Solid dispersion of alpha-ketoamide derivatives
A solid dispersion comprising ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester made amorphous in the presence of a water-soluble cellulosic polymer has improved storage stability. The solid dispersion also has improved solubility for an improved bioavailability.
1. A solid dispersion comprising ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester and a water-soluble cellulosic polymer, wherein the water-soluble cellulosic polymer is at least one kind selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose.
2. The solid dispersion according to claim 1 , wherein the water-soluble cellulosic polymer is hydroxypropyl methylcellulose.
3. The solid dispersion of claim 1 , wherein the concentration of ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester relative to the solid dispersion is within the range of 40 to 60% by mass.
4. A solid composition comprising the solid dispersion of claim 1 , further comprising an excipient selected from the group comprising a bulking agent, a binder, a disintegrant, a lubricant, a glidant and solubilizing agent.
5. A method for producing a solid dispersion comprising ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester in the presence of a water-soluble cellulosic polymer, the method comprising the steps of:
(1) dissolving ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester in a solvent,
(2) dissolving a water-soluble cellulosic polymer in the solution obtained in (1), wherein the water-soluble cellulosic polymer is at least one kind selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose, and
(3) lyophilizing the solution obtained in (2).
6. A method for improving the solubility of ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester comprising the steps of:
1) dissolving ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester and a water-soluble cellulosic polymer in a solvent, wherein the water-soluble cellulosic polymer is at least one polymer selected from the group consisting of hydroxypropyl methylcellulose and hydroxypropyl cellulose, and
2) removing the solvent to obtain amorphous ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester.
7. The method according to claim 6 , wherein the solvent is capable of dissolving both the ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester and the water-soluble cellulosic polymer.
8. The method according to claim 6 , wherein the water-soluble cellulosic polymer is hydroxypropyl methylcellulose.
9. The method according to claim 6 , wherein the amorphous ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester is in a solid dispersion and the amorphous ((1S)-1-((((1S)-1-benzyl-2,3-dioxo-3-(cyclopropylamino)propyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester is in a concentration of the solid dispersion within the range of 40 to 60% by mass.
10. The method according to claim 7 , wherein the solvent is a mixture of an alcohol and water.
11. The method according to claim 10 , wherein the alcohol is t-butyl alcohol.
12. The method according to claim 6 , wherein the solvent is removed by lyophilization.