3. The fiber of claim 2, wherein the therapeutic agent is present at a substantially uniform concentration throughout the width of one or more sections of the fiber.

4. The fiber of claim 1, wherein the therapeutic agent forms an inclusion complex with the cyclodextrin.

5. The fiber of claim 1, wherein the cyclodextrin and polymer are not covalently linked.

6. The fiber of claim 1, wherein the cyclodextrin and polymer are covalently linked.

7. The fiber of claim 6, further comprising a non-cyclodextrin containing polymer.

8. The fiber of claim 7, wherein the non-cyclodextrin containing polymer is poly(lactide-coglycolide) (PLGA).

9. The fiber of claim 6, wherein the cyclodextrin is incorporated in the backbone of the polymer.

10. The fiber of claim 6, wherein the cyclodextrin is borne in side chains of the polymer.

11. The fiber of claim 1, wherein the cyclodextrin is a modified cyclodextrin.

12. The fiber of claim 11, wherein the cyclodextrin is benzylated, acylated, or alkylated.

13. The fiber of claim 11, wherein the cyclodextrin is methylated cyclodextrin.

14. The fiber of claim 11, wherein the cyclodextrin is hydroxypropylated cyclodextrin.

15. The fiber of claim 11, wherein the cyclodextrin is sulfobutylether cyclodextrin.

16. The fiber of claim 1, wherein the polymer is biodegradable.

17. The fiber of claim 16, wherein the polymer is Dexon, Vicryl, Polysorb, poly(lactide-coglycolide) (PLGA), polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), polydioxanone (PDO), or a combination thereof.

18. The fiber of claim 17, wherein the polymer is PLGA.

19. The fiber of claim 1, wherein the therapeutic agent is a nucleic acid, a protein, a peptide, a small molecule, or a combination thereof.

20. The fiber of claim 19, wherein the therapeutic agent is a small molecule.

21. The fiber of claim 20, wherein the therapeutic agent is a steroid, a retinoid, a NSAID, a vitamin D3 analog, a human carbonic anhydrase inhibitor, or a combination thereof.

22. The fiber of claim 21, wherein the therapeutic agent is a steroid.

23. The fiber of claim 22, wherein the steroid is a corticosteroid.

24. The fiber of claim 22, wherein the therapeutic agent is prednisolone or dexamethasone.

25. The fiber of claim 19, wherein the therapeutic agent is a protein.

26. The fiber of claim 25, wherein the therapeutic agent is a neurotrophic factor.

27. The fiber of claim 26, wherein the therapeutic agent is a nerve growth factor.

28. The fiber of claim 1, wherein the therapeutic agent is an anti-cancer agent, an antibiotic agent, an anti-inflammatory agent, an immunosuppressant, an antiviral agent, an anti-proliferative agent, an antimicrobial agent, a nerve growth inducing agent, or a combination thereof.

29. The fiber of claim 28, wherein the therapeutic agent is an antibiotic agent or an anti-microbial agent.

30. The fiber of claim 29, wherein the therapeutic agent is chlorhexidine, metronidazole, minocycline, tetracycline, triclosan, ciprofloxacin or tobramycin.

31. The fiber of claim 28, wherein the therapeutic agent is a nerve growth inducing agent.

32. The fiber of claim 31, wherein the therapeutic agent is sabeluzole or inosine.

33. The fiber of claim 1, further comprising one or more adjuvants.

34. The fiber of claim 1, wherein the therapeutic agent is covalently linked to the polymer.

35. The fiber of claim 34, wherein the therapeutic agent is covalently linked to the polymer by one or more linking moieties.

36. The fiber of claim 35, wherein one or more linking moieties are cleaved under physiological conditions.

37. The fiber of claim 1, further comprising one or more coatings.

38. The fiber of claim 37, wherein the coating comprises one or more therapeutic agents or adjuvants.

39. The fiber of claim 1, wherein the fiber comprises one or more bulbs along the length of the fiber.

40. The fiber of claim 39, wherein at least one bulb comprises one or more therapeutic agents.

41. The fiber of claim 1, wherein the fiber gradually releases the therapeutic agent over a period of time after implantation in a patient.

42. The fiber of claim 1, wherein the fiber releases an initial surge of the therapeutic agent after implantation in a patient.

43. The fiber of claim 1, wherein the fiber releases a gradually increasing amount of the therapeutic agent over a period of time after implantation in a patient.

44. The fiber of claim 1, wherein the fiber includes a ribbon configuration portion.

45. The fiber of claim 1, wherein the fiber includes a tube configuration portion.

46. The fiber of claim 45, wherein the fiber includes a lumen.

47. The fiber of claim 46, wherein the lumen contains a medium that includes one or more auxiliary therapeutic agents.

48. The fiber of claim 47, wherein one or more auxiliary therapeutic agents is a nerve growth inducing agent.

49. A thread comprising one or more fibers of claim 1.

50. The thread of claim 49, wherein the thread is a monofilament.

51. The thread of claim 49, wherein the thread is a polyfilament.

52. The thread of claim 49, wherein the thread is braided.

53. The thread of claim 49, further comprising one or more fibers that are non-bioabsorbable.

54. The thread of claim 49, wherein at least one additional fiber comprises one or more therapeutic agents or adjuvants.

55. The thread of claim 49, further comprising one or more layers or plies.

56. The thread of claim 49, wherein the thread is implanted in a targeted tissue of a patient.

57. The thread of claim 56, wherein the tissue is the periodontal tissue.

58. The thread of claim 57, wherein the therapeutic agent is an antibiotic or antimicrobial agent.

59. The thread of claim 58, wherein the therapeutic agent is chlorhexidine, metronidazole, minocycline, triclosan, or tetracycline.

60. A suture comprising one or more threads of claim 49.

61. The suture of claim 60, wherein the suture comprises two or more threads.

62. The suture of claim 60, wherein two or more threads comprise different therapeutic agents.

63. The suture of claim 60, wherein the suture is attached to a needle.

64. The suture of claim 60, wherein the suture is implanted or tied to a targeted tissue of a patient.

65. The suture of claim 64, wherein the tissue is ocular tissue.

66. The suture of claim 65, wherein the tissue is the sub-conjunctival space.

67. The suture of claim 65, wherein the tissue is the conjunctival fornix.

68. A method for delivering one or more therapeutic agents to a targeted tissue in a patient, comprising introducing a fiber to the targeted tissue, the fiber comprising

a) one or more polymers;

b) one or more cyclodextrins; and

c) one or more therapeutic agents.

69. The method of claim 68, wherein the fiber includes a ribbon configuration portion.

70. The method of claim 68, wherein the fiber includes a tube configuration portion.

71. The method of claim 68, wherein the tissue is ocular tissue.

72. The method of claim 71, wherein the tissue is the sub-conjunctival space.

73. The method of claim 71, wherein the tissue is the conjunctival fornix.

74. The method of claim 68, wherein the tissue is periodontal tissue.

75. The method of claim 68, wherein the introduction of the fiber is reversible.

76. The method of claim 68, wherein the therapeutic agent treats cancer.

77. The method of claim 68, wherein the therapeutic agent is an antibiotic agent or an anti-microbial agent.

78. The method of claim 77, wherein the therapeutic agent is chlorhexidine, metronidazole, minocycline, tetracycline, triclosan, ciprofloxacin or tobramycin.

79. The method of claim 68, wherein the therapeutic agent treats an ocular disease or disorder.

80. The method of claim 79, wherein the ocular disease or disorder is corneal ulcer, uveitis, scleritis, glaucoma, or vernal conjunctivitis.

81. The method of claim 79, wherein the therapeutic agent is ciprofloxacin, 5-fluorouracil, tobramycin, dexamethasone, prednisolone, or combinations thereof.

82. The method of claim 68, wherein the therapeutic agent treats periodontitis.

83. The method of claim 82, wherein the therapeutic agent is chlorhexidine, metronidazole, minocycline, triclosan, or tetracycline.

84. The method of claim 68, wherein the tissue is nerve tissue.

85. The method of claim 68, wherein the therapeutic agent is a neurotrophic factor.

86. The method of claim 85, wherein the therapeutic agent induces nerve growth.

87. A method for the treatment of periodontitis, comprising administering to a patient a fiber comprising:

a) one or more polymers;

b) one or more cyclodextrins; and

c) one or more therapeutic agents.

88. The method of claim 87, wherein the therapeutic agent is an antibiotic agent.

89. The method of claim 87, additionally comprising treating the patient with scaling.

90. The method of claim 87, additionally comprising treating the patient with root planing.

91. A method for the treatment of nerve damage comprising administering to a patient a fiber comprising:

a) one or more polymers;

b) one or more cyclodextrins; and

c) one or more therapeutic agents.

92. The method of claim 91, wherein the therapeutic agent is a neurotrophic agent.

93. The method of claim 91, wherein the fiber includes a tube configuration.

94. A method for the preparation of a drug-eluting fiber comprising:

a) dissolving one or more polymers and one or more cyclodextrin-therapeutic agent inclusion complexes in a solvent to give a polymer solution; and

b) exposing the polymer solution to a coagulation fluid to prepare a drug-eluting fiber.

95. The method of claim 94, wherein exposing the polymer solution to a coagulation fluid comprises extruding the polymer solution into a coagulation fluid.

96. The method of claim 95, wherein exposing the polymer solution to a coagulation fluid comprises dip-coating.

97. The method of claim 94, wherein the polymer solution is homogeneous.

98. The method of claim 94, wherein one or more polymers is PLGA.

99. The method of claim 94, wherein the cyclodextrin is a modified cyclodextrin.

100. The method of claim 94, wherein, the therapeutic agent is nucleic acid, a protein, a peptide, a small molecule, or a combination thereof.

101. The method of claim 94, wherein the solvent is DMF.

102. The method of claim 94, wherein the solvent is DMSO.

103. The method of claim 94, wherein the coagulation fluid is water, an alcohol, or a combination thereof.

104. The method of claim 103, wherein the alcohol is isopropanol.

105. The method of claim 104, wherein the coagulation fluid is a water:

isopropanol mixture.

106. The method of claim 94, wherein the coagulation fluid includes a surfactant.

107. The method of claim 106, wherein the surfactant is an anionic surfactant.

108. The method of claim 107, wherein the surfactant is sodium dodecylsulfate.