OPHTHALMIC COMPOSITIONS COMPRISING CALCINEURIN INHIBITORS OR mTOR INHIBITORS

• US 20090092665A1
• Filed: 10/08/2008
• Published: 04/09/2009
• Est. Priority Date: 10/08/2007
• Status: Active Grant

• Current Assignee: Aurinia Pharmaceuticals Inc.
• Original Assignee: Lux Biosciences, Inc.
• Inventors: Natesan, Subramanian, Mitra, Ashim K., Velagaleti, Poonam R.
• Granted Patent: US 8,435,544 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• 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 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• 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

The embodiments disclosed herein relate to ophthalmic compositions comprising calcineurin inhibitors or mTOR inhibitors, and more particularly to methods for treating an ocular disease and/or condition using the disclosed compositions. According to aspects illustrated herein, there is provided a pharmaceutical composition that includes a calcineurin inhibitor or an mTOR inhibitor; a first surfactant with an HLB index greater than about 10; and a second surfactant with an HLB index of greater than about 13, wherein an absolute difference between the HLB index of the first surfactant and the HLB index of the second surfactant is greater than about 3, and wherein the composition forms mixed micelles.

Claims

1. A pharmaceutical composition comprising:

a calcineurin inhibitor or an mTOR inhibitor;

a first surfactant with an HLB index greater than about 10; and

a second surfactant with an HLB index of greater than about 13,

wherein an absolute difference between the HLB index of the first surfactant and the HLB index of the second surfactant is greater than about 3, and

wherein the composition forms mixed micelles.

2. The pharmaceutical composition of claim 1 wherein the calcineurin inhibitor or the mTOR inhibitor includes one of voclosporin, cyclosporine A, pimecrolimus, tacrolimus, sirolimus, temsirolimus, everolimus, analogs thereof, pharmaceutically acceptable salts thereof, or combinations thereof.

3. A pharmaceutical composition comprising:

a calcineurin inhibitor;

vitamin E TPGS; and

octoxynol-40,

wherein the composition is suitable for topical application to ocular tissue.

4. The pharmaceutical composition of claim 3 wherein the composition forms mixed micelles.

5. The pharmaceutical composition of claim 3 wherein the composition forms optically clear mixed micelles.

6. The pharmaceutical composition of claim 3 wherein the calcineurin inhibitor includes one of voclosporin, cyclosporine A, pimecrolimus, tacrolimus, analogs thereof, pharmaceutically acceptable salts thereof, or combinations thereof.

7. The pharmaceutical composition of claim 3 wherein the calcineurin inhibitor is voclosporin.

8. The pharmaceutical composition of claim 3 wherein the calcineurin inhibitor is present from about 0.01 weight percent to about 10 weight percent of a total volume of the composition.

9. The pharmaceutical composition of claim 3 wherein the vitamin E TPGS is present in from about 0.01 wt % to about 20 wt % of a total volume of the composition.

10. The pharmaceutical composition of claim 3 wherein the octoxynol-40 is present in from about 0.001 wt % to about 10 wt % of a total volume of the composition.

11. The pharmaceutical composition of claim 3 further comprising one or more bioadhesive polymers selected from the group consisting of PVP-K-30, PVP-K-90, HPMC, HEC, and polycarbophil.

12. The pharmaceutical composition of claim 3 further comprising one or more additives selected from the group consisting of trehalose, mannose, D-galactose, and lactose.

13. A pharmaceutical composition comprising:

an mTOR inhibitor;

vitamin E TPGS; and

octoxynol-40,

wherein the composition is suitable for topical application to ocular tissue.

14. The pharmaceutical composition of claim 13 wherein the composition forms mixed micelles.

15. The pharmaceutical composition of claim 13 wherein the composition forms optically clear mixed micelles.

16. The pharmaceutical composition of claim 13 wherein the mTOR inhibitor includes one of sirolimus, temsirolimus, everolimus, analogs thereof, pharmaceutically acceptable salts thereof, or combinations thereof.

17. A method of preparing a mixed micelle composition comprising:

mixing a calcineurin inhibitor or an mTOR inhibitor with a first surfactant having an HLB index greater than about 10 and a second surfactant having an HLB index of greater than about 13 in a solvent to form a solvent solution;

evaporating the solvent solution to form a near-solid matter;

hydrating the near-solid matter with an aqueous solution; and

dissolving the near-solid mixture to produce the mixed micelle composition,

wherein the mixed micelle composition is optically clear.

18. The method of claim 17 wherein the first surfactant is vitamin E TPGS and the second surfactant is octoxynol-40.

19. The method of claim 17 further comprising mixing a bioadhesive polymer into the aqueous solution, wherein the bioadhesive polymer is selected from the group consisting of PVP-K-30, PVP-K-90, HPMC, HEC, and polycarbophil.

20. The method of claim 17 wherein the calcineurin inhibitor is voclosporin.

21. The method of claim 20 wherein the voclosporin is present from about 0.01% to about 10% in the mixed micelle composition.

22. A method for treating an ocular disease in a patient in need thereof comprising administering topically to an eye of the patient a composition including a therapeutically effective amount of a calcineurin inhibitor or a mTOR inhibitor, the composition further having vitamin E TPGS and octoxynol-40, wherein the composition is an aqueous solution of mixed micelles.

23. The method of claim 22 wherein the ocular disease is an inflammatory ocular surface disease selected from the group consisting of dry eye syndrome (DES), Sjogren'"'"'s syndrome, uveitis, conjunctivitis (pink eye), keratitis, keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), autoimmune disorders of the ocular surface, including cicatrizing conjunctivitis, blepharitis, and scleritis.

24. The method of claim 22 wherein the ocular disease is the immune rejection of a corneal allograft.

25. The method of claim 23 wherein the inflammatory ocular surface disease is dry eye syndrome.

26. The method of claim 22 wherein the calcineurin inhibitor is voclosporin.

27. A method for treating, reducing, ameliorating, or alleviating an inflammatory ocular disease in an animal comprising:

providing a mixed micellar pharmaceutical composition having a calcineurin inhibitor or an mTOR inhibitor encapsulated in micelles, the micelles formed with a first surfactant with an HLB index greater than about 10 and a second surfactant with an HLB index of greater than about 13; and

administering to the animal an amount of the pharmaceutical composition at a frequency sufficient to treat, reduce, ameliorate, or alleviate the inflammatory ocular disease.

28. The method of claim 27 wherein the calcineurin inhibitor or the mTOR inhibitor includes one of voclosporin, cyclosporine A, pimecrolimus, tacrolimus, sirolimus, temsirolimus, everolimus, analogs thereof, pharmaceutically acceptable salts thereof, or combinations thereof.

29. The method of claim 28 wherein the calcineurin inhibitor is voclosporin.

30. The method of claim 27 wherein the first surfactant is vitamin E TPGS and the second surfactant is octoxynol-40.

31. The method of claim 27 wherein a weight percent of the calcineurin inhibitor or the mTOR inhibitor in the pharmaceutical composition ranges from about 0.01 weight percent to about 10 weight percent of a total volume of the pharmaceutical composition.

32. The method of claim 27 wherein the animal is selected from the group consisting of dogs, horses, cats, rabbits, gerbils, hamsters, rodents, birds, aquatic mammals, cattle, pigs, camelids, and other zoological animals.

33. The method of claim 27 wherein the pharmaceutical composition is administered topically.

34. The method of claim 27 wherein the inflammatory ocular disease is selected from the group consisting of dry eye syndrome (DES), Sjogren'"'"'s syndrome, uveitis, conjunctivitis (pink eye), keratitis, keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), autoimmune disorders of the ocular surface, including cicatrizing conjunctivitis, blepharitis, and scleritis.

35. A method for treating, reducing, ameliorating, or alleviating a back-of-the-eye condition or disorder in a subject comprising:

providing a mixed micellar pharmaceutical composition having a calcineurin inhibitor encapsulated in micelles formed with a first surfactant with an HLB index greater than about 10 and a second surfactant with an HLB index of greater than about 13; and

administering to the subject an amount of the pharmaceutical composition at a frequency sufficient to treat, reduce, ameliorate, or alleviate the back-of-the-eye condition or disorder.

36. The method of claim 35 wherein the first surfactant is vitamin E TPGS, and the second surfactant is octoxynol-40.

37. The method of claim 35 wherein the calcineurin inhibitor is voclosporin.

38. The method of claim 35 wherein the calcineurin inhibitor includes one of voclosporin, cyclosporine A, pimecrolimus, tacrolimus, analogs thereof, pharmaceutically acceptable salts thereof, or combinations thereof

39. The method of claim 35 wherein a weight percent of the calcineurin inhibitor in the pharmaceutical composition ranges from about 0.01 weight percent to about 10.0 weight percent of a total volume of the composition.

40. The method of claim 35 wherein the subject is a human.

41. The method of claim 35 wherein the subject is an animal.

42. The method of claim 41 wherein the animal is selected from the group consisting of dogs, horses, cats, rabbits, gerbils, hamsters, rodents, birds, aquatic mammals, cattle, pigs, camelids, and other zoological animals.

43. The method of claim 35 wherein the pharmaceutical composition is administered topically.

44. The method of claim 35 wherein the frequency of administration is once daily.

45. The method of claim 35 wherein the frequency of administration is in the range from about one to about eight times a day.

46. The method of claim 35 wherein the back-of-the-eye condition or disorder is selected from the group consisting of diabetic retinopathy (“

DR”

), age-related macular degeneration (“

AMD”

), diabetic macular edema (“

DME”

), posterior uveitis, and combinations thereof.

47. An artificial tear composition comprising an aqueous solution of mixed micelles, the mixed micelles formed from a vitamin E tocopherol polyethylene glycol succinate (TPGS) derivative and an ethoxylated octylphenol surfactant.

48. The composition of claim 47 wherein the ethoxylated octylphenol surfactant is octoxynol-40.

49. The composition of claim 47 wherein the aqueous solution includes various ingredients chosen from one of hydrophilic polymer excipients, tonicity agents, buffers, sugars such as trehalose, mannose, D-galactose, and lactose, preservatives, co-solvents or antioxidants.

50. The composition of claim 47 wherein the aqueous solution includes PVP-K-90, sodium chloride, at least one sodium phosphate and water.

51. The composition of claim 47 wherein the aqueous solution has a pH ranging from about 6.6 to about 7.0.