Rapamycin formulations and methods of their use

• US 20060264453A1
• Filed: 02/09/2006
• Published: 11/23/2006
• Est. Priority Date: 02/09/2005
• Status: Active Grant

• Current Assignee: Santen Pharmaceutical Company Limited
• Original Assignee: MacuSight, Inc (Santen Pharmaceutical Company Limited)
• Inventors: Dor, Philippe Jm, Nivaggioli, Thierry, Weber, David A., Mudumba, Sreenivasu, Farooq, Sidiq
• Granted Patent: US 8,637,070 B2
• Time in Patent Office: Days
• US Class Current: 514/291
• CPC Class Codes: A61K 31/045 Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• 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 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• 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 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• 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 9/0046 Ear
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/08 Mydriatics or cycloplegics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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

Described herein are liquid rapamycin formulations. Described herein are methods of treating or preventing diseases or conditions, such as choroidal neovascularization, wet AMD and dry AMD, and preventing transition of dry AMD to wet AMD, using the liquid rapamycin formulations described herein.

Claims

1. A liquid formulation comprising about 2% (w/w) of rapamycin, about 94% (w/w) PEG 400, and about 4% (w/w) of ethanol.

2. A method for treating wet age-related macular degeneration in a human subject, the method comprising administering to the human subject by intraocular or periocular delivery a volume of the liquid formulation of claim 1 containing an amount of rapamycin effective to treat wet age-related macular degeneration in the human subject.

3. A method for preventing wet age-related macular degeneration in a human subject, the method comprising administering to the human subject by intraocular or periocular delivery a volume of the liquid formulation of claim 1 containing an amount of rapamycin effective to prevent wet age-related macular degeneration in the human subject.

4. The method of claim 3, wherein the human subject is identified as being at heightened risk of developing wet age-related macular degeneration in the eye to which the liquid formulation is administered.

5. The method of claim 4, wherein the human subject has dry age-related macular degeneration in at least one eye.

6. The method of claim 4, wherein the human subject has wet age-related macular degeneration in one eye and the liquid formulation is administered to the eye without wet age-related macular degeneration.

7. A method for treating dry age-related macular degeneration in a human subject, the method comprising administering to the human subject by intraocular or periocular delivery a volume of the liquid formulation of claim 1 containing an amount of rapamycin effective to treat dry age-related macular degeneration in the human subject.

8. A method for preventing wet age-related macular degeneration in a human subject having dry age-related macular degeneration, the method comprising administering to a human subject having dry age-related macular degeneration a volume of the liquid formulation of claim 1 containing an amount of rapamycin effective to prevent wet age-related macular degeneration in the human subject, wherein the volume is administered by intraocular or periocular delivery.

9. A unit dosage form comprising a volume of the liquid formulation of claim 1 containing less than 4 mg of rapamycin.

10. The unit dosage form of claim 9, wherein the volume of liquid formulation contains less than 2 mg of rapamycin.

11. The unit dosage form of claim 9, wherein the volume of liquid formulation contains between 20 μ

g and 2.5 mg of rapamycin.

12. The unit dosage form of claim 9, wherein the volume of liquid formulation contains between 20 μ

g and 4 mg of rapamycin.

13. A unit dosage form comprising a volume of the liquid formulation of claim 1 containing less than 150 μ

L of PEG 400.

14. The unit dosage form of claim 13, containing less than 100 μ

L of PEG 400.

15. The unit dosage form of claim 14, containing less than 50 μ

L of PEG 400.

16. The unit dosage form of claim 15, containing 30 μ

L of PEG 400.

17. A unit dosage form comprising a volume of less than 200 μ

L of the liquid formulation of claim 1.

18. The unit dosage form of claim 17, comprising a volume of less than 100 μ

L.

19. The unit dosage form of claim 18, comprising a volume of less than 50 μ

L.

20. The unit dosage form of claim 19, comprising a volume of less than 20 μ

L.

21. The unit dosage form of claim 20, comprising a volume of less than 1 μ

L.

22. The method of claim 2, wherein the volume of liquid formulation is administered to the human subject by placement in the vitreous and the volume of liquid formulation contains less than 3 mg of rapamycin.

23. The method of claim 2, wherein the volume of liquid formulation is administered to the human subject by placement in the vitreous and the volume of liquid formulation contains less than 100 μ

L of PEG 400.

24. The method of claim 2, wherein the volume of liquid formulation is administered to the human subject by placement in the vitreous and the volume of liquid formulation contains less than 3 mg of rapamycin and less than 100 μ

L of PEG 400.

25. The method of claim 2, wherein the volume of liquid formulation is administered to the human subject by placement between the sclera and conjunctiva and the volume of liquid formulation contains less than 4 mg of rapamycin.

26. The method of claim 2, wherein the volume of liquid formulation is administered to the human subject by placement between the sclera and conjunctiva and the volume of liquid formulation contains less than 150 μ

L of PEG 400.

27. The method of claim 2, wherein the volume of liquid formulation is administered to the human subject by placement between the sclera and conjunctiva and the volume of liquid formulation contains less than 4 mg of rapamycin and contains less than 150 μ

L of PEG 400.

28. A liquid formulation comprising rapamycin and a non-aqueous liquid component, wherein the rapamycin is between 0.1% (w/w) and 6.0% (w/w) of the liquid formulation and the non-aqueous liquid component is at least 90% (w/w) of the liquid formulation;

and wherein the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 0.01 ng/mg for a period of time of at least 30 days following administration of the liquid formulation.

29. The liquid formulation of claim 28, wherein the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 0.01 ng/mg for a period of time of at least 120 days following administration of the liquid formulation.

30. The liquid formulation of claim 28, wherein the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 0.1 ng/mg for a period of time of at least 30 days following administration of the liquid formulation.

31. The liquid formulation of claim 30, wherein the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 0.1 ng/mg for a period of time of at least 90 days following administration of the liquid formulation.

32. A liquid formulation comprising rapamycin and a non-aqueous liquid component, wherein the rapamycin is between 0.1% (w/w) and 6.0% (w/w) of the liquid formulation and the non-aqueous liquid component is at least 90% (w/w) of the liquid formulation;

and wherein the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the vitreous of the rabbit eye of at least 1000 ng/ml for a period of time of at least 30 days following administration of the liquid formulation.

33. The liquid formulation of claim 32, wherein the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the vitreous of the rabbit eye of at least 1000 ng/ml for a period of time of at least 120 days following administration of the liquid formulation.

34. A liquid formulation comprising rapamycin and a non-aqueous liquid component, wherein the rapamycin is between 0.1% (w/w) and 6.0% (w/w) of the liquid formulation and the non-aqueous liquid component is at least 90% (w/w) of the liquid formulation;

and wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the vitreous of the rabbit eye of at least 0.01 ng/ml for a period of time of at least 30 days following administration of the liquid formulation.

35. The liquid formulation of claim 34, wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the vitreous of the rabbit eye of at least 0.01 ng/ml for a period of time of at least 120 days following administration of the liquid formulation.

36. The liquid formulation of claim 34, wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the vitreous of the rabbit eye of at least 0.1 ng/ml for a period of time of at least 30 days following administration of the liquid formulation.

37. The liquid formulation of claim 36, wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the vitreous of the rabbit eye of at least 0.1 ng/ml for a period of time of at least 120 days following administration of the liquid formulation.

38. A liquid formulation comprising rapamycin and a non-aqueous liquid component, wherein the rapamycin is between 0.1% (w/w) and 6.0% (w/w) of the liquid formulation and the non-aqueous liquid component is at least 90% (w/w) of the liquid formulation;

and wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 0.001 ng/mg for a period of time of at least 30 days following administration of the liquid formulation.

39. The liquid formulation of claim 38, wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 0.001 ng/mg for a period of time of at least 120 days following administration of the liquid formulation.

40. The liquid formulation of claim 38, wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 0.005 ng/mg for a period of time of at least 30 days following administration of the liquid formulation.

41. The liquid formulation of claim 40, wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 0.005 ng/mg for a period of time of at least 120 days following administration of the liquid formulation.

42. The liquid formulation of claim 40, wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of rapamycin sufficient to achieve an average concentration of rapamycin in the retina choroid of the rabbit eye of at least 0.01 ng/mg for a period of time of at least 30 days following administration of the liquid formulation.