Transscleral delivery

• US 20050064010A1
• Filed: 09/20/2004
• Published: 03/24/2005
• Est. Priority Date: 09/18/2003
• Status: Active Grant

• Current Assignee: Santen Pharmaceutical Company Limited
• Original Assignee: MacuSight, Inc (Santen Pharmaceutical Company Limited)
• Inventors: Cooper, Eugene R., Nivaggioli, Thierry, Kleinman, David M., Mudumba, Sreenivasu, Dor, Philippe JM
• Granted Patent: US 7,585,517 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Diseases associated with the tissues in the posterior segment of the eye can be effectively treated by administering therapeutic agents transsclerally to those tissues. Compositions, devices, and methods for delivering therapeutic agents so that they cross the sclera and reach these tissues include injecting solutions or suspensions adjacent to or within the sclera and implanting solid structures containing the therapeutic agent adjacent to or within the sclera. These methods may be used for administering rapamycin or related compounds to treat choroidal neovascularization associated with age-related macular degeneration.

Claims

1. A method for treating wet age-related macular degeneration in a human, the method comprising administering transsclerally to an eye of the human an amount of rapamycin effective to treat wet age-related macular degeneration.

2. The method of claim 1, wherein the eye has a sclera with an outer scleral surface and the rapamycin is administered transsclerally by placement of a rapamycin containing delivery system proximate to the outer scleral surface.

3. The method of claim 2, wherein the rapamycin containing delivery system comprises a solid rapamycin core.

4. The method of claim 3, wherein the rapamycin containing delivery system further contains a backing portion that is substantially impermeable to rapamycin.

5. The method of claim 2, wherein the rapamycin containing delivery system comprises a suspension of particles of rapamycin.

6. The method of claim 5, wherein the particles of rapamycin have an average diameter of less than about 50 μ

m.

7. The method of claim 2, wherein the rapamycin containing delivery system comprises rapamycin dispersed in a polymer implant.

8. The method of claim 7, wherein the polymer implant is a biodegradable polymer implant.

9. The method of claim 7, wherein the polymer implant is a non-biodegradable polymer implant.

10. The method of claim 8 or claim 9, wherein the polymer implant further comprises a rapamycin impermeable backing.

11. The method of claim 8 or claim 9, wherein the polymer implant is shaped as a suture.

12. The method of claim 11, wherein the suture has a length of less than about 10 cm and a diameter of less than about 2 mm.

13. The method of claim 8 or claim 9, wherein the polymer implant is shaped as a coiled fiber.

14. The method of claim 13, wherein the coiled fiber has a length of less than about 5 cm and a diameter of less than about 1 mm.

15. The method of claim 8 or claim 9, wherein the polymer implant is shaped as a disk.

16. The method of claim 8 or claim 9, wherein the polymer implant has a scleral surface portion for placement on the outer scleral surface of the eye and the scleral surface portion has an area through which the rapamycin is delivered to the outer scleral surface of less than about 0.5 cm².

17. The method of claim 8 or claim 9, wherein the polymer implant has a scleral surface portion for placement on the outer scleral surface of the eye, and the scleral surface portion comprises a bioadhesive layer.

18. The method of claim 8 or claim 9, wherein the polymer implant has a scleral surface portion comprises a number of protrusions, and whereby the scleral surface portion of the polymer implant anchors the polymer implant to the outer scleral surface of the eye.

19. The method of claim 8 or claim 9, wherein the polymer implant comprises a rapamycin containing portion coated with a coating, and wherein the concentration of rapamycin in the coating is less than the concentration of rapamycin in the rapamycin containing portion.

20. The method of claim 19, wherein the concentration of rapamycin in the coating is such that release of rapamycin from the coating does not deliver a wound healing inhibiting amount of rapamycin.

21. The method of claim 2, wherein the rapamycin containing delivery system comprises rapamycin dissolved in a solvent.

22. The method of claim 2, wherein the rapamycin containing delivery system delivers the rapamycin transsclerally in an amount sufficient to maintain an amount effective to treat wet age-related macular degeneration for an extended period of time.

23. The method of claim 22, wherein the rapamycin containing delivery system delivers the rapamycin transsclerally in an amount sufficient to treat wet age-related macular degeneration for at least about three weeks.

67. The method of claim 2, wherein the rapamycin containing delivery system maintains a concentration of rapamycin at the outer scleral surface of about 20 μ

g/ml or less.

68. The method of claim 67, wherein the rapamycin containing delivery system maintains a concentration of rapamycin at the outer scleral surface of about 5 μ

g/ml or less.

69. The method of claim 2, wherein the human eye has a posterior segment and the rapamycin containing delivery system delivers to the posterior segment an amount of rapamycin of about 5 μ

g/day or less.

70. The drug delivery system of claim 69, wherein the rapamycin containing delivery system delivers to the posterior segment an amount of rapamycin of about 1 μ

g/day or less.

24. A method for treating, inhibiting or preventing angiogenesis in the eye of a subject, the method comprising administering transsclerally to the eye an amount of a therapeutic agent effective to treat, inhibit or prevent angiogenesis.

25. The method of claim 24, wherein the angiogenesis is choroidal neovascularization.

26. The method of claim 24, wherein the subject has a predisposition for macular degeneration and the method prevents or delays onset of angiogenesis in the eye of the subject.

27. The method of claim 24, wherein the subject is suffering from macular degeneration and the method treats, inhibits or causes regression of angiogenesis in the eye of the subject.

28. The method of claim 26 or claim 27 wherein the macular degeneration is age-related macular degeneration.

29. The method of claim 28, wherein the age-related macular degeneration is wet age-related macular degeneration.

30. The method of claim 24, wherein the therapeutic agent is an immunophilin binding compound.

31. The method of claim 24, wherein the compound is selected from the limus family of compounds.

32. The method of claim 24, wherein the compound is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and analogs, salts and esters thereof.

33. The method of claim 24, wherein the eye has a sclera with an outer scleral surface and the therapeutic agent is administered transsclerally by placement of a therapeutic agent containing delivery system proximate to the outer scleral surface.

34. The method of claim 33, wherein the therapeutic agent containing delivery system comprises a solid therapeutic agent core.

35. The method of claim 34, wherein the therapeutic agent containing delivery system further contains a backing portion that is substantially impermeable to the therapeutic agent.

36. The method of claim 33, wherein the therapeutic agent containing delivery system comprises a suspension of particles of therapeutic agent.

37. The method of claim 36, wherein the particles of therapeutic agent have an average diameter of less than about 50 μ

m.

38. The method of claim 33, wherein the therapeutic agent containing delivery system comprises therapeutic agent dispersed in a polymer implant.

39. The method of claim 38, wherein the polymer implant is a biodegradable polymer implant.

40. The method of claim 38, wherein the polymer implant is a non-biodegradable polymer implant.

41. The method of claim 39 or claim 40, wherein the polymer implant further comprises a therapeutic agent impermeable backing.

42. The method of claim 39 or claim 40, wherein the polymer implant is shaped as a suture.

43. The method of claim 42, wherein the suture has a length of less than about 10 cm and a width of less than about 0.2 mm.

44. The method of claim 39 or claim 40, wherein the polymer implant is shaped as a coiled fiber.

45. The method of claim 44, wherein the coiled fiber has a length of less than about 5 cm and a width of less than about 1 mm.

46. The method of claim 39 or claim 40, wherein the polymer implant is shaped as a disk.

47. The method of claim 39 or claim 40, wherein the polymer implant has a scleral surface portion for placement on the outer scleral surface of the eye and the scleral surface portion has an area through which the rapamycin is delivered to the outer scleral surface of less than about 0.5 cm².

48. The method of claim 39 or claim 40, wherein the polymer implant has a scleral surface portion for placement on the outer scleral surface of the eye, and the scleral surface portion comprises a bioadhesive layer.

49. The method of claim 39 or claim 40, wherein the polymer implant has a scleral surface portion comprises a number of protrusions, and whereby the scleral surface portion of the polymer implant anchors the polymer implant to the outer scleral surface of the eye.

50. The method of claim 38 or claim 39, wherein the polymer implant comprises a therapeutic agent containing portion coated with a coating, and wherein the concentration of therapeutic agent in the coating is less than the concentration of therapeutic agent in the therapeutic agent containing portion.

51. The method of claim 50, wherein the coating is substantially free of therapeutic agent.

52. The method of claim 33, wherein the therapeutic agent containing delivery system comprises therapeutic agent dissolved in a solvent.

53. The method of claim 33, wherein the therapeutic agent containing delivery system delivers the therapeutic agent transsclerally in an amount sufficient to maintain an amount effective to treat, prevent or inhibit angiogenesis for an extended period of time.

54. The method of claim 33, wherein the therapeutic agent containing delivery system delivers the therapeutic agent transsclerally in an amount sufficient to maintain an amount effective to treat, prevent or inhibit angiogenesis for a period of greater than about 3 weeks.

55. The method of claim 24, wherein the subject is a mammal.

56. The method of claim 55, wherein the subject is a human subject.

57. A transscleral rapamycin drug delivery system for delivery of rapamycin to the posterior segment of a human eye, comprising a polymer implant containing rapamycin, wherein the drug delivery system when placed proximate to the outer scleral surface of the human eye delivers transsclerally an amount of rapamycin effective to treat, prevent, inhibit, delay the onset of, or cause regression of choroidal neovascularization in human.

58. The drug delivery system of claim 57, wherein the drug delivery system delivers an amount of rapamycin effective to treat choroidal neovascularization in a human.

59. The drug delivery system of claim 57, wherein the drug delivery system delivers an amount of rapamycin effective to prevent choroidal neovascularization in a human.

60. The drug delivery system of claim 57, wherein the drug delivery system delivers an amount of rapamycin effective to inhibit choroidal neovascularization in a human.

61. The drug delivery system of claim 57, wherein the drug delivery system delivers an amount of rapamycin effective to cause regression of choroidal neovascularization in a human.

62. The drug delivery system of any of claims 58 to 61, wherein the polymer implant has a scleral surface portion for placement on the outer scleral surface of the eye and the scleral surface portion has an area through which the rapamycin is delivered to the outer scleral surface of less than about 0.5 cm².

63. The drug delivery system of any of claims 58 to 61, wherein the drug delivery system maintains a concentration of rapamycin at the outer scleral surface of about 20 μ

g/ml or less.

64. The drug delivery system of claim 63, wherein the drug delivery system maintains a concentration of rapamycin at the outer scleral surface of about 5 μ

g/ml or less.

65. The drug delivery system of any of claims 58 to 61, wherein the drug delivery system delivers to the posterior segment an amount of rapamycin of about 5 μ

g/day or less.

66. The drug delivery system of claim 65, wherein the drug delivery system delivers to the posterior segment an amount of rapamycin of about 1 μ

g/day or less.