Claims for Patent: 7,332,472

Summary for Patent: 7,332,472

Title:	Cyclosporine analogue mixtures and their use as immunomodulating agents
Abstract:	The invention is directed to isomeric mixtures of cyclosporine analogues that are structurally similar to cyclosporine A. The mixtures possess enhanced efficacy and reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. Embodiments of the present invention are directed toward cis and trans-isomers of cyclosporin A analogs referred to as ISA.sub.TX247, and derivatives thereof. Mixtures of ISA.sub.TX247 isomers exhibit a combination of enhanced potency and reduced toxicity over the naturally occurring and presently known cyclosporins. ISA.sub.TX247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of stereoselectivity. The ratio of isomers in a mixture may range from about 10 to 90 percent by weight of the (E)-isomer to about 90 to 10 percent by weight of the (Z)-isomer, based on the total weight of the mixture.
Inventor(s):	Naicker; Selvaraj (Edmonton, CA), Yatscoff; Randall W. (Edmonton, CA), Foster; Robert T. (Edmonton, CA)
Assignee:	Isotechnika Inc. (Edmonton, CA)
Application Number:	11/118,830
Patent Claims:	1. A composition comprising an isomeric mixture of a cyclosporine analogue modified at the 1-amino acid residue with a 1,3-diene substituent, wherein the isomeric mixture comprises about 90% to about 95% of the E-isomer and about 10% to about 5% of the Z-isomer, wherein the isomers are the isomers E- and Z- as specified below: ##STR00003## 2. A composition comprising an isomeric mixture of a cyclosporine analogue modified at the 1-amino acid residue with a 1,3-diene substituent, wherein the isomeric mixture comprises greater than or equal to about 95% of the E-isomer and less than or equal to about 5% of the Z-isomer, wherein the isomers are the isomers E- and Z- as specified below: ##STR00004## 3. A pharmaceutical composition comprising an isomeric cyclosporine analogue mixture according to claim 1 or 2 and a pharmaceutically acceptable excipient. 4. The pharmaceutical composition of claim 3, which comprises a gelatin capsule containing the isomeric analogue mixture, a liquid solution containing a surfactant, ethanol, a lipophilic and/or ampiphilic solvent. 5. The pharmaceutical composition of claim 4, which contains about 50 mg isomeric mixture. 6. The pharmaceutical composition of claim 3, which comprises a liquid solution containing a surfactant, ethanol, a lipophilic and/or an ampiphilic solvent. 7. The pharmaceutical composition of claim 6, which comprises d-alpha Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), medium chain triglyceride (MCT) oil, Tween 40, and ethanol. 8. The pharmaceutical composition of claim 7, which is in unit dosage form. 9. The pharmaceutical composition of claim 8, which contains from about 5 mg to about 500 mg of the isomeric mixture. 10. The pharmaceutical composition of claim 6, wherein the solution contains 50 mg/mL isomeric mixture. 11. The pharmaceutical composition of claim 3, which is formulated for oral administration. 12. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is formulated to provide an amount of isomeric cyclosporine analogue that is about 0.05 mg to about 50 mg per kilogram of body weight per day. 13. The pharmaceutical composition of claim 12, wherein the amount of isomeric cyclosporine analogue mixture is about 0.1 mg to about 10 mg per kilogram of body weight per day. 14. The pharmaceutical composition of claim 13, wherein the amount of isomeric cyclosporine analogue mixture is about 0.5 to about 10 mg/kg/day. 15. The pharmaceutical composition of claim 14, wherein the amount of an isomeric cyclosporine analogue mixture is about 2 to about 6 mg/kg/day and wherein the pharmaceutical composition is formulated to be administered orally twice daily. 16. The pharmaceutical composition of claim 15, wherein the amount of isomeric cyclosporine analogue mixture is about 0.5 to about 3 mg/kg/day and wherein the pharmaceutical composition is formulated to be administered orally, twice daily. 17. A method for producing immunosuppression comprising administering a therapeutically effective amount of the isomeric cyclosporine analogue mixture according to claim 1 or 2 to an animal. 18. The method of claim 17, wherein said animal is a human. 19. The method of claim 17, wherein the amount of the isomeric cyclosporine analogue mixture to be administered is about 0.05 mg to about 50 mg per kilogram of body weight per day. 20. The method of claim 19 wherein the amount of the isomeric cyclosporine analogue mixture to be administered is about 0.1 mg to about 10 mg per kilogram of body weight per day. 21. The method of claim 20, wherein the amount of the isomeric cyclosporine analogue mixture to be administered is about 0.5 to about 10 mg/kg/day. 22. The method of claim 21, wherein the amount of an isomeric cyclosporine analogue mixture to be administered is about 2 to about 6 mg/kg/day and wherein the pharmaceutical composition is formulated to be administered orally, twice daily. 23. The method of claim 21, wherein the amount of an isomeric cyclosporine analogue mixture to be administered is about 0.5 to about 3 mg/kg/day and wherein the pharmaceutical composition is formulated to be administered orally, twice daily. 24. The method of claim 17, wherein said immunosuppression is to treat or alleviate acute organ or tissue transplant rejection. 25. The method of claim 24, wherein said transplant rejection is selected from the group consisting of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, bowel, and comeal transplant rejection. 26. The method of claim 17, wherein said immunosuppression is to treat or alleviate T-cell mediated rejection. 27. The method of claim 17, wherein said immunosuppression is to treat or alleviate graft-versus-host disease. 28. The method of claim 27 wherein said disease follows bone marrow transplantation. 29. The method of claim 17, wherein said immunosuppression to treat or alleviate chronic rejection of a transplanted organ. 30. The method of claim 29, wherein said chronic rejection is graft vessel disease. 31. The method of claim 17, wherein said immunosuppression is to treat or alleviate xenograft rejection. 32. The method of claim 31, wherein said xenograft rejection is selected from the group consisting of acute, hyperacute and chronic rejection of an organ occurring when the organ donor is of a different species from the recipient. 33. The method of claim 32, wherein said xenograft rejection is rejection mediated by B-cells or antibody-mediated rejection. 34. The method of claim 17, wherein said immunosuppression is to treat or alleviate an autoimmune disease or condition or an inflammatory disease or condition. 35. The method of claim 34, wherein said disease or condition is selected from the group consisting of arthritis, rheumatoid arthritis, arthritis chronica progrediente, arthritis deformans and other rheumatic diseases. 36. The method of claim 34, wherein said disease or condition is selected from the group consisting of hematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, (autoimmune) inflammatory bowel disease, ulcerative colitis, Crohn's disease, endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy and juvenile dermatomyositis. 37. The method of claim 34, wherein said disease or condition is selected from the group consisting of psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullous acquisita, other inflammatory or allergic conditions of the skin, inflammatory conditions of the lungs and airways, asthma, allergies and pneumoconiosis. 38. The method of claim 17, wherein the immunosuppression is to prevent allograft or xenograft rejection. 39. The method of claim 38, wherein the rejection is rejection of kidney, heart, or liver. 40. A method of reducing the toxicity of an immunosuppressive cyclosporine analogue by preparing an isomeric mixture of claim 1 or 2 for use as an immunosuppressive agent, the mixture having reduced toxicity relative to Cyclosporine A. 41. The method of claim 40, wherein the immunosuppressive agent comprises the isomeric cyclosporine analogue mixture in an amount selected from the group consisting of about 0.05 mg to about 50 mg per kilogram of body weight per day; about 0.1 mg to about 10 mg per kilogram of body weight per day; about 0.5 to about 10 mg/kg/day; about 2 to about 6 mg/kg/day, administered orally twice a day; and about 0.5 to about 3 mg/kg/day, administered orally twice a day. 42. A method of increasing the efficacy of an immunosuppressive cyclosporine analogue by preparing an isomeric mixture of claim 1 or 2 for use as an immunosuppressive agent, the mixture having increased efficacy relative to Cyclosporine A. 43. The method of claim 42, wherein the immunosuppressive agent comprises the isomeric cyclosporine analogue mixture in an amount selected from the group consisting of about 0.05 mg to about 50 mg per kilogram of body weight per day; about 0.1 mg to about 10 mg per kilogram of body weight per day; about 0.5 to about 10 mg/kg/day; about 2 to about 6 mg/kg/day, administered orally twice a day; and about 0.5 to about 3 mg/kg/day, administered orally twice a day.