Novel pharmaceutical composition containing hydroxamic acid derivative or salt thereof

Abstract

This pharmaceutical composition contains a hvdroxamic acid derivative, or a salt thereof, and a solubilizer, said hydroxamic acid derivative being selected from among (2S)-2-((4-((4-((1S)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2- dimethylmalonamide, (2S)-2-((4((4-((1R)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2-dimethylmalonamide, and (2S)-N-hydroxy-2-((4-((4-((1S)-1-hydroxy-2-methoxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N′,2-dimethylmalonamide. The pharmaceutical composition demonstrates strong antibacterial activity, has excellent solubility in water, and is useful as a drug.

1 . A pharmaceutical composition comprising
 (i) a hydroxamic acid derivative selected from the group consisting of: (2S)-2-((4-((4-((1S)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2-dimethylmalonamide, (2S)-2-((4-((4-((1R)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2-dimethylmalonamide and 2(S)-N-hydroxy-2-((4-((4-((1S)-1-hydroxy-2-methoxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N′,2-dimethylmalonamide, or a salt thereof, and   (ii) a solubilizing agent,   with the proviso that a 10% hydroxypropylated β-cyclodextrin/2.5% mannitol aqueous solution of the hydroxamic acid derivative or a solution of the hydroxamic acid derivative in dimethyl sulfoxide are not covered.   
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the solubilizing agent is a cyclodextrin or a cyclodextrin derivative. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the hydroxamic acid derivative is (2S)-2-((4-((4-((1S)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino-N-hydroxy-N′,2- dimethylmalonamide. 
     
     
         4 . The pharmaceutical composition according to  claim 2 , wherein the solubilizing agent is one or more selected from the group consisting of α-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, sulfobutylether-β-cyclodextrin, 2,3,6-tri-O-methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, heptakis-2,6-di-O-methyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, methyl-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin. 
     
     
         5 . The pharmaceutical composition according to  claim 2 , wherein the solubilizing agent is one or more selected from the group consisting of α-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is a liquid formulation. 
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein a pH of the liquid formulation is from 3 to 8. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is a frozen liquid formulation. 
     
     
         9 . The pharmaceutical composition according to  claim 8 , wherein a pH of the frozen liquid formulation when thawed is from 3 to 8. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is a lyophilized formulation. 
     
     
         11 . The pharmaceutical composition according to  claim 10 , wherein a pH of an aqueous solution of the lyophilized formulation is from 3 to 8. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the solubilizing agent is one or more selected from the group consisting of monoalcohols, polyhydric alcohols, amides, sulfoxides, amino acids, surfactants, acids and bases. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , wherein the hydroxamic acid derivative is (2S)-2-((4-((4-((1S)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2-dimethylmalonanide. 
     
     
         14 . The pharmaceutical composition according to  claim 12 , wherein the monoalcohol is an alcohol having 1 to 6 carbon atoms; the polyhydric alcohol is a diol; and the acid is an organic acid. 
     
     
         15 . The pharmaceutical composition according to  claim 12 , wherein the solubilizing agent is one or more selected from the group consisting of alcohols having 1 to 6 carbon atoms, diols, amino acids and organic acids in combination with an amide. 
     
     
         16 . The pharmaceutical composition according to  claim 12 , wherein the pharmaceutical composition is a liquid formulation. 
     
     
         17 . A method of inhibiting LpxC, comprising administering the pharmaceutical composition according to  claim 1  to a subject in need thereof. 
     
     
         18 . A method of inhibiting Gram-negative bacteria, comprising administering the pharmaceutical composition according to  claim 1  to a subject in need thereof. 
     
     
         19 . A method for producing a liquid formulation comprising a hydroxamic acid derivative or a salt thereof and a solubilizing agent, the method comprising:
 dissolving the hydroxamic acid derivative selected from the group consisting of (2S)-2-((4-((4-((1S)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2-dimethylmalonamide, (2S)-2-((4-((4-((1R)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino-N-hydroxy-N′,2-dimethylmalonamide and (2S)-N-hydroxy-2-((4-((4-((1S)-1-hydroxy-2-methoxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N′,2-dimethylmalonamide, or the salt thereof, and the solubilizing agent in water to obtain an aqueous solution of the hydroxamic acid derivative or the salt thereof, with the proviso that a 10% hydroxypropylated β-cyclodextrin/2.5% mannitol aqueous solution of the hydroxamic acid derivative or a solution of the hydroxamic acid derivative in dimethyl sulfoxide are not covered,   followed by adjusting a pH of the obtained aqueous solution to 3 to 8.   
     
     
         20 . The production method according to  claim 19 , wherein the solubilizing agent is a cyclodextrin or a cyclodextrin derivative. 
     
     
         21 . The production method according to  claim 19 , wherein the hydroxamic acid derivative is (2S)-2-((4-((4-((1S)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2- dimethylmalonanmide. 
     
     
         22 . The production method according to  claim 20 , wherein the solubilizing agent is one or more selected from the group consisting of α-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, sulfobutylether-β-cyclodextrin, 2,3,6-tri-O-methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, heptakis-2,6-di-O-methyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, methyl-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin. 
     
     
         23 . The production method according to  claim 20 , wherein the solubilizing agent is one or more selected from the group consisting of α-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cycodextrin and hydroxypropyl-γ-cyclodextrin.