Drug delivery systems for treatment of diseases or conditions

• US 20060257450A1
• Filed: 03/21/2006
• Published: 11/16/2006
• Est. Priority Date: 03/21/2005
• Status: Abandoned Application

• Current Assignee: Santen Pharmaceutical Company Limited
• Original Assignee: Santen Pharmaceutical Company Limited
• Inventors: Jm Dor, Philippe, Nivaggioli, Thierry, Weber, David A., Mudumba, Sreenivasu, Farooq, Sidiq
• Application Number:
  US11/386,290
• Publication Number:
  US 20060257450A1
• Time in Patent Office: Days
• US Class Current: 424/427
• 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 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics

Abstract

Diseases and conditions associated with tissues of the body, including but not limited to tissues in the eye, can be effectively treated, prevented, inhibited, onset delayed, or regression caused by administering therapeutic agents to those tissues. Described herein are solid drug delivery systems and methods for providing extended delivery of therapeutic agents to such tissues. A solid drug delivery system may be placed in a subject, including but not limited to placement between the sclera and the conjunctiva or transscleral placement. Described methods may be used to administer rapamycin to treat or prevent angiogenesis, choroidal neovascularization, age-related macular degeneration, or wet age-related macular degeneration in a subject. The solid drug delivery devices may comprise rapamycin or other therapeutic agents. Also described are methods of treating ocular diseases or disorders by administering an antiproliferative agent, including but not limited to rapamycin, proximal to an ocular device.

Claims

1. A solid drug delivery system comprising rapamycin, and wherein the solid drug delivery system when placed between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin with a delivery profile selected from the group consisting of

(a) the rapamycin is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of rapamycin in the vitreous of the rabbit eye of at least 0.01 ng/ml;

and

(b) the rapamycin is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 1 pg/mg.

2. The solid drug delivery system of claim 1, wherein the solid drug delivery system when placed between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin with a delivery profile selected from the group consisting of

(a) the rapamycin is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of rapamycin in the vitreous of the rabbit eye of at least 0.1 ng/ml;

and

(b) the rapamycin is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 10 pg/mg.

3. The solid drug delivery system of claim 1, wherein the solid drug delivery system when placed between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin with a delivery profile selected from the group consisting of

(a) the rapamycin is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of rapamycin in the vitreous of the rabbit eye of at least 1 ng/ml;

and

(b) the rapamycin is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 100 pg/mg.

8. The solid drug delivery system of either of claims 1 or 7, wherein the solid drug delivery system has a backing portion that is at least partially impermeable to the therapeutic agent.

11. The solid drug delivery system of claim 1, wherein the rapamycin is present in an amount between 1% and 60% w/w of the drug delivery system.

12. The solid drug delivery system of claim 1, comprising a polyvinylpyrrolidone in an amount between 15% and 45% w/w of the solid drug delivery system.

13. The solid drug delivery system of claim 1, comprising a polyacrylate in an amount between 5% and 30% w/w of the solid drug delivery system.

14. The solid drug delivery system of claim 1, wherein the rapamycin is present in an amount between 1% and 60% w/w of the drug delivery system, further comprising a polyvinylpyrrolidone in an amount between 15% and 45% w/w of the solid drug delivery system, and a polyacrylate in an amount between 5% and 30% w/w of the solid drug delivery system.

15. The solid drug delivery system of claim 1, wherein the solid drug delivery system contains between 20 μ

g and 4 mg of rapamycin.

16. The solid drug delivery system of claim 1, wherein the solid drug delivery system contains between 20 μ

g and 2.5 mg of rapamycin.

17. A method for treating wet age-related macular degeneration in a human subject, the method comprising placing the solid drug delivery system of either of claims 1 or 4 proximal to the eye of a human subject in need of treatment of age related macular degeneration.

18. A method for preventing wet age-related macular degeneration in a human subject, the method comprising placing the solid drug delivery system of either of claims 1 or 4 proximal to the eye of the human subject in need of prevention of age related macular degeneration.

19. The method of claim 17, wherein the eye has a sclera with an outer scleral surface and the solid drug delivery system is placed proximal to the outer scleral surface or within a scleral flap.

20. The method of claim 17, wherein the solid drug delivery system is placed between the sclera and conjunctiva.

21. The method of claim 18, wherein the human subject is identified as being at heightened risk of developing wet age-related macular degeneration in the eye to which the solid drug delivery system is administered.

22. The method of claim 21, wherein the human subject has dry age-related macular degeneration in at least one eye.

23. The method of claim 21, wherein the human subject has wet age-related macular degeneration in one eye and the solid drug delivery system is administered to the eye without wet age-related macular degeneration.

4. A solid drug delivery system comprising a therapeutic agent, wherein the solid drug delivery system when placed between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent with a delivery profile selected from the group consisting of

(a) the the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/ml;

and

(b) the the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the retina choroid of the rabbit eye equivalent to a rapamycin concentration of at least 1 pg/mg.

5. The solid drug delivery system of claim 4, wherein the therapeutic agent is a limus compound.

6. The solid drug delivery system of claim 4, wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilins, TAFA-93, RAD-001, temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester derivatives of rapamycin, 27-oximes of rapamycin;

42-oxo analogs of rapamycin;

bicyclic rapamycins;

rapamycin dimers;

silyl ethers of rapamycin;

rapamycin arylsulfonates, rapamycin sulfamates, monoesters at positions 31 and 42, diesters at positions 31 and 42, 30-demethoxy rapamycin, and pharmaceutically acceptable salts and esters thereof.

7. The solid drug delivery system of claim 6, wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof.

9. The solid drug delivery system of claim 4, wherein the solid drug delivery system when placed between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent with a delivery profile selected from the group consisting of

(a) the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 0.1 ng/ml;

and

(b) the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the retina choroid of the rabbit eye equivalent to a rapamycin concentration of at least 10 pg/mg.

10. The solid drug delivery system of claim 9, wherein the solid drug delivery system when placed between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent with a delivery profile selected from the group consisting of

(a) the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 1 ng/ml;

and

(b) the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the retina choroid of the rabbit eye equivalent to a rapamycin concentration of at least 0.05 pg/mg.

24. A solid drug delivery system comprising a therapeutic agent, a polyvinylpyrrolidone, and a polyacrylate, wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilins, TAFA-93, RAD-001, temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester derivatives of rapamycin, 27-oximes of rapamycin;

42-oxo analogs of rapamycin;

bicyclic rapamycins;

rapamycin dimers;

silyl ethers of rapamycin;

rapamycin arylsulfonates, rapamycin sulfamates, monoesters at positions 31 and 42, diesters at positions 31 and 42, 30-demethoxy rapamycin, and pharmaceutically acceptable salts and esters thereof.

26. The solid drug delivery system of claim 24, wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof.

27. The solid drug delivery system of claim 26 which further comprises a polyethylene glycol.

28. The solid drug delivery system of claim 26, wherein the solid drug delivery system when placed between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent with a delivery profile selected from the group consisting of

(a) the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 0.1 ng/ml;

and

(b) the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the retina choroid of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/mg.

29. The solid drug delivery system of claim 28, wherein the solid drug delivery system when placed between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent with a delivery profile selected from the group consisting of

(a) the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 0.5 ng/ml;

and

(b) the therapeutic agent is delivered in an amount sufficient to achieve, for a period of time of at least 90 days following administration of the solid drug delivery system, an average concentration of the therapeutic agent in the retina choroid of the rabbit eye equivalent to a rapamycin concentration of at least 0.05 ng/mg.

30. The solid drug delivery system of claim 24, wherein the therapeutic agent is present in an amount between 1% and 60% w/w of the drug delivery system.

31. The solid drug delivery system of claim 24, wherein the polyvinylpyrrolidone is present in an amount between 15% and 45% w/w of the solid drug delivery system.

32. The solid drug delivery system of claim 24, wherein the polyacrylate is present in an amount between 5% and 30% w/w of the solid drug delivery system.

33. The solid drug delivery system of claim 24, wherein the polyacrylate is a polymethacrylate.

34. The solid drug delivery system of claim 24, wherein the therapeutic agent is present in an amount between 1% and 60% w/w of the drug delivery system, the polyvinylpyrrolidone is present in an amount between 15% and 45% w/w of the solid drug delivery system, and the polyacrylate is present in an amount between 5% and 30% w/w of the solid drug delivery system.

35. The solid drug delivery system of claim 26 which comprises a backing portion at least partially impermeable to the therapeutic agent.

25. A solid drug delivery system comprising a limus compound, a polyvinylpyrrolidone, and a polyacrylate.

36. A method of treating an ocular condition in a subject requiring placement of an ocular device, comprising administering a formulation comprising an anti-proliferative agent proximal to the site selected for placement of the ocular device.

37. The method of claim 36, wherein the formulation is administered prior to, contemporaneous with, or subsequent to placement of the ocular device.

38. The method of claim 36, wherein the anti-proliferative agent is a limus compound, or a pharmaceutically acceptable salt or ester thereof.

39. The method of claim 38, wherein the limus compound is rapamycin.

40. The method of claim 36, wherein the ocular device is a glaucoma drainage device.

41. The method of claim 39, wherein the ocular device comprises a shunt, stent, tube, membrane, valve, or combination of one or more thereof.

42. The method of claim 36, wherein the method reduces cellular proliferation proximal to the ocular device.

43. The method of claim 36, wherein the formulation is a solution, suspension, emulsion, self-emulsifying formulation, in situ gelling formulation, or a solid drug delivery system.

44. The method of claim 36, wherein the formulation delivers an amount of the antiproliferative agent effective to reduce cellular proliferation proximal to the ocular device for a period of at least about 30 days.

45. The method of claim 44, wherein the formulation delivers an amount of the therapeutic agent effective to reduce cellular proliferation proximal to the ocular device for a period of at least about 60 days.

46. The method of claim 45, wherein the formulation delivers an amount of the therapeutic agent effective to reduce cellular proliferation proximal to the ocular device for a period of at least about 90 days.

47. The method of claim 36, wherein the antiproliferative agent is rapamycin and the ocular device is a glaucoma drainage device.