Method for stabilizing arylcarboxylic acid, stabilizer thereof and aqueous solution containing stabilized arylcarboxylic acid

Abstract

A method for stabilizing an arylcarboxylic acid, which comprises adding a heterocyclic base to the arylcarboxylic acid or a pharmacologically acceptable salt thereof, a stabilizer thereof and an aqueous solution containing a stabilized arylcarboxylic acid. According to the stabilization method of the present invention, arylcarboxylic acid and pharmacologically acceptable salts thereof, particularly pranoprofen, can be stabilized at every temperature range, particularly at lower temperatures, thereby making the production of an aqueous solution to be used as an eye drop, nasal drop, ear drop and the like possible.

What is claimed is;  
     
         1 . A method for stabilizing an arylcarboxylic acid or a pharmacologically acceptable salt thereof, which comprises adding a heterocyclic base of the formula (II):  
       
         
           
           
               
               
           
         
         wherein  
         A and A′ are each a carbon atom or a nitrogen atom;  
         X is a carbon atom or a nitrogen atom;  
         Y and Z are each a carbon atom or Y and Z taken together optionally form CH;  
         R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,  
         wherein R 4  and R 5  optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R 6  and R 7  optionally form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when x is a nitrogen atom, R 5  is void; and  is a single bond or a double bond, provided that when a is a carbon atom, y and z are each ch and  is a double bond, and when a is a nitrogen atom, y and z combinedly form CH and  is a single bond, to an arylcarboxylic acid of the formula (I):  
         L 1 —R 1 COOH   (I)  
         wherein  
         L 1  is an optionally substituted heterocyclic group or aryl group having not more than 14 carbon atoms; and  
         R 1  is an optionally substituted alkyl group having not more than 4 carbon atoms or a single bond, or a pharmacologically acceptable salt thereof.  
       
     
     
         2 . The method of    claim 1   , wherein the heterocyclic base is a purine base of the formula (III):  
       
         
           
           
               
               
           
         
         wherein  
         R 9 , R 10  and R 11  are the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.  
       
     
     
         3 . The method of    claim 2   , wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.  
     
     
         4 . The method of    claim 1   , wherein the heterocyclic base is a pyridonecarboxylic acid of the formula (IV):  
       
         
           
           
               
               
           
         
         wherein  
         X is a carbon atom or a nitrogen atom; and  
         R 12 , R 13 , R 14  and R 15  are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;  
         wherein R 12  and R 13  optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R 14  and R 15  optionally form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R 13  is void, or a pharmacologically acceptable salt thereof.  
       
     
     
         5 . The method of    claim 4   , wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.  
     
     
         6 . The method of    claim 1   , wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alolofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.  
     
     
         7 . The method of    claim 1   , wherein the heterocyclic base is added in a proportion of 0.001-5 parts by weight per 100 parts by weight of the arylcarboxylic acid.  
     
     
         8 . A stabilizer of an arylcarboxylic acid or a pharmacologically acceptable salt thereof, which comprises, as an active ingredient, a heterocyclic base of the formula (II):  
       
         
           
           
               
               
           
         
         wherein  
         A and A′ are each a carbon atom or a nitrogen atom;  
         X is a carbon atom or a nitrogen atom;  
         Y and Z are each a carbon atom or Y and Z taken together optionally form CH;  
         R 2  R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,  
         wherein R 4  and R 5  optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R 6  and R 7  optionally form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R 5  is void; and  is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH and  is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and  is a single bond.  
       
     
     
         9 . The stabilizer of    claim 8   , wherein the heterocyclic base is a purine base of the formula (III):  
       
         
           
           
               
               
           
         
         wherein  
         R 9 , R 10  and R 11  are the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.  
       
     
     
         10 . The stabilizer of    claim 9   , wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.  
     
     
         11 . The stabilizer of    claim 8   , wherein the heterocyclic base is a pyridonecarboxylic acid of the formula (IV):  
       
         
           
           
               
               
           
         
         wherein  
         X is a carbon atom or a nitrogen atom; and  
         R 12 , R 13 , R 14  and R 15  are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;  
         wherein R 12  and R 13  optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R 1  4 and R 15  optionally form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R 13  is void, or a pharmacologically acceptable salt thereof.  
       
     
     
         12 . The stabilizer of    claim 11   , wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.  
     
     
         13 . The stabilizer of    claim 8   , wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.  
     
     
         14 . The stabilizer of    claim 8   , wherein the heterocyclic base is contained in a proportion of 0.001-5 parts by weight per 100 parts by weight of the arylcarboxylic acid.  
     
     
         15 . An aqueous solution containing an arylcarboxylic acid or a pharmacologically acceptable salt thereof stabilized by the method of    claim 1    and a heterocyclic base of the formula (II):  
       
         
           
           
               
               
           
         
         wherein  
         A and A′ are each a carbon atom or a nitrogen atom;  
         X is a carbon atom or a nitrogen atom;  
         Y and Z are each a carbon atom or Y and Z taken together optionally form CH;  
         R 2  R 3  R 4 , R 5 , R 6 , R 7  and R 8  are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group,  
         wherein R 4  and R 5  optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R 6  and R 7  optionally form a 4- to 6-membered heterocyclic group with the adjacent Y and Z, provided that when X is a nitrogen atom, R 5  is void; and  is a single bond or a double bond, provided that when A is a carbon atom, Y and Z are each CH and  is a double bond, and when A is a nitrogen atom, Y and Z combinedly form CH and  is a single bond.  
       
     
     
         16 . The aqueous solution of    claim 15   , wherein the heterocyclic base is a purine base of the formula (III):  
       
         
           
           
               
               
           
         
         wherein  
         R 9 , R 10  and R 11  are the same or different and each is a hydrogen atom or an optionally substituted alkyl group, or a pharmacologically acceptable salt thereof.  
       
     
     
         17 . The aqueous solution of    claim 16   , wherein the purine base is at least one compound selected from the group consisting of caffeine, theobromine and theophylline.  
     
     
         18 . The aqueous solution of    claim 15   , wherein the heterocyclic base is a pyridonecarboxylic acid of the formula (IV):  
       
         
           
           
               
               
           
         
         wherein  
         X is a carbon atom or a nitrogen atom; and  
         R 12 , R 13 , R 14  and R 15  are the same or different and each is a hydrogen atom, a halogen, a carboxyl group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;  
         wherein R 12  and R 13  optionally form a 4- to 6-membered heterocyclic group with the adjacent nitrogen atom and X, and R 14  and R 15  optionally form a 4- to 6-membered heterocyclic group with the adjacent carbon atom, provided that when X is a nitrogen atom, R 13  is void, or a pharmacologically acceptable salt thereof.  
       
     
     
         19 . The aqueous solution of    claim 18   , wherein the pyridonecarboxylic acid is at least one compound selected from the group consisting of lomefloxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin and tosufloxacin.  
     
     
         20 . The aqueous solution of    claim 15   , wherein the arylcarboxylic acid is at least one compound selected from the group consisting of ibuprofen, diclofenac, 2-naphthoic acid, 2-naphthylacetic acid, 2-naphthoxyacetic acid, bromfenac, pranoprofen, salicylic acid, aspirin, flufenisal, ibufenac, alclofenac, flurbiprofen, ketoprofen, naproxen, mefenamic acid, niflumic acid, metiazinic acid, protizinic acid, clonixin, indomethacin and fenclozic acid.  
     
     
         21 . The aqueous solution of any one of    claims 15    to    20   , which is an eye drop.  
     
     
         22 . The aqueous solution of any one of    claims 15    to    20   , which is a nasal drop.  
     
     
         23 . The aqueous solution of any one of    claims 15    to    20   , which is an ear drop.