Liquid Preparation of Physiologically Active Peptide

Abstract

An effective liquid preparation achieves high bioavailability (BA) of physiologically active peptides or proteins, including ghrelins, that are administered as drugs. Also provided is a method for improving the BA of physiologically active peptides or proteins, including ghrelins, that are subcutaneously injected in aqueous solutions. The liquid preparation contains: a physiologically active peptide or protein, such as ghrelins, as an active ingredient; an acid solution including one or a combination of two or more selected form the group consisting of acetic acid, lactic acid, phosphoric acid, glycine, citric acid, hydrochloric acid, propionic acid, butyric acid, benzoic acid and salts thereof; an alcohol; and a polar organic liquid including one or a combination of two or more selected from the group consisting of N-methyl-2-pyrrolidone, dimethylformamide, dimethylsulfoxide and methylparaben.

1 . A liquid preparation comprising a physiologically active peptide or a physiologically active protein as an active ingredient in combination with an acidic solution. 
     
     
         2 . The liquid preparation according to  claim 1 , wherein the acidic solution comprises one or more of acetic acid, lactic acid, phosphoric acid, glycine, citric acid, hydrochloric acid, propionic acid, butyric acid, benzoic acid and salts thereof. 
     
     
         3 . The liquid preparation according to  claim 1 , wherein the acidic solution comprises one or more of acetic acid, lactic acid, propionic acid, butyric acid and/or phosphoric acid, and salts thereof. 
     
     
         4 . The liquid preparation according to  claim 1 , having a pH in a range of 3.0 to 7.0. 
     
     
         5 . The liquid preparation according to  claim 1 , wherein the concentration of the acidic solution is from 1 to 1000 mM. 
     
     
         6 . The liquid preparation according to  claim 1 , wherein the concentration of the acidic solution is from 10 to 500 mM. 
     
     
         7 . The liquid preparation according to  claim 1 , wherein the acidic solution is an acid buffer having a pH in a range of 3.0 to 7.0. 
     
     
         8 . A liquid preparation comprising a physiologically active peptide or a physiologically active protein as an active ingredient in combination with a polar organic liquid. 
     
     
         9 . The liquid preparation according to  claim 1 , further comprising a polar organic liquid. 
     
     
         10 . The liquid preparation according to  claim 8 , wherein the polar organic liquid comprises one or more of an alcohol, N-methyl-2-pyrrolidone, dimethylformamide, dimethylsulfoxide and methylparaben. 
     
     
         11 . The liquid preparation according to  claim 8 , wherein the polar organic liquid comprises one or more of benzyl alcohol, ethanol, phenol, tert-butanol, chlorobutanol, N-methyl-2-pyrrolidone, dimethylformamide and dimethylsulfoxide. 
     
     
         12 . The liquid preparation according to  claim 8 , wherein the concentration of the polar organic liquid is from 0.001 to 80% (w/v). 
     
     
         13 . The liquid preparation according to  claim 8 , wherein the concentration of the polar organic liquid is from 0.1 to 10% (w/v). 
     
     
         14 . The liquid preparation according to  claim 1 , further comprising a sugar. 
     
     
         15 . The liquid preparation according to  claim 8 , further comprising a sugar. 
     
     
         16 . The liquid preparation according to  claim 1 , further containing comprising a polar organic liquid and a sugar. 
     
     
         17 . The liquid preparation according to  claim 14 , wherein the sugar comprises one or more of mannitol, sucrose, glucose and cyclodextrin. 
     
     
         18 . The liquid preparation according  claim 14 , wherein the sugar is cyclodextrin. 
     
     
         19 . The liquid preparation according to  claim 14 , wherein the concentration of the sugar is from 0.1 to 20% (w/v). 
     
     
         20 . The liquid preparation according to any one of  claims 1  and  8 , wherein the physiologically active peptide or the physiologically active protein comprises one or more of ghrelins, human glucagon-like peptide-1 (hGLP-1), human atrial natriuretic peptide (hANP), human adrenomedulin, human parathyroid hormone (hPTH(1-34)), and human insulin. 
     
     
         21 . The liquid preparation according to any one of  claims 1  and  8 , wherein the physiologically active peptide or the physiologically active protein is one of said ghrelins. 
     
     
         22 . The liquid preparation according to  claim 21 , wherein the one of said ghrelins is ghrelin. 
     
     
         23 . The liquid preparation according to  claim 22 , wherein the ghrelin is human ghrelin. 
     
     
         24 . The liquid preparation according to  claim 20 , wherein the concentration of the one or more of said ghrelins is from 0.03 nmol/mL to 15 μmol/mL. 
     
     
         25 . The liquid preparation according to any one of  claims 1  and  8 , in a form suitable for injection. 
     
     
         26 . The liquid preparation according to  claim 25 , in a form suitable for subcutaneous injection or intramuscular injection. 
     
     
         27 . A liquid preparation, comprising:
 (i): one or more ghrelins as an active ingredient;   (ii): an acid solution comprising one or more of acetic acid, lactic acid, propionic acid, butyric acid and/or phosphoric acid; and   (iii): a polar organic liquid comprising one or more of benzyl alcohol, ethanol, phenol, tert-butanol, N-methyl-2-pyrrolidone, dimethylformamide and dimethylsulfoxide,   wherein the liquid preparation has a pH in the range of 3.0 to 7.0.   
     
     
         28 . A method for improving bioavailability of one or more ghrelins, comprising adding an acidic solution and a polar organic liquid to an aqueous solution of said one or more ghrelins.