Ophthalmic compositions comprising calcineurin inhibitors or mTOR inhibitors

• US 8,435,544 B2
• Filed: 10/08/2008
• Issued: 05/07/2013
• Est. Priority Date: 10/08/2007
• Status: Active Grant

• Current Assignee: Aurinia Pharmaceuticals Inc.
• Original Assignee: Lux Biosciences, Inc.
• Inventors: Mitra, Ashim K., Velagaleti, Poonam R., Natesan, Subramanian
• Primary Examiner(s): Sullivan, Daniel
• Assistant Examiner(s): JAVIER, MELISSA L
• Application Number:
  US12/247,701
• Publication Number:
  US 20090092665A1
• Time in Patent Office: 1,672 Days
• Field of Search: None
• US Class Current: 424/400
• 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 in the form of mixed micelles, comprising:

a calcineurin inhibitor or a mammalian target of rapamycin (mTOR) inhibitor;

vitamin E tocopherol polyethylene glycol succinate (TPGS) with a hydrophilic/lipophilic balance (HLB) index greater than about 10; and

octoxynol-40 with an HLB index of greater than about 13,

wherein an absolute difference between the HLB index of the vitamin E TPGS and the HLB index of the octoxynol-40 is greater than about 3, and

wherein the composition is in the form of mixed micelles having the vitamin E TPGS and the octoxynol-40.

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.

40. The pharmaceutical composition of claim 1 wherein the composition is suitable for topical application to ocular tissue.

41. The pharmaceutical composition of claim 1 wherein the calcineurin inhibitor or mTOR inhibitor is capable of reaching a back of an eye.

42. The pharmaceutical composition of claim 1 wherein the calcineurin inhibitor or mTOR inhibitor is present from about 0.01 wt % to about 10 wt % of a total volume of the composition.

43. The pharmaceutical composition of claim 1 wherein the composition is an aqueous solution.

3. A pharmaceutical composition in the form of mixed micelles, comprising:

a calcineurin inhibitor;

vitamin E tocopherol polyethylene glycol succinate (TPGS); and

octoxynol-40,

wherein the composition is in the form of mixed micelles having the vitamin E TPGS and the octoxynol-40 and is suitable for topical application to ocular tissue.

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

5. 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.

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

7. 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.

8. 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.

9. 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.

10. The pharmaceutical composition of claim 3 further comprising one or more bioadhesive polymers selected from the group consisting of polyvinylpyrrolidone (PVP)-K-30, PVP-K-90, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HEC), and polycarbophil.

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

44. The pharmaceutical composition of claim 3 wherein the composition is an aqueous solution.

12. A pharmaceutical composition in the form of mixed micelles, comprising:

a mammalian target of rapamycin (mTOR) inhibitor;

vitamin E tocopherol polyethylene glycol succinate (TPGS); and

octoxynol-40,

wherein the composition is in the form of mixed micelles having the vitamin E TPGS and the octoxynol-40 and is suitable for topical application to ocular tissue.

13. The pharmaceutical composition of claim 12 wherein the composition forms optically clear mixed micelles.

14. The pharmaceutical composition of claim 12 wherein the mTOR inhibitor includes one of sirolimus, temsirolimus, everolimus, analogs thereof, pharmaceutically acceptable salts thereof, or combinations thereof.

45. The pharmaceutical composition of claim 12 wherein the composition is an aqueous solution.

15. An artificial tear composition comprising an aqueous solution of mixed micelles, the mixed micelles formed from vitamin E tocopherol polyethylene glycol succinate (TPGS) and octoxynol-40, wherein the composition is in the form of mixed micelles having the vitamin E TPGS and the octoxynol-40.

16. The composition of claim 15 wherein the aqueous solution includes various ingredients chosen from one of hydrophilic polymer excipients, tonicity agents, buffers, sugars selected from trehalose, mannose, D-galactose, and lactose, preservatives, co-solvents or antioxidants.

17. The composition of claim 15 wherein the aqueous solution includes polyvinylpyrrolidone (PVP)-K-90, sodium chloride, at least one sodium phosphate and water.

18. The composition of claim 15 wherein the aqueous solution has a pH ranging from about 6.6 to about 7.0.

19. A pharmaceutical composition in the form of mixed micelles, comprising:

voclosporin;

vitamin E tocopherol polyethylene glycol succinate (TPGS); and

octoxynol-40,

wherein the composition is in the form of mixed micelles having the vitamin E TPGS and the octoxynol-40 and is suitable for topical application to ocular tissue.

20. The pharmaceutical composition of claim 19 wherein the voclosporin is a trans-version of the voclosporin.

21. The pharmaceutical composition of claim 19 wherein the voclosporin is present from about 0.01 wt % to about 10 wt % of a total volume of the composition.

22. The pharmaceutical composition of claim 19 wherein the vitamin E TPGS is present in from about 0.01 wt % to about 20 wt % of a total volume of the composition, and the octoxynol-40 is present in from about 0.001 wt % to about 10 wt % of a total volume of the composition.

23. The pharmaceutical composition of claim 19 wherein the voclosporin is capable of reaching a back of an eye.

24. The pharmaceutical composition of claim 19 wherein the voclosporin includes a trans-version of the voclosporin.

46. The pharmaceutical composition of claim 19 wherein the composition is an aqueous solution.

25. A pharmaceutical composition in the form of mixed micelles, comprising:

cyclosporine A;

vitamin E tocopherol polyethylene glycol succinate (TPGS); and

octoxynol-40,

wherein the composition is in the form of mixed micelles having the vitamin E TPGS and the octoxynol-40 and is suitable for topical application to ocular tissue.

26. The pharmaceutical composition of claim 25 wherein the cyclosporine A is present from about 0.01 wt % to about 10 wt % of a total volume of the composition.

27. The pharmaceutical composition of claim 25 wherein the cyclosporine A is present at about 0.2 wt % of a total volume of the composition.

28. The pharmaceutical composition of claim 25 wherein the vitamin E TPGS is present in from about 0.01 wt % to about 20 wt % of a total volume of the composition, and the octoxynol-40 is present in from about 0.001 wt % to about 10 wt % of a total volume of the composition.

29. The pharmaceutical composition of claim 25 wherein the cyclosporine A is capable of reaching a back of an eye.

47. The pharmaceutical composition of claim 25 wherein the composition is an aqueous solution.

30. A pharmaceutical composition in the form of mixed micelles, comprising:

tacrolimus;

vitamin E tocopherol polyethylene glycol succinate (TPGS); and

octoxynol-40,

wherein the composition is in the form of mixed micelles having the vitamin E TPGS and the octoxynol-40 and is suitable for topical application to ocular tissue.

31. The pharmaceutical composition of claim 30 wherein the tacrolimus is present from about 0.01 wt % to about 10 wt % of a total volume of the composition.

32. The pharmaceutical composition of claim 30 wherein the tacrolimus is present at about 0.2 wt % of a total volume of the composition.

33. The pharmaceutical composition of claim 30 wherein the vitamin E TPGS is present in from about 0.01 wt % to about 20 wt % of a total volume of the composition, and the octoxynol-40 is present in from about 0.001 wt % to about 10 wt % of a total volume of the composition.

34. The pharmaceutical composition of claim 30 wherein the tacrolimus is capable of reaching a back of an eye.

48. The pharmaceutical composition of claim 30 wherein the composition is an aqueous solution.

35. A pharmaceutical composition in the form of mixed micelles, comprising:

sirolimus;

vitamin E tocopherol polyethylene glycol succinate (TPGS); and

octoxynol-40,

wherein the composition is in the form of mixed micelles having the vitamin E TPGS and the octoxynol-40 and is suitable for topical application to ocular tissue.

36. The pharmaceutical composition of claim 35 wherein the sirolimus is present from about 0.01 wt % to about 10 wt % of a total volume of the composition.

37. The pharmaceutical composition of claim 35 wherein the sirolimus is present at about 0.2 wt % of a total volume of the composition.

38. The pharmaceutical composition of claim 35 wherein the vitamin E TPGS is present in from about 0.01 wt % to about 20 wt % of a total volume of the composition, and the octoxynol-40 is present in from about 0.001 wt % to about 10 wt % of a total volume of the composition.

39. The pharmaceutical composition of claim 35 wherein the sirolimus is capable of reaching a back of an eye.

49. The pharmaceutical composition of claim 35 wherein the composition is an aqueous solution.