Pharmaceutical cyclosporin compositions

Abstract

An oral cyclosporin composition comprises minicapsules having a core containing a cyclosporin, especially cyclosporin A in a solubilised liquid form. The minicapsules have a release profile to release the pre-solubilised cyclosporin, at least in the colon. The composition may be used for treating a range of intestinal diseases.

1 . (canceled) 
     
     
         2 . A method of treating ulcerative colitis by administering to a subject a composition, the method comprising orally administering the composition, wherein the composition comprises cyclosporin in a solubilised liquid form in combination with a pharmaceutically acceptable carrier(s) or excipient(s), wherein the cyclosporin and the pharmaceutically acceptable carrier(s) or excipient(s) are contained within a gelling agent and the composition comprises a modified release coating suitable to provide the release of the cyclosporin in the colon. 
     
     
         3 . The method of  claim 2 , wherein the method further comprises administering to the subject any one or a combination of tacrolimus, sirolimus, EPA or DHA. 
     
     
         4 . The method of  claim 3 , wherein the composition has a dissolution profile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, in pH 6.8 buffer as follows: 1 hour: less than or equal to about 20% drug released. 
     
     
         5 . The method of  claim 4 , wherein at 4 hours: about 20% to about 35% drug released. 
     
     
         6 . The method of  claim 5 , wherein at 6 hours: about 35% to about 50% drug released. 
     
     
         7 . The method of  claim 6 , wherein at 12 hours: about 50% to about 60% drug released. 
     
     
         8 . The method of  claim 7 , wherein at 16 hours: about 60% to about 75% drug released. 
     
     
         9 . The method of  claim 8 , wherein at 24 hours from about 75% to about 100% drug released. 
     
     
         10 . The method of  claim 2 , wherein the composition has a dissolution profile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, in pH 6.8 buffer as follows: 4 hours: about 30% to about 50% drug released. 
     
     
         11 . The method of  claim 10 , wherein at 6 hours: about 40% to about 70% drug is released. 
     
     
         12 . The method of  claim 10 , wherein at 12 hours: about 70% to about 80% drug is released. 
     
     
         13 . The method of  claim 2 , wherein the composition has a dissolution profile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, in pH 6.8 buffer as follows: 4 hours: about 15% to about 60% drug released. 
     
     
         14 . The method of  claim 13 , wherein at 6 hours: about 25% to about 70% drug is released. 
     
     
         15 . The method of  claim 14 , wherein at 12 hours: about 45% to about 80% drug is released. 
     
     
         16 . The method of  claim 2 , wherein the composition has a dissolution profile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, in pH 6.8 buffer as follows: 4 hours: about 45% to about 60% drug released. 
     
     
         17 . The method of  claim 16 , wherein at 6 hours: about 60% to about 70% drug is released. 
     
     
         18 . The method of  claim 17 , wherein at 12 hours: about 70% to about 80% drug is released. 
     
     
         19 . The method of  claim 2 , wherein the minicapsules have a dissolution profile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, in pH 6.8 buffer as follows: up to 4 hours: less than or equal to about 20% cyclosporin released; 24 hours: from about 75% to about 100% cyclosporin released. 
     
     
         20 . The method of  claim 19  wherein, in the dissolution profile, less than or equal to about 20% cyclosporin is released in 1 hour. 
     
     
         21 . The method of  claim 2 , wherein the composition comprises minicapsules. 
     
     
         22 . The method of  claim 21 , wherein the minicapsules have the characteristics of minicapsules obtained by utilisation of surface tensions of a hydrophobic core solution comprising the cyclosporin in a solubilised form and a shell solution comprising the gelling agent, which solutions are ejected through a nozzle having one orifice and subject to specific frequencies and which form into a spherical form and fall into a cooling air flow or a cooling or hardening solution where the shell solution is gelled or solidified. 
     
     
         23 . The method of  claim 21 , wherein the minicapsules are seamless minicapsules. 
     
     
         24 . The method of  claim 21 , wherein the minicapsule are coated with the modified release coating. 
     
     
         25 . The method of  claim 24 , wherein the modified release coating comprises two types of polymers that are applied as separate coats to the minicapsule. 
     
     
         26 . The method of  claim 2 , wherein the modified release coating comprises a controlled release polymer. 
     
     
         27 . The method of  claim 26 , wherein the controlled release polymer is ethylcellulose. 
     
     
         28 . The method of  claim 2 , wherein the modified release coating is without the inclusion of a dissolution enhancing agent. 
     
     
         29 . The method of  claim 2 , wherein the gelling agent is gelatin. 
     
     
         30 . The method of  claim 2 , wherein the cyclosporin is solubilized in a hydrophobic solution. 
     
     
         31 . The method of  claim 21 , wherein the minicapsules have applied thereto:
 the modified release coating comprising a first polymer selected from a methacrylate; ethylcellulose; and a composite of methacrylate and ethylcellulose; and   an optional separate coating comprising a second polymer.   
     
     
         32 . The method of  claim 21 , wherein the minicapsules are seamless, and wherein the release profile comprises sustained and delayed release of the solubilised cyclosporin. 
     
     
         33 . The method of  claim 2 , wherein the minicapsules are further adapted to allow abrupt and/or sustained release of the solubilised cyclosporin into the proximal colon. 
     
     
         34 . The method of  claim 2 , wherein the cyclosporin is protected from absorption in the upper gastrointestinal tract. 
     
     
         35 . The method of  claim 2 , wherein the release profile comprises sustained release of the cyclosporin. 
     
     
         36 . The method of  claim 21 , wherein said minicapsules comprise minicapsules that have a coating comprising a sustained release polymer. 
     
     
         37 . The method of  claim 2 , wherein the composition further comprises immediate release minicapsules comprising cyclosporin in a solubilised liquid form. 
     
     
         38 . The method of  claim 2 , wherein the minicapsules have a release profile to also release solubilised cyclosporin in the ileum. 
     
     
         39 . The method of  claim 2 , wherein the composition further comprises minicapsules that have a release profile to release solubilised cyclosporin in the small intestine. 
     
     
         40 . The method of  claim 2 , wherein the method further comprises administering to the subject hydralazine, DMOG, or another prolyl- and/or asparaginyl hydroxylase inhibitor. 
     
     
         41 . The method of  claim 2 , wherein the treating is exerting a protective effect against ulcerative colitis.