PHARMACEUTICAL COMPOSITIONS FOR COMBINATION THERAPY
The present invention relates to a pharmaceutical composition comprising a combination of an FXR agonist and at least one lipid lowering agent (e.g., PPAR-alpha agonist, PPAR-delta agonist, PPAR-alpha and delta dual agonist, and/or statin). Also disclosed is use of the combination for the treatment or prevention of a FXR mediated disease or condition, such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, NAFLD (nonalcoholic fatty liver disease), NASH (non-alcohol-induced steatohepatitis), and other chronic liver diseases. The combination of the present invention is useful for the treatment or prevention of conditions related to elevated lipid and liver enzyme levels. The present invention also relates to packs or kits including the pharmaceutical combination.
1 . (canceled)
2 . A method of treating or preventing an FXR mediated disease or condition or a condition related to elevated lipid levels in a subject in need thereof, comprising administering to the subject a compound of formula (1):
or a pharmaceutically acceptable salt or amino acid conjugate thereof, and a fibrate.
3 . The method of claim 2 , wherein the FXR mediated disease or condition is selected from primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, a chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, an alcoholic liver disease, liver damage due to progressive fibrosis, liver fibrosis, a cardiovascular disease, and hyperlipidemia.
4 . The method of claim 2 , wherein the FXR mediated disease or condition is a cholestatic liver disease selected from primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.
5 . The method of claim 4 , wherein the cholestatic liver disease is PBC.
6 . The method of claim 3 , wherein the FXR mediated disease or condition is NASH.
7 . The method of claim 3 , wherein the FXR mediated disease or condition is liver fibrosis.
8 . The method of claim 2 , wherein the compound of formula (1) is in an amount of 1-30 mg.
9 . The method of claim 2 , wherein the compound of formula (1) is in an amount of 5-25 mg.
10 . The method of claim 2 , wherein the fibrate is in an amount of 80-400 mg.
11 . The method of claim 2 , wherein the fibrate is in an amount of 100-300 mg.
12 . The method of claim 2 , wherein the fibrate is in an amount of 100 mg.
13 . The method of claim 2 , wherein the fibrate is in an amount of 200 mg.
14 . The method of claim 2 , wherein the fibrate is in an amount of 400 mg.
15 . The method of claim 2 , wherein the fibrate is fenofibrate, gemfibrozil, bezafibrate, or ciprofibrate.
16 . A method of treating or preventing an FXR mediated disease or condition or a condition related to elevated lipid levels in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a combination of therapeutic agents consisting of a compound of formula (1):
or a pharmaceutically acceptable salt or amino acid conjugate thereof, and a fibrate; wherein the pharmaceutical composition further optionally comprises one or more pharmaceutically acceptable carriers.
17 . The method of claim 16 , wherein the FXR mediated disease or condition is selected from primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, a chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, an alcoholic liver disease, liver damage due to progressive fibrosis, liver fibrosis, a cardiovascular disease, and hyperlipidemia.
18 . The method of claim 16 , wherein the FXR mediated disease or condition is a cholestatic liver disease selected from primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.
19 . The method of claim 18 , wherein the cholestatic liver disease is PBC.
20 . The method of claim 17 , wherein the FXR mediated disease or condition is NASH.
21 . The method of claim 17 , wherein the FXR mediated disease or condition is liver fibrosis.
22 . The method of claim 16 , wherein the compound of formula (1) is in an amount of 1-30 mg.
23 . The method of claim 16 , wherein the compound of formula (1) is in an amount of 5-25 mg.
24 . The method of claim 16 , wherein the fibrate is in an amount of 80-400 mg.
25 . The method of claim 16 , wherein the fibrate is in an amount of 100-300 mg.
26 . The method of claim 16 , wherein the fibrate is in an amount of 100 mg.
27 . The method of claim 16 , wherein the fibrate is in an amount of 200 mg.
28 . The method of claim 16 , wherein the fibrate is in an amount of 400 mg.
29 . The method of claim 16 , wherein the fibrate is fenofibrate, gemfibrozil, bezafibrate, or ciprofibrate.
30 . A method of treating or preventing an FXR-mediated disease or condition or a condition related to elevated lipid levels in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a combination of therapeutic agents consisting of a compound of formula (1):
or a pharmaceutically acceptable salt or amino acid conjugate thereof, and bezafibrate; wherein the pharmaceutical composition further optionally comprises one or more pharmaceutically acceptable carriers.
31 . The method of claim 30 , wherein the FXR mediated disease or condition is selected from primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, a chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, an alcoholic liver disease, liver damage due to progressive fibrosis, liver fibrosis, a cardiovascular disease, and hyperlipidemia.
32 . The method of claim 30 , wherein the FXR mediated disease or condition is a cholestatic liver disease selected from primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.
33 . The method of claim 32 , wherein the cholestatic liver disease is PBC.
34 . The method of claim 31 , wherein the FXR mediated disease or condition is NASH.
35 . The method of claim 31 , wherein the FXR mediated disease or condition is liver fibrosis.
36 . The method of claim 30 , wherein the compound of formula (1) is in an amount of 1-30 mg.
37 . The method of claim 30 , wherein the compound of formula (1) is in an amount of 5-25 mg.
38 . The method of claim 30 , wherein bezafibrate is in an amount of 80-400 mg.
39 . The method of claim 30 , wherein bezafibrate is in an amount of 100-300 mg.
40 . The method of claim 30 , wherein bezafibrate is in an amount of 100 mg.
41 . The method of claim 30 , wherein bezafibrate is in an amount of 200 mg.
42 . The method of claim 30 , wherein bezafibrate is in an amount of 400 mg.
43 . The method of claim 30 , wherein the composition is a single unit dosage form.
44 . The method of claim 43 , wherein the single unit dosage form is a tablet or capsule.
45 . The method of claim 44 , wherein the compound of formula (1) is in an amount of 5-25 mg and bezafibrate is in an amount of 100-300 mg.
46 . The method of claim 44 , wherein the compound of formula (1) is in an amount of 4-26 mg and bezafibrate is in an amount of 100-300 mg.