	US 11,938,133 B2
	Stable pharmaceutical composition for oral administration
Masakazu Miyazaki, Tokyo (JP); Ryohei Ishiba, Tokyo (JP); Yuki Takaishi, Tokyo (JP); and Fumiaki Uejo, Tokyo (JP)
Assigned to ASTELLAS PHARMA INC., Tokyo (JP)
Filed by ASTELLAS PHARMA INC., Tokyo (JP)
Filed on May 12, 2023, as Appl. No. 18/316,373.
Application 18/316,373 is a continuation of application No. 18/085,842, filed on Dec. 21, 2022.
Application 18/085,842 is a continuation of application No. 17/000,763, filed on Aug. 24, 2020, abandoned.
Application 17/000,763 is a continuation of application No. 15/741,377, granted, now 10,786,500, issued on Sep. 29, 2020, previously published as PCT/JP2016/069615, filed on Jul. 1, 2016.
Claims priority of application No. 2015-134817 (JP), filed on Jul. 3, 2015.
Prior Publication US 2023/0277532 A1, Sep. 7, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/497 (2006.01); A61K 9/20 (2006.01); A61K 47/10 (2017.01); A61K 47/26 (2006.01)

CPC A61K 31/497 (2013.01) [A61K 9/20 (2013.01); A61K 9/2095 (2013.01); A61K 47/10 (2013.01); A61K 47/26 (2013.01)]

23 Claims

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.