Antimicrobial compositions

Abstract

The present invention relates to antimicrobial compositions and more specifically compositions of quinolone carboxylic acid derivatives. These compositions have improved solubility, stability, and tolerability. These compositions are useful for intravenous administration for treating, preventing, or reducing the risk of infection.

1 - 97 . (canceled) 
     
     
         98 . A pharmaceutical composition comprising:
 (a) a quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof, wherein said quinolone carboxylic acid derivative corresponds to the following compound (A)   
       
         
           
           
               
               
           
         
         and 
         (b) a cyclodextrin. 
       
     
     
         99 . A pharmaceutical composition according to  claim 98  wherein said cyclodextrin is a beta-cyclodextrin. 
     
     
         100 . A pharmaceutical composition according to  claim 99  wherein said beta-cyclodextrin is a hydroxyalkyl-beta-cyclodextrin. 
     
     
         101 . A pharmaceutical composition according to  claim 100  wherein said hydroxyalkyl-beta-cyclodextrin is a hydroxypropyl-beta-cyclodextrin. 
     
     
         102 . A pharmaceutical composition according to  claim 99  wherein said cyclodextrin is a beta-cyclodextrin corresponding to Formula (3)
   (beta-cyclodextrin)-OR,   (3)
 
 wherein R is hydroxypropyl, the beta-cyclodextrin ether having a water-solubility of more than 1.8 g in 1000 ml water. 
 
     
     
         103 . A pharmaceutical composition according to  claim 101  wherein said hydroxypropyl beta-cyclodextrin corresponds to the CAS Registry Number 128446-35-5. 
     
     
         104 . A pharmaceutical composition according to  claim 98  wherein said cyclodextrin is a sulfoalkyl ether cyclodextrin derivative of Formula (1) 
       
         
           
           
               
               
           
         
         wherein n is 4, 5 or 6; 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  in Formula (1) are each, independently, O −  or a O—(C 2-6  alkylene)-SO 3   −  group, and at least one of R 1  and R 2  is, independently, said O—(C 2-6 alkylene)-SO 3   −  group; and 
         S 1 , S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8  and S 9  are each, independently, a pharmaceutically acceptable cation, and wherein said composition shows an absence of underivatized cyclodextrin as measured by thin-layer chromatography. 
       
     
     
         105 . The pharmaceutical composition according to  claim 104  wherein at least one of R 4 , R 6  and R 8  is, independently, said O—(C 2-6 -alkylene)-SO 3   −  group; and R 5 , R 7  and R 9  are each —O − . 
     
     
         106 . A pharmaceutical composition according to  claim 104  wherein said sulfoalkyl ether cyclodextrin is sulfobutyl ether beta-cyclodextrin. 
     
     
         107 . A pharmaceutical composition according to  claim 106  wherein said sulfoalkyl ether beta-cyclodextrin corresponds to the CAS Registry Number 194615-04-8. 
     
     
         108 . A pharmaceutical composition according to  claim 98  wherein said quinolone carboxylic acid derivative is a D-glucito1,1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (salt). 
     
     
         109 . A pharmaceutical composition according to  claim 98  wherein said quinolone carboxylic acid derivative is D-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate trihydrate (salt). 
     
     
         110 . A pharmaceutical composition according to  claim 98  further comprising a chelating agent. 
     
     
         111 . A pharmaceutical composition according to  claim 110  wherein said chelating agent is disodium EDTA. 
     
     
         112 . A pharmaceutical composition according to  claim 98  further comprising a polyhydroxyamine compound. 
     
     
         113 . A pharmaceutical composition according to  claim 112  wherein said polyhydroxyamine compound is meglumine. 
     
     
         114 . A pharmaceutical composition according to  claim 98  wherein said quinolone carboxylic acid derivative has a measurable improvement in solubility compared to the quinolone carboxylic acid derivative in water, and/or the composition has improved stability, and/or the composition provides a measurable enhancement in venous toleration. 
     
     
         115 . A pharmaceutical composition comprising:
 (a) from about 100 mg to about 500 mg of delafloxacin meglumine,   (b) from about 15 mg to about 125 mg meglumine,   (c) from about 500 mg to about 5000 mg of sulfobutyl ether beta-cyclodextrin corresponding to the CAS Registry Number 194615-04-8; and   (d) from 0 mg to about 4 mg disodium EDTA.   
     
     
         116 . A pharmaceutical composition according to  claim 115  which is in the form of a lyophile. 
     
     
         117 . A method of treating, preventing, or reducing the risk of a bacterial infection comprising administering to a patient in need thereof a composition according to  claim 98 .