COMPOSITIONS AND METHODS FOR TREATING MACULAR DEGENERATION

• US 20110034554A1
• Filed: 09/12/2008
• Published: 02/10/2011
• 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
• Granted Patent: US 8,877,809 B2
• Time in Patent Office: Days
• US Class Current: 514/546
• 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
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents

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 formation of a lipofuscin pigment in the retina comprising 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.

2. The method according to claim 1, wherein the substituted C₂₀-retinoid is selected from the group consisting of a C₂₀-D₃-retinoid, a C₂₀-T₃-retinoid, and a C₂₀-F₃-retinoid.

3. The method according to claim 1, wherein the lipofuscin pigment is selected from the group consisting of A2E, all-trans-retinal (ATR)-dimer, and combinations thereof.

4. The method according to claim 1, wherein the substituted C₂₀-retinoid is administered as part of a pharmaceutical or a nutraceutical composition.

5. The method according to claim 1, wherein the substituted C₂₀-retinoid is administered as a unit dosage form.

6. A method of treating or ameliorating the effects of a disease characterized by an accumulation of a lipofuscin pigment in a retina comprising 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.

7. The method according to claim 6, wherein the substituted C₂₀-retinoid is selected from the group consisting of a C₂₀-D₃-retinoid, a C₂₀-T₃-retinoid, and a C₂₀-F₃-retinoid.

8. The method according to claim 6, wherein the lipofuscin pigment is selected from the group consisting of A2E, ATR-dimer, and combinations thereof.

9. The method according to claim 6, wherein the substituted C₂₀-retinoid is administered as part of a pharmaceutical nutraceutical composition

10. The method according to claim 6, wherein the substituted C₂₀-retinoid is administered as a unit dosage form.

11. The method according to claim 6, wherein the disease is macular degeneration.

12. The method according to claim 6, wherein the disease is selected from the group consisting of Stargardt, Vitelliform or Best (VMD), Sorsby'"'"'s Fundus Dystrophy, age related macular degeneration, and Malattia Leventinese.

13. The method according to claim 6, wherein the administration step comprises replacing a component of the patient'"'"'s diet that contains an all-trans-retinoid with a component that contains a substituted C₂₀-retinoid.

14. A composition for retarding formation of a lipofuscin pigment in the retina comprising a substituted C₂₀-retinoid and pharmaceutically acceptable carrier.

15. A composition according to claim 14, wherein the substituted C₂₀-retinoid is selected from the group consisting of a C₂₀-D₃-retinoid, a C₂₀-T₃-retinoid, and a C₂₀-F₃-retinoid.

16. A unit dosage form comprising the composition of claim 15.

17. A composition according to claim 15, which is a vitamin supplement.

18. A composition according to claim 15, which is a pharmaceutical formulation.

19. A method of retarding formation of a lipofuscin pigment selected from the group consisting of an A2E, an ATR dimer, and combinations thereof, the method comprising replacing an all-trans-retinal (ATR) substrate with a C₂₀-D₃-retinoid substrate under conditions sufficient to impede formation of A2E, ATR dimer, or both A2E and ATR dimer.

20. A composition comprising a pharmaceutically acceptable carrier and a compound according to formula I:

21. The composition according to claim 20, wherein the halogen is F.

22. The composition according to claim 21, wherein the compound is formula II:

23. The composition of claim 20, wherein R₄, R₅, and R₆ are independently selected from H or a substituent that slows lipofuscin formation.

24. The composition of claim 20, wherein R₄, R₅, and R₆ are independently selected from H or a substituent that slows the formation of at least one of A2E or ATR dimer.

25. The composition of claim 20, wherein R₄, R₅, and R₆ are independently selected from H or a substituent that slows hydrogen abstraction or migration at the C₂₀ position.

26. A composition according to claim 20 further comprising a supplement selected from the group consisting of a visual cycle antagonist, a molecule that inhibits influx of a retinoid into an eye, and combinations thereof.

27. A composition according to claim 26, wherein the visual cycle antagonist is selected from the group consisting of TDH, TDT, 13-cis-retinoic acid, ret-NH₂, and combinations thereof.

28. A composition according to claim 26, wherein the molecule that inhibits influx of a retinoid into an eye is fenretinide.

29. The composition according to claim 26 further comprising one or more additives.

30. The composition according to claim 29, wherein the additives are selected from the group consisting of zinc, vitamin E, vitamin D, and combinations thereof.

31. The composition according to claim 30, wherein the zinc is present in the composition at between about 3 to about 80 mg.

32. The composition according to claim 30, wherein the zinc is present in the composition at between about 3 to about 10 mg.

33. The composition according to claim 30, wherein the zinc is present in the composition at between about 10 to about 80 mg.

34. The composition according to claim 30, wherein the vitamin E is present in the composition at between about 3 to about 3,000 mg.

35. The composition according to claim 30, wherein the vitamin E is present in the composition at between about 3 to about 15 mg.

36. The composition according to claim 30, wherein the vitamin E is present in the composition at between about 15 to about 3,000 mg.

37. The composition according to claim 30, wherein the vitamin D is present in the composition at between about 0.005 to about 0.1 mg.

38. The composition according to claim 30, wherein the vitamin D is present in the composition at between about 0.005 to about 0.015 mg.

39. The composition according to claim 30, wherein the vitamin D is present in the composition at between about 0.015 to about 0.1 mg.

40. The composition according to claim 20, wherein the compound is present in the composition at a level sufficient to deliver about 0.1 to about 90 mg/day to a patient.

41. The composition according to claim 20 further comprising an additional active.

42. The composition according to claim 41, wherein the additional active is selected from the group consisting of eye antioxidants, minerals, negatively-charged phospholipids, carotenoids, and combinations thereof.

43. The composition according to claim 42, 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.

44. The composition according to claim 42, wherein the mineral is selected from the group consisting of cupric oxide, zinc oxide;

selenium-containing compounds, and combinations thereof.

45. The composition according to claim 42, wherein the negatively charged phospholipid is selected from the group consisting of cardiolipin, phosphatidylglycerol, and combinations thereof.

46. The composition according to claim 42, wherein the carotenoid is selected from the group consisting of zeaxanthin, lutein, and combinations thereof.

47. A method of retarding formation of A2E in a patient comprising replacing an all-trans-retinal (ATR) substrate with a substituted C₂₀-D₃-retinoid substrate in a patient under conditions sufficient to impede the formation of A2E.

48. The method according to claim 47, wherein the replacing step comprises administering to the patient a substituted C₂₀-D₃-retinoid substrate.

49. The method according to claim 48, wherein the substituted C₂₀-D₃-retinoid substrate is administered directly to the eye.