Microcrystals and pharmaceutical formulations comprising the same
The present invention provides microcrystals of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide represented by the following formula which has an average particle size of 80 μm or less, a pharmaceutical formulation comprising the microcrystals, and the like.
1 . A microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide represented by the following formula
which has an average particle size of 80 μm or less.
2 . The microcrystal according to claim 1 , wherein the average particle size of the microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide is from 1 to 40 μm.
3 . The microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide according to claim 1 , wherein a crystallinity thereof is 15% or more.
4 . The microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide according to claim 1 , wherein the crystallinity thereof is 25% or more.
5 . The microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide according to claim 1 , wherein the crystallinity thereof is 45% or more.
6 . The microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide according to claim 1 , wherein the crystallinity thereof is 75% or more.
7 . A pharmaceutical formulation comprising the microcrystals described in any one of claims 1 to 6 or 10 to 13 , together with a pharmaceutically acceptable carrier.
8 . A process for producing the microcrystals described in any one of claims 1 to 6 or 10 to 13 , comprising a step of dry-pulverizing (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide which has an average particle size of 80 μm or more.
9 . The process for producing the microcrystals according to the claim 8 , wherein a jet mill is used in the pulverization step.
10 . The microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide according to claim 2 , wherein a crystallinity thereof is 15% or more.
11 . The microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide according to claim 2 , wherein the crystallinity thereof is 25% or more.
12 . The microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide according to claim 2 , wherein the crystallinity thereof is 45% or more.
13 . The microcrystal of (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propaneamide according to claim 2 , wherein the crystallinity thereof is 75% or more.