Ophthalmic compositions comprising calcineurin inhibitors or mTOR inhibitors

1. 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 mammalian target of rapamycin (mTOR) inhibitor, the composition further having vitamin E tocopherol polyethylene glycol succinate (TPGS) and octoxynol-40, wherein the composition is an aqueous solution of mixed micelles formed with vitamin E TPGS and octoxynol-40.

2. The method of claim 1 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, or an immune rejection of a corneal allograft.

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

4. The method of claim 1 wherein the calcineurin inhibitor is voclosporin.

5. The method of claim 1 further comprising allowing the calcineurin inhibitor or the mTOR inhibitor to reach a back of the eye.

6. 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 a mammalian target of rapamycin (mTOR) inhibitor encapsulated in micelles, the micelles formed with 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; and

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

7. The method of claim 6 wherein the calcineurin inhibitor or the mTOR inhibitor includes voclosporin, cyclosporine A, pimecrolimus, tacrolimus, sirolimus, temsirolimus, everolimus, analogs thereof, pharmaceutically acceptable salts thereof, or combinations thereof.

8. The method of claim 6 wherein the calcineurin inhibitor is voclosporin.

9. The method of claim 6 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.

10. The method of claim 6 further comprising administering topically the pharmaceutical composition to an eye of the animal and allowing the calcineurin inhibitor or the mTOR inhibitor to reach a back of the eye.

11. 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 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; and

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

12. The method of claim 11 wherein the calcineurin inhibitor includes voclosporin, cyclosporine A, pimecrolimus, tacrolimus, analogs thereof, pharmaceutically acceptable salts thereof, or combinations thereof.

13. The method of claim 11 wherein the calcineurin inhibitor is voclosporin.

14. The method of claim 11 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.

15. The method of claim 11 further comprising further comprising administering topically the pharmaceutical composition to an eye of the subject and allowing the calcineurin inhibitor to reach a back of the eye.

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

mixing a calcineurin inhibitor or a mammalian target of rapamycin (mTOR) inhibitor with vitamin E tocopherol polyethylene glycol succinate (TPGS) having a hydrophilic/lipophilic balance (HLB) index greater than about 10 and octoxynol-40 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 a mixed micelle composition having mixed micelles formed with vitamin E TPGS and octoxynol-40,

wherein the mixed micelle composition is optically clear.

17. The method of claim 16 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.

18. The method of claim 16 wherein the calcineurin inhibitor or the mTOR inhibitor includes voclosporin, cyclosporine A, pimecrolimus, tacrolimus, sirolimus, temsirolimus, everolimus, analogs thereof, pharmaceutically acceptable salts thereof, or combinations thereof.

19. The method of claim 16 wherein the calcineurin inhibitor is voclosporin.

20. The method of claim 1 wherein the calcineurin inhibitor is pimecrolimus.

21. The method of claim 1 wherein the calcineurin inhibitor is tacrolimus.

22. The method of claim 1 wherein the mTOR inhibitor is sirolimus.