Transmucosal delivery of peptides and proteins

Abstract

Provided are methods and compositions for enhancing the transmucosal absorption of bioactive peptides and proteins. More particularly, the invention provides compositions for enhancing the transmucosal absorption of bioactive peptides and proteins, such as exendin-4, PYY, PYY 3-36 , and GLP-1 and their analogs and derivatives, wherein the compositions comprise an absorption enhancing mixture of a cationic polyamino acid and a buffer that is compatible with the polyamino acid. Also provided are methods for enhancing the transmucosal absorption and bioavailability of bioactive peptides and proteins using such compositions.

1 . An aqueous pharmaceutical composition for transmucosal administration of a bioactive peptide or protein of interest comprising
 said bioactive peptide or protein of interest,   a cationic polyamino acid, and   a compatible buffer,   wherein at the pH of the composition said compatible buffer does not cause precipitation of the cationic polyamino acid, and has a mono-anionic or neutral net charge; and   wherein the transmucosal absorption of said bioactive peptide or protein is increased relative to the absorption of said bioactive peptide or protein in the absence of said cationic polyamino acid.   
     
     
         2 . The composition of  claim 1 , further comprising at least one additional absorption enhancing agent. 
     
     
         3 . The composition of  claim 2 , wherein said additional absorption enhancing agent is selected from the group consisting of chitosan, phospholipids, cyclodextrins, surfactants, and any combination thereof. 
     
     
         4 . The composition of  claim 1 , wherein the pH of said composition is between about pH 3.0 and about pH 8.0. 
     
     
         5 . The composition of  claim 1 , wherein the pH of said composition is between about pH 4.0 and about pH 6.0. 
     
     
         6 . The composition of  claim 1 , wherein the pH of said composition is between about pH 4.0 and pH 5.0. 
     
     
         7 . The composition of  claim 1 , wherein said compatible buffer is selected from the group consisting of acetic acid, ε-aminocaproic acid or glutamic acid. 
     
     
         8 . The composition of  claim 1 , wherein said compatible buffer comprises glutamic acid. 
     
     
         9 . The composition of  claim 1 , further comprising a tonicifying agent, a viscosity-increasing agent, a bioadhesive agent, a preservative, or any combination thereof. 
     
     
         10 . The composition of  claim 1 , wherein said cationic polyamino acid comprises poly-histidine, poly-arginine, poly-lysine, or any combination thereof. 
     
     
         11 . The composition of  claim 10 , wherein said cationic polyamino acid has an average molecular weight of between about 10 kDa and about 300 kDa. 
     
     
         12 . The composition of  claim 1 , wherein said bioactive peptide or protein is an exendin, an exendin analog, or an exendin derivative. 
     
     
         13 . The composition of  claim 1 , wherein said bioactive peptide or protein is selected from the group consisting of exendin-3, exendin-4, exendin-4 acid, exendin-4(1-30), exendin-4 (1-30) amide, exendin-4 (1-28), exendin-4 (1-28) amide,  14 Leu,  25 Phe exendin-4 amide, and  14 Leu,  25 Phe exendin-4(1-28) amide. 
     
     
         14 . An aqueous pharmaceutical composition for transmucosal administration comprising about 0.5% (w/v) of exendin-4;
 about 0.5% to about 1.0% (w/v) of poly-arginine having an average molecular weight of about 141 kDa;   and about 0.56% monosodium glutamate monohydrate (w/v) at a pH of about 4.5.   
     
     
         15 . The composition of  claim 14 , further comprising at least one additional absorption enhancing agent. 
     
     
         16 . The composition of  claim 15 , wherein the absorption enhancing agent is selected from the group consisting of chitosan, phospholipids, cyclodextrins, surfactants, and any combination thereof. 
     
     
         17 . The composition of  claim 14 , wherein said poly-arginine is poly-L-arginine. 
     
     
         18 . The composition of  claim 14 , wherein said composition further comprises a tonicifying agent, a viscosity-increasing agent, a bioadhesive agent, a preservative, or any combination thereof. 
     
     
         19 . The composition of  claim 14 , further comprising about 0.72% sodium chloride (w/v).