Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof

Abstract

The invention relates to a new administration form for the oral application of the active substance ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate and the pharmacologically acceptable salts thereof.

We claim:  
     
         1 . Pharmaceutical composition for oral administration comprising: 
 a) ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or one of the pharmaceutically acceptable salts thereof and    b) one or more pharmaceutically acceptable organic acids with a water solubility of >1 g/250 ml at 20° C.    
     
     
         2 . Pharmaceutical composition according to  claim 1 , wherein the pharmaceutically acceptable organic acid is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartic acid and one of the hydrates or acid salts thereof.  
     
     
         3 . Pharmaceutical composition according to  claim 2 , wherein the pharmaceutically acceptable organic acid is selected from the group consisting of tartaric acid, fumaric acid, citric acid and succinic acid.  
     
     
         4 . Pharmaceutical composition according to  claim 3 , wherein the pharmaceutically acceptable organic acid is tartaric acid.  
     
     
         5 . Pharmaceutical composition according to  claim 1 , wherein the content of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or the salts thereof in the pharmaceutical composition is 5 to 60%.  
     
     
         6 . Pharmaceutical-composition according to  claim 1 , wherein the content of pharmaceutically acceptable organic acid is 20 to 90%.  
     
     
         7 . Pharmaceutical composition according to  claim 1  comprising a substantially spherical core material further comprised of a pharmaceutically acceptable organic acid, and active substance layer comprised of a binder and optionally a separating agent, which encloses said core material.  
     
     
         8 . Pharmaceutical composition according to  claim 7 , wherein said binder is selected from the group consisting of hydroxypropylcelluloses, hydroxypropyl-methylcelluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethyl-celluloses, the polyvinylpyrrolidones, the copolymers of N-vinylpyrrolidone and vinyl acetate or combinations thereof.  
     
     
         9 . Pharmaceutical composition according to  claim 7 , wherein said core material has an average particle size of 0.4 to 1.5 mm.  
     
     
         10 . Pharmaceutical composition according to  claim 7 , wherein said core material and the active substance layer are separated from one another by an insulating layer comprised of a water-soluble polymer, optionally with the addition of suitable plasticisers, separating agents and pigments.  
     
     
         11 . Pharmaceutical composition according to  claim 10 , wherein said water-soluble polymer is comprised of gum arabic.  
     
     
         12 . Pharmaceutical composition according to  claim 10 , wherein said water-soluble polymer is comprised of a partially or totally synthetic polymer selected from the group consisting of hydroxypropylcelluloses, hydroxypropylmethyl-celluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses, the polyvinylpyrrolidones, the copolymers of N-vinylpyrrolidone and vinyl acetate, or a combination thereof.  
     
     
         13 . Pharmaceutical composition according to  claim 7 , wherein the composition containing the active substance is packed into hard capsules.  
     
     
         14 . Pharmaceutical composition according to  claim 1 , wherein ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mesylate is used as the active substance.  
     
     
         15 . Process for preparing a pharmaceutical composition for oral administration containing ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or one of the physiologically acceptable salts thereof, comprising the steps of: 
 a) forming the core material from one or more pharmaceutically acceptable organic acid(s) with a water solubility of >1 g/250 ml at 20° C., optionally with the addition of binders or other technological adjuvants, by pan methods, on pelleting plates or by extrusion/spheronisation,    b) applying to the core material an insulating layer comprised of one or more water-soluble, pharmaceutically acceptable polymers optionally with the addition of plasticisers, separating agents and/or pigments,    c) applying the active substance from a dispersion which contains a binder and optionally separating agents and simultaneously and/or subsequently drying to eliminate the dispersant,    d) optionally applying a coating of film-forming agents, plasticisers and optionally pigments and    e) packing the active substance-containing pellets thus obtained into capsules.    
     
     
         16 . A composition comprised of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate methanesulphonate.