Cyclosporine emulsion

Abstract

The present invention relates to cyclosporine emulsions containing: (i) a cyclosporine, (ii) a natural oil (long chain triglyceride), (iii) a phosphatidylcholine, (iv) glycerol, (v) a pharmaceutically tolerable alkali salt of a free fatty acid, (vi) a medium chain triglyceride-oil, (vii) optionally, hydrochloric acid or sodium hydroxide for pH adjustment and (viii) water, and to therapeutic methods using them.

1 - 18 . (canceled) 
     
     
         19 . A cyclosporine oil-in-water emulsion comprising:
 (i) cyclosporine at a concentration of 1-15 g/L,   (ii) long chain triglyceride at a concentration of 50-150 g/L,   (iii) phosphatidylcholine at a concentration of 5-25 g/L,   (iv) glycerol at a concentration of 10-50 g/L,   (v) pharmaceutically acceptable alkali salt of a free fatty acid at a concentration of 0.1-1 g/L,   (vi) medium chain triglyceride-oil at a concentration of 5-140 g/L, and   (vii) water for injection,   wherein the emulsion is isoosmolar and has an osmolarity of from 280 to 305 mosm/l, and wherein the composition does not contain polyethoxylated castor oil.   
     
     
         20 . The cyclosporine emulsion according to  claim 19 , having an osmolarity of from about 295 to about 300 mosm/1. 
     
     
         21 . The cyclosporine emulsion of  claim 19 , wherein the pH of the emulsion is from about 6 to about 8.8. 
     
     
         22 . The cyclosporine emulsion of  claim 21 , further comprising hydrochloric acid or sodium hydroxide at a concentration to provide a pH of from about 6 to about 8.8. 
     
     
         23 . The cyclosporine emulsion of  claim 19 , wherein the long chain triglyceride comprises soy bean oil. 
     
     
         24 . The cyclosporine emulsion of  claim 19 , wherein the phosphatidylcholine comprises egg lecithin. 
     
     
         25 . The cyclosporine emulsion of  claim 19 , wherein the pharmaceutically acceptable alkali salt of a free fatty acid comprises sodium oleate. 
     
     
         26 . The cyclosporine emulsion of  claim 19 , wherein the medium chain triglyceride-oil comprises one or more selected from the group consisting of coconut oil and palm oil. 
     
     
         27 . The cyclosporine emulsion of  claim 19 , wherein the emulsion is stable for 12-36 months when stored at 25° C. and 60% relative humidity and protected from light. 
     
     
         28 . The cyclosporine emulsion of  claim 19 , wherein the emulsion has a shelf-life of 12 months when stored at 40° C. and 75% relative humidity. 
     
     
         29 . The cyclosporine emulsion according to  claim 19 , wherein the emulsion has a shelf-life of at least 30 months when stored below 25° C. and protected from light. 
     
     
         30 . A therapeutic method comprising administering the cyclosporine emulsion according to  claim 19  to a subject in need thereof. 
     
     
         31 . The method of  claim 30 , wherein the cyclosporine emulsion comprises 5 g/L cyclosporine, 100 g/L soya bean oil, 12 g/L egg lecithin, 25 g/L water-free glycerol, 0.3 g/L sodium oleate, 100 g/L medium chain triglyceride-oil selected from the group consisting of coconut oil, palm oil, and combinations thereof, and water for injection. 
     
     
         32 . The method of  claim 30 , wherein the cyclosporine emulsion is administered without any premedication with corticosteroids. 
     
     
         33 . A method for reducing the rate of anaphylactic reactions in patients subjected to cyclosporine treatment, the method comprising administering the cyclosporine emulsion of  claim 19  to the subject. 
     
     
         34 . A method for providing immunosuppressive cyclosporine treatment, comprising administering the cyclosporine emulsion of  claim 19  to a subject in need thereof. 
     
     
         35 . A method of preventing cardiac reperfusion injury (cardioprotection), comprising administering the cyclosporine emulsion of  claim 19  to a subject in need thereof. 
     
     
         36 . A method of preventing brain damage (neuroprotection), comprising administering the cyclosporine emulsion of  claim 19  to a subject in need thereof. 
     
     
         37 . A method of preventing reperfusion injury (organ oprotection), comprising administering the cyclosporine emulsion of  claim 19  to a subject in need thereof. 
     
     
         38 . A method of preventing kidney reperfusion injury (nephroprotection), comprising administering the cyclosporine emulsion of  claim 19  to a subject in need thereof. 
     
     
         39 . A method of preventing liver reperfusion injury (hepatoprotection), comprising administering the cyclosporine emulsion of  claim 19  to a subject in need thereof.