Methods and compositions for treating nafld, hepatic steatosis, and sequelae thereof

Abstract

Provided herein are oral pharmaceutical compositions containing a GLP-1 analogue and/or insulin for treating and reducing the incidence of nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, and sequelae thereof and methods of utilizing same.

1 . An oral pharmaceutical composition for inhibiting the development of or treating nonalcoholic fatty liver disease (NAFLD), said pharmaceutical composition comprising an insulin, a GLP-1 analogue, or a combination thereof; a protease inhibitor; and a chelator of divalent cations. 
     
     
         2 . The oral pharmaceutical composition of  claim 1 , where said pharmaceutical composition is administered for more than one month. 
     
     
         3 . The oral pharmaceutical composition of  claim 1 , where said pharmaceutical composition is administered once daily or twice daily. 
     
     
         4 . The oral pharmaceutical composition of  claim 1 , where said pharmaceutical composition comprises a liquid formulation; where said insulin, GLP-1 analogue, or combination thereof, said protease inhibitor, and said chelator of divalent cations are in said liquid formulation. 
     
     
         5 . The oral pharmaceutical composition of  claim 4 , where said liquid formulation is inside a capsule. 
     
     
         6 . The oral pharmaceutical composition of  claim 5 , where said capsule is surrounded by a coating that resists degradation in the stomach. 
     
     
         7 . The oral pharmaceutical composition of  claim 4 , where said liquid formulation is an oil-based liquid formulation. 
     
     
         8 . The oral pharmaceutical composition of  claim 1 , where said pharmaceutical composition is a solid formulation. 
     
     
         9 . The oral pharmaceutical composition of any of  claims 1 - 8 , where said GLP-1 analogue is present in an amount between 100-600 micrograms (inclusive) per dose for an adult patent or a corresponding amount per body weight for a pediatric patient. 
     
     
         10 . The oral pharmaceutical composition of  claim 9 , where said GLP-1 analogue is present in an amount between 100-300 micrograms (inclusive) per dose for an adult patent or a corresponding amount per body weight for a pediatric patient. 
     
     
         11 . The oral pharmaceutical composition of  claim 9  or  10 , where said GLP-1 analogue is exenatide. 
     
     
         12 . The oral pharmaceutical composition of any of  claims 1 - 8 , where said insulin is present in an amount between 8-32 mg (inclusive) per dose for an adult patent or a corresponding amount per body weight for a pediatric patient. 
     
     
         13 . The oral pharmaceutical composition of any of  claims 1 - 8 , where said insulin is present in an amount between 4-12 mg (inclusive) per dose for an adult patent or a corresponding amount per body weight for a pediatric patient. 
     
     
         14 . The oral pharmaceutical composition of  claim 13 , where, in addition to said insulin, said GLP-1 analogue is present in an amount between 100-300 micrograms (inclusive) per dose for an adult patent or a corresponding amount per body weight for a pediatric patient. 
     
     
         15 . The oral pharmaceutical composition of  claim 14 , where said GLP-1 analogue is exenatide. 
     
     
         16 . The oral pharmaceutical composition of any of  claims 1 - 15 , where said protease inhibitor is selected from the group consisting of soybean trypsin inhibitor (SBTI), Bowman-Birk inhibitor (BBI), Kunitz Trypsin Inhibitor 3 (KTI3), and aprotinin, each of which may be present either alone or in combination with another protease inhibitor. 
     
     
         17 . The oral pharmaceutical composition of any of  claims 1 - 15 , where one or more protease inhibitors are present, and said protease inhibitors collectively inhibit both trypsin and chymotrypsin. 
     
     
         18 . The oral pharmaceutical composition of any of  claims 1 - 15 , where two protease inhibitors are present in said composition, and said two protease inhibitors are SBTI and aprotinin. 
     
     
         19 . The oral pharmaceutical composition of any of  claims 1 - 15 , where two protease inhibitors are present in said composition, and said two protease inhibitors are isolated KTI3 and isolated BBI. 
     
     
         20 . The oral pharmaceutical composition of any of  claims 1 - 15 , where two protease inhibitors are present in said composition, and said two protease inhibitors are (i) isolated KTI3 and (ii) aprotinin. 
     
     
         21 . The oral pharmaceutical composition of any of  claims 1 - 15 , where one protease inhibitor is present in said composition, and said protease inhibitor is isolated BBI. 
     
     
         22 . The oral pharmaceutical composition of any of  claims 1 - 21 , where said chelator is EDTA. 
     
     
         23 . The oral pharmaceutical composition of any of  claims 7 - 22 , where said oil is selected from olive oil, flaxseed oil, sesame oil, avocado oil, walnut oil, canola oil, and fish oil. 
     
     
         24 . The oral pharmaceutical composition of  claim 23 , where said oil is fish oil. 
     
     
         25 . The oral pharmaceutical composition of any of  claims 7 - 24 , where said oil-based liquid formulation is water-free. 
     
     
         26 . The oral pharmaceutical composition of any of  claims 1 - 10 ,  12 - 14 , and  16 - 25 , where said GLP-1 analogue is exenatide. 
     
     
         27 . A method for inhibiting the development of or treating NAFLD in a human subject, said method comprising the step of administering said subject the oral pharmaceutical composition of any of  claims 1 - 26 , thereby inhibiting the development of or treating NAFLD. 
     
     
         28 . The method of  claim 27 , where said pharmaceutical composition is administered for more than one month. 
     
     
         29 . A method for inhibiting the development of or treating NAFLD in a non-human subject, said method comprising the step of administering to said non-human animal the oral pharmaceutical composition of any one of  claims 1 - 26 , thereby inhibiting the development of or treating NAFLD. 
     
     
         30 . The method of  claim 29 , where said pharmaceutical composition is administered for more than one month.