Pharmaceutical compositions of berberine with epa and dha, and methods thereof

Abstract

The invention provides various novel compositions of berberine in combination with pharmacologically active EPA and DHA, and related methods of their use in treating various diseases or disorders. The pharmaceutical compositions of the invention are useful in treating and/or preventing various diseases or disorders, including metabolic diseases or disorders such as dyslipidemia, hyperglycemia, hypertriglyceridemia, hyperlipidemia, diabetic dyslipidemia, diabetic hyperlipidemia, dyslipidemia in statin-intolerance patients, diabetes, diabetic complications, hypercholesterolemia, or obesity. Additionally, the pharmaceutical compositions of the invention are useful in treating and/or preventing atherosclerosis, heart diseases, neurodegenerative diseases, inflammation, cancers, as well as various liver diseases or disorders, such as fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cholestatic liver diseases or graft-versus-host disease of the liver. Furthermore, the pharmaceutical compositions of the invention are useful in improving liver functions in chronic viral associated liver diseases and alcohol-related liver diseases.

1 . A pharmaceutical composition comprising:
 (a) berberine, or a pharmaceutically acceptable salt thereof;   (b) one or both of eicosapentaenoic acid, or a pharmaceutically acceptable ester thereof, and docosahexaenoic acid, or a pharmaceutically acceptable ester thereof; and   (c) optionally a pharmaceutically acceptable excipient, carrier, or diluent, wherein   the berberine, or a pharmaceutically acceptable salt thereof, and   the one or both of eicosapentaenoic acid, or a pharmaceutically acceptable ester thereof, and docosahexaenoic acid, or a pharmaceutically acceptable ester thereof,   
       are present in amounts that, when administered to a subject, are sufficient to treat, prevent, or reduce one or more diseases or disorders selected from metabolic diseases or disorders, heart diseases or disorders, neurodegenerative diseases or disorders, inflammation, cancers and liver diseases or disorders, or a related condition thereof in a mammal, including a human. 
     
     
         2 . The pharmaceutical composition of  claim 1 , comprising both of eicosapentaenoic acid, or a pharmaceutically acceptable ester thereof, and docosahexaenoic acid, or a pharmaceutically acceptable ester thereof. 
     
     
         3 . (canceled) 
     
     
         4 . The pharmaceutical composition of  claim 1 , further comprising one or more agents selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate and vanadium. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the disease or disorder is selected from lipid and glucose diseases or disorders, is type 1 or type 2 diabetes, fatty liver, NAFLD and NASH. 
     
     
         6 . (canceled) 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the disease or disorder is type 1 or type 2 diabetes. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the disease or disorder is diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, or macrovascular complications comprising heart attacks, strokes or insufficiency in blood flow to legs. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the disease or disorder is a heart disease or atherosclerosis or a neurodegenerative disease. 
     
     
         10 - 13 . (canceled) 
     
     
         14 . The pharmaceutical composition of claim  13 , comprising
 (a) berberine, or a pharmaceutically acceptable salt thereof;   (b) ethyl ester of eicosapentaenoic acid and ethyl ester of docosahexaenoic acid; and   (c) a pharmaceutically acceptable excipient, carrier, or diluent.   
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutically acceptable salt of berberine is a chloride salt or a sulfate salt. 
     
     
         16 . (canceled) 
     
     
         17 . The pharmaceutical composition of  claim 14 , wherein the weight ratio of BBR to EPA/DHA is from about 3:1 to about 1:8. 
     
     
         18 . A unit dosage form comprising a pharmaceutical composition of  claim 1 , wherein the unit dosage form comprises BBR ranging from about 100 mg to about 300 mg and EPA/DHA ranging from about 100 mg to about 800 mg. 
     
     
         19 . A method for treating, reducing, or preventing a disease or disorder, comprising
 administering to a subject in need thereof a pharmaceutical composition comprising
 (a) berberine, in a therapeutically effective amount; 
 (b) one or both of eicosapentaenoic acid, or a pharmaceutically acceptable ester thereof, and docosahexaenoic acid, or a pharmaceutically acceptable ester thereof, in therapeutically effective amounts, and 
 (c) optionally a pharmaceutically acceptable excipient, carrier, or diluent, 
   wherein the disease or disorder is selected from metabolic diseases or disorders, heart diseases or disorders, neurodegenerative diseases or disorders, sarcopenia, muscle atrophy, inflammation, cancers and liver diseases or disorders, or a related condition thereof in a mammal, including a human.   
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 19 , wherein the pharmaceutical composition further comprises one or more agents selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate and vanadium. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 23 , wherein the pharmaceutical composition comprises:
 (a) berberine, or a pharmaceutically acceptable salt thereof;   (b) ethyl ester of eicosapentaenoic acid and ethyl ester of docosahexaenoic acid; and   (c) a pharmaceutically acceptable excipient, carrier, or diluent.   
     
     
         25 . The method of  claim 24 , wherein the pharmaceutically acceptable salt of berberine is a chloride salt or a sulfate salt. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 24 , wherein the weight ratio of BBR to EPA/DHA is from about 3:1 to about 1:8. 
     
     
         28 . The method of  claim 24 , comprising administering a unit dosage form comprising about 100 mg to about 300 mg of BBR and about 100 mg to about 800 mg of EPA/DHA once, twice or three times daily. 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 19 , wherein the disease or disorder is selected from lipid and glucose diseases or disorders, type 1 or type 2 diabetes, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, or macrovascular complications comprising heart attacks, strokes or insufficiency in blood flow to legs, fatty liver, NAFLD and NASH. 
     
     
         32 - 34 . (canceled) 
     
     
         35 . The method of  claim 19 , wherein the disease or disorder is selected from a heart disease or atherosclerosis, or a neurodegenerative disease. 
     
     
         36 - 42 . (canceled) 
     
     
         43 . A kit comprising:
 (i) berberine, or a pharmaceutically acceptable salt thereof;   (ii) one or both of eicosapentaenoic acid, or a pharmaceutically acceptable ester thereof, and docosahexaenoic acid, or a pharmaceutically acceptable ester thereof; (iii) optionally one or more agent(s) selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate and vanadium; and (iv) instructions for administering agents (i), (ii) and (iii) to a patient having or at risk of having one or more diseases or disorders selected from metabolic disorders, atherosclerosis, heart diseases, neurodegenerative diseases and liver diseases.   
     
     
         44 - 48 . (canceled)