Sustained release glp-1 receptor modulators

Abstract

The present invention provides novel pharmaceutical compositions comprising a human glucagon-like peptide-1 (GLP-1)-receptor modulator as an active ingredient in a sustained release formulation.

1 - 32 . (canceled) 
     
     
         33 . A pharmaceutical composition or a pharmaceutically-acceptable salt thereof, wherein said pharmaceutical composition comprises:
 (a) an effective amount of a glucagon-like peptide-1 (GLP-1) receptor modulator, or salt thereof, as an active ingredient, wherein said GLP-1 receptor modulator comprises at least one phenyl-heteroaryl-alanine analog; and   (b) a metal ion, or a protamine vehicle, or a combination thereof.   
     
     
         34 . The pharmaceutical composition of  claim 33  wherein said GLP-1 receptor modulator is a peptide selected from the group consisting of SEQ ID NO.s 1-166. 
     
     
         35 . The pharmaceutical composition of  claim 33  wherein said GLP-1 receptor modulator is a peptide selected from the group consisting of SEQ ID NO.s 9, 15, 118, 151, and 158. 
     
     
         36 . The pharmaceutical composition of  claim 33  wherein said metal ion is a divalent cation. 
     
     
         37 . The pharmaceutical composition of  claim 33 , wherein said pharmaceutical composition comprises a protamine vehicle. 
     
     
         38 . The pharmaceutical composition of  claim 33 , wherein said composition is prepared by spray drying, precipitation, or lyophilization. 
     
     
         39 . The pharmaceutical composition of  claim 33 , wherein said metal ion is a divalent metal cation selected from the group consisting of zinc, manganese, and iron. 
     
     
         40 . The pharmaceutical composition of  claim 38  wherein said divalent metal cation is zinc. 
     
     
         41 . The pharmaceutical composition of  claim 34  further comprising a co-precipitated, lyophilized, or spray dried zinc adduct, in a Zn:GLP-1 receptor modulator ratio of from about 1:10 to about 50:1. 
     
     
         42 . The pharmaceutical composition of  claim 34  further comprising a co-precipitated, lyophilized, or spray dried zinc adduct, in a Zn:GLP-1 receptor modulator ratio of from about 1:10 to about 50:1, with a weight to volume ratio of surfactants, suspending agents, and/or thickening agents, of 0% to about 30%. 
     
     
         43 . The pharmaceutical composition of  claim 42  wherein the Zn:GLP-1 receptor modulator ratio is about 1.5:1 to about 5:1 and the weight to volume ratio of surfactants is 0% to about 1%, suspending agents is 0% to about 5%, and/or thickening agents is 0% to about 1%. 
     
     
         44 . The pharmaceutical composition of  claim 33  further comprising a co-precipitated, lyophilized, or spray dried zinc adduct, in a Zn:GLP-1 receptor modulator ratio of from about 1:10 to about 50:1, with a weight to volume ratio of surfactants, suspending agents, and/or thickening agents, of 0% to about 30%. 
     
     
         45 . A method for making a pharmaceutical composition comprising:
 a) obtaining a GLP-1 receptor modulator comprising at least one phenyl-heteroaryl-alanine analog;   b) suspending said GLP-1 receptor modulator to form a GLP-1 suspension;   c) adjusting the pH of the GLP-1 suspension to about 8.5 to obtain a GLP-1 solution;   d) dissolving zinc acetate in a solution to obtain a zinc acetate solution;   e) adding the zinc acetate solution drop wise, with stirring, to the GLP-1 solution; and   f) obtaining a composition having a molar ratio of zinc:GLP-1 receptor modulator of about 3:1, and having a final pH of about 6.0.   
     
     
         46 . The method of  claim 45  wherein said GLP-1 receptor modulator is selected from the group consisting of SEQ ID NOs: 1-166. 
     
     
         47 . The method of  claim 45  wherein said GLP-1 receptor modulator is selected from the group consisting of SEQ ID NOs: 9, 15, 118, 151, and 158.