Gastrin Compositions And Formulations, And Methods Of Use And Preparation

Abstract

An embodiment of the invention provided herein is a pharmaceutical composition comprising a gastrin compound having an extended activity upon administration to a subject in comparison with native gastrin. Methods are provided of conjugating portions of the amino acid sequence of gastrin having functional ability to bind to the gastrin/CCK receptor, to various carrier moieties, including the use of amino acid spacer regions, and use of bifunctional cross-linking reagents. Methods of treating a diabetes patient with the compositions are provided.

1 - 28 . (canceled) 
     
     
         29 . A gastrin compound which comprises an amino acid sequence comprising from the amino acid terminus Z-Y m -X n -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 , wherein Z is polyethylene glycol (PEG); X n  is Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala (SEQ ID NO:9); AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6  is Tyr-Gly-Trp-Leu-Asp-Phe (SEQ ID NO:6) or Tyr-Gly-Trp-Met-Asp-Phe (SEQ ID NO:5), Y m  is an optional spacer region comprising m amino acid residues of a small neutral amino acid, and wherein there is a cysteine residue at the amino terminus of Y wherein m is 1 or greater, or at the amino terminus of X when m is 0, providing that the gastrin compound binds a gastrin/CCK B  receptor. 
     
     
         30 . A gastrin compound according to  claim 29  which comprises Y m  wherein m is 5 and Y is (Gly-Ala). 
     
     
         31 . A gastrin compound according to  claim 29  wherein m is 0. 
     
     
         32 . A pharmaceutical composition for use in the treatment of diabetes comprising a gastrin compound according to  claim 29  and a pharmaceutically acceptable carrier or excipient. 
     
     
         33 . A pharmaceutical composition for use in the treatment of diabetes comprising a gastrin compound according to  claim 30  and a pharmaceutically acceptable carrier or excipient. 
     
     
         34 . A pharmaceutical composition for use in the treatment of diabetes comprising a gastrin compound according to  claim 31  and a pharmaceutically acceptable carrier or excipient. 
     
     
         35 . A gastrin compound according to claim  28  wherein AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6  is Tyr-Gly-Trp-Leu-Asp-Phe (SEQ ID NO:6). 
     
     
         36 . A gastrin compound according to claim  28  wherein AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6  is Tyr-Gly-Trp-Met-Asp-Phe (SEQ ID NO:5). 
     
     
         37 . A gastrin compound according to claim  28  wherein said gastrin has extended activity upon administration to a subject in comparison with native gastrin. 
     
     
         38 . The gastrin compound of claim  28  wherein Y m  is a spacer region comprising m amino acid residues of a small neutral amino acid. 
     
     
         39 . The gastrin compound of  claim 30  wherein Y m  is alternately glycine and alanine amino acids. 
     
     
         40 . A pharmaceutical composition according to  claim 30  wherein said gastrin has extended activity upon administration to a subject in comparison with native gastrin. 
     
     
         41 . A pharmaceutical composition according to  claim 30  wherein said gastrin prevents severe hypoglycemia or increases pancreatic insulin content upon administration to a subject. 
     
     
         42 . A pharmaceutical composition comprising a gastrin compound according to  claim 35  and a pharmaceutically acceptable carrier or excipient. 
     
     
         43 . A pharmaceutical composition comprising a gastrin compound according to  claim 36  and a pharmaceutically acceptable carrier or excipient.