Biodegradable ocular implant

• US 20040137059A1
• Filed: 01/09/2003
• Published: 07/15/2004
• Est. Priority Date: 01/09/2003
• Status: Abandoned Application

• Current Assignee: Allergan Incorporated (Abbvie Incorporated)
• Original Assignee: Allergan Incorporated (Abbvie Incorporated)
• Inventors: Nivaggioli, Thierry, Peng, Lin, Chou, David, Weber, David
• Application Number:
  US10/340,237
• Publication Number:
  US 20040137059A1
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention provides biodegradable implants sized for implantation in an ocular region and methods for treating medical conditions of the eye. The implants are formed from a mixture of hydrophilic end and hydrophobic end PLGA, and deliver active agents into an ocular region without a high burst release.

Claims

1. A bioerodible implant for treating a medical condition of the eye comprising an active agent dispersed within a biodegradable polymer matrix, wherein the bioerodible implant has an in vivo in rabbit eye cumulative release profile in which less than about 15 percent of the active agent is released about one day after implantation of the bioerodible implant and greater than about 80 percent of the active agent is released about 28 days after implantation of the bioerodible implant, and wherein the biodegradable polymer matrix comprises a mixture of hydrophilic end group PLGA and hydrophobic end group PLGA.

2. The bioerodible implant of claim 1 wherein the active agent is selected from the group consisting of ace-inhibitors, endogenous cytokines, agents that influence basement membrane, agents that influence the growth of endothelial cells, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics, anti-inflammatory agents, antihypertensives, pressors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infective agents, antitumor agents, antimetabolites, and antiangiogenic agents.

3. The bioerodible implant of claim 1 wherein the active agent comprises an anti-inflammatory agent or any derivative thereof.

4. The bioerodible implant of claim 1 wherein the active agent comprises a steroidal anti-inflammatory agent or any derivative thereof.

5. The bioerodible implant of claim 4 wherein the active agent is selected from the group consisting of cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and any derivative thereof.

6. The bioerodible implant of claim 4 wherein the active agent comprises dexamethasone.

70. A method for treating a medical condition of the eye in a subject comprising implanting into an ocular region of the subject a bioerodible implant of any one of claims 1-69 and delivering a therapeutic amount of an active agent to the ocular region.

71. The method of claim 70, wherein the subject is human.

72. The method of claim 70, wherein the medical condition of the eye is selected from the group consisting of uveitis, macular edema, macular degeneration, retinal detachment, ocular tumors, fungal infections, viral infections, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic opthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, and vascular occlusion.

73. The method of claim 70 wherein the step of implantation of the bioerodible implant results in an approximately 10-fold less concentration of the active agent in vivo in rabbit aqueous humor than in rabbit vitreous humor.

74. The method of claim 70 further comprising the step of varying the size of the bioerodible implant to modify the therapeutic amount of active agent in the ocular region.

7. The bioerodible implant of claim I wherein the implant is sized for implantation in an ocular region.

8. The bioerodible implant of claim 7 wherein the ocular region is selected from the group consisting of the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicorneal space, the sclera, the pars plana, surgically-induced avascular regions, the macula, and the retina.

9. The bioerodible implant of claim 7 wherein the ocular region is the vitreous cavity.

10. A bioerodible implant for treating a medical condition of the eye comprising an active agent dispersed within a biodegradable polymer matrix, wherein the bioerodible implant is formed by an extrusion method, and wherein the bioerodible implant has an in vivo in rabbit eye cumulative release profile in which greater than about 80 percent of the active agent is released about 28 days after implantation of the bioerodible implant.

11. The bioerodible implant of claim 10 wherein the active agent is selected from the group consisting of ace-inhibitors, endogenous cytokines, agents that influence basement membrane, agents that influence the growth of endothelial cells, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics, anti-inflammatory agents, antihypertensives, pressors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infective agents, antitumor agents, antimetabolites, and antiangiogenic agents.

12. The bioerodible implant of claim 10 wherein the active agent comprises an anti-inflammatory agent or any derivative thereof.

13. The bioerodible implant of claim 10 wherein the active agent comprises a steroidal anti-inflammatory agent or any derivative thereof.

14. The bioerodible implant of claim 13 wherein the active agent is selected from the group consisting of cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and any derivative thereof.

15. The bioerodible implant of claim 13 wherein the active agent comprises dexamethasone.

16. The bioerodible implant of claim 10 wherein the active agent is about 10 to about 90 percent by weight of the bioerodible implant.

17. The bioerodible implant of claim 16 wherein the active agent is about 60 percent by weight of the bioerodible implant.

18. The bioerodible implant of claim 10 wherein the biodegradable polymer matrix comprises a polyester.

19. The bioerodible implant of claim 18 wherein the biodegradable polymer matrix comprises poly(lactic-co-glycolic)acid (PLGA) copolymer.

20. The bioerodible implant of claim 19 wherein the ratio of lactic to glycolic acid monomers is about 50/50 weight percentage.

21. The bioerodible implant of claim 19 wherein the PLGA copolymer is about 20 to about 90 weight percent of the bioerodible implant.

22. The bioerodible implant of claim 21 wherein the PLGA copolymer is about 40 percent by weight of the bioerodible implant.

23. The bioerodible implant of claim 10 wherein the implant is sized for implantation in an ocular region.

24. The bioerodible implant of claim 23 wherein the ocular region is selected from the group consisting of the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicorneal space, the sclera, the pars plana, surgically-induced avascular regions, the macula, and the retina.

25. The bioerodible implant of claim 23 wherein the ocular region is the vitreous cavity.

26. A bioerodible implant for treating a medical condition of the eye comprising an active agent dispersed within a biodegradable polymer matrix, wherein the bioerodible implant exhibits a cumulative release profile in which greater than about 80 percent of the active agent is released about 28 days after implantation of the bioerodible implant, and wherein the cumulative release profile is approximately sigmoidal in shape over about 28 days after implantation.

27. The bioerodible implant of claim 26 wherein the cumulative release profile is an in vivo in rabbit eye cumulative release profile.

28. The bioerodible implant of claim 26 wherein the cumulative release profile is an in vitro cumulative release profile.

29. The bioerodible implant of claim 26 wherein the active agent is selected from the group consisting of ace-inhibitors, endogenous cytokines, agents that influence basement membrane, agents that influence the growth of endothelial cells, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics, anti-inflammatory agents, antihypertensives, pressors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infective agents, antitumor agents, antimetabolites, and antiangiogenic agents.

30. The bioerodible implant of claim 26 wherein the active agent comprises an anti-inflammatory agent or any derivative thereof.

31. The bioerodible implant of claim 26 wherein the active agent comprises a steroidal anti-inflammatory agent or any derivative thereof.

32. The bioerodible implant of claim 31 wherein the active agent is selected from the group consisting of cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and any derivative thereof.

33. The bioerodible implant of claim 31 wherein the active agent comprises dexamethasone.

34. The bioerodible implant of claim 26 wherein the active agent is about 10 to about 90 percent by weight of the bioerodible implant.

35. The bioerodible implant of claim 34 wherein the active agent is about 60 percent by weight of the bioerodible implant.

36. The bioerodible implant of claim 26 wherein the biodegradable polymer matrix comprises a polyester.

37. The bioerodible implant of claim 36 wherein the biodegradable polymer matrix comprises poly(lactic-co-glycolic)acid (PLGA) copolymer.

38. The bioerodible implant of claim 37 wherein the ratio of lactic to glycolic acid monomers is about 50/50 weight percentage.

39. The bioerodible implant of claim 37 wherein the PLGA copolymer is about 20 to about 90 weight percent of the bioerodible implant.

40. The bioerodible implant of claim 39 wherein the PLGA copolymer is about 40 percent by weight of the bioerodible implant.

41. The bioerodible implant of claim 26 wherein the implant is sized for implantation in an ocular region.

42. The bioerodible implant of claim 41 wherein the ocular region is selected from the group consisting of the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicorneal space, the sclera, the pars plana, surgically-induced avascular regions, the macula, and the retina.

43. The bioerodible implant of claim 41 wherein the ocular region is the vitreous cavity.

44. A bioerodible implant for treating a medical condition of the eye comprising an active agent dispersed within a biodegradable polymer matrix, wherein the biodegradable polymer matrix comprises a mixture of PLGA having hydrophilic end groups and PLGA having hydrophobic end groups, and wherein the bioerodible implant is sized for implantation in an ocular region.

45. The bioerodible implant of claim 44 wherein the active agent is selected from the group consisting of ace-inhibitors, endogenous cytokines, agents that influence basement membrane, agents that influence the growth of endothelial cells, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics, anti-inflammatory agents, antihypertensives, pressors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infective agents, antitumor agents, antimetabolites, and antiangiogenic agents.

46. The bioerodible implant of claim 44 wherein the active agent comprises an anti-inflammatory agent or any derivative thereof.

47. The bioerodible implant of claim 44 wherein the active agent comprises a steroidal anti-inflammatory agent or any derivative thereof.

48. The bioerodible implant of claim 47 wherein the active agent is selected from the group consisting of cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and any derivative thereof.

49. The bioerodible implant of claim 47 wherein the active agent comprises dexamethasone.

50. The bioerodible implant of claim 44 wherein the active agent is about 10 to about 90 percent by weight of the bioerodible implant.

51. The bioerodible implant of claim 50 wherein the active agent is about 60 percent by weight of the bioerodible implant.

52. The bioerodible implant of claim 44 wherein said hydrophilic end group is carboxyl, hydroxyl, polyethylene glycol, or a combination thereof.

53. The bioerodible implant of claim 44 wherein said hydrophobic end group is an alkyl ester or aromatic ester.

54. The bioerodible implant of claim 44 wherein the mixture has a weight ratio of hydrophilic end group PLGA to hydrophobic end group PLGA of about 3:

1.

55. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vivo in rabbit eye in which less than about 15 percent of the active agent is released about one day after implantation of the bioerodible implant.

56. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vivo in rabbit eye in which less than about 20 percent of the active agent is released about three days after implantation of the bioerodible implant.

57. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vivo in rabbit eye in which greater than about 65 percent of the active agent is released about 21 days after implantation of the bioerodible implant.

58. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vivo in rabbit eye in which greater than about 80 percent of the active agent is released about 28 days after implantation of the bioerodible implant.

59. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vivo in rabbit eye in which greater than about 95 percent of the active agent is released about 35 days after implantation of the bioerodible implant.

60. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vivo in rabbit eye in which less than about 15 percent of the active agent is released about one day after implantation of the bioerodible implant and greater than about 80 percent of the active agent is released about 28 days after implantation of the bioerodible implant.

61. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vitro in which less than about 5 percent of the active agent is released about one day after implantation of the bioerodible implant.

62. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vitro in which less than about 7 percent of the active agent is released about four days after implantation of the bioerodible implant.

63. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vitro in which greater than about 70 percent of the active agent is released about 21 days after implantation of the bioerodible implant.

64. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vitro in which greater than about 85 percent of the active agent is released about 28 days after implantation of the bioerodible implant.

65. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vitro in which greater than about 95 percent of the active agent is released about 35 days after implantation of the bioerodible implant

66. The bioerodible implant of claim 44 wherein the bioerodible implant has a cumulative release profile in vitro in which less than about 5 percent of the active agent is released about one day after implantation of the bioerodible implant and in which greater than about 85 percent of the active agent is released about 28 days after implantation of the bioerodible implant.

67. The bioerodible implant of claim 44 wherein the bioerodible implant is formed by an extrusion method.

68. The bioerodible implant of claim 44 wherein the ocular region is selected from the group consisting of the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicorneal space, the sclera, the pars plana, surgically-induced avascular regions, the macula, and the retina.

69. The bioerodible implant of claim 44 wherein the ocular region is the vitreous cavity.

75. A bioerodible implant for treating a medical condition of the eye comprising an active agent dispersed within a biodegradable polymer matrix, wherein the bioerodible implant has an in vivo in rabbit eye cumulative release profile in which less than about 15 percent of the active agent is released about one day after implantation of the bioerodible implant and greater than about 80 percent of the active agent is released about 28 days after implantation of the bioerodible implant.

76. The bioerodible implant of claim 75 wherein the active agent is selected from the group consisting of ace-inhibitors, endogenous cytokines, agents that influence basement membrane, agents that influence the growth of endothelial cells, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics, anti-inflammatory agents, antihypertensives, pressors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infective agents, antitumor agents, antimetabolites, and antiangiogenic agents.

77. The bioerodible implant of claim 75 wherein the active agent comprises an anti-inflammatory agent or any derivative thereof.

78. The bioerodible implant of claim 75 wherein the active agent comprises a steroidal anti-inflammatory agent or any derivative thereof.

79. The bioerodible implant of claim 78 wherein the active agent is selected from the group consisting of cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and any derivative thereof.

80. The bioerodible implant of claim 78 wherein the active agent comprises dexamethasone.

81. The bioerodible implant of claim 75 wherein the active agent is about 10 to about 90 percent by weight of the bioerodible implant.

82. The bioerodible implant of claim 81 wherein the active agent is about 60 percent by weight of the bioerodible implant.

83. The bioerodible implant of claim 75 wherein biodegradable polymer matrix comprises a mixture of hydrophilic end group PLGA and hydrophobic end group PLGA.

84. The bioerodible implant of claim 83 wherein said hydrophilic end group is carboxyl, hydroxyl, polyethylene glycol, or a combination thereof.

85. The bioerodible implant of claim 83 wherein said hydrophobic end group is an alkyl ester or aromatic ester.

86. The bioerodible implant of claim 83 wherein the mixture has a weight ratio of hydrophilic end group PLGA to hydrophobic end group PLGA of about 3:

1.

87. The bioerodible implant of claim 75 wherein the implant is sized for implantation in an ocular region.

88. The bioerodible implant of claim 87 wherein the ocular region is selected from the group consisting of the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicorneal space, the sclera, the pars plana, surgically-induced avascular regions, the macula, and the retina.

89. The bioerodible implant of claim 87 wherein the ocular region is the vitreous cavity.