Methods and compositions for oral delivery of fts

Abstract

Disclosed are oral dosage forms containing a Ras antagonist including FTS and structural analogs thereof, and at least one pharmaceutically acceptable excipient other than a cyclodextrin, and methods of orally administering same to treat diseases and disorders responsive to the Ras antagonists.

1 . An oral dosage form comprising an amount of a Ras antagonist effective to treat a disease or disorder involving abnormal cell proliferation, and a pharmaceutically acceptable carrier other than a cyclodextrin, wherein said Ras antagonist is represented by the formula 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  represents farnesyl, geranyl or geranyl-geranyl; 
         R 2  is COOR 7 , or CONR 7 R 8 , wherein R 7  and R 8  are each independently hydrogen, alkyl or alkenyl; 
         R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl, alkenyl, alkoxy, halo, trifluoromethyl, trifluoromethoxy, or alkylmercapto; and 
         X represents S, wherein said dosage form is a tablet or capsule. 
       
     
     
         2 . The oral dosage form of  claim 1 , wherein the Ras antagonist is farnesyl-thiosalicyclic acid (FTS). 
     
     
         3 . The oral dosage form of  claim 1 , wherein the Ras antagonist is 5-fluoro-FTS. 
     
     
         4 . The oral dosage form of  claim 1 , wherein the Ras antagonist is 5-chloro-FTS. 
     
     
         5 . The oral dosage form of  claim 1 , wherein the Ras antagonist is 4-chloro-FTS. 
     
     
         6 . The oral dosage form of  claim 1 , wherein the Ras antagonist is S-farnesyl-thiosalicylic acid methyl ester. 
     
     
         7 . The oral dosage form of  claim 1 , wherein the effective amount is about 5 mg to about 500 mg. 
     
     
         8 . The oral dosage form of  claim 1 , wherein the effective amount is about 10 mg to about 250 mg. 
     
     
         9 . The oral dosage form of  claim 1 , wherein said carrier comprises one or more of a bulking agent, binder, disintegrant, glidant or lubricant. 
     
     
         10 . The oral dosage form of  claim 1 , wherein said tablet has a coating on an outer surface thereof. 
     
     
         11 . The oral dosage form of  claim 1 , which is in the form of a soft or hard gelatin capsule. 
     
     
         12 . A method of treating a disease or disorder involving abnormal cell proliferation, comprising administering to a human in need thereof an oral dosage form comprising an amount of a Ras antagonist effective to treat the disease or disorder, and a pharmaceutically acceptable carrier other than a cyclodextrin, wherein said Ras antagonist is represented by the formula I 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  represents farnesyl, geranyl or geranyl-geranyl; 
         R 2  is COOR 7 , or CONR 7 R 8 , wherein R 7  and R 8  are each independently hydrogen, alkyl or alkenyl; 
         R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl, alkenyl, alkoxy, halo, trifluoromethyl, trifluoromethoxy, or alkylmercapto; and 
         X represents S, wherein the oral dosage form is a tablet or capsule. 
       
     
     
         13 . The method of  claim 12 , wherein the disease is cancer. 
     
     
         14 . The method of  claim 13 , wherein the cancer is breast cancer. 
     
     
         15 . The method of  claim 13 , wherein the cancer is pancreatic cancer. 
     
     
         16 . The method of  claim 12 , wherein the disease or disorder is cirrhosis of the liver. 
     
     
         17 . The method of  claim 12 , wherein the disease or disorder is post-angioplasty restenosis. 
     
     
         18 . The method of  claim 17 , wherein the oral dosage form is administered prophylactically. 
     
     
         19 . The method of  claim 12 , wherein the disease or disorder is atherosclerosis. 
     
     
         20 . The method of  claim 12 , wherein the disease or disorder is graft rejection. 
     
     
         21 . The method of  claim 12 , wherein the disease or disorder is an autoimmune disease.