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 and a pharmaceutical additive,
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
wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week.
2 . The pharmaceutical composition according to claim 1 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less.
3 . The pharmaceutical composition according to claim 1 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 90% by weight.
4 . The pharmaceutical composition according to claim 1 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, calcium stearate, and talc.
5 . The pharmaceutical composition according to claim 1 , wherein the pharmaceutical additive is D-mannitol.
6 . The pharmaceutical composition according to claim 1 , wherein the pharmaceutical additive is lactose.
7 . The pharmaceutical composition according to claim 3 , wherein the pharmaceutical additive is D-mannitol.
8 . The pharmaceutical composition according to claim 6 , wherein a total content of lactose is 50% by weight to 70% by weight with respect to a total weight of the pharmaceutical composition.
9 . The pharmaceutical composition according to claim 5 , 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.
10 . The pharmaceutical composition according to claim 1 , which is a tablet.
11 . 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 and a pharmaceutical additive,
herein 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,
wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 90% by weight, and
wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week.
12 . The tablet according to claim 11 , wherein the pharmaceutical additive is lactose.
13 . The tablet according to claim 11 , wherein the pharmaceutical additive is D-mannitol.
14 . 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 or a pharmaceutically acceptable salt thereof and a pharmaceutical additive,
wherein the pharmaceutical composition exhibits a loss on drying of 2.0% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,
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) x 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.
15 . The pharmaceutical composition according to claim 14 , 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.
16 . The pharmaceutical composition according to claim 14 , 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.
17 . The pharmaceutical composition according to claim 14 , 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.
18 . The pharmaceutical composition according to claim 17 , wherein the pharmaceutical additive content is 50% by weight to 60% by weight.
19 . The pharmaceutical composition according to claim 14 , 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.
20 . The pharmaceutical composition according to claim 14 , 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.
21 . The pharmaceutical composition according to claim 14 , wherein the pharmaceutical additive is lactose or D-mannitol.
22 . The pharmaceutical composition according to claim 15 , wherein
a proportion of crystals of the 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 98% or less 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.
23 . The pharmaceutical composition according to claim 22 , 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.
24 . The pharmaceutical composition according to claim 22 , 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.
25 . The pharmaceutical composition according to claim 22 , 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.
26 . The pharmaceutical composition according to claim 22 , 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.
27 . The pharmaceutical composition according to claim 22 , 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.
28 . The pharmaceutical composition according to claim 22 , wherein the pharmaceutical additive is lactose or D-mannitol.
29 . The pharmaceutical composition according to claim 23 , which is a tablet.
30 . 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 a pharmaceutical additive,
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 98% or less 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 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,
wherein the pharmaceutical composition exhibits a loss on drying of 2.0% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,
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) x 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.
31 . The pharmaceutical composition according to claim 30 , 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.
32 . The pharmaceutical composition according to claim 30 , 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.
33 . The pharmaceutical composition according to claim 30 , wherein the pharmaceutical additive is lactose or D-mannitol.
34 . The pharmaceutical composition according to claim 31 , which is a tablet.
35 . 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 or a pharmaceutically acceptable salt thereof and a pharmaceutical additive,
wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,
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) x 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.
36 . The pharmaceutical composition according to claim 35 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less.
37 . The pharmaceutical composition according to claim 35 , wherein 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.
38 . The pharmaceutical composition according to claim 35 , 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.
39 . The pharmaceutical composition according to claim 35 , 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.
40 . The pharmaceutical composition according to claim 35 , 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.
41 . The pharmaceutical composition according to claim 35 , 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.
42 . The pharmaceutical composition according to claim 35 , 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.
43 . The pharmaceutical composition according to claim 42 , wherein the pharmaceutical additive is lactose or D-mannitol.
44 . The pharmaceutical composition according to claim 37 , 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 98% or less 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.
45 . The pharmaceutical composition according to claim 44 , wherein a loss on drying of the pharmaceutical additive is 1.0% or less.
46 . The pharmaceutical composition according to claim 44 , 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.
47 . The pharmaceutical composition according to claim 44 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight 70% by weight with respect to 100% by weight of the pharmaceutical composition.
48 . The pharmaceutical composition according to claim 44 , 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.
49 . The pharmaceutical composition according to claim 44 , 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.
50 . The pharmaceutical composition according to claim 44 , 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.
51 . The pharmaceutical composition according to claim 44 , wherein the pharmaceutical additive is lactose or D-mannitol.
52 . The pharmaceutical composition according to claim 37 , which is a tablet.
53 . The pharmaceutical composition according to claim 46 , which is a tablet.
54 . 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 a pharmaceutical additive,
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 98% or less 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 additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,
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) x 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.
55 . The pharmaceutical composition according to claim 54 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less.
56 . The pharmaceutical composition according to claim 54 , 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.
57 . The pharmaceutical composition according to claim 54 , 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.
58 . The pharmaceutical composition according to claim 54 , wherein the pharmaceutical additive is lactose or D-mannitol.
59 . The pharmaceutical composition according to claim 56 , which is a tablet.
60 . A method of manufacturing a pharmaceutical composition for oral administration, 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 a pharmaceutical additive to produce a mixture; and
granulating the mixture using fluidized bed granulation with an aqueous pharmaceutical additive solution to produce a granulated product,
wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,
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) x 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 from injection, 96% mobile phase A and 4% mobile phase B.
61 . The method according to claim 60 , further comprising:
drying the granulated product to produce a dried product; and
optionally 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.
62 . The method according to claim 60 , 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 a pharmaceutical additive to produce a 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 98% or less 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, as determined by the near-infrared spectroscopy.
63 . The method according to claim 62 , further comprising:
drying the granulated product to produce a dried product;
optionally 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.
64 . The method according to claim 60 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less.
65 . The method according to claim 60 , 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.
66 . The method according to claim 60 , 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.
67 . The method according to claim 60 , 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.
68 . The method according to claim 60 , wherein the pharmaceutical additive content is 50% by weight to 60% by weight.
69 . The method according to claim 60 , 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.
70 . The method according to claim 60 , wherein the pharmaceutical additive is lactose or D-mannitol.
71 . The method according to claim 60 , wherein the pharmaceutical composition is a tablet.
72 . A pharmaceutical composition for oral administration produced by the method according to claim 60 .
73 . The pharmaceutical composition according to claim 72 , 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.
74 . The method according to claim 73 , 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.
75 . The pharmaceutical composition according to claim 74 , which is a tablet.
76 . A pharmaceutical composition for oral administration produced by the method according to claim 61 .
77 . The pharmaceutical composition according to claim 76 , 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.
78 . The method according to claim 77 , 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.
79 . The pharmaceutical composition according to claim 78 , which is a tablet.
80 . A pharmaceutical composition for oral administration produced by the method according to claim 63 .
81 . The pharmaceutical composition according to claim 80 , 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.
82 . The method according to claim 81 , 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.
83 . The pharmaceutical composition according to claim 82 , which is a tablet.
84 . A method of manufacturing a pharmaceutical composition for oral administration, the method comprising:
mixing 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 a 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 drier and producing a dried product,
wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,
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) x 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.
85 . The method according to claim 84 , further comprising mixing the dried product with magnesium stearate and producing a mixture of granules; and
optionally compression-molding the mixed of granules and producing a tablet; and
optionally film-coating the tablet and producing a coated tablet.
86 . The method according to claim 84 , 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 a pharmaceutical additive to produce a 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 98% or less 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.
87 . The method according to claim 86 , further comprising:
drying the granulated product to produce a dried product; and
optionally 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.
88 . The method according to claim 84 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less.
89 . The method according to claim 84 , 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.
90 . The method according to claim 84 , 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.
91 . The method according to claim 84 , 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.
92 . The method according to claim 84 , wherein the pharmaceutical additive content is 50% by weight to 60% by weight.
93 . The method according to claim 84 , 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.
94 . The method according to claim 84 , wherein the pharmaceutical additive is lactose or D-mannitol.
95 . The method according to claim 84 , wherein the pharmaceutical composition is a tablet.
96 . A pharmaceutical composition for oral administration produced by the method according to claim 84 .
97 . The pharmaceutical composition according to claim 96 , 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.
98 . The method according to claim 97 , 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.
99 . The pharmaceutical composition according to claim 98 , which is a tablet.
100 . A pharmaceutical composition for oral administration produced by the method according to claim 85 .
101 . The pharmaceutical composition according to claim 100 , 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.
102 . The method according to claim 101 , 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.
103 . The pharmaceutical composition according to claim 102 , which is a tablet.
104 . A pharmaceutical composition for oral administration produced by the method according to claim 87 .
105 . The pharmaceutical composition according to claim 104 , 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.
106 . The method according to claim 105 , 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.
107 . The pharmaceutical composition according to claim 106 , which is a tablet.