METHODS AND COMPOSITIONS FOR ORAL DELIVERY OF FTS
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 cirrohsis 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.