Ophthalmic compositions comprising calcineurin inhibitors or mTOR inhibitors

• US 8,535,694 B2
• Filed: 08/19/2011
• Issued: 09/17/2013
• 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:
  US13/213,451
• Publication Number:
  US 20110300195A1
• Time in Patent Office: 760 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 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.

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.

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.