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 phenylamino)-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 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 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,
wherein a pharmaceutical additive 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,
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-carboxamidein 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, % mobile phase A and 4% mobile phase B.
2. The pharmaceutical composition 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.
3. The pharmaceutical composition according to claim 1 , comprising 40 mg to 50 mg 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.
4. The pharmaceutical composition according to claim 1 , wherein the at least one pharmaceutical additive is lactose or D-mannitol.
5. The pharmaceutical composition according to claim 1 , which is a tablet.
6. The pharmaceutical composition according to claim 2 , which is a tablet.
7. The pharmaceutical composition according to claim 3 , which is a tablet.