Pharmaceutical composition containing hydroxamic acid derivative or salt thereof
This pharmaceutical composition contains a hydroxamic 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 (2S)-N-hydroxy-2-((4-((4-(1S)-1-hydroxy-2-methoxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N′,2-dimethylmalonamide, or a salt thereof, and
(ii) at least one solubilizing agent selected from the group consisting of α-cyclodextrin, β-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.
2. 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.
3. The pharmaceutical composition according to claim 1 , wherein the solubilizing agent is one or more selected from the group consisting of α-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, sulfobutylether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, heptakis-2,6-di-O-methvl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, and methyl-β-cyclodextrin.
4. The pharmaceutical composition according to claim 1 , 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.
5. The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is a liquid formulation.
6. The pharmaceutical composition according to claim 5 , wherein a pH of the liquid formulation is from 3 to 8.
7. The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is a frozen liquid formulation.
8. The pharmaceutical composition according to claim 7 , wherein a pH of the frozen liquid formulation when thawed is from 3 to 8.
9. The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is a lyophilized formulation.
10. The pharmaceutical composition according to claim 9 , wherein a pH of an aqueous solution of the lyophilized formulation is from 3 to 8.
11. A method of inhibiting LpxC, comprising administering the pharmaceutical composition according to claim 1 to a subject in need thereof.
12. A method of inhibiting Gram-negative bacteria, comprising administering the pharmaceutical composition according to claim 1 to a subject in need thereof.
13. 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;
followed by adjusting a pH of the obtained aqueous solution to 3 to 8,
wherein the solubilizing agent is at least one selected from the group consisting of α-cyclodextrin, β-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.
14. The production method according to claim 13 , wherein the hydroxamic acid derivative is (2S)-2-((4-((4-((1S)-1,2-dihydroxyethyl)phenyl)ethynyl)benzoyl)(methyl)amino)-N-hydroxy-N′,2-dimethylmalonamide.
15. The production method according to claim 13 , wherein the solubilizing agent is one or more selected from the group consisting of α-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, sulfobutylether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, heptakis-2,6-di-O-methyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin, and methyl-β-cyclodextrin.
16. The production method according to claim 13 , 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.