Dissolution aids for oral peptide delivery comprising a biguanide

Abstract

A pharmaceutical composition comprising a mixture of: (c) an active macromolecular principle; (d) an aromatic alcohol absorption enhancer chosen from propyl gallate, butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA) and analogues and derivatives thereof, or mixtures thereof; and (d) a biguanide or a pharmaceutically acceptable salt thereof, capable of increasing the solubility of the aromatic alcohol absorption enhancer in an aqueous medium, wherein the aromatic alcohol absorption enhancer is present in an amount by weight greater than or equal to that of the active principle.

1 - 28 . (canceled) 
   
   
       29 . A pharmaceutical composition comprising a mixture of:
 (a) an active macromolecular principle;   (b) an aromatic alcohol absorption enhancer chosen from propyl gallate, butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA) and analogues and derivatives thereof, or mixtures thereof; and   (c) a biguanide or a pharmaceutically acceptable salt thereof, capable of increasing the solubility of the aromatic alcohol absorption enhancer in an aqueous medium,   wherein the aromatic alcohol absorption enhancer is present in an amount by weight greater than or equal to that of the active principle.   
   
   
       30 . A composition according to  claim 29 , which comprises less than 5% by weight of water. 
   
   
       31 . A composition according to  claim 29 , wherein the composition is coated with an enteric coating which becomes permeable at a pH from 3 to 7. 
   
   
       32 . A composition according  claim 29 , wherein the mixture comprises from 5 to 30% by weight of the aromatic alcohol absorption enhancer. 
   
   
       33 . A composition according to  claim 29 , wherein the biguanide is chosen from metformin, phenformin and chlorhexidine and pharmaceutically acceptable salts thereof. 
   
   
       34 . A composition according to  claim 29 , wherein the mixture is in the form of a solution or a microparticulate dispersion. 
   
   
       35 . A composition according to  claim 29 , wherein the mixture is in solid form. 
   
   
       36 . A composition according to  claim 29 , wherein the active macromolecular principle is a polypeptide or protein, polynucleotide, polysaccharide or a mixture thereof. 
   
   
       37 . A composition according to  claim 36 , where the active macromolecular principle is chosen from calcitonin, insulin, low molecular weight heparin, erythropoeitin, granulocyte colony stimulating factor, interferon, C-peptide, GLP-1, human growth hormone and parathyroid hormone or analogues or fragments thereof. 
   
   
       38 . A composition according to  claim 36 , where the active macromolecular principle is insulin, calcitonin or parathyroid hormone or an analogue or a derivative thereof. 
   
   
       39 . A composition according to  claim 38 , wherein the active macromolecular principle is insulin or an analogue or derivative thereof. 
   
   
       40 . A composition according to  claim 29 , for use in the therapeutic or diagnostic treatment of the human or animal body. 
   
   
       41 . A composition according to  claim 29 , wherein the analogues and derivatives of propyl gallate are linear or branched chain C 1-12  alkyl, C 1-12  alkyloxy, C 1-12  alkylthio or C 2-12  alkenyl esters of gallic acid, which are optionally substituted with halogen, linear or branched chain C 1-12  alkyl, C 1-12  alkyloxy, C 1-12  alkylthio or C 2-12  alkenyl and the analogues and derivatives of BHT or BHA are hydroxy toluene or hydroxy anisole wherein the methyl group or the methoxy group linked to the aromatic ring and/or the hydrogen ortho to the hydroxy group are replaced by linear or branched chain C 1-12  alkyl, C 1-12  alkyloxy, C 1-12  alkylthio or C 2-12  alkenyl, either unsubstituted or substituted in any position by halogen. 
   
   
       42 . A composition according to  claim 29 , wherein the aromatic alcohol absorption enhancer is chosen from propyl gallate, butylated hydroxy toluene and butylated hydroxy anisole. 
   
   
       43 . A method of enhancing the absorption of an active macromolecular principle in a patient, which method comprises administering to said patient an aromatic alcohol chosen from propyl gallate, BHT, BHA and analogues and derivatives thereof, together with a biguanide or a pharmaceutically acceptable salt thereof, capable of enhancing the solubility of the aromatic alcohol in an aqueous medium. 
   
   
       44 . A method according to  claim 43 , wherein the active macromolecular principle to be absorbed is a polypeptide or protein, polynucleotide, polysaccharide or a mixture thereof. 
   
   
       45 . A method according to  claim 44 , wherein the active macromolecular principle to be absorbed is chosen from calcitonin, insulin, low molecular weight heparin, erythropoeitin, granulocyte colony stimulating factor, interferon, C-peptide, GLP-1, human growth hormone and parathyroid hormone or analogues or fragments thereof. 
   
   
       46 . A method according to  claim 45 , wherein the active macromolecular principle to be absorbed is insulin, calcitonin or parathyroid hormone or analogues or fragments thereof. 
   
   
       47 . A method according to  claim 46 , wherein the active macromolecular principle to be absorbed is insulin or an analogue or fragment thereof. 
   
   
       48 . A method of enhancing the absorption of an active macromolecular principle in a patient, which method comprises administering to said patient a composition as defined in  claim 29 . 
   
   
       49 . A method according to  claim 48 , wherein the composition comprises less than 5% by weight of water. 
   
   
       50 . A method according to  claim 48 , wherein the composition is in the form of a solution, as a microparticulate dispersion or as a solid. 
   
   
       51 . A method according to  claim 48 , wherein the active macromolecular principle is chosen from insulin, C-peptide, GLP-1 or a mixture thereof, and the method is for treating diabetes. 
   
   
       52 . A method according to  claim 48 , wherein the active macromolecular principle is chosen from calcitonin and PTH, and the method is for treating osteoporosis. 
   
   
       53 . A method according to  claim 48 , wherein the active macromolecular principle is calcitonin, and the method is for treating osteoarthritis. 
   
   
       54 . A method according to  claim 48 , wherein the active macromolecular principle is chosen from peptide YY, oxyntomodulin and a mixture thereof, and the method is for treating obesity. 
   
   
       55 . A method according to  claim 48 , wherein the active macromolecular principle is chosen from erythropoetin, GCST, GMCSF and mixtures thereof, and the method is for treating cancer.