Stable pharmaceutical composition for oral administration
Provided is a stable pharmaceutical composition for oral administration comprising 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide (hereinafter referred to as compound A) or a pharmaceutically acceptable salt thereof, wherein the generation of related substances during storage is inhibited. In the stable pharmaceutical composition for oral administration, the proportion of crystals of compound A or a pharmaceutically acceptable salt thereof is 60% or more with respect to the total amount of compound A or a pharmaceutically acceptable salt thereof.
1. A pharmaceutical composition for oral administration comprising:
6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate, wherein a proportion of crystals of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 62% or more with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the pharmaceutical composition; and
at least one pharmaceutical additive selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, calcium stearate, and talc.
2. The pharmaceutical composition according to claim 1 , wherein a pharmaceutical additive content is 50% by weight to 90% by weight with respect to a total weight of the pharmaceutical composition.
3. The pharmaceutical composition according to claim 1 , wherein the at least one pharmaceutical additive is D-mannitol.
4. The pharmaceutical composition according to claim 1 , wherein the at least one pharmaceutical additive is lactose and/or D-mannitol.
5. The pharmaceutical composition according to claim 2 , wherein the at least one pharmaceutical additive is D-mannitol.
6. The pharmaceutical composition according to claim 4 , wherein a total content of lactose and/or D-mannitol is 50% by weight to 70% by weight with respect to a total weight of the pharmaceutical composition.
7. The pharmaceutical composition according to claim 3 , wherein a total content of D-mannitol is 50% by weight to 70% by weight with respect to a total weight of the pharmaceutical composition.
8. The pharmaceutical composition according to any one of claims 1 , 2 - 5 , 6 , and 7 , which is a tablet.
9. A tablet comprising 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate;
at least one pharmaceutical additive selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, calcium stearate, an talc,
wherein a total pharmaceutical additive content is from 50% to 90% by weight with respect to a total weight of the tablet, and
wherein a proportion of crystals of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 62% or more with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the tablet.
10. The tablet according to claim 9 , wherein the pharmaceutical additive is lactose and/or D-mannitol.
11. The tablet according to claim 9 , wherein the pharmaceutical additive is D-mannitol.