Compositions and methods for treating macular degeneration

• US RE47,045 E1
• Filed: 11/03/2016
• Issued: 09/18/2018
• Est. Priority Date: 09/12/2007
• Status: Active Grant

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Washington, Ilyas
• Primary Examiner(s): Railey, Johnny F
• Application Number:
  US15/343,016
• Time in Patent Office: 684 Days
• CPC Class Codes: A23L 33/10 using additives addition of substantially indigestible substances A23L33/21
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/203 Retinoic acids ; Salts thereof
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

Methods of retarding formation of a lipofuscin pigment in the retina and of treating or ameliorating the effects of a disease characterized by an accumulation of a lipofuscin pigment in a retina are provided. These methods include the step of administering to a patient in need thereof a substituted C₂₀-retinoid in an amount sufficient to reduce accumulation of a lipofuscin pigment in the retina. Further provided are methods of retarding formation of A2E and/or ATR-dimer by replacing an all-frans-retinal (ATR) substrate with a C₂₀-D₃-retinal substrate under conditions sufficient to impede the formation of A2E. Compositions for retarding formation of a lipofuscin pigment in the retina containing a substituted C₂₀-retinoid and a pharmaceutically acceptable carrier are also provided.

Claims

1. A method of retarding the accumulation of a lipofuscin pigment in a retina, comprising administering an effective amount of a pharmaceutical composition to a patient in need thereof, wherein the pharmaceutical composition comprises a substituted C₂₀-D_1-3-retinoid, wherein the C₂₀-D_1-3-retinoid is selected from the group consisting of C₂₀-D_1-3-retinol, C₂₀-D_1-3-retinol ester, C₂₀-D_1-3-retinal, and C₂₀-D_1-3-pro-vitamin A carotenoids, and a pharmaceutically acceptable carrier.

2. The method according to claim 1, wherein the substituted C₂₀-D_1-3-retinoid is a C₂₀-D₃-retinoid.

3. The method according to claim 1, wherein the pharmaceutical composition is suitable for use as a nutraceutical composition.

4. The method according to claim 1, wherein the patient is in need of treatment for a macular degeneration.

5. The method according to claim 4, wherein the macular degeneration is age-related macular degeneration.

6. The method according to claim 5, wherein the C₂₀-D_1-3-retinoid is C₂₀-D_1-3-retinol or a C₂₀-D_1-3-retinol ester.

7. The method according to claim 5, wherein the C₂₀-D_1-3-retinoid is C₂₀-D₃-retinol, a C₂₀-D₃-retinol ester, C₂₀-D₃-retinal, or a C₂₀-D₃-pro-vitamin A carotenoid.

8. The method according to claim 5, wherein the C₂₀-D_1-3-retinoid is C₂₀-D₃-retinol acetate.

9. The method according to claim 8, wherein the C₂₀-D₃-retinal, corresponding to the aldehyde of the C₂₀-D₃-retinol acetate, forms A2E in vitro about 7 times slower than non-deuterium-enriched retinal retinol acetate.

10. The method according to claim 5, wherein the patient is in need of treatment for dry (non-neovascular) age-related macular degeneration.

11. The method according to claim 1, wherein the patient is in need of treatment for Stargardt disease.

12. The method according to claim 11, wherein the C₂₀-D_1-3-retinoid is C₂₀-D_1-3-retinol or a C₂₀-D_1-3-retinol ester.

13. The method according to claim 11, wherein the C₂₀-D_1-3-retinoid is C₂₀-D₃-retinol, a C₂₀-D₃-retinol ester, C₂₀-D₃-retinal, or a C₂₀-D₃-pro-vitamin A-carotenoid.

14. The method according to claim 11, wherein the C₂₀-D_1-3-retinoid is C₂₀-D₃-retinol acetate.

15. The method according to claim 14, wherein the C₂₀-D₃-retinal, corresponding to the aldehyde of the C₂₀-D₃-retinol acetate, forms A2E in vitro about 7 times slower than non-deuterium-enriched retinal retinol acetate.

16. The method according to claim 1, wherein the patient is in need of treatment for a macular degeneration selected from the group consisting of Vitelliform or Best disease, Sorsby'"'"'s fundus dystrophy, retinitis pigmentosa, and Malattia Leventinese.

17. The method according to claim 16, wherein the C₂₀-D_1-3-retinoid is C₂O-D₃-retinol C₂₀-D₃-retinol acetate.

18. The method according to claim 1, wherein the patient is in need of treatment for a macular degeneration characterized by one or more mutation(s) in the ABCA4 gene.

19. The method according to claim 1, wherein the substituted C₂₀-D_1-3-retinoid is present in the pharmaceutical composition at a level sufficient to deliver on average about 0.1 to about 90 mg/day to a patient.

20. The method according to claim 1, further comprising an additional active.

21. The method according to claim 20, wherein the additional active is selected from the group consisting of eye antioxidants, minerals, negatively-charged phospholipids, carotenoids, and combinations thereof.

22. The method according to claim 21, wherein the eye antioxidant is selected from the group consisting of vitamin C, vitamin E, beta-carotene, coenzyme Q, OT-551, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, butylated hydroxytoluene, resveratrol, a trolox analogue (PNU-83836-E), bilberry extract, and combinations thereof.

23. The method according to claim 21, wherein the mineral is selected from the group consisting of cupric oxide, zinc oxide;

selenium-containing compounds, and combinations thereof.

24. The method according to claim 21, wherein the negatively charged phospholipid is selected from the group consisting of cardiolipin, phosphatidylglycerol, and combinations thereof.

25. The method according to claim 21, wherein the carotenoid is selected from the group consisting of zeaxanthin, lutein, and combinations thereof.

26. The method according to claim 1 2, wherein the C₂₀-D₃-retinal, corresponding to the aldehyde of the C₂₀-D₃-retinol acetate, C₂₀-D_1-3-retinoid forms A2E in vitro about 7 times slower than non-deuterium-enriched retinal the corresponding non-deuterated retinoid.

27. The method according to claim 1 2, wherein the pharmaceutical composition is administered directly to the eye.

28. A method of treating a macular degeneration, comprising administering an effective amount of a substituted C₂₀-D_1-3-retinoid to a patient in need thereof, wherein the substituted C₂₀-D_1-3-retinoid is selected from the group consisting of C₂₀-D_1-3-retinol, C₂₀-D_1-3-retinol ester, C₂₀-D_1-3-retinal and C₂₀-D_1-3-pro-vitamin A carotenoids.

29. A method of treating a macular degeneration, comprising administering an effective amount of a pharmaceutical composition to a patient in need thereof, wherein the pharmaceutical composition comprises a substituted C₂₀-D_1-3-retinoid, wherein the C₂₀-D_1-3-retinoid is selected from the group consisting of C₂₀-D_1-3-retinol, C₂₀-D_1-3-retinol ester, C₂₀-D_1-3-retinal and C₂₀-D_1-3-pro-vitamin A carotenoids, and a pharmaceutically acceptable carrier.

30. The method according to claim 29, wherein the substituted C₂₀-D_1-3-retinoid is a C₂₀-D₃-retinoid.

31. The method according to claim 29, wherein the pharmaceutical composition is suitable for use as a nutraceutical composition.

32. The method according to claim 29, wherein the macular degeneration is age-related macular degeneration.

33. The method according to claim 32, wherein the C₂₀-D_1-3-retinoid is C₂₀-D_1-3-retinol or a C₂₀-D_1-3-retinol ester.

34. The method according to claim 32, wherein the C₂₀-D_1-3-retinoid is C₂₀-D₃-retinol, a C₂₀-D₃-retinol ester, C₂₀-D₃-retinal, or a C₂₀-D₃-pro-vitamin A carotenoid.

35. The method according to claim 32, wherein the C₂₀-D_1-3-retinoid is C₂₀-D₃-retinol acetate.

36. The method according to claim 35, wherein the C₂₀-D₃-retinol acetate forms A2E about 7 times slower than non-deuterium-enriched retinol acetate.

37. The method according to claim 32, wherein the patient is in need of treatment for dry (non-neovascular) age-related macular degeneration.

38. The method according to claim 29, wherein the macular degeneration is Stargardt disease.

39. The method according to claim 38, wherein the C₂₀-D_1-3-retinoid is C₂₀-D_1-3-retinol or a C₂₀-D_1-3-retinol ester.

40. The method according to claim 38, wherein the C₂₀-D_1-3-retinoid is C₂₀-D₃-retinol, a C₂₀-D₃-retinol ester, C₂₀-D₃-retinal, or a C₂₀-D₃-pro-vitamin A-carotenoid.

41. The method according to claim 38, wherein the C₂₀-D_1-3-retinoid is C₂₀-D₃-retinol acetate.

42. The method according to claim 41, wherein the C₂₀-D₃-retinol acetate forms A2E about 7 times slower than non-deuterium-enriched retinal acetate.

43. The method according to claim 29, wherein the macular degeneration is selected from the group consisting of Vitelliform or Best disease, Sorsby'"'"'s fundus dystrophy, retinitis pigmentosa, and Malattia Leventinese.

44. The method according to claim 43, wherein the C₂₀-D_1-3-retinoid is C₂₀-D₃-retinol acetate.

45. The method according to claim 29, wherein the macular degeneration is characterized by one or more mutation(s) in the ABCA4 gene.

46. The method according to claim 29, wherein the substituted C₂₀-D_1-3-retinoid is present in the pharmaceutical composition at a level sufficient to deliver on average about 0.1 to about 90 mg/day to a patient.

47. The method according to claim 29, further comprising an additional active.

48. The method according to claim 47, wherein the additional active is selected from the group consisting of eye antioxidants, minerals, negatively-charged phospholipids, carotenoids, and combinations thereof.

49. The method according to claim 47, wherein the eye antioxidant is selected from the group consisting of vitamin C, vitamin E, beta-carotene, coenzyme Q, OT-551, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, butylated hydroxytoluene, resveratrol, a trolox analogue (PNU-83836-E), bilberry extract, and combinations thereof.

50. The method according to claim 47, wherein the mineral is selected from the group consisting of cupric oxide, zinc oxide, selenium-containing compounds, and combinations thereof.

51. The method according to claim 47, wherein the negatively charged phospholipid is selected from the group consisting of cardiolipin, phosphatidylglycerol, and combinations thereof.

52. The method according to claim 47, wherein the carotenoid is selected from the group consisting of zeaxanthin, lutein, and combinations thereof.

53. The method according to claim 29, wherein the C₂₀-D_1-3-retinoid forms A2E about 7 times slower than non-deuterium enriched retinoid.

54. The method according to claim 29, wherein the pharmaceutical composition is administered directly to the eye.