Drug Delivery Enhancement Agents

Abstract

A peptide comprising a sequence for opening a tight junction of an epithelial surface and optionally a cell penetrating sequence; and related compositions, optionally comprising further pharmaceutical agents; and related methods.

1 .- 18 . (canceled) 
     
     
         19 . A peptide comprising the amino acid sequence of Formula 1: 
       
         
           
                 
                 
               
                     
                   Formula 1 
                 
                     
                   (SEQ ID NO: 1) 
                 
                     
                   X 4 -X 5 -X 6 -X 7 -X 8   
                 
             
                
                
                
               
            
           
         
         wherein: 
         X 4  is a negatively charged amino acid residue; 
         X 5  is a hydrophobic amino acid residue; 
         X 6  is a positively charged amino acid residue; 
         X 7  is an amino acid residue selected from Tyr, Phe, Thr or Ser; and 
         X 8  is a negatively charged amino acid residue, 
         wherein all amino acid residues are in D-configuration and wherein the order of the amino acid sequence of Formula 1 is reversed. 
       
     
     
         20 . A peptide as claimed in  claim 19  further comprising a cell penetrating peptide CPP sequence. 
     
     
         21 . A peptide as claimed in  claim 19 , wherein:
 X 4  is pTyr, Asp or Glu;   X 5  is Val or Ala;   X 6  is Lys or Arg;   X 7  is Tyr, Phe, Thr or Ser; and   X 8  is pTyr, Asp or Glu.   
     
     
         22 . A peptide as claimed in  claim 19  comprising the amino acid sequence according to Formula 1a: 
       
         
           
                 
                 
               
                     
                   Formula 1a 
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10   
                 
             
                
                
                
               
            
           
         
       
       wherein:
 X 1  is up to 10 positively charged amino acid residues; 
 X 2  is a positively charged amino acid residue; 
 X 3  is absent or a hydrophobic amino acid residue; 
 X 4  is a negatively charged amino acid residue; 
 X 5  is a small hydrophobic amino acid residue; 
 X 6  is a positively charged amino acid residue; 
 X 7  is an amino acid residue selected from Tyr, Phe, Thr or Ser; 
 X 8  is a negatively charged amino acid residue; 
 X 9  is a positively charge amino acid residue; and 
 X 10  is up to 10 positively charged amino acid residues, 
 wherein all amino acid residues are in D-configuration and the order of the amino acid sequence of Formula 1a is reversed. 
 
     
     
         23 . A peptide as claimed in  claim 22  wherein X 1  is Lys or Arg; X 2  is Lys or Arg; X 3  is Ala or Val; X 4  is Asp or Glu; X 5  is Val; X 6  is Lys; X 7  is Tyr; X 8  is Asp or Glu; X 9  is Lys or Arg; and X 10  is Lys or Arg. 
     
     
         24 . A peptide as claimed in claim  3 , wherein
 X 4  1 S Glu;   X 5  is Val;   X 6  is Lys;   X 7  is Tyr; and   X 8  is Asp.   
     
     
         25 . A pharmaceutical composition comprising a peptide as defined in  claim 19  and a pharmaceutically-acceptable carrier. 
     
     
         26 . A pharmaceutical composition as claimed in  claim 25  further comprising a therapeutic agent. 
     
     
         27 . A pharmaceutical composition as claimed in  claim 26 , wherein said therapeutic agent is insulin, or a derivative, analogue or mimic thereof. 
     
     
         28 . A pharmaceutical composition as claimed in  claim 25 , wherein said composition is suitable for oral administration. 
     
     
         29 . A method of opening the tight junctions of an epithelial surface comprising administering an effective amount of a peptide according to  claim 19  to the epithelium. 
     
     
         30 . A method of delivering an agent across an epithelial surface comprising administering said agent in conjunction with a peptide as claimed in  claim 19 . 
     
     
         31 . A method of opening the tight junctions of an epithelial surface comprising administering an effective amount of a pharmaceutical composition according to  claim 26  to the epithelium. 
     
     
         32 . A method of delivering an agent across an epithelial surface comprising administering said agent in conjunction with a pharmaceutical composition as claimed in  claim 25 . 
     
     
         33 . A pharmaceutical composition as claimed in  claim 26 , wherein said therapeutic agent is GLP-1 or a derivative, analogue or mimic thereof. 
     
     
         34 . A method as claimed in  claim 29 , wherein the pharmaceutical composition comprises insulin, or a derivative, analogue or mimic thereof, or GLP-1, or a derivative, analogue or mimic thereof. 
     
     
         34 . A method as claimed in  claim 30 , wherein the pharmaceutical composition comprises insulin, or a derivative, analogue or mimic thereof, or GLP-1, or a derivative, analogue or mimic thereof. 
     
     
         35 . A method as claimed in  claim 31 , wherein the pharmaceutical composition comprises insulin, or a derivative, analogue or mimic thereof, or GLP-1, or a derivative, analogue or mimic thereof. 
     
     
         36 . A method as claimed in  claim 32 , wherein the pharmaceutical composition comprises insulin, or a derivative, analogue or mimic thereof, or GLP-1, or a derivative, analogue or mimic thereof.