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 method of manufacturing a pharmaceutical composition for oral administration, the pharmaceutical composition 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 or a pharmaceutically acceptable salt thereof and at least one pharmaceutical additive selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium, 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 or the pharmaceutically acceptable salt thereof is at least 62% 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 or the pharmaceutically acceptable salt thereof in the pharmaceutical composition,
the method comprising:
combining 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 or a pharmaceutically acceptable salt thereof with the at least one pharmaceutical additive to produce a mixture;
granulating the mixture using water and producing a granulated product; and
drying the granulated product using a fluidized bed granulation dryer and producing a dried product,
wherein the pharmaceutical composition exhibits an increase of no more than 0.11% of an oxidative decomposition product having a relative retention time of 1.06 with respect to a retention time 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, as measured by a high-performance liquid chromatography method, after storage under opened conditions of 40° C. and 75% relative humidity for 1 month, and
wherein the high-performance liquid chromatography method is performed under following conditions:
a Kinetex XB-C18 column, particle size: 2.6 μm, 4.6 mm (an inner diameter)×75 mm;
a column temperature maintained at 40° C.;
a mobile phase A of a perchlorate solution (pH 2.2);
a mobile phase B of an acetonitrile solution;
a sample solution having a sample concentration of 0.8 mg/ml 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 in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution;
a standard solution having a standard solution concentration of 0.008 mg/ml 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 in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution;
an ultraviolet absorption spectrophotometer detector with a wavelength at 220 nm; and
a gradient of the mobile phase A and mobile phase B is as follows:
(a) from 0 minutes to 2 minutes since sample injection, 96% mobile phase A and 4% mobile phase B;
(b) from 2 minutes to 5 minutes since sample injection, 96% incrementing down to 85% mobile phase A and 4% incrementing up to 15% mobile phase B;
(c) from 5 minutes to 20 minutes since sample injection, 85% incrementing down to 68% mobile phase A and 15% incrementing up to 32% mobile phase B;
(d) from 20 minutes to 25 minutes since sample injection, 68% incrementing down to 30% mobile phase A and 32% incrementing up to 70% mobile phase B;
(e) from 25 minutes to 26 minutes since sample injection, 30% mobile phase A and 70% mobile phase B;
(f) from 26 minutes to 26.1 minutes since sample injection, 30% incrementing up to 96% mobile phase A and 70% incrementing down to 4% mobile phase B; and
(g) from 26.1 minutes to 30 minutes since sample injection, 96% mobile phase A and 4% mobile phase B.
2. The method according to claim 1 , further comprising:
mixing the dried product with magnesium stearate and producing a mixture of granules; and
optionally compression-molding the mixture of granules and producing a tablet; and
optionally film-coating the tablet and producing a coated tablet.
3. The method according to claim 1 , wherein:
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 combined with the at least one pharmaceutical additive to produce the mixture; and
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% to 98% 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.
4. The method according to claim 3 , further comprising:
mixing the dried product with magnesium stearate and producing a mixture of granules; and
optionally compression-molding the mixture of granules and producing a tablet; and
optionally film-coating the tablet and producing a coated tablet.
5. The method according to claim 1 , wherein the at least one pharmaceutical additive exhibits a loss on drying of 1.0% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week.
6. The method according to claim 1 , wherein a content 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 or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is 10% by weight to 40% by weight with respect to 100% by weight of the pharmaceutical composition.
7. The method according to claim 1 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that 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 or the pharmaceutically acceptable salt thereof.
8. The method according to claim 1 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 70% by weight with respect to 100% by weight of the pharmaceutical composition.
9. The method according to claim 1 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 60% by weight with respect to 100% by weight of the pharmaceutical composition.
10. The method according to claim 1 , wherein the at least one pharmaceutical additive is lactose or D-mannitol.
11. The method according to claim 1 , wherein the pharmaceutical composition is a tablet.
12. A pharmaceutical composition for oral administration produced by the method according to claim 1 .
13. The pharmaceutical composition according to claim 12 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium.
14. The pharmaceutical composition according to claim 13 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that 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 or the pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition according to claim 14 , which is a tablet.
16. A pharmaceutical composition for oral administration produced by the method according to claim 2 .
17. The pharmaceutical composition according to claim 16 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium.
18. The pharmaceutical composition according to claim 17 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that 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 or the pharmaceutically acceptable salt thereof.
19. The pharmaceutical composition according to claim 18 , which is a tablet.
20. A pharmaceutical composition for oral administration produced by the method according to claim 4 .
21. The pharmaceutical composition according to claim 20 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium.
22. The pharmaceutical composition according to claim 21 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that 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.
23. The pharmaceutical composition according to claim 22 , which is a tablet.