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 .- 26 . (canceled) 
     
     
         27 . A method for inhibiting the development of or treating nonalcoholic fatty liver disease (NAFLD) in a human subject in need thereof, said method comprising the step of orally administering to the said subject a water-free pharmaceutical composition comprising a therapeutic protein that inhibits the development of or treats the subject's NAFLD, a protease inhibitor, and a chelator of divalent cations,
 thereby inhibiting the development of or treating the subject's NAFLD,   wherein the therapeutic protein consists of insulin,   and   wherein the protease inhibitor comprises a trypsin inhibitor, a chymotrypsin inhibitor, an inhibitor that collectively inhibits both trypsin and chymotrypsin, or a combination thereof.   
     
     
         28 .- 30 . (canceled) 
     
     
         31 . The method of  claim 27 , wherein the protease inhibitor comprises soybean trypsin inhibitor (SBTI), Bowman-Birk inhibitor (BBI), Kunitz trypsin inhibitor 3 (KTI3) or a combination thereof. 
     
     
         32 . The method of  claim 27 , wherein the pharmaceutical composition comprises a liquid formulation, wherein the insulin, protease inhibitor, and chelator of divalent cations are in the liquid formulation and the liquid formulation is inside a capsule. 
     
     
         33 . The method of  claim 32 , wherein the liquid formulation is an oil-based liquid formulation. 
     
     
         34 . The method of  claim 33 , wherein the oil comprises an omega-3 fatty acid. 
     
     
         35 . The method of  claim 33 , wherein the oil comprises fish oil. 
     
     
         36 . The method of  claim 27 , wherein the composition comprises a chelator selected from the group consisting of citrate, ethylenediamine tetracetic acid (EDTA); ethylene glycol tetraacetic acid (EGTA); diethylene triamine pentaacetic acid (DTPA); 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA); and a salt thereof. 
     
     
         37 . The method of  claim 36 , wherein the composition comprises ethylenediamine tetracetic acid (EDTA) or a salt thereof. 
     
     
         38 . The method of  claim 27 , wherein the insulin is present in said pharmaceutical composition in an amount between 8-32 mg inclusive, per dose for an adult patient or a corresponding amount per body weight for a pediatric patient. 
     
     
         39 . The method of  claim 38 , wherein the insulin is present in said pharmaceutical composition in an amount between 6-14 mg inclusive, per dose for an adult patient or a corresponding amount per body weight for a pediatric patient. 
     
     
         40 . The method of  claim 27 , wherein the pharmaceutical composition is administered once daily or twice daily. 
     
     
         41 . The method of  claim 27 , wherein administering the composition treats the nonalcoholic fatty liver disease (NAFLD). 
     
     
         42 . The method of  claim 27 , wherein administering said composition inhibits the development of nonalcoholic fatty liver disease (NAFLD). 
     
     
         43 . A method for inhibiting the development of or treating nonalcoholic fatty liver disease (NAFLD) in a non-human subject in need thereof, the method comprising the step of orally administering to the subject a water-free pharmaceutical composition comprising a therapeutic protein that inhibits the development of or treats the subject's NAFLD, a protease inhibitor, and a chelator of divalent cations,
 thereby inhibiting the development of or treating the subject's NAFLD,   wherein the therapeutic protein consists of insulin,   and   wherein the protease inhibitor comprises a trypsin inhibitor, a chymotrypsin inhibitor, an inhibitor that collectively inhibits both trypsin and chymotrypsin, or a combination thereof.   
     
     
         44 . The method of  claim 43 , wherein the protease inhibitor comprises soybean trypsin inhibitor (SBTI), Bowman-Birk inhibitor (BBI), Kunitz trypsin inhibitor 3 (KTI3) or a combination thereof. 
     
     
         45 . The method of  claim 43 , wherein the pharmaceutical composition comprises a liquid formulation, wherein the insulin, protease inhibitor, and chelator of divalent cations are in the liquid formulation and the liquid formulation is inside a capsule. 
     
     
         46 . The method of  claim 45 , wherein the liquid formulation is an oil-based liquid formulation. 
     
     
         47 . The method of  claim 46 , wherein the oil comprises an omega-3 fatty acid. 
     
     
         48 . The method of  claim 46 , wherein the oil comprises fish oil.