Formulation of nitrogen-containing heterocyclic compound having myt1 inhibitory activity

Abstract

The present invention provides a composition comprising: a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt; and a dissolution aid.

Description

Preparation of nitrogen-containing heterocyclic compound having MYT1 inhibitory activity

[0001] The present invention relates to a preparation of a nitrogen-containing heterocyclic compound having MYT1 inhibitory activity.

[0002] Cells are exposed to exogenous or endogenous stressors daily, resulting in DNA damage. Normally, cells with DNA damage repair the DNA damage by activating the DNA Damage Response (DDR) pathway. It is known that many cancers have abnormalities in genes and proteins involved in the DDR pathway, and therapeutic approaches are being investigated (Non-Patent Documents 1-2). One method for treating cancers with abnormalities in genes and proteins involved in the DDR pathway is the use of PARP inhibitors, which are used to treat cancers with BRCA1 or BRCA2 mutations (Non-Patent Document 3). Currently, genes and proteins involved in the DDR pathway, such as ATM, ATR, CHK1, DNA-PK, and WEE1, are being identified as potential targets, and active research is being conducted on these targets (Non-Patent Document 4).

[0003] MYT1 is an enzyme of the WEE1 family and is known to be a negative regulator of CDK1. MYT1 phosphorylates CDK1, inactivating it and playing an important role in regulating the cell cycle. In recent years, new MYT1 inhibitors have been reported, which have been shown to induce synthetic lethality in certain cancers (Non-Patent Document 5). However, no approved drugs have yet been developed, and new therapeutic agents are desired.

[0004] International Publication No. 2024 / 048687

[0005] Cancers (Basel), 2020 Apr 23; 12(4):1050. Front Pharmacol., 2021 Feb 8;11: 629266. N. Engl. J. Med., 2018 Dec 27; 379(26): 2495-2505. Nat. Rev. Cancer, 2023, 23, 78-94. Nature,2022 Apr;604(7907):749-756. T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis(5th Edition, John Wiley & Sons 2014) Tetrahedron Lett., 2019 vol.60, 151147 Chem. Rev., 1995, vol.95, no.7, p.2457-2483. Acc. Chem. Res., 2008, vol.41, No.11, p.1461-1473. Synthesis 1992,vol.9,p.803-815. Org. Process Res. Dev., 2018, vol.22, no.4, p.430-445. Tetrahedron 1992, vol.48, no.44, p.9577-9648. Aldrichimica Acta, 2005, vol.38, no.4, p.71-88. Chem. Soc. Rev., 2011, vol.40, p.5084-5121. Chem. Rev., 2016, vol.116, p.12564-12649. Org. Process Res.Dev.,2022, vol.26, no.6, p.1690-1750. J. Am. Chem. Soc., 2016, vol.138, no.26, p.8084-8087. ACS Med. Chem. Lett., 2020, vol.11, no.4, p.597-604. Nature 2021, 598, p.451-456. ACS Cent. Sci. 2017, vol.3, issue 6, p.647-653. Tetrahedron 2008, vol.64, p.5139-5146. Nature 2019 May; 569(7757): 503-508.PLoS Comput Biol. 2019 May 20;15(5): e1006752.

[0006] The compound represented by formula (1), which was found to have MYT1 inhibitory activity, is poorly water-soluble, and therefore its solubility needed to be improved. Furthermore, it was necessary to consider a formulation design that would provide sufficient dissolution properties for a pharmaceutical suitable for achieving the desired efficacy. Furthermore, when a composition containing the compound of the present invention as an API (active pharmaceutical ingredient) was prepared, it tended to exhibit increased adhesion to the formulation equipment (particularly to the punch during tableting).

[0007] The present invention solves at least one of the above problems. That is, an object of one aspect of the present invention is to provide a composition that can improve the solubility of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt. Another object of another aspect of the present invention is to provide a composition having sufficient dissolution properties. Still another object of another aspect of the present invention is to provide a composition with reduced adhesion.

[0008] That is, in one aspect, the present invention provides the following invention: [A1] A composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, and a solubilizing agent: [A2] The composition according to [A1], further comprising a disintegrant. [A3] The composition according to [A1] or [A2], further comprising a lubricant. [B1] A composition comprising the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, and a disintegrant. [B2] The composition according to [B1], further comprising a lubricant. [B3] The composition according to [B1] or [B2], further comprising a solubilizing agent. [C1] A composition comprising the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, and a lubricant. [C2] The composition according to [C1], further comprising a solubilizing agent. [C3] The composition according to [C1] or [C2], further comprising a disintegrant.

[0009] [E1] The composition according to any one of [A1] to [A3], [B3], [C2] and [C3], wherein the solubilizing agent comprises a polymer, and the polymer comprises poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [E1-1] The composition according to any one of [A1] to [A3], [B3], [C2] and [C3], wherein the solubilizing agent comprises the following polymers (i) and (ii): (i) a first polymer which is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and (ii) a second polymer which is neither poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) nor polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [E1-2] The composition according to any one of [A1] to [A3], [B3], [C2] and [C3], wherein the solubilizing agent is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), and the composition further comprises a polymer other than poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol). [E2] The composition according to any one of [A1] to [A3], [B3], [C2], [C3] and [E1], wherein the solubilizing agent comprises poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hydroxypropyl methylcellulose.[E2-1] The composition according to any one of [A1] to [A3], [B3], [C2], [C3] and [E1], wherein the solubilizing agent is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), and the composition further contains hydroxypropyl methylcellulose. [E3] The composition according to any one of [A1] to [A3], [B3], [C2] and [C3], wherein the solubilizing agent is a surfactant or a polymer, and the polymer is neither poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) nor polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [E4] The composition according to any one of [A1] to [A3], [B3], [C2], [C3] and [E3], wherein the solubilizing agent is a surfactant. [E5] The composition according to [E3] or [E4], wherein the surfactant is an alkyl sulfate or a fatty acid ester. [E6] The composition according to any one of [E3] to [E5], wherein the surfactant is an alkyl sulfate. [E7] The composition according to [E5] or [E6], wherein the alkyl sulfate has an alkyl group having 5 to 17 carbon atoms. [E8] The composition according to any one of [E3] to [E7], wherein the alkyl sulfate is lauryl sulfate. [E9] The composition according to [E8], wherein the lauryl sulfate is sodium lauryl sulfate. [E10] The composition according to any one of [E3] to [E5], wherein the surfactant is a fatty acid ester. [E11] The composition according to any one of [E3] to [E5] and [E10], wherein the surfactant is at least one selected from the group consisting of sucrose fatty acid esters, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, D-α-tocopherol polyethylene glycol 1000 succinate, lauroyl-L-carnitine hydrochloride, lauroyl-L-carnitine, palmitoyl-L-carnitine, sodium caprylate, and polyoxyethylene castor oil.[E12] The composition according to [E5] or [E10], wherein the fatty acid ester is a sucrose fatty acid ester. [E13] The composition according to [E3] or [E4], wherein the surfactant is a nonionic surfactant or an anionic surfactant. [E14] The composition according to [E3] or [E4], wherein the surfactant is an anionic surfactant. [E15] The composition according to [E13] or [E14], wherein the anionic surfactant is a carboxylate, sulfonate, or sulfate ester salt. [E16] The composition according to [E13] or [E14], wherein the anionic surfactant is a sulfate ester salt. [E17] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], and [E3], wherein the solubilizing agent comprises a polymer, and the polymer is neither poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) nor polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [E18] The composition according to [E3] and [E5] to [E17], wherein the polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol, polyvinylpyrrolidone-vinylpyrrolidone-vinyl acetate copolymer, methacrylic acid copolymer, dry methacrylic acid copolymer, aminoalkyl methacrylate copolymer, and polyvinyl acetate phthalate. [E19] The composition according to any one of [E3] and [E5] to [E18], wherein the polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol, polyvinylpyrrolidone-vinylpyrrolidone-vinyl acetate copolymer, methacrylic acid copolymer, and dry methacrylic acid copolymer.[E19-1] The composition according to any one of [E3] and [E5] to [E18], wherein the polymer is hydroxypropyl methylcellulose. [E20] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E19], which is in the form of a solid. [E21] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E20], which is in the form of a tablet. [E22] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], and [E1] to [E21], wherein the content of the solubilizing agent is 0.1 to 70.0 wt % relative to the weight of the total composition. [E23] The composition according to any one of [A1] to [A3], [B3], [C2], [C3] and [E1] to [E22], wherein the content of the solubilizing agent is 0.1 to 40.0 wt % relative to the total weight of the composition. [E24] The composition according to any one of [A1] to [A3], [B3], [C2], [C3] and [E1] to [E23], wherein the content of the solubilizing agent is 0.1 to 20.0 wt % relative to the total weight of the composition. [E25] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3] and [E1] to [E20], which is in the form of a capsule. [E26] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], [E1] to [E20], and [E25], wherein the content of the solubilizing agent is 0.1 to 70.0 wt % relative to the weight of the total composition, where the weight of the total composition does not include the weight of the capsule. [E27] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], [E1] to [E20], [E25], and [E26], wherein the content of the solubilizing agent is 0.1 to 40.0 wt % relative to the weight of the total composition, where the weight of the total composition does not include the weight of the capsule.[E28] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], [E1] to [E20], and [E25] to [E27], wherein the content of the solubilizing agent is 0.1 to 20.0 wt % based on the weight of the total composition, wherein the weight of the total composition does not include the weight of a capsule. [E29] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], and [E1] to [E28], wherein the content of the solubilizing agent is 0.1 to 250.0 wt % based on the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, contained in the composition. [E30] The composition according to any one of [A1] to [A3], [B3], [C2], [C3] and [E1] to [E29], wherein the content of the solubilizing agent is 0.1 to 150.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E31] The composition according to any one of [A1] to [A3], [B3], [C2], [C3] and [E1] to [E30], wherein the content of the solubilizing agent is 0.1 to 75.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E32] The composition according to any one of [E29] to [E31], wherein the content of the solubilizing agent is a numerical value relative to the weight of the monohydrate of the hydrochloride of the compound represented by formula (1) contained in the composition. [E33] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], and [E1] to [E32], wherein the concentration of the compound represented by formula (1), the salt, or the solvate in FaSSIF after stirring for 240 minutes from the time the composition is added to FaSSIF at normal pressure and 37°C is higher than the concentration in a composition not containing the solubilizing agent.[E34] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], and [E1] to [E33], wherein the concentration of the compound represented by formula (1), the salt, or the solvate in FaSSIF is 1.2 times or more higher than the concentration in the composition not containing the solubilizing agent after stirring for 240 minutes from the time the composition is added to FaSSIF at normal pressure and 37°C. [E35] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], and [E1] to [E34], wherein, when the concentrations of the compound represented by formula (1), the salt, or the solvate in FaSSIF are compared after stirring at 37°C under normal pressure for 60 minutes and 240 minutes from the time the composition is added to FaSSIF, the concentration of the compound represented by formula (1), the salt, or the solvate after 240 minutes is equivalent to the concentration of the compound represented by formula (1), the salt, or the solvate after 60 minutes. [E36] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], and [E1] to [E34], wherein, when the concentrations of the compound represented by formula (1), the salt, or the solvate in FaSSIF are compared after stirring at 37°C under normal pressure for 60 minutes and 180 minutes from the time the composition is added to FaSSIF, the concentration of the compound represented by formula (1), the salt, or the solvate after 180 minutes is equivalent to the concentration of the compound represented by formula (1), the salt, or the solvate after 60 minutes. [E37] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], and [E1] to [E35], wherein, when the concentrations of the compound represented by formula (1), the salt, or the solvate in FaSSIF are compared after stirring at 37°C under normal pressure for 60 minutes and 240 minutes from the time the composition is added to FaSSIF, the rate of decrease in the concentration of the compound represented by formula (1), the salt, or the solvate after 240 minutes relative to the concentration of the compound represented by formula (1), the salt, or the solvate after 60 minutes is 20% or less.[E38] The composition according to any one of [A1] to [A3], [B3], [C2], [C3], [E1] to [E34], and [E36], wherein, when the concentrations of the compound represented by formula (1), the salt, or the solvate in FaSSIF are compared after stirring at 37°C under normal pressure for 60 minutes and 180 minutes from the time the composition is added to FaSSIF, the rate of decrease in the concentration of the compound represented by formula (1), the salt, or the solvate after 180 minutes relative to the concentration of the compound represented by formula (1), the salt, or the solvate after 60 minutes is 20% or less. [E39] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], and [E1] to [E38], wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, starch, pregelatinized starch, agar, gelatin powder, calcium carbonate, sodium chloride, sodium bicarbonate, calcium citrate, anhydrous silicic acid, dextrin, pectin, carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate. [E40] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], and [E1] to [E39], wherein the disintegrant is croscarmellose sodium or crospovidone. [E41] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], and [E1] to [E40], wherein the disintegrant is croscarmellose sodium. [E42] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], [E1] to [E24], and [E29] to [E41], wherein the content of the disintegrant is 0.1 to 40.0 wt% relative to the total weight of the composition. [E43] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], [E1] to [E24], and [E29] to [E42], wherein the content of the disintegrant is 0.1 to 25.0 wt% relative to the total weight of the composition. [E44] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], [E1] to [E24], and [E29] to [E43], wherein the content of the disintegrant is 0.1 to 10.0 wt % relative to the total weight of the composition.[E45] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], [E1] to [E20], and [E25] to [E41], wherein the content of the disintegrant is 0.1 to 40.0 wt % relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E45-1] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], [E1] to [E20], and [E25] to [E41], wherein the content of the disintegrant is 0.1 to 25.0 wt % relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E45-2] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], [E1] to [E20], and [E25] to [E41], wherein the content of the disintegrant is 0.1 to 10.0 wt % based on the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E46] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], and [E1] to [E45], wherein the content of the disintegrant is 0.1 to 80.0 wt % based on the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E47] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], and [E1] to [E46], wherein the content of the disintegrant is 0.1 to 60.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E48] The composition according to any one of [A2], [A3], [B1] to [B3], [C3], and [E1] to [E47], wherein the content of the disintegrant is 0.1 to 40.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E49] The composition according to any one of [E47] to [E48], wherein the content of the disintegrant is a numerical value relative to the monohydrate of the hydrochloride of the compound represented by formula (1) contained in the composition.[E50] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E49], wherein the lubricant is at least one selected from the group consisting of stearates, light anhydrous silicic acid, hydrogenated oils, sodium stearyl fumarate, shellac, talc, carnauba wax, and paraffin. [E50-1] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E49], wherein the lubricant is two selected from the group consisting of stearates, light anhydrous silicic acid, hydrogenated oils, sodium stearyl fumarate, shellac, talc, carnauba wax, and paraffin. [E50-2] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E49], wherein the lubricant is three selected from the group consisting of stearates, light anhydrous silicic acid, hydrogenated oils, sodium stearyl fumarate, shellac, talc, carnauba wax, and paraffin. [E51] The composition according to [E50], wherein the hydrogenated oil is at least one selected from the group consisting of hydrogenated castor oil, hydrogenated soybean oil, and hydrogenated rapeseed oil. [E51-1] The composition according to [E50], wherein the hydrogenated oil is hydrogenated castor oil or hydrogenated soybean oil. [E51-2] The composition according to [E50], wherein the hydrogenated oil is hydrogenated castor oil. [E52] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E49], wherein the lubricant is at least one selected from the group consisting of stearates, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, and sodium stearyl fumarate. [E52-1] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E49], wherein the lubricant is two selected from the group consisting of stearates, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, and sodium stearyl fumarate.[E52-2] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E49], wherein the lubricant is three selected from the group consisting of stearates, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, and sodium stearyl fumarate. [E53] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E49], wherein the lubricant comprises magnesium stearate. [E54] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E50], wherein the lubricant is a stearate. [E54-1] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E50], and [E52], wherein the lubricant is magnesium stearate. [E54-2] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E50], and [E52], wherein the lubricant comprises magnesium stearate and at least one selected from the group consisting of light anhydrous silicic acid, sodium stearyl fumarate, and hydrogenated castor oil. [E54-3] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E50], and [E52], wherein the lubricant is magnesium stearate and light anhydrous silicic acid. [E54-4] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E50] and [E52], wherein the lubricant is magnesium stearate, sodium stearyl fumarate, and light anhydrous silicic acid. [E54-5] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E50] and [E52], wherein the lubricant is magnesium stearate, light anhydrous silicic acid, and hydrogenated castor oil.

[0010] [E55] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], and [E46] to [E54], wherein the content of the lubricant is 0.1 to 20.0 wt % relative to the weight of the total composition. [E56] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], and [E46] to [E55], wherein the content of the lubricant is 0.1 to 15.0 wt % relative to the weight of the total composition. [E57] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], and [E46] to [E56], wherein the content of the lubricant is 0.1 to 10.0 wt % relative to the total weight of the composition. [E58] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], and [E46] to [E57], wherein the content of the lubricant is 0.5 to 10.0 wt % relative to the total weight of the composition. [E59] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], and [E46] to [E58], wherein the content of the lubricant is 1.0 to 8.0 wt % relative to the weight of the total composition. [E60] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], and [E45] to [E54], wherein the content of the lubricant is 0.1 to 20.0 wt % relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E60-2] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], and [E45] to [E54], wherein the content of the lubricant is 0.1 to 15.0 wt % of the total weight of the composition, wherein the weight of the total weight of the composition does not include the weight of the capsule.[E60-3] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], and [E45] to [E54], wherein the content of the lubricant is 0.1 to 10.0 wt% relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E60-4] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], and [E45] to [E54], wherein the content of the lubricant is 0.5 to 10.0 wt% relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E60-5] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], and [E45] to [E54], wherein the content of the lubricant is 1.0 to 8.0 wt % relative to the weight of the total composition, where the weight of the total composition does not include the weight of the capsule. [E61] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E60], wherein the content of the lubricant is 0.1 to 20.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E61-1] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E60], wherein the content of the lubricant is 0.1 to 15.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E61-3] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E60], wherein the content of the lubricant is 0.1 to 10.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition.[E61-4] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E60], wherein the content of the lubricant is 0.1 to 50.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E61-5] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E60], wherein the content of the lubricant is 1.0 to 40.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E61-6] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E60], wherein the content of the lubricant is 3.0 to 35.0 wt % based on the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [E62] The composition according to [E61], wherein the content of the lubricant is the numerical value relative to the monohydrate of the hydrochloride of the compound represented by formula (1) contained in the composition. [E63] The composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E62], wherein the adhesion to punches during tableting of a composition containing the compound represented by formula (1), the salt, or the solvate is improved compared to the adhesion of a composition not containing the lubricant. [E64] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E63], wherein the compound represented by formula (1), the salt, or the solvate is contained in the composition in the form of particles, and the volume-based particle size d50 of the compound represented by formula (1), the salt, or the solvate is 0.2 to 60 μm.[E65] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3] and [E1] to [E64], wherein the compound represented by formula (1), the salt or the solvate is contained in the composition in a particulate form, and the volume-based particle size d50 of the compound represented by formula (1), the salt or the solvate is 0.2 to 40 μm. [E66] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3] and [E1] to [E65], wherein the compound represented by formula (1), the salt or the solvate is contained in the composition in a particulate form, and the volume-based particle size d50 of the compound represented by formula (1), the salt or the solvate is 0.2 to 20 μm. [E67] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3] and [E1] to [E66], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, is a pharmaceutically acceptable solvate of the compound or salt. [E68] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3] and [E1] to [E67], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, is a solvate of a pharmaceutically acceptable salt of the compound represented by formula (1). [E69] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3] and [E1] to [E68], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is a solvate of the hydrochloride salt of the compound represented by formula (1). [E70] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3] and [E1] to [E69], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is a hydrate of the pharmaceutically acceptable salt of the compound represented by formula (1).[E71] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3] and [E1] to [E70], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is an anhydrate of the hydrochloride salt of the compound represented by formula (1). [E72] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3] and [E1] to [E71], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is a hydrate of the hydrochloride salt of the compound represented by formula (1). [E73] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E72], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt thereof is a monohydrate of the hydrochloride salt of the compound represented by formula (1). [E74] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E73], further comprising a pharmaceutically acceptable excipient. [E75] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E74], wherein the content of the compound represented by formula (1), the salt, or the solvate contained in the composition after storing the composition at 40°C, a storage humidity of 75%, and an airtight state for one month is 80% or more of the initial content of the compound represented by formula (1), the salt, or the solvate contained in the composition. [E75-1] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E75], wherein the content of the compound represented by formula (1), the salt, or the solvate contained in the composition after storing the composition at 40°C, a storage humidity of 75%, and an airtight state for one month is 90% or more of the initial content of the compound represented by formula (1), the salt, or the solvate contained in the composition.[E76] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], [E46] to [E59], and [E61] to [E75], wherein the content of the compound represented by formula (1), the salt, or the solvate is 0.1 to 95.0 wt % relative to the total weight of the composition. [E76-1] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], [E46] to [E59], and [E61] to [E75], wherein the content of the compound represented by formula (1), the salt, or the solvate is 0.1 to 80.0 wt % relative to the total weight of the composition. [E76-2] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], [E46] to [E59], and [E61] to [E75], wherein the content of the compound represented by formula (1), the salt, or the solvate is 0.1 to 65.0 wt % relative to the weight of the entire composition. [E76-3] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], [E46] to [E59], and [E61] to [E75], wherein the content of the compound represented by formula (1), the salt, or the solvate is 1.0 to 50.0 wt % relative to the total weight of the composition. [E76-4] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], [E46] to [E59], and [E61] to [E75], wherein the content of the compound represented by formula (1), the salt, or the solvate is 10.0 to 40.0 wt % relative to the total weight of the composition. [E76-5] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E24], [E29] to [E44], [E46] to [E59], and [E61] to [E75], wherein the content of the compound represented by formula (1), the salt, or the solvate is 12.5 to 30.0 wt % relative to the total weight of the composition.[E77] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], [E45] to [E54], and [E60] to [E76], wherein the content of the compound represented by formula (1), the salt, or the solvate is 0.1 to 95.0 wt % relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E77-1] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], [E45] to [E54], and [E60] to [E76], wherein the content of the compound represented by formula (1), the salt, or the solvate is 0.1 to 80.0 wt % relative to the weight of the total composition, and wherein the weight of the total composition does not include the weight of the capsule. [E77-2] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], [E45] to [E54], and [E60] to [E76], wherein the content of the compound represented by formula (1), the salt, or the solvate is 0.1 to 65.0 wt % relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E77-3] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], [E45] to [E54], and [E60] to [E76], wherein the content of the compound represented by formula (1), the salt, or the solvate is 1.0 to 50.0 wt % relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E77-4] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], [E45] to [E54], and [E60] to [E76], wherein the content of the compound represented by formula (1), the salt, or the solvate is 10.0 to 40.0 wt % relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule.[E77-5] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], [E1] to [E20], [E25] to [E41], [E45] to [E54], and [E60] to [E76], wherein the content of the compound represented by formula (1), the salt, or the solvate is 12.5 to 30.0 wt % relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [E78] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E77], which is a pharmaceutical composition. [E79] The composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E78], for treating or preventing cancer. [E80] A method for producing the composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E79], the method comprising a step of mixing the compound represented by formula (1), the salt, or the solvate with at least one selected from the group consisting of a solubilizing agent, a disintegrant, and a lubricant. [E81] A method for producing the composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E79], comprising the step of mixing the compound represented by formula (1), the salt, or the solvate with at least two selected from the group consisting of a solubilizing agent, a disintegrant, and a lubricant. [E82] A method for producing the composition according to any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E79], comprising the step of mixing the compound represented by formula (1), the salt, or the solvate with a solubilizing agent, a disintegrant, and a lubricant. [E83] A solubilizing agent for improving the solubility of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt. [E84] A disintegrant for improving the dissolution property of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.[E85] A lubricant for improving adhesion to punches during tableting of a composition comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[0011] [F1] Use of the composition described in any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E79] in the manufacture of a medicament for treating a patient in need of treatment with the compound represented by formula (1), the salt, or the solvate. [F2] A method for treating a patient in need of treatment with the compound represented by formula (1), the salt, or the solvate, comprising administering to the patient a composition described in any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E79]. [F3] The method according to [F2], wherein the treatment is treatment or prevention of cancer. [F4] Use of the composition described in any one of [A1] to [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E79] in the manufacture of a medicament for treatment or prevention of cancer. [G1] Use of a solubilizing agent for producing the composition according to any one of [A1] to [A3], [B3], [C2], [C3], and [E1] to [E79]. [G1-1] The use according to [G1], wherein the composition is for treating or preventing cancer. [G2] Use of a disintegrant for producing the composition according to any one of [A2], [A3], [B1] to [B3], [C3], and [E1] to [E79]. [G2-1] The use according to [G2], wherein the composition is for treating or preventing cancer. [G3] Use of a lubricant for producing the composition according to any one of [A3], [B2], [B3], [C1] to [C3], and [E1] to [E79]. [G3-1] The use according to [G3], wherein the composition is for treating or preventing cancer. [G4] Use of a solubilizing agent and a disintegrating agent for producing the composition according to any one of [A1] to [A3], [B1] to [B3], [C2], [C3], and [E1] to [E79]. [G4-1] The use according to [G4], wherein the composition is a composition for treating or preventing cancer. [G5] Use of a solubilizing agent and a lubricant for producing the composition according to any one of [A1] to [A3], [B2], [B3], [C1] to [C3], and [E1] to [E79].[G5-1] The use according to [G5], wherein the composition is a composition for treating or preventing cancer. [G6] Use of a disintegrant and a lubricant for the manufacture of a composition according to any one of [A2], [A3], [B1] to [B3], [C1] to [C3], and [E1] to [E79]. [G6-1] The use according to [G6], wherein the composition is a composition for treating or preventing cancer.

[0012] [H1] A method for improving the solubility of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt in a composition, the method comprising making a solubilizing agent coexist in the composition. [H2] The method according to [H1], wherein the solubility is the solubility of the compound represented by formula (1), the salt, or the solvate in FaSSIF. [H3] The method according to [H1] or [H2], wherein the composition further comprises a disintegrant. [H4] The method according to any one of [H1] to [H3], wherein the composition further comprises a lubricant. [J1] A method for improving the dissolution property of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt in a composition, the method comprising allowing a disintegrant to coexist in the composition. [J2] The method according to [J1], wherein the dissolution property is the dissolution property of the compound represented by formula (1), the salt, or the solvate in FaSSIF. [J3] The method according to [J1] or [J2], wherein the composition further comprises a lubricant. [J4] The method according to any one of [J1] to [J3], wherein the composition further comprises a solubilizer. [K1] A method for improving adhesion to punches during tableting of a composition comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, the method comprising allowing a lubricant to be present in the composition. [K2] The method according to [K1], wherein the composition further comprises a solubilizing agent. [K3] The method according to [K1] or [K2], wherein the composition further comprises a disintegrant.

[0013] [Q1] The use or method according to any one of [H1] to [H4], [J4], [K2] and [K3], wherein the solubilizing agent comprises a polymer, and the polymer comprises poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [Q1-1] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1], wherein the solubilizing agent comprises the following polymers (i) and (ii): (i) a first polymer which is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and (ii) a second polymer which is neither poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) nor polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [Q1-2] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1], wherein the solubilizing agent is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), and the composition further comprises a polymer other than poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol). [Q2] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1], wherein the solubilizing agent comprises poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hydroxypropyl methylcellulose.[Q2-1] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1], wherein the solubilizing agent is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), and the composition further contains hydroxypropyl methylcellulose. [Q3] The use or method according to any one of [H1] to [H4], [J4], [K2] and [K3], wherein the solubilizing agent contains a surfactant or a polymer, and the polymer is neither poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) nor polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [Q4] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q3], wherein the solubilizing agent is a surfactant. [Q5] The use or method according to [Q3] or [Q4], wherein the surfactant is an alkyl sulfate ester salt or a fatty acid ester. [Q6] The use or method according to [Q3] or [Q4], wherein the surfactant is an alkyl sulfate ester salt. [Q7] The use or method according to [Q5] or [Q6], wherein the alkyl sulfate ester salt has an alkyl group having 5 to 17 carbon atoms. [Q8] The use or method according to any one of [Q5] to [Q7], wherein the alkyl sulfate ester salt is lauryl sulfate. [Q9] The use or method according to [Q8], wherein the lauryl sulfate salt is sodium lauryl sulfate. [Q10] The use or method according to any one of [Q3] to [Q5], wherein the surfactant is a fatty acid ester.[Q11] The use or method according to any one of [Q3] to [Q5] and [Q10], wherein the surfactant is at least one selected from the group consisting of sucrose fatty acid esters, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, D-α-tocopherol polyethylene glycol 1000 succinate, lauroyl-L-carnitine hydrochloride, lauroyl-L-carnitine, palmitoyl-L-carnitine, sodium caprylate, and polyoxyethylene castor oil. [Q12] The use or method according to [Q5] or [Q10], wherein the fatty acid ester is a sucrose fatty acid ester. [Q13] The use or method according to [Q3] or [Q4], wherein the surfactant is a nonionic surfactant or an anionic surfactant. [Q14] The use or method according to [Q3] or [Q4], wherein the surfactant is an anionic surfactant. [Q15] The use or method according to [Q14], wherein the anionic surfactant is a carboxylate, sulfonate, or sulfate ester salt. [Q16] The use or method according to [Q14] or [Q15], wherein the anionic surfactant is a sulfate ester salt. [Q17] The use or method according to [H1] to [H4], [J4], [K2], [K3], and [Q3], wherein the solubilizing agent comprises a polymer, and the polymer is neither poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) nor polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.[Q18] The use or method according to any one of [Q3] and [Q5] to [Q17], wherein the polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol, polyvinylpyrrolidone-vinylpyrrolidone-vinyl acetate copolymer, methacrylic acid copolymer, dry methacrylic acid copolymer, aminoalkyl methacrylate copolymer, and polyvinyl acetate phthalate. [Q19] The use or method according to any one of [Q3] and [Q5] to [Q18], wherein the polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, methylcellulose, polyvinylpyrrolidone-vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, and dry methacrylic acid copolymer. [Q19-1] The use or method according to any one of [Q3] and [Q5] to [Q18], wherein the polymer is hydroxypropyl methylcellulose. [Q20] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], and [Q1] to [Q19], wherein the composition is in the form of a solid. [Q21] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], and [Q1] to [Q20], wherein the composition is in the form of a tablet. [Q22] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3], and [Q1] to [Q21], wherein the content of the solubilizing agent is 0.1 to 70.0 wt % based on the weight of the total composition. [Q23] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1] to [Q22], wherein the content of the solubilizing agent is 0.1 to 40.0 wt % based on the weight of the total composition.[Q24] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1] to [Q23], wherein the content of the solubilizing agent is 0.1 to 20.0 wt % relative to the weight of the total composition. [Q25] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q20], wherein the composition is in the form of a capsule. [Q26] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3], [Q1] to [Q20] and [Q25], wherein the content of the solubilizing agent is 0.1 to 70.0 wt % relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [Q27] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3], [Q1] to [Q20], [Q25] and [Q26], wherein the content of the solubilizing agent is 0.1 to 40.0 wt% based on the weight of the total composition, where the weight of the total composition does not include the weight of the capsule. [Q28] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3], [Q1] to [Q20] and [Q25] to [Q27], wherein the content of the solubilizing agent is 0.1 to 20.0 wt% based on the weight of the total composition, where the weight of the total composition does not include the weight of the capsule. [Q29] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3], and [Q1] to [Q28], wherein the content of the solubilizing agent is 0.1 to 250.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [Q30] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3], and [Q1] to [Q29], wherein the content of the solubilizing agent is 0.1 to 150.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition.[Q31] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1] to [Q30], wherein the content of the solubilizing agent is 0.1 to 75.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [Q32] The use or method according to any one of [Q29] to [Q31], wherein the content of the solubilizing agent is the numerical value relative to the monohydrate of the hydrochloride of the compound represented by formula (1) contained in the composition. [Q33] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1] to [Q32], wherein the concentration of the compound represented by formula (1), the salt or the solvate in FaSSIF is higher than the concentration in the composition not containing the solubilizing agent 240 minutes after addition of the composition to FaSSIF at normal pressure and 37°C. [Q34] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1] to [Q33], wherein the concentration of the compound represented by formula (1), the salt or the solvate in FaSSIF is higher by 1.2 times or more than the concentration in the composition not containing the solubilizing agent 240 minutes after addition of the composition to FaSSIF at normal pressure and 37°C. [Q35] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3], and [Q1] to [Q34], wherein, when the concentrations of the compound represented by formula (1), the salt, or the solvate in FaSSIF are compared after stirring at 37°C under normal pressure for 60 minutes and 240 minutes from the time the composition is added to FaSSIF, the concentration of the compound represented by formula (1), the salt, or the solvate after 240 minutes is equivalent to the concentration of the compound represented by formula (1), the salt, or the solvate after 60 minutes.[Q36] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3], and [Q1] to [Q35], wherein, when the concentrations of the compound represented by formula (1), the salt, or the solvate in FaSSIF are compared after stirring at 37°C under normal pressure for 60 minutes and 180 minutes from the time the composition is added to FaSSIF, the concentration of the compound represented by formula (1), the salt, or the solvate after 180 minutes is equivalent to the concentration of the compound represented by formula (1), the salt, or the solvate after 60 minutes. [Q37] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1] to [Q36], wherein, when the concentrations of the compound represented by formula (1), the salt or the solvate in FaSSIF are compared after stirring at 37°C under normal pressure for 60 minutes and 240 minutes from the time the composition is added to FaSSIF, the rate of decrease in the concentration of the compound represented by formula (1), the salt or the solvate after 240 minutes relative to the concentration of the compound represented by formula (1), the salt or the solvate after 60 minutes is 20% or less. [Q38] The use or method according to any one of [H1] to [H4], [J4], [K2], [K3] and [Q1] to [Q37], wherein, when the concentrations of the compound represented by formula (1), the salt or the solvate in FaSSIF are compared after stirring at 37°C under normal pressure for 60 minutes and 180 minutes from the time the composition is added to FaSSIF, the rate of decrease in the concentration of the compound represented by formula (1), the salt or the solvate after 180 minutes relative to the concentration of the compound represented by formula (1), the salt or the solvate after 60 minutes is 20% or less. [Q39] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3], and [Q1] to [Q38], wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, starch, pregelatinized starch, agar, gelatin powder, calcium carbonate, sodium chloride, sodium bicarbonate, calcium citrate, anhydrous silicic acid, dextrin, pectin, carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate.[Q40] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3] and [Q1] to [Q39], wherein the disintegrant is croscarmellose sodium or crospovidone. [Q41] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3] and [Q1] to [Q40], wherein the disintegrant is croscarmellose sodium.

[0014] [Q42] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3], [Q1] to [Q24], and [Q29] to [Q41], wherein the content of the disintegrant is 0.1 to 40.0 wt % relative to the total weight of the composition. [Q43] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3], [Q1] to [Q24], and [Q29] to [Q42], wherein the content of the disintegrant is 0.1 to 25.0 wt % relative to the total weight of the composition. [Q44] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3], [Q1] to [Q24], and [Q29] to [Q43], wherein the content of the disintegrant is 0.1 to 10.0 wt% relative to the weight of the total composition. [Q45] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3], [Q1] to [Q20], and [Q25] to [Q41], wherein the content of the disintegrant is 0.1 to 40.0 wt% relative to the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [Q46] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3], [Q1] to [Q20], [Q25] to [Q41], and [Q45], wherein the content of the disintegrant is 0.1 to 25.0 wt % based on the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [Q47] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3], [Q1] to [Q20], [Q25] to [Q41], [Q45], and [Q46], wherein the content of the disintegrant is 0.1 to 10.0 wt % based on the weight of the total composition, wherein the weight of the total composition does not include the weight of the capsule. [Q48] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3] and [Q1] to [Q47], wherein the content of the disintegrant is 0.1 to 80.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition.[Q49] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3] and [Q1] to [Q48], wherein the content of the disintegrant is 0.1 to 60.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [Q50] The use or method according to any one of [H3], [H4], [J1] to [J4], [K3] and [Q1] to [Q49], wherein the content of the disintegrant is 0.1 to 40.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [Q51] The use or method according to any one of [Q48] to [Q50], wherein the content of the disintegrant is a numerical value relative to the monohydrate of the hydrochloride of the compound represented by formula (1) contained in the composition. [Q52] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q51], wherein the lubricant is at least one selected from the group consisting of stearates, light anhydrous silicic acid, hydrogenated oil, sodium stearyl fumarate, shellac, talc, carnauba wax, and paraffin. [Q52-1] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q51], wherein the lubricant is two selected from the group consisting of stearates, light anhydrous silicic acid, hydrogenated oils, sodium stearyl fumarate, shellac, talc, carnauba wax, and paraffin. [Q52-2] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q51], wherein the lubricant is three selected from the group consisting of stearates, light anhydrous silicic acid, hydrogenated oils, sodium stearyl fumarate, shellac, talc, carnauba wax, and paraffin. [Q53] The use or method according to [Q52], wherein the hydrogenated oil is at least one selected from the group consisting of hydrogenated castor oil, hydrogenated soybean oil, and hydrogenated rapeseed oil. [Q53-1] The use or method according to [Q52], wherein the hydrogenated oil is hydrogenated castor oil or hydrogenated soybean oil.[Q53-2] The use or method according to [Q52], wherein the hydrogenated oil is hydrogenated castor oil. [Q53-3] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q51], wherein the lubricant is at least one selected from the group consisting of stearates, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, and sodium stearyl fumarate. [Q53-4] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q51], wherein the lubricant is two selected from the group consisting of stearates, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, and sodium stearyl fumarate. [Q53-5] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q51], wherein the lubricant is three selected from the group consisting of stearates, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, and sodium stearyl fumarate. [Q53-6] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q52], wherein the lubricant comprises magnesium stearate. [Q53-7] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q52], wherein the lubricant is a stearate. [Q53-8] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q52], wherein the lubricant is magnesium stearate. [Q53-9] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q52], wherein the lubricant comprises magnesium stearate and at least one selected from the group consisting of light anhydrous silicic acid, sodium stearyl fumarate, and hydrogenated castor oil. [Q53-10] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q51], wherein the lubricant is magnesium stearate and light anhydrous silicic acid.[Q53-11] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q51], wherein the lubricant is magnesium stearate, sodium stearyl fumarate, and light anhydrous silicic acid. [Q53-12] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q51], wherein the lubricant is magnesium stearate, light anhydrous silicic acid, and hydrogenated castor oil. [Q54] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], and [Q48] to [Q53], wherein the content of the lubricant is 0.1 to 20.0 wt % relative to the total weight of the composition. [Q55] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], and [Q48] to [Q54], wherein the content of the lubricant is 0.1 to 15.0 wt % relative to the total weight of the composition. [Q56] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], and [Q48] to [Q55], wherein the content of the lubricant is 0.1 to 10.0 wt % relative to the total weight of the composition. [Q56-1] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], and [Q48] to [Q55], wherein the content of the lubricant is 0.5 to 10.0 wt % relative to the total weight of the composition. [Q56-2] The use or method described in any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], and [Q48] to [Q55], wherein the content of the lubricant is 1.0 to 8.0 wt % relative to the total weight of the composition.[Q57] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], and [Q45] to [Q53], wherein the content of the lubricant is 0.1 to 20.0 wt% based on the weight of the total composition, where the weight of the total composition does not include the weight of the capsule. [Q57-1] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], and [Q45] to [Q53], wherein the content of the lubricant is 0.1 to 15.0 wt% based on the weight of the total composition, where the weight of the total composition does not include the weight of the capsule. [Q57-2] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], and [Q45] to [Q53], wherein the content of the lubricant is 0.1 to 10.0 wt% based on the weight of the total composition, excluding the weight of the capsule. [Q57-3] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], and [Q45] to [Q53], wherein the content of the lubricant is 0.5 to 10.0 wt% based on the weight of the total composition, excluding the weight of the capsule. [Q57-4] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], and [Q45] to [Q53], wherein the content of the lubricant is 1.0 to 8.0 wt % based on the weight of the total composition, where the weight of the total composition does not include the weight of the capsule. [Q58] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q57], wherein the content of the lubricant is 0.1 to 20.0 wt % based on the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, contained in the composition.[Q58-1] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q57], wherein the content of the lubricant is 0.1 to 15.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [Q58-3] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q57], wherein the content of the lubricant is 0.1 to 10.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [Q58-4] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q57], wherein the content of the lubricant is 0.1 to 50.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [Q58-5] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q57], wherein the content of the lubricant is 1.0 to 40.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [Q58-6] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q57], wherein the content of the lubricant is 3.0 to 35.0 wt % relative to the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition. [Q59] The use or method according to [Q58], wherein the content of the lubricant is the numerical value relative to the monohydrate of the hydrochloride of the compound represented by formula (1) contained in the composition.[Q60] The use or method according to any one of [H4], [J3], [J4], [K1] to [K3], and [Q1] to [Q59], wherein the adhesion to punches during tableting of a composition containing the compound represented by formula (1), the salt, or the solvate is improved compared to the adhesion of a composition not containing a lubricant. [Q61] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], and [Q1] to [Q60], wherein the compound represented by formula (1), the salt, or the solvate is contained in the composition in the form of particles, and the volume-based particle size d50 of the compound represented by formula (1), the salt, or the solvate is 0.2 to 60 μm. [Q61-1] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q60], wherein the compound represented by formula (1), the salt or the solvate is contained in the composition in particulate form, and the volume-based particle size d50 of the compound represented by formula (1), the salt or the solvate is 0.2 to 40 μm. [Q61-2] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q60], wherein the compound represented by formula (1), the salt or the solvate is contained in the composition in particulate form, and the volume-based particle size d50 of the compound represented by formula (1), the salt or the solvate is 0.2 to 20 μm. [Q62] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q61], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, is a pharmaceutically acceptable solvate of the compound or salt. [Q62-1] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q61], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, is a solvate of a pharmaceutically acceptable salt of the compound represented by formula (1).[Q62-2] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q61], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is a solvate of the hydrochloride salt of the compound represented by formula (1). [Q62-3] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q61], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is a hydrate of the pharmaceutically acceptable salt of the compound represented by formula (1). [Q62-4] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q61], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is an anhydrous hydrochloride salt of the compound represented by formula (1). [Q62-5] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q61], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is a hydrate of the hydrochloride salt of the compound represented by formula (1). [Q62-6] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q61], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt thereof is a monohydrate of the hydrochloride salt of the compound represented by formula (1). [Q63] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q62], wherein the composition further comprises a pharmaceutically acceptable excipient.[Q64] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q63], wherein the content of the compound represented by formula (1), the salt or the solvate contained in the composition after storing the composition in an airtight state at 40°C, a storage humidity of 75%, for one month is 80% or more of the initial content of the compound of formula (1), the salt or the solvate contained in the composition. [Q65] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3] and [Q1] to [Q64], wherein the content of the compound represented by formula (1), the salt or the solvate contained in the composition after storing the composition in an airtight state at 40°C, a storage humidity of 75%, for one month is 90% or more of the initial content of the compound of formula (1), the salt or the solvate contained in the composition. [Q66] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], [Q48] to [Q56] and [Q58] to [Q65], wherein the content of the compound represented by formula (1), the salt or the solvate is 0.1 to 95.0 wt % relative to the total weight of the composition. [Q66-1] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], [Q48] to [Q56], and [Q58] to [Q65], wherein the content of the compound represented by formula (1), the salt, or the solvate is 0.1 to 80.0 wt % relative to the total weight of the composition. [Q66-2] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], [Q48] to [Q56], and [Q58] to [Q65], wherein the content of the compound represented by formula (1), the salt, or the solvate is 0.1 to 65.0 wt % relative to the total weight of the composition.[Q66-3] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], [Q48] to [Q56], and [Q58] to [Q65], wherein the content of the compound represented by formula (1), the salt, or the solvate is 1.0 to 50.0 wt % relative to the total weight of the composition. [Q66-4] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], [Q48] to [Q56], and [Q58] to [Q65], wherein the content of the compound represented by formula (1), the salt, or the solvate is 10.0 to 40.0 wt % relative to the total weight of the composition. [Q66-5] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q24], [Q29] to [Q44], [Q48] to [Q56] and [Q58] to [Q65], wherein the content of the compound represented by formula (1), the salt or the solvate is 12.5 to 30.0 wt % relative to the total weight of the composition. [Q67] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], [Q45] to [Q53] and [Q57] to [Q65], wherein the content of the compound represented by formula (1), the salt or the solvate is 0.1 to 95.0 wt % relative to the weight of the total composition, and the weight of the total composition does not include the weight of the capsule. [Q67-1] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], [Q45] to [Q53] and [Q57] to [Q65], wherein the content of the compound represented by formula (1), the salt or the solvate is 0.1 to 80.0 wt % relative to the weight of the total composition, and the weight of the total composition does not include the weight of the capsule.[Q67-2] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], [Q45] to [Q53] and [Q57] to [Q65], wherein the content of the compound represented by formula (1), the salt or the solvate is 0.1 to 65.0 wt % relative to the weight of the total composition, and the weight of the total composition does not include the weight of the capsule. [Q67-3] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], [Q45] to [Q53] and [Q57] to [Q65], wherein the content of the compound represented by formula (1), the salt or the solvate is 1.0 to 50.0 wt % relative to the weight of the total composition, and the weight of the total composition does not include the weight of the capsule. [Q67-4] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], [Q45] to [Q53] and [Q57] to [Q65], wherein the content of the compound represented by formula (1), the salt or the solvate is 10.0 to 40.0 wt % relative to the weight of the total composition, and the weight of the total composition does not include the weight of the capsule. [Q67-5] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], [Q1] to [Q20], [Q25] to [Q41], [Q45] to [Q53], and [Q57] to [Q65], wherein the content of the compound represented by formula (1), the salt, or the solvate is 12.5 to 30.0 wt % relative to the weight of the total composition, where the weight of the total composition does not include the weight of the capsule. [Q68] The use or method according to any one of [H1] to [H4], [J1] to [J4], [K1] to [K3], and [Q1] to [Q67], wherein the composition is a pharmaceutical composition. [Q69] The use or method according to [Q68], wherein the composition is a pharmaceutical composition for treating or preventing cancer.

[0015] In the above numbering scheme, unless otherwise specified, the numbers referred to in the dependent claims also include numbers with branch numbers attached to them. For example, [E1] referred to in the dependent claims indicates that it includes not only [E1] but also [E1-1], etc. The same applies to other numbering schemes.

[0016] According to one aspect of the present invention, a composition having improved solubility of the API of the present invention can be provided. According to another aspect of the present invention, a composition having sufficient dissolution properties as a pharmaceutical suitable for obtaining a desired medicinal effect can be provided. According to another aspect of the present invention, a composition can be provided that can reduce adhesion of a composition containing the API of the present invention to a punch during tableting. Therefore, the composition of the present invention is suitable for producing a pharmaceutical formulation containing the API of the present invention, and can provide a composition with high reliability in formulation.

[0017] 1 is a graph showing cell viability when Compound 1 and pemetrexed are used in combination at various concentrations.

[0034] FIG. 1 is a graph showing X-ray diffraction patterns for Examples 1-1-1, 1-1-4, and 1-1-18.

[0035] FIG. 1 is a graph showing the effect of different amounts of solubilizing agent on the solubility of the monohydrate of the hydrochloride of Compound 1.

[0036] FIG. 1 is a graph showing the effect of different amounts of solubilizing agent on the solubility of the monohydrate of the hydrochloride of Compound 1.

[0037] FIG. 1 is a graph showing the effect of the presence or absence of a capsule on the solubility of the monohydrate of the hydrochloride of Compound 1.

[0038] FIG. 1 is a graph showing the change in concentration of Compound 1 over time.

[0039] FIG. 2 is a graph showing the X-ray diffraction patterns for Examples 2-1-1 and 2-1-2.

[0039] FIG. 2 is a graph showing the change in concentration of Compound 1 over time in Examples 2-2-1 and 2-2-2.

[0039] FIG. 3 is a graph showing the change in concentration of Compound 1 over time in Examples 2-2-1, 2-3-1, and 2-3-2. 1 is a graph showing the change in concentration of Compound 1 over time in Examples 2-2-1 and 2-4-1. (a) is a photograph showing the state of adhesion of the composition to the punch when produced by adding 0.5 wt% magnesium stearate, and (b) is a photograph showing the state of adhesion of the composition to the punch when produced by adding 1.5 wt% magnesium stearate.

[0034] FIG. 1 is a graph showing the change in concentration of Compound 1 over time in Examples 2-2-1 and 2-5-1.

[0035] FIG. 1 is a graph showing the change in concentration of Compound 1 over time in the composition of Example 2-6-1 during storage. The graphs show the concentration of Compound 1 after storage of the composition of Example 2-6-1 in an environment with or without silica gel, or in the initial state before storage, respectively.

[0036] FIG. 1 is a graph showing the change in concentration of Compound 1 over time in the composition of Example 2-6-2 during storage. The graphs show the concentration of Compound 1 in the composition of Example 2-6-2 after storage in an environment with or without silica gel, or in the initial state before storage. The graphs show the change in the concentration of Compound 1 over time in the composition of Example 2-6-3 during storage. The graphs show the concentration of Compound 1 in the composition of Example 2-6-3 after storage in an environment with or without silica gel, or in the initial state before storage.1 is a graph showing the change in concentration of compound 1 over time in Examples 2-7-1 and 2-7-2. 2-7-1 is a graph showing the change in concentration of compound 1 over time in Examples 2-7-1 and 2-8-1. 2-7-2 is a graph showing the change in concentration of compound 1 over time in Examples 2-8-2. 3-1-1 is a graph showing the change in concentration of compound 1 over time in Examples 3-1-1, 3-1-2, and 3-1-3. 3-2-1 is a graph showing the change in concentration of compound 1 over time in Example 3-2-1 and Comparative Example 3-2-1. 4-1-1 is a graph showing the ejection force during the production of tablets containing compound 1 in Examples 4-1-1 and 4-1-2. 4-2-1 is a graph showing the ejection force during the production of tablets containing compound 1 in Examples 4-2-1, 4-2-2, and 4-2-3. 4-3-1 is a graph showing the ejection force during the production of tablets containing compound 1 in Examples 4-3-1 and 4-3-2. 1 is a graph showing the ejection force during the production of tablets containing Compound 1 in Examples 4-4-1 and 4-4-2.

[0018] The present invention will be described in detail below by showing definitions of symbols, terms, etc. used in this specification, and embodiments of the present invention.

[0019] As used herein, "halogen" means fluorine, chlorine, bromine, or iodine.

[0020] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means a number from one to the maximum number of substituents permitted by the group.

[0021] In this specification, the term "to" indicating a range of values ​​includes both ends of the range. For example, "A to B" means a range of values ​​equal to or greater than A and equal to or less than B.

[0022] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus and minus 10% of that numerical value.

[0023] As used herein, the term "and / or" includes any combination of "and" and "or." Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B, and C.

[0024] As used herein, "FaSSIF" means fasting artificial intestinal fluid, and "FaSSGF" means fasting artificial gastric fluid.

[0025] [First Embodiment] One embodiment of the present invention is a composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, and a solubilizing agent:

[0026]

[0023] As used herein, "a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt" includes a compound represented by formula (1), a pharmaceutically acceptable salt of the compound represented by formula (1), a pharmaceutically acceptable solvate of the compound represented by formula (1), and a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the compound represented by formula (1). For convenience, as used herein, "a compound represented by formula (1)" will be referred to as "Compound 1," and "a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt" may be collectively referred to as "the API of the present invention."

[0027] Pharmaceutically acceptable salts of the compound represented by formula (1) include, for example, hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonate such as methanesulfonate or p-toluenesulfonate; carboxylate such as acetate, citrate, malate, tartrate, succinate, or salicylate; alkali metal salt such as sodium salt or potassium salt; alkaline earth metal salt such as magnesium salt or calcium salt; ammonium salt such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, or tetraalkylammonium salt. These salts are produced, for example, by contacting the compound with an acid or a base. As used herein, the term "solvate" refers to a compound that forms a molecular group together with a solvent, and is not particularly limited as long as it is a solvate formed with a solvent that is acceptable for ingestion accompanying the administration of a pharmaceutical. Examples of the solvate include not only hydrates, alcoholates (ethanolates, methanolates, 1-propanolates, 2-propanolates, etc.), and solvates with a single solvent such as dimethyl sulfoxide, but also solvates formed with multiple solvents per molecule of the compound, or solvates formed with multiple types of solvents per molecule of the compound. When the solvent is water, the solvate is called a hydrate. As the pharmaceutically acceptable solvate of the compound represented by formula (1), hydrates are preferred, and specific examples of such hydrates include mono- to decahydrates, preferably mono- to pentahydrates, and more preferably mono- to trihydrates.

[0028] When the compound represented by formula (1) is obtained in a free form, the compound can be converted into a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable solvate thereof (e.g., hydrate) in a conventional manner. Examples include hydrates and ethanolates of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof. Specific examples include, but are not limited to, pharmaceutically acceptable hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, or monoethanolate of the compound represented by formula (1), or hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, or monoethanolate of the sodium salt of the compound represented by formula (1), or a hydrate or ethanolate of the hydrochloride salt of the compound represented by formula (1). The hydrate or solvate may be produced in a crystalline or amorphous form, and in the case of a crystalline form, it may take the form of a crystalline polymorph. As a method for producing a hydrate or solvate, for example, a solvent such as ethanol and / or water can be added to a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, and the mixture can be stirred, cooled, concentrated, and / or dried, or the like, to obtain a hydrate or solvate by a conventional method.

[0029] Furthermore, when the compound represented by formula (1) is obtained as a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable solvate thereof, the compound can be converted to its free form by a conventional method. The compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is preferably a solvate of a pharmaceutically acceptable salt of the compound represented by formula (1), more preferably a solvate of the hydrochloride of the compound represented by formula (1), even more preferably a hydrate of the hydrochloride of the compound represented by formula (1), and most preferably a monohydrate of the hydrochloride of the compound represented by formula (1). Furthermore, in a specific embodiment, the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt is an anhydrous hydrochloride of the compound represented by formula (1).

[0030] The compounds described herein may contain unnatural proportions of isotope atoms in one or more atoms constituting such compounds. The present invention also includes compounds in which any atom in a compound is substituted with another isotope atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons), thereby replacing the isotope with an abundance ratio different from the abundance ratio of the isotopes in nature, i.e., compounds labeled with isotope atoms. Examples of isotope elements contained in the compounds of the present specification include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, etc., and each of these isotopes is 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 35 S, 18 F, 36 Isotopically labeled compounds include Cl and the like. Compounds labeled with isotope atoms are useful as therapeutic or preventive agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging diagnostic agents). Compounds herein containing radioactive or non-radioactive isotopes in all proportions are encompassed within the scope of the present invention. Compounds labeled with isotope atoms can be produced using reagents and solvents containing the corresponding isotope atoms in the same manner as for producing unlabeled compounds.

[0031] The compounds described herein, their salts, or solvates thereof include all stereoisomers thereof (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of such isomers, and other mixtures thereof. For example, the compounds of the present invention may have axial chirality, and the present invention includes each stereoisomer of such compounds and mixtures thereof.

[0032] The content of the API of the present invention is not particularly limited, and may be, for example, 0.1 to 95.0 wt%, 0.1 to 80.0 wt%, or 0.1 to 65.0 wt%, preferably 1.0 to 50.0 wt%, more preferably 10.0 to 40.0 wt%, and most preferably 12.5 to 30.0 wt%, relative to the total weight of the composition. When the composition of this embodiment is in the form of a tablet, an API content within the above range can reduce adhesion to equipment during formulation (particularly adhesion to punches during tableting). Furthermore, when the composition of this embodiment is used to produce capsules, the composition of this embodiment can be the content of the capsule. The content of the API of the present invention may be 0.1 to 95.0 wt %, 0.1 to 80.0 wt %, or 0.1 to 65.0 wt %, preferably 1.0 to 50.0 wt %, more preferably 10.0 to 40.0 wt %, and most preferably 12.5 to 30.0 wt %, based on the weight of the entire capsule minus the weight of the empty capsule (i.e., the weight of the contents of the capsule).

[0033] The solubilizing agent is a component useful for improving the solubility of the API of the present invention in FaSSIF. Examples of the solubilizing agent include a surfactant or a polymer. The inclusion of such a solubilizing agent makes the API of the present invention more soluble in FaSSIF.

[0034] Surfactants have a chemical structure containing a hydrophilic group and a lipophilic group, and act at the boundary between water and oil to change its properties. Examples of hydrophilic groups include salts of hydrophilic functional groups such as carboxyl groups, sulfo groups, and sulfate groups, as well as hydrophilic functional groups derived from polyethylene glycol, sugars, glycerin, sorbitan, amino acids (e.g., carnitine), and dicarboxylic acids (e.g., succinic acid, phthalic acid, and adipic acid). Examples of lipophilic groups include alkyl, alkenyl, or alkynyl groups derived from fatty acids (e.g., alkyl, alkenyl, or alkynyl groups having 6 or more carbon atoms), and tocopherol.

[0035] In certain embodiments, the surfactant may be a nonionic surfactant or an anionic surfactant. In certain embodiments, the surfactant is an anionic surfactant. Examples of anionic surfactants include carboxylates, sulfonates, and sulfate ester salts, with sulfate ester salts being preferred. In certain embodiments, preferred surfactants are alkyl sulfate ester salts, fatty acid esters, tocopherol derivatives, or fatty acid salts. When the surfactant is an alkyl sulfate ester salt (particularly lauryl sulfate), the dissolution property of the composition of the present invention is also excellent. "Dissolution property" can be determined, for example, by the time it takes for the API of the present invention to dissolve at a certain concentration in FaSSIF.

[0036] The alkyl sulfate salt has one alkyl group having 1 to 20 carbon atoms, and the other forms a salt. In certain embodiments, the number of carbon atoms in the alkyl group in the ester portion of the alkyl sulfate salt may be 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, or 15 or more. In certain embodiments, the number of carbon atoms in the alkyl group may be 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less, 14 or less, 13 or less, 12 or less, or 11 or less. In certain embodiments, the number of carbon atoms in the alkyl group is 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20, 5 to 19, 6 to 19, 7 to 19, 8 to 19, 9 to 19, 10 to 19, 11 to 19, 12 to 19, 13 to 19, 14 to 19, 15 to 19, 5 to 18, 6 to 18, 7 to 18, 8 to 18, 9 to 18, 10 to 18, 11 to 18, 12 to 18, 13 to 18, 14 to 18, It is preferable that the range is 18, 15 to 18, 5 to 17, 6 to 17, 7 to 17, 8 to 17, 9 to 17, 10 to 17, 11 to 17, 12 to 17, 13 to 17, 14 to 17, or 15 to 17, 5 to 16, 6 to 16, 7 to 16, 8 to 16, 9 to 16, 10 to 16, 11 to 16, 12 to 16, 13 to 16, 14 to 16, 15 to 16, 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to 15, or 14 to 15. Preferred alkyl sulfates include, for example, octyl sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate, lauryl sulfate, myristyl sulfate, pentadecyl sulfate, palmitoyl sulfate, heptadecyl sulfate, stearyl sulfate, and oleyl sulfate.The salt moiety of the alkyl sulfates includes alkali metal salts (e.g., lithium salt, sodium salt, and potassium salt), alkaline earth metal salts (e.g., magnesium salt and calcium salt), and ammonium salt.Preferred alkyl sulfates include lauryl sulfate, and more preferably sodium lauryl sulfate.

[0037] Fatty acid esters are surfactant-active esters of fatty acids (e.g., saturated or unsaturated alkylcarboxylic acids having 6 or more carbon atoms) with hydrophilic groups. Examples of fatty acid esters include sucrose fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene glycerin fatty acid esters (e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil), polyoxyethylene sorbitan fatty acid esters, and esters of fatty acids and amino acids.

[0038] In certain embodiments, the fatty acid portion of the fatty acid ester may be a saturated or unsaturated alkyl carboxylic acid having 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, or 15 or more carbon atoms, or a saturated or unsaturated alkyl fatty acid having 25 or fewer, 24 or fewer, 23 or fewer, 22 or fewer, 21 or fewer, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, or 12 or fewer carbon atoms. Preferred fatty acid esters are esters of saturated or unsaturated alkylcarboxylic acids having 6 to 25, 6 to 24, 6 to 23, 6 to 22, 6 to 21, 6 to 20, 6 to 19, 6 to 18, 6 to 17, 6 to 16, 6 to 15, 7 to 25, 7 to 24, 7 to 23, 7 to 22, 7 to 21, 7 to 20, 7 to 19, 7 to 18, 7 to 17, 7 to 16, 7 to 15, 8 to 25, 8 to 24, 8 to 23, 8 to 22, 8 to 21, 8 to 20, 8 to 19, 8 to 18, 8 to 17, 8 to 16, or 8 to 15 carbon atoms.

[0039] In certain embodiments, the hydrophilic group of the fatty acid ester may be a sugar, sorbitan, glycerin, polyoxyethylene glycol, an amino acid, or a combination thereof. Examples of sugars include monosaccharides such as glucose, fructose, galactose, xylose, and arabinose, and disaccharides such as mannose, sucrose, and lactose. A preferred sugar is sucrose. Examples of preferred fatty acid esters include lauroyl-L-carnitine, palmitoyl-L-carnitine, or salts thereof.

[0040] Polyoxyethylene glycol has a structure in which a plurality of oxyethylene units are connected, and the number of oxyethylene units is, for example, 100 to 30,000, 200 to 30,000, 300 to 30,000, 400 to 30,000, 500 to 30,000, 600 to 30,000, 700 to 30,000, 800 to 30,000, 900 to 30,000, 1,000 to 30,000, 100 to 20,000, 200 to 20,000, 300 to 20,000, 400 to 20,000, 500 to 20,000, 600 to 20,000, 700 to 20,000, 800 to 20,000, 900 to 20,000, 1,000 to 20,000, 100 to 10,000, 200 to 10 000, 300-10000, 400-10000, 500-10000, 600-10000, 700-10000, 800-10000, 900-10000, 1000-10000, 100-5000, 200-5000, 300-5000, 400-5000, 500-5000, 600-5000 , 700 to 5000, 800 to 5000, 900 to 5000, 1000 to 5000, 100 to 4000, 200 to 4000, 300 to 4000, 400 to 4000, 500 to 4000, 600 to 4000, 700 to 4000, 800 to 4000, 900 to 4000, or 1000 to 4000.

[0041] The fatty acid salt may be a salt of a saturated or unsaturated alkylcarboxylic acid having 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, or 15 or more carbon atoms. Examples of such fatty acid salts include alkali metal salts (e.g., lithium salt, sodium salt, potassium salt), alkaline earth metal salts (e.g., magnesium salt, calcium salt), and ammonium salt. Examples of carboxylic acid salts include caprylate, nonanoate, laurate, myristate, pentadecylate, palmitate, palmitoleate, margarate, stearate, oleate, linoleate, arachidate, behenate, and linolenate. A preferred fatty acid salt is caprylate, more preferably sodium caprylate.

[0042] Since tocopherol is lipophilic, the tocopherol derivative may be a compound in which tocopherol is bonded to a hydrophilic group, which may be a sugar, sorbitan, glycerin, polyoxyethylene glycol, an amino acid, or a combination thereof. Polyoxyethylene glycol has a structure in which a plurality of oxyethylene units are connected, and the number of oxyethylene units is, for example, 100 to 30,000, 200 to 30,000, 300 to 30,000, 400 to 30,000, 500 to 30,000, 600 to 30,000, 700 to 30,000, 800 to 30,000, 900 to 30,000, 1,000 to 30,000, 100 to 20,000, 200 to 20,000, 300 to 20,000, 400 to 20,000, 500 to 20,000, 600 to 20,000, 700 to 20,000, 800 to 20,000, 900 to 20,000, 1,000 to 20,000, 100 to 10,000, 200 to 10 000, 300-10000, 400-10000, 500-10000, 600-10000, 700-10000, 800-10000, 900-10000, 1000-10000, 100-5000, 200-5000, 300-5000, 400-5000, 500-5000, 600-5000 , 700-5000, 800-5000, 900-5000, 1000-5000, 100-4000, 200-4000, 300-4000, 400-4000, 500-4000, 600-4000, 700-4000, 800-4000, 900-4000, or 1000-4000. In certain embodiments, a preferred tocopherol derivative is D-α-tocopherol polyethylene glycol 1000 succinate.

[0043] In a specific embodiment, the fatty acid ester of a preferred surfactant is at least one selected from the group consisting of sucrose fatty acid esters, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, D-α-tocopherol polyethylene glycol 1000 succinate, lauroyl-L-carnitine hydrochloride, lauroyl-L-carnitine, palmitoyl-L-carnitine, sodium caprylate, and polyoxyethylene castor oil.

[0044] The HLB (Hydrophile Lipophile Balance) value of the surfactant is preferably 0 to 45, and more preferably 10 to 45. The HLB value can be determined by methods well known to those skilled in the art, and can be calculated, for example, by the Davis method or the Kawakami method.

[0045] Examples of polymers include cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone derivatives, acrylic acid or methacrylic acid copolymers, polyvinyl acetate phthalate, vinyl acetate resins, carboxyvinyl polymers, guar gum, and zein. Examples of cellulose derivatives include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose, methylcellulose (MC), ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and hydroxyethyl methylcellulose. Examples of polyvinylpyrrolidone derivatives include polyvinylpyrrolidone-vinylpyrrolidone-vinyl acetate copolymers. Examples of acrylic acid or methacrylic acid copolymers include (co)polymers of acrylic acid, methacrylic acid, acrylic acid esters, and methacrylic acid esters. Specific examples of acrylic acid or methacrylic acid copolymers include polyacrylic acid, polymethacrylic acid, and aminoalkyl methacrylate copolymers. When the polymer is a cellulose derivative (particularly HPMC), the dissolved API of the present invention is less likely to precipitate, and the dissolved state is more likely to be maintained for a long period of time.

[0046] In certain embodiments, the polymer is not poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0047] In certain embodiments, the preferred polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol, polyvinylpyrrolidone-vinylpyrrolidone-vinyl acetate copolymer, methacrylic acid copolymer, dry methacrylic acid copolymer, aminoalkyl methacrylate copolymer, and polyvinyl acetate phthalate.

[0048] In certain embodiments, the preferred polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol, polyvinylpyrrolidone-vinylpyrrolidone-vinyl acetate copolymer, methacrylic acid copolymer, and dry methacrylic acid copolymer.

[0049] In certain embodiments, the solubilizing agent comprises a polymer, which comprises poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0050] In certain embodiments, the solubilizing agent comprises the following polymers (i) and (ii): (i) a first polymer that is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; and (ii) a second polymer that is neither poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) nor polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0051] In certain embodiments, the solubilizing agent comprises poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and hydroxypropyl methylcellulose.

[0052] In certain embodiments, the solubilizing agent is a surfactant or a polymer, and the polymer is not poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0053] In certain embodiments, the content of the solubilizing agent may be 0.1 to 70.0 wt %, preferably 0.1 to 40.0 wt %, and more preferably 0.1 to 20.0 wt %, based on the weight of the entire composition. When the composition of this embodiment is in the form of a capsule, as described below, the content of the solubilizing agent may be 0.1 to 70.0 wt %, preferably 0.1 to 40.0 wt %, and more preferably 0.1 to 20.0 wt %, based on the weight of the entire composition (excluding the weight of the capsule; the weight of the entire composition of this embodiment minus the weight of the empty capsule, i.e., the weight of the contents of the capsule). Furthermore, in certain embodiments, the content of the solubilizing agent is 0.1 to 250.0 wt %, preferably 0.1 to 150.0 wt %, and more preferably 0.1 to 75.0 wt %, based on the weight of the API of the present invention. When the content of the solubilizing agent is within the above range, the API of the present invention becomes more easily dissolved in the intestinal tract after oral administration as a tablet or capsule. The above range is preferably a numerical value relative to the weight of the monohydrate of the hydrochloride of the compound represented by formula (1).

[0054] The composition according to this embodiment may further contain pharmaceutically acceptable additives, such as excipients, binders, disintegrants, lubricants, colorants, flavoring agents, and, if necessary, stabilizers, emulsifiers, absorption enhancers, pH adjusters, preservatives, and antioxidants.

[0055] In particular, the composition according to this embodiment preferably further contains a disintegrant and / or a lubricant.

[0056] Examples of pharmaceutically acceptable additives used in solid preparations include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, and polyethylene glycol; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as propylene glycol, dipropylene glycol, and sorbitol; sugars such as lactose, lactose hydrate, fructose, and sucrose; inorganic powders such as silicic anhydride, aluminum magnesium silicate, and aluminum silicate; and purified water.

[0057] Examples of excipients include sugars (e.g., lactose, lactose hydrate, fructose, sucrose, etc.), sugar alcohols (e.g., mannitol, etc.), cellulose (e.g., crystalline cellulose), inorganic salts (e.g., calcium silicate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc.), etc. Examples of crystalline cellulose include Pharmacel 101, Pharmacel 102, and Pharmacel 103 (all trade names, manufactured by DFE Pharma), Ceolus PH-101, Ceolus PH-102, Ceolus PH-301, Ceolus PH-302, Ceolus PH-F20JP, Ceolus KG-802, Ceolus KG-1000, Ceolus UF-711, Ceolus UF-702, and Ceolus OD-20P (registered trademarks, manufactured by Asahi Kasei Corporation), VIVAPUR 12, VIVAPUR 101, VIVAPUR 102, VIVAPUR 105, and VIVAPUR 031 (registered trademarks, manufactured by JRS Pharma), Avicel PH-101, Avicel PH-102, Avicel PH-105, Avicel PH-200, and Avicel PH-201. PH-200LM, Avicel PH-102SCG, Avicel Avicel PH-301, Avicel PH-302, Avicel PH-103, Avicel PH-113, or Avicel PH-112, Avicel DG (registered trademark, manufactured by International N&H), etc. can be used.

[0058] Examples of binders include polyvinyl ether, gum arabic, tragacanth, shellac, polypropylene glycol-polyoxyethylene block polymer, and the like.

[0059] Disintegrants are components that help facilitate dissolution of the API of the present invention, and examples of disintegrants include croscarmellose sodium, carmellose sodium, carmellose, carmellose calcium, methylcellulose, polysorbate, etc.

[0060] In certain embodiments, the preferred disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, starch, pregelatinized starch, agar, gelatin powder, calcium carbonate, sodium chloride, sodium bicarbonate, calcium citrate, anhydrous silicic acid, dextrin, pectin, carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate. The inclusion of such a disintegrant facilitates dissolution of the API of the present invention after oral administration as a tablet or capsule. Furthermore, in certain embodiments, the preferred disintegrant is croscarmellose sodium or crospovidone, with croscarmellose sodium being more preferred.

[0061] In certain embodiments, the content of the disintegrant may be 0.1 to 40.0 wt %, preferably 0.1 to 25.0 wt %, and more preferably 0.1 to 10.0 wt %, based on the weight of the total composition. Furthermore, in certain embodiments, the content of the disintegrant is 0.1 to 80.0 wt %, preferably 0.1 to 60.0 wt %, and more preferably 0.1 to 40.0 wt %, based on the weight of the API of the present invention. When the content of the disintegrant is within the above range, the API of the present invention is more easily dissolved after oral administration as a tablet or capsule. The above range is preferably a numerical value relative to the weight of the monohydrate of the hydrochloride salt of the compound represented by formula (1).

[0062] When the composition according to the present embodiment is used to manufacture a capsule, the composition according to the present embodiment may be the content of the capsule. The content of the disintegrant may be 0.1 to 40.0 wt %, preferably 0.1 to 25.0 wt %, and more preferably 0.1 to 10.0 wt %, based on the weight of the entire capsule minus the weight of the empty capsule (i.e., the weight of the content of the capsule).

[0063] Lubricants are components that adhere to the powder surface to reduce the adhesive force between powder particles and help improve the flowability of the powder. Examples of lubricants include stearates (e.g., magnesium stearate, calcium stearate, sodium stearate), stearic acid, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, sodium stearyl fumarate, fumaric acid, stearyl alcohol, magnesium aluminometasilicate, hydrogenated oils (e.g., hydrogenated castor oil, hydrogenated soybean oil, hydrogenated rapeseed oil), glycerin, etc. The stearate may be a salt of stearic acid, including metal salts and ammonium salts of stearic acid. In a specific embodiment, the stearate is at least one selected from the group consisting of magnesium stearate, calcium stearate, and sodium stearate, preferably magnesium stearate or sodium stearate, and more preferably magnesium stearate. Hydrogenated oil refers to an oil or fat obtained by hydrogenating unsaturated fatty acids to convert them into saturated fatty acids. In a specific embodiment, the hydrogenated oil is at least one selected from the group consisting of hydrogenated castor oil, hydrogenated soybean oil, and hydrogenated rapeseed oil, preferably hydrogenated castor oil or hydrogenated soybean oil, and more preferably hydrogenated castor oil.

[0064] In certain embodiments, the lubricant is preferably at least one, at least two, or at least three selected from the group consisting of stearates, light anhydrous silicic acid, hydrogenated oils, sodium stearyl fumarate, shellac, talc, carnauba wax, and paraffin. The inclusion of these lubricants tends to reduce adhesion to equipment during formulation (particularly adhesion to punches during tableting). When the composition according to this embodiment contains two or more lubricants, the lubricants may be of the same type, such as two types of stearic acid (e.g., magnesium stearate and sodium stearate) or two types of hydrogenated oil (e.g., hydrogenated castor oil and hydrogenated soybean oil), or may be of different types, such as magnesium stearate and hydrogenated castor oil. The inclusion of two or more lubricants may improve adhesion to equipment during formulation while ensuring dissolution.

[0065] In certain embodiments, the lubricant is preferably at least one, at least two, or at least three selected from the group consisting of stearates, light anhydrous silicic acid, sodium stearyl fumarate, shellac, talc, carnauba wax, and paraffin.

[0066] In certain embodiments, the lubricant is preferably stearates, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, or sodium stearyl fumarate, more preferably stearates, and most preferably magnesium stearate. In certain embodiments, the lubricant comprises magnesium stearate. In certain embodiments, the lubricant comprises magnesium stearate and at least one selected from the group consisting of light anhydrous silicic acid, sodium stearyl fumarate, and hydrogenated castor oil. In certain embodiments, the lubricant is magnesium stearate and light anhydrous silicic acid. In certain embodiments, the lubricant is magnesium stearate, sodium stearyl fumarate, and light anhydrous silicic acid. In certain embodiments, the lubricant is magnesium stearate, light anhydrous silicic acid, and hydrogenated castor oil.

[0067] In certain embodiments, the content of the lubricant may be 0.1 to 20.0 wt%, 0.1 to 15.0 wt%, or 0.1 to 10.0 wt%, preferably 0.5 to 10.0 wt%, and more preferably 1.0 to 8.0 wt%, based on the weight of the total composition. Also, in certain embodiments, the content of the lubricant is 0.1 to 50.0 wt%, 0.1 to 20.0 wt%, 0.1 to 15.0 wt%, 0.1 to 10.0 wt%, 1.0 to 40.0 wt%, or 3.0 to 35.0 wt%, preferably 1.0 to 40.0 wt%, and more preferably 3.0 to 35.0 wt%, based on the weight of the API of the present invention. Preferably, the above ranges are values ​​relative to the weight of the monohydrate of the hydrochloride salt of the compound represented by formula (1).

[0068] When the composition according to the present embodiment is used to manufacture a capsule, the composition according to the present embodiment may be the content of the capsule. The content of the lubricant may be 0.1 to 20.0 wt %, 0.1 to 15.0 wt %, or 0.1 to 10.0 wt %, preferably 0.5 to 10.0 wt %, and more preferably 1.0 to 8.0 wt %, based on the weight of the entire capsule minus the weight of the empty capsule (i.e., the weight of the content of the capsule).

[0069] Coloring agents that are permitted to be added to pharmaceuticals are used, and flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, cinnamon powder, etc.

[0070] The composition according to this embodiment is preferably in a solid form, for example, a solid pharmaceutical preparation (solid preparation) such as a tablet, a powder, fine granules, granules, coated tablets, a capsule (as the contents of a capsule), a dry syrup, a lozenge, or a suppository. In a specific embodiment, the composition according to this embodiment is preferably in the form of a tablet or a capsule (as the contents of a capsule), and more preferably a tablet.

[0071] The composition according to the present embodiment improves the solubility of the API of the present invention in FaSSIF. The specific method for confirming this improved solubility is as follows: The concentration of the API of the present invention in FaSSIF is measured at 60, 180, and 240 minutes after adding the composition according to the present embodiment to FaSSIF at normal pressure and 37°C. "Normal pressure" refers to typical atmospheric pressure, such as "1 atmosphere" or "760 mmHg." A control composition having the same composition but without the solubilizing agent is prepared, and the concentration is measured in the same manner. When compared, the composition according to the present embodiment exhibits a higher concentration of the API of the present invention (i.e., improved solubility) compared to the control composition. In certain embodiments, the composition according to the present embodiment exhibits a concentration of the API of the present invention that is 1.2 times or more higher than the control composition. Furthermore, the composition according to the present embodiment maintains a similarly high solubility 60, 180, or 240 minutes after adding the composition to FaSSIF. In a specific embodiment, the composition of this embodiment exhibits a 20% or less decrease in concentration 180 or 240 minutes after addition to FaSSIF compared to the concentration measured at 60 minutes. The improvement in the solubility of the API of the present invention in FaSSIF can be confirmed in more detail by the method described in the Examples.

[0072] Another aspect of this embodiment is a method for improving the solubility of an API of the present invention in a composition, the method comprising the co-presence of a solubilizing agent in said composition. Preferably, the "solubility" referred to herein is the solubility concentration of the API of the present invention in FaSSIF.

[0073] As used herein, the term "volume-based particle size" refers to the particle size distribution value of a powder weighted by volume, representing the particle size at a specific volume in a powder sample. The volume-based particle size d50 (abbreviated as d50) refers to the particle size at 50% of the sample volume when the cumulative frequency distribution curve of particle sizes is calculated, assuming the total volume of the particles to be 100%. Those skilled in the art can measure the volume-based particle size using a commercially available particle size measurement instrument and following its instruction manual. For example, the volume-based particle size measured using a laser diffraction particle size distribution analyzer can be determined by dispersing the powder to be measured in a solvent (dispersion medium), irradiating the dispersion medium with a laser beam, and measuring the change in the diffraction of the laser beam over time. For example, this can be performed according to a conventional method, such as the "Particle Size Measurement Method" described in the Japanese Pharmacopoeia (17th or 18th revision). For example, the volume-based particle size of the API of the present invention can also be determined according to the following method. In the following examples, a laser diffraction particle size distribution analyzer (trade name: Mastersizer 3000 (manufactured by Spectris Inc.)) is used for explanation. (1) Compound 1 (10 mg) is added to 2-propanol (15 mL) and dispersed by ultrasonic treatment for at least 2 minutes to prepare a sample solution. (2) An "automatic wet dispersion unit" is filled with the dispersion medium (2-propanol) and circulated for at least 3 minutes. (3) The optical axis is adjusted, and the background of 2-propanol is measured. (4) The sample solution is added, circulated for at least 30 seconds, and the particle diameter is measured. (5) The average value of the measured values ​​measured twice is used. In principle, when the sample particles are arranged in order of volume, the particle diameter of the particles that make up 50% of the total, counting from the smallest sample particles, is recorded as d50; however, this can be measured automatically using a dedicated device. The volume-based particle size d50 of the API of the present invention is 0.2 to 60 μm, preferably 0.2 to 40 μm, and more preferably 0.2 to 20 μm.

[0074] In the composition according to one embodiment of the present invention, the content of the API of the present invention contained in the composition after storage for one month at 40°C, 75% storage humidity and in an airtight state may be 80% or more, or 90% or more of the initial content of the API of the present invention contained in the composition.

[0075] In the present specification, "the content of the API of the present invention contained in the composition after storing the composition in an airtight state at 40°C and 75% storage humidity for one month" may be determined, for example, by a quantitative NMR method using a commercially available internal standard (e.g., dimethyl sulfone), or by HPLC analysis. More specifically, this can be carried out according to the method described in the Examples.

[0076] The "initial content of the API of the present invention" means the content of the API of the present invention before the start of storage of the composition under the above conditions. The initial value may be determined by a method similar to the above method, or may be a target value (also referred to as a "set value" in this specification) set when producing the composition with a specific content, or may be the weight of the API of the present invention per composition actually weighed during the production, or may be the content of the API of the present invention per composition described in the package insert of the drug after the drug is marketed.

[0077] [Second Embodiment] One embodiment of the present invention is a composition comprising the API of the present invention and a disintegrant. The description of the first embodiment can be taken into consideration for the API of the present invention. According to this embodiment, a composition excellent in dissolution property of the API of the present invention can be provided. The "dissolution property" can be determined, for example, by the time it takes for the API of the present invention to dissolve to a certain concentration in FaSSIF.

[0078] The disintegrant is a component that helps to facilitate dissolution of the API of the present invention. Examples of the disintegrant in this embodiment include croscarmellose sodium, carmellose sodium, carmellose, carmellose calcium, polysorbate, etc.

[0079] In certain embodiments, the preferred disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, starch, pregelatinized starch, agar, gelatin powder, calcium carbonate, sodium chloride, sodium bicarbonate, calcium citrate, anhydrous silicic acid, dextrin, pectin, carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate. The inclusion of such a disintegrant facilitates dissolution of the API of the present invention after oral administration as a tablet or capsule. Furthermore, in certain embodiments, the preferred disintegrant is croscarmellose sodium or crospovidone, with croscarmellose sodium being more preferred.

[0080] In certain embodiments, the content of the disintegrant may be 0.1 to 40.0 wt %, preferably 0.1 to 25.0 wt %, and more preferably 0.1 to 10.0 wt %, based on the weight of the total composition. Furthermore, in certain embodiments, the content of the disintegrant is 0.1 to 80.0 wt %, preferably 0.1 to 60.0 wt %, and more preferably 0.1 to 40.0 wt %, based on the weight of the API of the present invention. When the content of the disintegrant is within the above range, the API of the present invention is more easily dissolved after oral administration as a tablet. The above range is preferably a numerical value relative to the weight of the monohydrate of the hydrochloride of the compound represented by formula (1).

[0081] When the composition according to the present embodiment is used to manufacture a capsule, the composition according to the present embodiment may be the content of the capsule. The content of the disintegrant may be 0.1 to 40.0 wt %, preferably 0.1 to 25.0 wt %, and more preferably 0.1 to 10.0 wt %, based on the weight of the entire capsule minus the weight of the empty capsule (i.e., the weight of the content of the capsule).

[0082] The composition according to this embodiment may further contain a pharmaceutically acceptable additive. Examples of the pharmaceutically acceptable additive include excipients, binders, solubilizers, lubricants, colorants, flavorings, stabilizers, emulsifiers, absorption enhancers, pH adjusters, preservatives, and antioxidants. The description of the first embodiment can be referred to for details of these additives.

[0083] In particular, the composition according to this embodiment preferably further contains a solubilizing agent and / or a lubricant.

[0084] The solubilizing agent is a component useful for improving the solubility of the API of the present invention in FaSSIF. Examples of the solubilizing agent include the surfactants or polymers described in the first embodiment. The inclusion of these solubilizing agents facilitates the dissolution of the API of the present invention in FaSSIF. When the surfactant is an alkyl sulfate ester salt (particularly lauryl sulfate), the dissolution properties of the composition of the present invention are excellent. When the polymer is a cellulose derivative (particularly HPMC), the dissolved API of the present invention is less likely to precipitate, and the dissolved state is more likely to be maintained for a long period of time.

[0085] Lubricants are components that adhere to the powder surface to reduce the adhesive force between powder particles and help improve the flowability of the powder. Examples of lubricants include stearates (e.g., magnesium stearate, calcium stearate), stearic acid, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, sodium stearyl fumarate, fumaric acid, stearyl alcohol, magnesium aluminometasilicate, hardened oil, glycerin, etc., and stearates, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, and sodium stearyl fumarate are preferred, stearates are more preferred, and magnesium stearate is most preferred.

[0086] In certain embodiments, the content of the lubricant may be 0.1 to 20.0 wt%, 0.1 to 15.0 wt%, or 0.1 to 10.0 wt%, preferably 0.5 to 10.0 wt%, and more preferably 1.0 to 8.0 wt%, based on the weight of the total composition. Also, in certain embodiments, the content of the lubricant is 0.1 to 50.0 wt%, 0.1 to 20.0 wt%, 0.1 to 15.0 wt%, 0.1 to 10.0 wt%, 1.0 to 40.0 wt%, or 3.0 to 35.0 wt%, preferably 1.0 to 40.0 wt%, and more preferably 3.0 to 35.0 wt%, based on the weight of the API of the present invention. Preferably, the above ranges are values ​​relative to the weight of the monohydrate of the hydrochloride salt of the compound represented by formula (1).

[0087] When the composition according to the present embodiment is used to manufacture a capsule, the composition according to the present embodiment may be the content of the capsule. The content of the lubricant may be 0.1 to 20.0 wt %, 0.1 to 15.0 wt %, or 0.1 to 10.0 wt %, preferably 0.5 to 10.0 wt %, and more preferably 1.0 to 8.0 wt %, based on the weight of the entire capsule minus the weight of the empty capsule (i.e., the weight of the content of the capsule).

[0088] Another aspect of this embodiment is a method for improving the dissolution of an API of the present invention in a composition, the method comprising the co-presence of a disintegrant in said composition. Preferably, the "dissolution" referred to herein refers to the dissolution of the API of the present invention in FaSSIF.

[0089] [Third Embodiment] One embodiment of the present invention is a composition comprising the API of the present invention and a lubricant. The description of the first embodiment can be referred to for the API of the present invention. According to this embodiment, a composition can be provided that can reduce adhesion of the composition containing the API of the present invention to a punch during formulation (tabletting).

[0090] Adhesion to punches during tableting can be evaluated by calculating the "ejection force." It has been reported that a decrease in ejection force is positively correlated with a decrease in adhesion to punches (see, for example, Bekuechukwu U. et al. Int. J. Pharmacol. 2018, 543, 234-244; S. Paul et al. Int. J. Pharmacol. 2017, 521, 374-383; and B. Uzondu et al. Int. J. Pharmacol. 2018, 543, 234-244). As used herein, "ejection force" refers to the maximum force applied to the lower punch when a tablet is ejected from a tablet compressed using, for example, a Huxley Bertram compression simulator HB100 under conditions such as a compression speed of 20.0 RPM, a pre-compression pressure of 1.8 kN, and a main compression pressure of 11.9 kN to obtain oval-shaped tablets (major radius: 12.15 mm, minor radius: 6.42 mm). This force can be used as an indicator of tablet adhesion to the punch during compression. For example, "reduced adhesion" means that the ejection force is significantly lower than that of a composition having the same composition except that it does not contain a lubricant. The compression simulator HB100 (Huxley Bertram) can be used as the compression simulator.

[0091] Examples of lubricants in this embodiment include stearates (e.g., magnesium stearate, calcium stearate), stearic acid, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, sodium stearyl fumarate, fumaric acid, stearyl alcohol, magnesium aluminometasilicate, hardened oil, and glycerin, with stearates, light anhydrous silicic acid, shellac, talc, carnauba wax, paraffin, and sodium stearyl fumarate being preferred, stearates being more preferred, and magnesium stearate being most preferred.

[0092] In certain embodiments, the content of the lubricant may be 0.1 to 20.0 wt%, 0.1 to 15.0 wt%, or 0.1 to 10.0 wt%, preferably 0.5 to 10.0 wt%, and more preferably 1.0 to 8.0 wt%, based on the weight of the total composition. Also, in certain embodiments, the content of the lubricant is 0.1 to 50.0 wt%, 0.1 to 20.0 wt%, 0.1 to 15.0 wt%, 0.1 to 10.0 wt%, 1.0 to 40.0 wt%, or 3.0 to 35.0 wt%, preferably 1.0 to 40.0 wt%, and more preferably 3.0 to 35.0 wt%, based on the weight of the API of the present invention. Preferably, the above ranges are values ​​relative to the weight of the monohydrate of the hydrochloride salt of the compound represented by formula (1).

[0093] When the composition according to the present embodiment is used to manufacture a capsule, the composition according to the present embodiment may be the content of the capsule. The content of the lubricant may be 0.1 to 20.0 wt %, 0.1 to 15.0 wt %, or 0.1 to 10.0 wt %, preferably 0.5 to 10.0 wt %, and more preferably 1.0 to 8.0 wt %, based on the weight of the entire capsule minus the weight of the empty capsule (i.e., the weight of the content of the capsule).

[0094] The composition according to this embodiment may further contain a pharmaceutically acceptable additive. Examples of the pharmaceutically acceptable additive include an excipient, a binder, a solubilizing agent, a disintegrant, a colorant, a flavoring agent, a stabilizer, an emulsifier, an absorption enhancer, a pH adjuster, a preservative, and an antioxidant. The description of the first embodiment can be referred to for details of these additives.

[0095] In particular, the composition according to this embodiment preferably further contains a solubilizing agent and / or a disintegrating agent.

[0096] The solubilizing agent is a component useful for improving the solubility of the API of the present invention in FaSSIF. Examples of the solubilizing agent include the surfactants or polymers described in the first embodiment. The inclusion of these solubilizing agents makes the API of the present invention more soluble in FaSSIF. When the surfactant is an alkyl sulfate ester salt (particularly lauryl sulfate), the dissolution of the API composition of the present invention is also excellent. When the polymer is a cellulose derivative (particularly HPMC), the dissolved API of the present invention is less likely to precipitate, and the dissolved state is more likely to be maintained for a long period of time.

[0097] Disintegrants are components that help facilitate dissolution of the API of the present invention, and examples of disintegrants include croscarmellose sodium, carmellose sodium, carmellose, carmellose calcium, methylcellulose, and polysorbate.

[0098] In certain embodiments, the preferred disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, starch, pregelatinized starch, agar, gelatin powder, calcium carbonate, sodium chloride, sodium bicarbonate, calcium citrate, anhydrous silicic acid, dextrin, pectin, carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate. The inclusion of such a disintegrant facilitates dissolution of the API of the present invention after oral administration as a tablet. Furthermore, in certain embodiments, the preferred disintegrant is croscarmellose sodium or crospovidone, with croscarmellose sodium being more preferred.

[0099] In certain embodiments, the content of the disintegrant may be 0.1 to 40.0 wt %, preferably 0.1 to 25.0 wt %, and more preferably 0.1 to 10.0 wt %, based on the weight of the total composition. Furthermore, in certain embodiments, the content of the disintegrant is 0.1 to 80.0 wt %, preferably 0.1 to 60.0 wt %, and more preferably 0.1 to 40.0 wt %, based on the weight of the API of the present invention. When the content of the disintegrant is within the above range, the API of the present invention is more easily dissolved after oral administration as a tablet. The above range is preferably a numerical value relative to the weight of the monohydrate of the hydrochloride of the compound represented by formula (1).

[0100] When the composition according to the present embodiment is used to manufacture a capsule, the composition according to the present embodiment may be the content of the capsule. The content of the disintegrant may be 0.1 to 40.0 wt %, preferably 0.1 to 25.0 wt %, and more preferably 0.1 to 10.0 wt %, based on the weight of the entire capsule minus the weight of the empty capsule (i.e., the weight of the content of the capsule).

[0101] Another aspect of this embodiment is a method for improving adhesion of an API of the present invention in a composition to a punch during tableting, the method comprising the co-presence of a lubricant in the composition.

[0102] In this specification, the compositions of the first, second, and / or third embodiments may be referred to as "compositions of the present invention."

[0103] [Method for Producing Composition] The composition according to this embodiment can be produced by a method comprising the step of mixing the API of the present invention, a solubilizing agent, and, if necessary, a pharmaceutically acceptable carrier.

[0104] In certain embodiments, the method for producing a composition according to this embodiment comprises mixing the API of the present invention with at least one selected from the group consisting of a solubilizing agent, a disintegrant, and a lubricant.

[0105] In certain embodiments, the method for producing a composition according to this embodiment comprises mixing the API of the present invention with at least two selected from the group consisting of a solubilizing agent, a disintegrant, and a lubricant.

[0106] In certain embodiments, the method for producing the composition according to this embodiment comprises mixing the API of the present invention, a solubilizing agent, a disintegrant, and a lubricant.

[0107] When the composition according to this embodiment is in the form of a tablet, the API of the present invention, a solubilizer, and, if necessary, a pharmaceutically acceptable carrier are mixed to obtain a mixture, which is then compressed to obtain granules (hereinafter, this process is referred to as the granulation process). In the granulation process, the pressing speed may be 1.0 to 3.0 RPM, and the pressure may be 3.0 to 14.0 kN, or 3.0 to 8.0 kN. Here, increasing the pressure (granulation pressure) in the granulation process may reduce adhesion to punches during tableting. Granulation may be either dry granulation or wet granulation. The granules are then sized using a mill, and a lubricant is added before tableting (hereinafter, this process is referred to as the tableting process). In the tableting process, the pressing speed may be 20.0 to 40.0 RPM, and the pressure may be 1.0 to 15.0 kN. The tableting step is preferably carried out by pressing in two stages, the first pressing being carried out at a pressure of 1.0 to 2.0 kN, and the second pressing being carried out at a pressure of 5.0 to 15.0 kN.

[0108] When the composition according to this embodiment is in the form of a tablet, the content of the solubilizing agent is, relative to the weight of the total composition, 0.1 to 25.0 wt%, 0.1 to 24.0 wt%, 0.1 to 23.0 wt%, 0.1 to 22.0 wt%, 0.1 to 21.0 wt%, 0.1 to 20.0 wt%, 0.1 to 19.0 wt%, 0.1 to 18.0 wt%, 0.1 to 17.0 wt%, 0.2 to 25.0 wt%, 0.2 to 24.0 wt%, 0.2 to 23.0 wt%, 0. 2 to 22.0 wt%, 0.2 to 21.0 wt%, 0.2 to 20.0 wt%, 0.2 to 19.0 wt%, 0.2 to 18.0 wt%, 0.2 to 17.0 wt%, 0.3 to 25.0 wt%, 0.3 to 24.0 wt%, 0.3 to 23.0 wt%, 0.3 to 22.0 wt%, 0.3 to 21.0 wt%, 0.3 to 20.0 wt%, 0.3 to 19.0 wt%, 0.3 to 18.0 wt%, or 0.3 to 17.0 wt% is preferred.

[0109] The tablets may be further coated (coated tablets) by spraying a coating solution obtained by mixing HPMC, talc, titanium oxide, and water, for example.

[0110] When the composition according to this embodiment is in the form of a capsule, the API of the present invention, a solubilizer, and, if necessary, a pharmaceutically acceptable carrier are mixed to obtain a mixture, which is then sieved as necessary, and the mixture is then filled into an empty capsule. The capsule may be a hard capsule, a soft capsule, or an enteric-coated capsule. The capsule may be made of gelatin, HPMC, placenta, or the like. The capsule size can be set arbitrarily, and standards are listed, for example, in the Japanese Pharmacopoeia. Capsule size 1 has a filling weight of 0.30 to 0.60 g and a volume of approximately 0.47 mL.

[0111] When the composition according to this embodiment is in the form of a capsule, the content of the solubilizing agent is 0.1 to 25.0 wt%, 0.1 to 24.0 wt%, 0.1 to 23.0 wt%, 0.1 to 22.0 wt%, 0.1 to 21.0 wt%, 0.1 to 20.0 wt%, 0.1 to 19.0 wt%, 0.1 to 18.0 wt%, 0.1 to 17.0 wt%, 0.2 to 25.0 wt%, or 0.2 to 24.0 wt% based on the weight of the entire composition excluding the capsule (i.e., the weight of only the capsule contents). , 0.2 to 23.0 wt%, 0.2 to 22.0 wt%, 0.2 to 21.0 wt%, 0.2 to 20.0 wt%, 0.2 to 19.0 wt%, 0.2 to 18.0 wt%, 0.2 to 17.0 wt%, 0.3 to 25.0 wt%, 0.3 to 24.0 wt%, 0.3 to 23.0 wt%, 0.3 to 22.0 wt%, 0.3 to 21.0 wt%, 0.3 to 20.0 wt%, 0.3 to 19.0 wt%, 0.3 to 18.0 wt%, or 0.3 to 17.0 wt% is preferred.

[0112] When the composition according to this embodiment is used to produce capsules, the content of the disintegrant may be 0.1 to 40.0 wt %, preferably 0.1 to 25.0 wt %, and more preferably 0.1 to 10.0 wt %, based on the weight of the entire capsule minus the weight of the empty capsule (i.e., the weight of the contents of the capsule).

[0113] When the composition according to this embodiment is used to produce capsules, the content of the lubricant may be 0.1 to 20.0 wt %, 0.1 to 15.0 wt %, or 0.1 to 10.0 wt %, preferably 0.5 to 10.0 wt %, and more preferably 1.0 to 8.0 wt %, based on the weight of the entire capsule minus the weight of the empty capsule (i.e., the weight of the contents of the capsule).

[0114] A further aspect of this embodiment is the use of a composition of the invention in the manufacture of a medicament for treating a patient in need of treatment with an API of the invention.

[0115] [Treatment or Prevention of Cancer] The composition of the present invention may be a pharmaceutical composition. One embodiment of the present invention is a method of treating a patient in need of treatment with an API of the present invention, comprising administering to the patient a composition of the present invention.

[0116] In certain embodiments, the method comprises administering a composition of the present invention in combination with a chemotherapeutic agent (concomitant administration) to treat or prevent cancer in a patient who has been detected as having a positive RB1 gene mutation or reduced expression of the RB1 gene or protein.

[0117] In certain embodiments, the method comprises administering a composition of the present invention in combination with a chemotherapeutic agent (concomitant administration) to treat or prevent cancer in a cancer patient who is positive for an RB1 gene mutation or has reduced expression of the RB1 gene or protein.

[0118] Since the API of the present invention has MYT1 inhibitory activity, use of the composition of the present invention improves the solubility of the API of the present invention or reduces adhesion to equipment during formulation (particularly adhesion to punches during tableting), making it easier to produce pharmaceuticals (particularly tablets and capsules) that are more suitable for the treatment or prevention of cancer.

[0119] "Cancer treatment" in the present invention means a reduction in the number of cancer cells in an individual, inhibition of cancer cell proliferation, reduction in tumor volume, reduction in tumor weight, inhibition of cancer cell metastasis, or amelioration of various symptoms caused by cancer, or a combination thereof. Furthermore, "cancer prevention" in the present invention means preventing the development of new cancer cells, preventing an increase in the number of cancer cells due to the re-proliferation of reduced cancer cells, preventing the regrowth of cancer cells whose proliferation has been inhibited, preventing a re-increase in the volume or weight of reduced tumors, or a combination thereof.

[0120] RB1 (retinoblastoma gene, also known as Rb or RB) is a gene encoding the RB1 protein, a representative cell cycle regulator, and is involved in the G1 / S checkpoint. The RB1 protein (also known as RB1 or pRb) forms a complex with E2F, a transcription factor responsible for inducing the expression of genes involved in the transition from the G1 phase to the S phase of the cell cycle, thereby suppressing the activity of E2F. When E2F activity is suppressed, the transition from the G1 phase to the S phase is inhibited.

[0121] As used herein, "positive for RB1 gene mutation" means that, when the nucleotide sequence corresponding to the RB1 gene of interest is analyzed, some mutation (e.g., a mutation resulting in the insertion, substitution, deletion, and / or addition of at least one amino acid residue relative to the wild-type RB1 protein) is found in the nucleotide sequence compared to the nucleotide sequence of the wild-type RB1 gene, or, if a mutation in the nucleotide sequence of the RB1 gene is reflected in a base change in a transcription product or an amino acid change in a translation product, the change is detected in the transcription product or translation product. In certain embodiments, a positive RB1 gene mutation is detected in a biological sample (e.g., cancer cells) derived from a cancer patient. As used herein, "detecting a mutation" generally means detecting a mutation in genomic DNA, but also includes detecting the change in the transcription product or translation product (i.e., indirect detection) when the mutation in the genomic DNA is reflected in a base change in a transcription product or an amino acid change in a translation product. A preferred embodiment of the method herein is a method of detecting a mutation by directly determining the nucleotide sequence of the RB1 gene region in a cancer cell. There are no particular limitations on the method for detecting a positive RB1 gene mutation, and for example, confirmation and determination can be performed by NGS (next generation sequencer).

[0122] In the present invention, the term "RB1 gene region" refers to a certain region on genomic DNA that contains the RB1 gene. This region independently includes, in addition to the translated region, untranslated regions such as expression control regions of each gene (e.g., promoter regions and enhancer regions) and the 3'-terminal untranslated region of each gene. In this method, a DNA sample is first prepared from a biological sample. Examples of DNA samples include genomic DNA samples and cDNA samples prepared by reverse transcription from RNA.

[0123] In this embodiment, DNA containing the RB1 gene region is then isolated, and the nucleotide sequence of the isolated DNA is determined. The DNA can be isolated, for example, by PCR using genomic DNA or RNA as a template, using a pair of oligonucleotide primers designed to flank all or part of the RB1 gene region. The nucleotide sequence of the isolated DNA can be determined by methods known to those skilled in the art, such as the Maxam-Gilbert method or the Sanger method, and a next-generation sequencer or the like capable of rapid and comprehensive analysis of gene nucleotide sequences can also be used.

[0124] By comparing the determined DNA or cDNA base sequence with a control (for example, if the biological sample is derived from a cancer patient, with the DNA or cDNA base sequence derived from non-cancerous tissue of the same patient or with a publicly known database), it is possible to determine whether or not there is a mutation in the RB1 gene region in the cancer cells of the biological sample.

[0125] Mutations in the RB1 gene region can be detected by various methods that allow detection of mutations, in addition to direct determination of the base sequence of DNA or cDNA.

[0126] If the mutation involves an amino acid change in the RB1 protein, the sample prepared from the biological sample may be a protein. In such cases, the mutation can be detected by a method using a molecule (e.g., an antibody) that specifically binds to the site where the amino acid change occurs due to the mutation, peptide mass fingerprinting (PMF), protein sequencer (Edman degradation), or the like.

[0127] As used herein, "decreased expression of the RB1 gene or protein" means that, when the RB1 gene or protein of a subject is analyzed, the expression level of the RB1 gene or protein is lower than that of a control (e.g., expression level in a healthy subject or in non-cancerous tissue of the same patient). In a specific embodiment, the decreased expression level of the RB1 gene or protein is detected in a biological sample (e.g., cancer cells) derived from a cancer patient.

[0128] Methods for detecting decreased expression of the RB1 gene are not particularly limited, and examples include methods in which the expression level of RB1 is detected at the transcription level or translation level and compared with the control. In methods for detecting the expression level of the RB1 gene at the transcription level, RNA or cDNA is first prepared from a biological sample. Methods for extracting RNA from a biological sample and preparing cDNA from the extracted RNA are not particularly limited, and known methods can be appropriately selected and used. Examples include extraction methods using phenol and chaotropic salts (more specifically, extraction methods using commercially available kits such as Trizol (Invitrogen) and Isogen (Wako Pure Chemical Industries)), and methods using other commercially available kits (RNAPrep Total RNA Extraction Kit (Beckman Coulter), RNeasy Mini (QIAGEN), RNA Extraction Kit (Pharmacia Biotech), etc.). Furthermore, the reverse transcriptase used to prepare cDNA from the extracted RNA is not particularly limited, and examples thereof include reverse transcriptases derived from retroviruses such as RAV (Rous associated virus) and AMV (Avian myeloblastosis virus), and reverse transcriptases derived from mouse retroviruses such as MMLV (Moloney murine leukemia virus).

[0129] The oligonucleotide primers or oligonucleotide probes are then used in an amplification reaction or hybridization reaction, respectively, to detect the amplified product or hybrid product. Examples of such methods include RT-PCR, Northern blotting, dot blotting, DNA arrays, in situ hybridization, RNase protection assays, and mRNA-seq. Those skilled in the art can routinely design oligonucleotide primers or oligonucleotide probes suitable for each method based on the nucleotide sequence of RB1 cDNA.

[0130] It is known in the art that promoter hypermethylation is one of the factors that contribute to decreased gene expression. Therefore, in detecting whether or not RB1 function is inhibited, it is conceivable to use methylation of the RB1 gene promoter as an indicator. Promoter methylation can be detected by known methods, such as a method in which a change in the base sequence after bisulfite treatment, which has the activity of converting methylated cytosine to uracil, is directly detected by base sequencing, or a method in which a restriction endonuclease that can recognize (cleave) the base sequence before bisulfite treatment but cannot recognize (cleave) the base sequence after bisulfite treatment.

[0131] The method for detecting decreased expression of RB1 protein is not particularly limited, and can be confirmed and determined, for example, by IHC (immunohistochemical staining) using an antibody specific to RB1 protein. In antibody-based protein detection methods, a protein sample is first prepared from a biological sample. Then, RB1 protein is detected by an antigen-antibody reaction using an antibody specific to RB1 protein. When the antibody specific to RB1 protein is labeled, RB1 protein can be detected directly. However, when the antibody is unlabeled, RB1 protein can be detected indirectly by further reacting it with a labeled molecule that recognizes the antibody (e.g., a secondary antibody or protein A), utilizing the label of the molecule. Examples of such methods include immunohistochemistry (immunostaining), Western blotting, ELISA, flow cytometry, imaging cytometry, radioimmunoassay, immunoprecipitation, and analysis using an antibody array. This method also has the advantage of simultaneously obtaining additional information, such as the morphology and distribution of cancer cells in tissue, through immunohistochemistry.

[0132] As used herein, the amplification of the copy number of the CCNE1 gene can be determined in a diagnostic or prognostic assay by assessing the copy number of the CCNE1 gene using a biological sample derived from a cancer patient (e.g., by next-generation sequencing, digital PCR, array CGH, or FISH).

[0133] As used herein, a "patient" may be a mouse, rat, guinea pig, monkey, dog, sheep, horse, or human. A "patient" is preferably a human. In the present invention, a "cancer patient" refers not only to a person currently suffering from cancer, but also to a person suspected of suffering from cancer. The composition of the present invention can be suitably used in humans.

[0134] As used herein, the term "biological sample derived from a cancer patient" is not particularly limited as long as it is a biological sample capable of detecting the presence or absence of an RB1 gene mutation or reduced expression of the RB1 gene or protein, but is preferably a sample such as a cancer biopsy specimen, blood, urine, body cavity fluid, or tumor cell-derived circulating tumor DNA (ctDNA). Protein extracts or nucleic acid extracts (e.g., mRNA extracts, cDNA preparations or cRNA preparations prepared from mRNA extracts) obtained from the specimens may also be used. As used herein, "biological sample" includes samples derived from cancer patients and samples derived from cancer cell cultures.

[0135] The RB1 gene mutation may include a mutation that results in the insertion, deletion, or addition of at least one amino acid residue relative to the wild-type RB1 protein, or a mutation that results in the substitution of an existing amino acid residue. The RB1 gene mutation may also be a nonsense mutation, a frameshift mutation, a splice site mutation, a heterozygous deletion, or a homozygous deletion. Preferably, the RB1 gene mutation is a mutation that reduces the function of RB1. "Mutations that reduce the function of RB1" can be confirmed, for example, via the Internet at: https: / / www.oncokb.org / gene / RB1 [searched February 20, 2023].

[0136] A typical DNA (cDNA) nucleotide sequence of a human wild-type RB1 gene is shown in SEQ ID NO: 1 (NCBI Reference No.: NM_000321.3), and a typical amino acid sequence of a human wild-type RB1 protein is shown in SEQ ID NO: 2 (NCBI Reference No.: NP_000312.2). In the case of a human RB1 gene, an RB1 gene mutation refers to a nucleotide sequence that is different from the human RB1 genomic sequence set forth at positions 48,303,751 to 48,481,890 in NCBI Reference No. NC_13.11, a nucleotide sequence that is different from the human RB1 genomic sequence set forth at positions 4921 to 5161 in NCBI Reference No. NG_9009.1, or a mutation that results in an amino acid sequence that is different from the amino acid sequence of the human RB1 protein set forth in SEQ ID NO: 2, and may result in at least one of the following (1) to (5): Even in RB1 without mutation, individual differences in the sequence may occur due to polymorphism, etc. (1) The codon corresponding to the serine residue (S) at position 82 in the amino acid sequence of SEQ ID NO: 2 is replaced with a stop codon, (2) The codon corresponding to the arginine residue (R) at position 467 in the amino acid sequence of SEQ ID NO: 2 is replaced with a stop codon, (3) At least one base is inserted or deleted in the codon corresponding to the amino acid residue at position 182 in the amino acid sequence of SEQ ID NO: 2, forming a new reading frame starting with an isoleucine residue (I), and the third reading frame therefrom is a stop codon, (4) The glutamic acid residue (E) at position 837 in the amino acid sequence of SEQ ID NO: 2 is replaced with a lysine residue (K), and a portion of the RB1 gene is homozygously deleted, or (5) The glycine residue (G) at position 449 in the amino acid sequence of SEQ ID NO: 2 is replaced with a glutamic acid residue (E), and a portion of the RB1 gene is homozygously deleted.

[0137] As used herein, decreased expression of the RB1 gene or protein includes decreased gene expression due to methylation of the RB1 gene or via microRNA.

[0138] The composition of the present invention can be used to treat or prevent cancer, and is particularly suitable for treating or preventing cancer in cancer patients who have been detected as positive for RB1 gene mutation or in whom reduced expression of the RB1 gene or protein has been detected, or in cancer patients who have been detected as positive for RB1 gene mutation or in whom reduced expression of the RB1 gene or protein has occurred. The composition of the present invention can be used alone or in combination with a chemotherapeutic agent.

[0139] In a particular embodiment, the cancer is lung cancer. The compositions of the present invention are particularly suitable for the treatment or prevention of cancer, and particularly for the treatment or prevention of lung cancer.

[0140] The compositions of the present invention may be used in combination with chemotherapeutic agents. In one embodiment, the compositions of the present invention are administered simultaneously with or separately from the chemotherapeutic agents. In another embodiment, the compositions of the present invention are administered as a combination drug with the chemotherapeutic agents.

[0141] The term "combination" refers to the use of two or more components in combination. For example, the combination of an API of the present invention (hereinafter sometimes referred to as the "first component") and a chemotherapeutic agent (hereinafter sometimes referred to as the "second component") includes "administration as a single formulation containing the first component and the second component" (i.e., administration of the first component and the second component as a combined drug) and "administration of the first component and the second component as separate formulations, either simultaneously or separately." In the latter embodiment, the formulation containing the first component may be administered first, or the formulation containing the second component may be administered first. The latter embodiment may be any of "an embodiment in which the first component and the second component are formulated separately and administered simultaneously via the same administration route," "an embodiment in which the first component and the second component are formulated separately and administered separately via the same administration route at different times," "an embodiment in which the first component and the second component are formulated separately and administered simultaneously via different administration routes (administered from different sites in the same patient)," and "an embodiment in which the first component and the second component are formulated separately and administered separately via different administration routes at different times." In the case of "an embodiment in which the first component and the second component are formulated separately and administered simultaneously via the same administration route," the two formulations may be mixed immediately before administration. "Separately" means that one formulation is administered before or after the other formulation.

[0142] In other words, "combined use" can also be said to be a method of use in which one component is present in the patient's body while the other component is present in the patient's body. That is, a preferred embodiment is one in which the first component and the second component are administered so that they are simultaneously present in the patient's body, for example, in the blood, and a preferred embodiment is one in which one formulation is administered to the patient simultaneously, or one formulation is administered to the patient within 48 hours of the other formulation being administered.

[0143] A chemotherapeutic agent is a substance that has anti-cancer activity (also called anti-tumor activity). A chemotherapeutic agent can be, for example, an antimetabolite.

[0144] An antimetabolite is a substance that has a chemical structure similar to that of a metabolic substance (e.g., folic acid) and antagonizes or inhibits the metabolic mechanism of an organism. Examples of an antimetabolite include antifolates.

[0145] Antifolates are substances that inhibit DNA biosynthesis by suppressing or inhibiting the activity of enzymes that reduce folic acid to active folic acid, which is essential for nucleic acid synthesis. Examples of antifolates include methotrexate and pemetrexed. A more preferred antifolate is pemetrexed.

[0146] In this embodiment, the preferred chemotherapeutic agent to combine with the compositions of the present invention is pemetrexed.

[0147] The dosage of the API of the present invention is preferably 0.001 to 50 mg per kg of body weight of the subject per day (0.001 to 50 mg / kg / day), more preferably 0.001 to 20 mg / kg / day, and even more preferably 0.002 to 10 mg / kg / day. When the dosage of the API of the present invention is within these ranges, the cancer treatment or prevention effect is further enhanced. The frequency of administration of the API of the present invention can be, for example, once or more per week, twice per week, once per day, or twice per day.

[0148] The dosage of the chemotherapeutic agent is preferably 0.005 to 300 mg per kg of body weight of the subject per day (0.005 to 300 mg / kg / day), more preferably 0.01 to 250 mg / kg / day, and even more preferably 0.02 to 200 mg / kg / day. When the dosage of the chemotherapeutic agent is within these ranges, the cancer treatment or prevention effect is further enhanced. The frequency of administration of the chemotherapeutic agent can be, for example, once or more per week, twice per week, once per day, or twice per day.

[0149] In the present invention, administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous, transdermal), intracisternal, intravaginal, intraperitoneal, intravesical, or topical (injection, infusion, powder, ointment, gel, or cream) administration, and inhalation (buccal or nasal spray). Dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for individual dosages. Dosage forms can also be adapted for various administration methods, including controlled-release formulations such as subcutaneous implants.

[0150] The first component can be, for example, administered by any of the methods described above, and the second component can be, for example, administered by the same or different method as the first component.

[0151] Another aspect of this embodiment is the use of a composition of the invention for the manufacture of a medicament to be administered in combination with a chemotherapeutic agent for the treatment or prevention of cancer in a patient in whom RB1 gene mutation or reduced expression of the RB1 gene or protein has been detected. Another aspect of this embodiment is the use of a composition of the invention for the manufacture of a medicament to be administered in combination with a chemotherapeutic agent for the treatment or prevention of cancer in a patient in whom RB1 gene mutation or reduced expression of the RB1 gene or protein has occurred.

[0152] [Second Embodiment Relating to Cancer Treatment or Prevention] A second embodiment of the present invention relating to cancer treatment or prevention is a method for treating or preventing cancer in a patient in whom a positive RB1 gene mutation or reduced expression of the RB1 gene or protein has been detected, the method comprising administering to the cancer patient a combination of a chemotherapeutic agent and a composition of the present invention. One aspect of this embodiment is a method for treating or preventing cancer, the method comprising detecting, or having a third party detect, a positive RB1 gene mutation or reduced expression of the RB1 gene or protein in a biological sample derived from the cancer patient, and administering to the cancer patient a combination of a chemotherapeutic agent and a composition of the present invention.

[0153] When administering a chemotherapeutic agent in combination with the composition of the present invention, both the composition of the present invention and the chemotherapeutic agent may be administered simultaneously, or may be administered separately at a fixed interval. The administration routes of the composition of the present invention and the chemotherapeutic agent may be the same or different. The composition of the present invention may also be administered in the form of a combination drug containing the composition of the present invention and the chemotherapeutic agent. The pharmaceutical composition of the present invention may contain both the API of the present invention and the chemotherapeutic agent.

[0154] The present invention will be described in more detail below with reference to examples and comparative examples. The abbreviations used in the examples have the meanings commonly used in the fields of organic chemistry or medicine, and specific examples are given below. ATP: Adenosine triphosphate EG: Ethylene glycol ELISA: Enzyme-linked immunosorbent assay FaSSGF: Fasting artificial gastric fluid FaSSIF: Fasting artificial intestinal fluid FBS: Fetal bovine serum HDPE: High density polyethylene HPC: Hydroxypropyl cellulose HPLC: High performance liquid chromatography HPMC: Hydroxypropyl methylcellulose NaOH: Sodium hydroxide RH: Relative humidity SLS: Sodium lauryl sulfate UPLC: Ultra performance liquid chromatography XRD: X-ray crystal diffraction 21NE: 2-(1-naphthylethanol) DIPEA: N,N-diisopropyl-N-ethylamine DMA: N,N-dimethylacetamide DMSO: Dimethyl sulfoxide TFA: Trifluoroacetic acid THF: Tetrahydrofuran３ P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TBME: tert-butyl methyl ether TFE: 2,2,2-trifluoroethanol FA: formic acid CH ３ CN: acetonitrile

[0155] Mass spectral data were obtained using a Shimadzu Corporation ultra-high performance liquid chromatograph (product name: Nexera UC) equipped with a single quadrupole mass spectrometer (product name: LCMS-2020) or a Waters Corporation Acquity ultra-high performance liquid chromatograph (UPLC or UPLC I-Class) equipped with a single quadrupole mass spectrometer (SQD or SQD2).

[0156] In Example 1, the high performance liquid chromatography conditions used were either those shown in Table 1 or Table 2 below.

[0157]

[0158]

[0159] Commercially available reagents were used without further purification. All non-aqueous reactions were carried out using commercially available anhydrous solvents. Concentration under reduced pressure or solvent evaporation was carried out using a rotary evaporator.

[0160] As used herein, "room temperature" means a temperature of about 20°C to about 25°C.

[0161] The FaSSIF used in this example was prepared using 3F Powder and FaSSIF Buffer Concentrate manufactured by Biorelevant according to the manufacturer's instructions. FaSSGF was prepared using 3F Powder and FaSSGF Buffer Concentrate manufactured by Biorelevant according to the manufacturer's instructions.

[0162] Example 1: Preparation of compound 1 3-amino-4-[6,7-difluoro-1-(oxan-2-yl)indazol-4-yl]-6-methyl-1H-1,7-phenanthrolin-2-one (compound 1) and the monohydrate of the hydrochloride of compound 1 were prepared according to the following method.

[0163] 6,7-difluoro-1H-indazole-4-carboxylic acid

[0164] 4-Bromo-6,7-difluoro-1H-indazole (10 g, 42.92 mmol), oxalic acid dihydrate (8.12 g, 64.37 mmol), palladium acetate (0.48 g, 2.15 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.24 g, 2.15 mmol) were added to a reaction vessel, and the reaction vessel was degassed under reduced pressure and purged with nitrogen. To this mixture, acetic anhydride (6.09 mL, 64.37 mmol) and DMF (90 mL) were added, and the reaction vessel was purged with nitrogen. The reaction mixture was heated to 80°C, and DIPEA (11.99 mL, 68.66 mmol) was added dropwise over 1 hour. The reaction mixture was stirred at 80°C for 1 hour, after which oxalic acid dihydrate (5.41 g, 42.92 mmol) and acetic anhydride (4.06 mL, 42.92 mmol) were added, and DIPEA (7.5 mL, 42.9 mmol) was added dropwise over 1 hour. The reaction mixture was stirred at 80°C for 1 hour. After cooling the reaction mixture to 0°C, 5 M aqueous potassium hydroxide solution (103 mL, 0.51 mol) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes and then at room temperature for 1 hour. Isopropyl acetate (100 mL) was added to the reaction mixture, and the insoluble matter was filtered off. The organic layer was discarded, and the aqueous layer was washed with isopropyl acetate (100 mL). Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 3-4. The resulting solid was collected by filtration and washed twice with water (20 mL). The resulting solid was dried under reduced pressure at 50° C. to give the title compound (8.47 g, yield 96%) as a pale brown solid. LCMS: m / z 199 [M+H] ＋ HPLC retention time: 2.03 minutes (Analysis conditions: LC-A)

[0165] 6,7-difluoro-1-(oxan-2-yl)-1H-indazole-4-carboxylic acid

[0166] 6,7-Difluoro-1H-indazole-4-carboxylic acid (3.00 g, 15 mmol) was added to acetonitrile (60 mL) in a reaction vessel, and the mixture was stirred at 40° C. Methanesulfonic acid (72.8 mg, 0.76 mmol) and 3,4-dihydro-2H-pyran (1.91 g, 22.7 mmol) were added sequentially, and the mixture was stirred at 40° C. for 2 hours. The reaction solution was cooled to 25° C. and stirred for 1 hour. The precipitate was collected by filtration and washed twice with acetonitrile (15 mL). The obtained solid was dried under reduced pressure to give the title compound (3.81 g, yield 89%) as a white solid. LCMS: m / z 283.08 [M+H] ＋ HPLC retention time: 3.47 minutes (measurement conditions: LC-A)

[0167] 6,7-difluoro-N-methoxy-N-methyl-1-(oxan-2-yl)-1H-indazole-4-carboxamide

[0168] DIPEA (15.22 g, 117.78 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.73 g, 38.28 mmol) were added to a suspension of 6,7-difluoro-1-(oxan-2-yl)-1H-indazole-4-carboxylic acid (8.31 g, 29.45 mmol) and acetonitrile (58 mL) in a reaction vessel cooled to 10°C, and the mixture was stirred at 0°C. 50% T ３ A solution of P in ethyl acetate (37.48 g, 58.89 mmol) was added over 60 minutes, and after completion of the addition, the temperature was raised to 25°C and stirred for 1 hour. The mixture was concentrated under reduced pressure to 42 mL. Toluene (42 mL) was added, and the mixture was concentrated under reduced pressure to 42 mL. After cooling to 10°C, the mixture was washed twice with 10% aqueous potassium carbonate and then with 10% brine. The obtained organic layer was concentrated under reduced pressure to 21 mL. Toluene (42 mL) was added to the concentrated solution, and the mixture was concentrated under reduced pressure to 21 mL. Toluene (25 mL) was added to the concentrated solution, and the mixture was concentrated under reduced pressure to 21 mL to obtain the title compound (21.22 g, content 31.7%, yield 70%) as a toluene solution. LCMS: m / z 326.12 [M+H] ＋ HPLC retention time: 3.61 minutes (measurement conditions: LC-A)

[0169] 6-iodo-8-methylquinolin-5-amine

[0170] A reaction vessel containing 8-methylquinolin-5-amine (15.0 g, 95 mmol), acetonitrile (75.0 mL), and water (75.0 mL) was cooled with ice, and TFA (21.62 g, 190 mmol) and N-iodosuccinimide (20.48 g, 91 mmol) were added, followed by stirring under ice cooling for 3 hours. A 5% L-ascorbic acid solution (150 g) was added to the reaction mixture, and the mixture was stirred at room temperature. The resulting aqueous solution was divided equally into three vessels, and the following procedure was carried out on one of them: 2 mol / L aqueous sodium hydroxide solution (45.0 mL) was added and stirred. The solid was collected by filtration and washed with a mixture of acetonitrile (2.5 mL), water (22.5 mL), and a mixture of ethanol (2.5 mL), and heptane (22.5 mL), to obtain the title compound (7.56 g, 84% yield) as a brown solid. LCMS: m / z 285 [M+H] ＋ HPLC retention time: 2.45 minutes (Analysis conditions: LC-A)

[0171] Seed crystals of (E)-N'-(6-iodo-8-methylquinolin-5-yl)-N,N-dimethylmethanimidamide N,N-Dimethylformamide dimethyl acetal (3.77 mL, 28.2 mmol) was added to a suspension of 6-iodo-8-methylquinolin-5-amine (4.00 g, 14.08 mmol) in ethanol (20.0 mL) in a reaction vessel, and the mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and 10% aqueous sodium chloride solution (30 mL) was added, followed by extraction with isopropyl acetate (30 mL). The resulting organic layer was concentrated under reduced pressure, and TBME and n-heptane were added to the concentrated residue, followed by stirring. The solid was collected by filtration and washed with n-heptane to obtain the title compound (3.8 g, yield 80%) as a pale brown solid. LCMS: m / z 340 [M+H] ＋ HPLC retention time: 0.77 minutes (Analysis conditions Y)

[0172] (E)-N'-(6-iodo-8-methylquinolin-5-yl)-N,N-dimethylmethanimidamide

[0173] N,N-Dimethylformamide dimethyl acetal (4.68 mL, 35.2 mmol) was added to a suspension of 6-iodo-8-methylquinolin-5-amine (compound c-270, 5.00 g, 17.6 mmol) in ethanol (20.0 mL) in a reaction vessel, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to 25°C, and water (10 mL) was added. Seed crystals of (E)-N'-(6-iodo-8-methylquinolin-5-yl)-N,N-dimethylmethanimidamide (5.0 mg) were added, and the mixture was stirred for 1 hour. Water (36.5 mL) was added over 1 hour, and the mixture was stirred. The solid was collected by filtration and washed twice with water (20.0 mL) to obtain the title compound (5.3 g, 88% yield) as a light brown solid. LCMS: m / z 340 [M+H] ＋ HPLC retention time: 2.20 minutes (Analysis conditions: LC-A)

[0174] Seed crystals of (E)-N'-[6-[6,7-difluoro-1-(oxan-2-yl)-1H-indazole-4-carbonyl]-8-methylquinolin-5-yl]-N,N-dimethylmethanimidamide A toluene solution (1.5 mL) of (E)-N'-(6-iodo-8-methylquinolin-5-yl)-N,N-dimethylmethanimidamide (146 mg, 0.430 mmol) in a reaction vessel was cooled to -10°C, and a 1.3 M solution of isopropylmagnesium chloride lithium chloride complex in THF (0.355 mL, 0.461 mmol) was added, followed by stirring at -10°C for 1 hour. To the reaction mixture, a toluene solution (0.25 mL) of 6,7-difluoro-N-methoxy-N-methyl-1-(oxan-2-yl)indazole-4-carboxamide (100 mg, 0.307 mmol) was added dropwise. The reaction mixture was stirred at -10°C for 10 minutes and then at 0°C for 30 minutes. A 17% aqueous ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate and concentrated under reduced pressure. Acetonitrile (1.0 mL) was added to the residue, and the mixture was dissolved at 70° C. and then cooled to 35° C. The solid was collected by filtration and washed with acetonitrile (2 mL) to give the title compound (36 mg, yield 24%) as a yellow solid. LCMS: m / z 478 [M+H] ＋ HPLC retention time: 1.84 minutes (Analysis conditions Y)

[0175] (E)-N'-[6-[6,7-difluoro-1-(oxan-2-yl)-1H-indazole-4-carbonyl]-8-methylquinolin-5-yl]-N,N-dimethylmethaneimidamide

[0176] Toluene (14 mL) was added to (E)-N'-(6-iodo-8-methylquinolin-5-yl)-N,N-dimethylmethanimidamide (2.92 g, 8.61 mmol) in a reaction vessel, and the mixture was cooled to -15°C. A THF solution of isopropyl magnesium chloride-lithium chloride complex (6.6 mL, 8.61 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. A toluene solution of 6,7-difluoro-N-methoxy-N-methyl-1-(oxan-2-yl)-1H-indazole-4-carboxamide (9.35 g, 6.15 mmol) in a separately prepared reaction vessel was transferred to the previously prepared reaction solution. After the transfer was complete, the reaction solution was warmed to 0°C and stirred for 4 hours. 20% aqueous ammonium chloride solution (22 mL) and THF (14 mL) were added, and the mixture was separated. 15% brine (20 mL) was added to the resulting organic layer, and the mixture was separated. The obtained organic layer was concentrated under reduced pressure to 6 ml. Toluene (2 mL) and isopropanol (2 mL) were added to the concentrated solution, and the mixture was heated to 70°C to obtain a homogeneous solution. The temperature was lowered to 40°C, isopropanol (32 mL) was added, and the mixture was cooled to 0°C. The precipitate was collected by filtration and washed with a mixture of toluene (1.1 mL) and isopropanol (4.9 mL) cooled to 5°C, and methanol (6 mL). The obtained solid was dried under reduced pressure to obtain the title compound (2.28 g, yield 78%) as a yellow solid. LCMS: m / z 478.20 [M+H] ＋ HPLC retention time: 3.20 minutes (Analysis conditions: LC-A)

[0177] (5-amino-8-methylquinolin-6-yl)[6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]methanone DMSO solvate

[0178] DMSO (60 mL), water (9.0 mL), and 50% aqueous potassium hydroxide solution (1.1 g, 9.4 mmol) were added to a reaction vessel and cooled to 7 ° C. N'-{6-[6,7-difluoro-1-(oxan-2-yl)-1H-indazole-4-carbonyl]-8-methylquinolin-5-yl}-N,N-dimethylmethaneimidamide (1.5 g, 3.1 mmol) was added to THF (15 mL) in a separately prepared reaction vessel, and after forming a homogeneous solution, it was transferred to the reaction solution prepared previously and stirred at 7 ° C. for 4 hours. Acetic acid (1.5 g, 9.4 mmol) and seed crystals of (5-amino-8-methylquinolin-6-yl)[6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]methanone DMSO solvate were added, and the temperature was raised to 40 ° C., followed by concentration under reduced pressure, and the THF was distilled off. After cooling to 20°C, water (6.0 mL) was added and stirred for 2 hours. The precipitate was collected by filtration and washed twice with water (7.5 mL). The obtained solid was dried under reduced pressure to obtain the DMSO solvate of the title compound (0.92 g, yield 70.8%) as a yellow solid. LCMS: m / z 423.16 [M+H] ＋ HPLC retention time: 3.48 minutes (Analysis conditions: LC-A)

[0179] (5-amino-8-methylquinolin-6-yl)[6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]methanone

[0180] THF (22.0 mL) was added to the DMSO solvate of (5-amino-8-methylquinolin-6-yl) [6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]methanone (4.82 g, containing 4.00 g of (5-amino-8-methylquinolin-6-yl) [6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]methanone, 9.47 mmol) in a reaction vessel, and the mixture was stirred at 60 ° C. to form a homogeneous solution. A mixture of ethanol (2.40 mL) / water (7.20 mL) was added to the solution over 5 minutes, and the temperature was then lowered to 40 ° C. over 30 minutes. (5-Amino-8-methylquinolin-6-yl)[6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]methanone (4.3 mg, 10.18 μmol) was added to the solution and stirred for 30 minutes. Then, a mixture of ethanol (8.00 mL) and water (24.0 mL) was added over 1 hour, and the mixture was stirred for another 1 hour. The temperature was lowered to 5°C over 1 hour, and the mixture was stirred for 3 hours. The precipitate was filtered and washed once with ethanol (16.0 mL) and twice with n-heptane (16.0 mL). The residue was dried under reduced pressure to give the title compound (3.82 g, 95% yield) as a yellow solid. LCMS: m / z = 423.21 [M+H] ＋ HPLC retention time: 3.55 minutes (Analysis conditions: LC-A)

[0181] (5-amino-8-methylquinolin-6-yl)[6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]methanone

[0182] The title compound can also be produced by the following method. N'-{6-[6,7-difluoro-1-(oxan-2-yl)-1H-indazole-4-carbonyl]-8-methylquinolin-5-yl}-N,N-dimethylmethanimidamide (1.0 g, 2.1 mmol) and THF (15 mL) were added to a reaction vessel to form a homogeneous solution, which was then cooled to -10°C. 40% tetrabutylammonium hydroxide aqueous solution (1.6 g, 2.5 mmol) was added, and the mixture was stirred for 8 hours. Acetic acid (0.28 g, 4.6 mmol) was added, and the mixture was heated to 0°C and stirred for 10 minutes. 15% brine (10 mL) was added, and the mixture was separated. The obtained organic layer was concentrated under reduced pressure to 10 mL. Ethanol (0.6 mL) / water (1.8 mL) was added, and the mixture was heated to 60°C to form a homogeneous solution, which was then cooled to 40°C over 30 minutes. To the solution was added (5-amino-8-methylquinolin-6-yl)[6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]methanone (1.0 mg), and the mixture was stirred for 30 minutes. A mixture of ethanol (4.0 mL) and water (12.0 mL) was then added over 2 hours, followed by stirring for an additional 1 hour. The temperature was lowered to 5°C over 3 hours and 30 minutes, and the mixture was stirred for 14 hours. The precipitate was filtered and washed once with ethanol (4.0 mL) and twice with n-heptane (4.0 mL). The residue was dried under reduced pressure to give the title compound (0.66 g, yield 75.2%) as a yellow solid. LCMS: m / z 423.16 [M+H] ＋ HPLC retention time: 3.48 minutes (Analysis conditions: LC-A)

[0183] 3-amino-4-[6,7-difluoro-1-(oxan-2-yl)indazol-4-yl]-6-methyl-1H-1,7-phenanthrolin-2-one

[0184] Chloroacetyl chloride (706 μL, 8.88 mmol) was added to a DMA solution (32.5 mL) of (5-amino-8-methylquinolin-6-yl)[6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]methanone (2.5 g, 5.92 mmol) in a reaction vessel, and the mixture was stirred at 7° C. for 30 minutes. Pyridine (10.0 mL, 0.12 mmol) was added to the reaction mixture, and the mixture was stirred at 70° C. for 4 hours. 80% aqueous hydrazine solution (1.80 mL, 29.6 mmol) was added to the reaction mixture over 1 hour, and the mixture was stirred at 63° C. for 1 hour. To the reaction mixture was added a suspension of 3-amino-4-[6,7-difluoro-1-(oxan-2-yl)-1H-indazol-4-yl]-6-methyl-1,7-phenanthrolin-2(1H)-one (50.0 mg, 108 μmol) in DMA (250 μL, 2.7 mmol) / water (250 μL, 14 mmol), and the mixture was stirred for 3 hours. Water (15.0 mL, 0.83 mmol) was then added over 1 hour. After stirring for 30 minutes, water (15.0 mL, 0.83 mmol) was added over 1 hour, and the mixture was cooled to 25°C. The precipitate was filtered and washed twice with water (12.5 mL) and once with ethanol (12.5 mL), successively. The residue was dried under reduced pressure to give the title compound (2.67 g, 98% yield) as a tan solid. LCMS: m / z = 462.25 [M+H] ＋ HPLC retention time: 3.23 minutes, 3.29 minutes (Analysis conditions: LC-A)

[0185] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one (Compound 1)

[0186] A suspension of 3-amino-4-[6,7-difluoro-1-(oxan-2-yl)indazol-4-yl]-6-methyl-1H-1,7-phenanthrolin-2-one (2.0 g, 4.33 mmol) in 2,2,2-trifluoroethanol (20.0 mL) was placed in a reaction vessel and stirred at 30°C. 6M aqueous hydrochloric acid solution (1.59 mL, 9.53 mmol) was added and stirred at 30°C for 14 hours. Ethanol (20.0 mL) was added to the reaction mixture and stirred at 30°C. Triethylamine (1.63 mL, 11.7 mmol) was added over 1 hour and stirred. The solid was collected by filtration and washed three times with ethanol (10 mL). The solid was dried at 40°C to obtain the title compound (1.5 g, yield 92.9%) as a brown solid. LCMS: m / z 378.06 [M+H] ＋ HPLC retention time: 4.96 minutes (Analysis conditions: LC-C)

[0187] Seed crystals of the monohydrate of the hydrochloride salt of 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one

[0188] A 1M aqueous solution of hydrochloric acid (25.0 mL) was added to a reaction vessel and the temperature was raised to 60°C. A solution of 3-amino-4-(6,7-difluoro-2H-indazol-4-yl)-6-methyl-1,7-phenanthrolin-2(1H)-one (2.50 g, 6.63 mmol) in THF / water (9:1, 62.5 mL) was added dropwise over 1 hour and stirred for 1 hour. The temperature was lowered to 30°C and stirred for 1 hour. The temperature was lowered to 10°C and stirred for 1 hour. The solid was collected by filtration and washed twice with ethanol (12.5 mL). The solid was dried at 40°C to obtain the title compound (2.67 g, yield 92.4%) as a yellow solid. LCMS: m / z 378.15 [M+H] ＋ HPLC retention time: 2.47 minutes (Analysis conditions: LC-A)

[0189] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one hydrochloride monohydrate

[0190] A 1M aqueous solution of hydrochloric acid (8.0 mL) was added to a reaction vessel, the temperature was raised to 55°C, and seed crystals of the title compound (1.2 mg) were added. A solution of 3-amino-4-(6,7-difluoro-2H-indazol-4-yl)-6-methyl-1,7-phenanthrolin-2(1H)-one (800 mg, 2.12 mmol) in THF / water (9:1, 22.4 mL) was added dropwise over 4 hours, and the mixture was stirred for 4 hours. The temperature was lowered to 25°C over 1 hour, and the mixture was stirred for 1 hour. The solid was collected by filtration and washed three times with ethanol (4.0 mL). The mixture was dried at 40°C to obtain the title compound (879.0 mg, 96%) as a yellow solid. LCMS: m / z 378.06 [M+H] ＋ HPLC retention time: 4.96 minutes (Analysis conditions: LC-C)

[0191] Pharmacological Test (6) Evaluation of Compound 1 (6-1) Binding Test to the ATP Binding Site of MYT1 The binding ability of Compound 1 to the ATP binding site of MYT1 kinase protein was evaluated. 5X Kinase Buffer A (PV3189, manufactured by Thermo Fisher Scientific) was diluted 5-fold with Milli-Q water to prepare 1X Kinase Buffer. MYT1 protein (manufactured by Carnabiosciences) was diluted to a concentration of 0.005 μM, and Eu-Anti-GST Antibody was diluted to a concentration of 1 μM with 1X Kinase Buffer. Kinase Tracer 178 (PV5593, manufactured by Thermo Fisher Scientific) was also diluted to a concentration of 0.1 μM with 1X Kinase Buffer. 2.5 μL of Compound 1 diluted in DMSO was added to a 96-well plate, followed by 5 μL of a 1:1 mixture of the diluted MYT1 protein and Eu-GST-Antibody. 2.5 μL of the diluted Kinase Tracer 178 was then added, mixed well, and allowed to stand at room temperature for 30 minutes. Fluorescence at 665 nm and 615 nm generated by irradiation with 340 nm excitation light was then detected using Envision (PerkinElmer). The intensity of the 665 nm fluorescence wavelength was divided by the intensity of the 615 nm fluorescence wavelength to calculate the percentage of Tracer binding to MYT1 protein for each condition. The signal without Compound 1 was set to 100% and the signal without MYT1 protein was set to 0%, and the inhibition rate was calculated for each concentration of Compound 1 added, giving the IC ５０ The results are shown in Table 1. IC of 10 μM or less ５０ When the above expression is observed, it can be determined that the compound exhibits binding activity to the ATP binding site of the MYT1 protein.

[0192] (6-2) MYT1 Kinase Activity Inhibition Test The ability of Compound 1 to inhibit MYT1 kinase activity was evaluated by assessing the phosphorylation level of Y15 of CDK1 protein by MYT1 protein using ELISA. The Cyclex Wee1 Kinase Assay / Inhibitor Screening Kit Ver. 3 (MBL, CY-1172V3) was used. 10 μL of 5 nM MYT1 protein (Carnabiosciences) was prepared using Kinase Buffer. 30 μL of 83.3 μM ATP was also prepared using Kinase Buffer. Compound 1 was diluted to each concentration in 10 μL increments using Kinase Buffer. 30 μL of ATP was added to the kit plate, followed by 10 μL of compound. 10 μL of the diluted MYT1 protein solution was added, mixed, and allowed to stand at room temperature for 60 minutes. The reaction solution was removed from each well, and the wells were washed with Wash Buffer. After removing the wash buffer, 100 μL of HRP-conjugated anti-phospho-tyrosine antibody was added and the wells were left to stand at room temperature for 60 minutes. The reaction solution was then removed from the wells, and the wells were washed with wash buffer. After removing the wash buffer, 100 μL of substrate reagent was added to each well and the wells were left to stand at room temperature for 8 minutes. Then, 100 μL of stop solution (1N sulfuric acid) was added to each well according to the protocol. The absorbance at 450 nm and 590 nm was measured using Envision (PerkinElmer). The absorbance at 590 nm was subtracted from the absorbance at 450 nm to evaluate the phosphorylation level of CDK1 protein in each well. The inhibition rate was calculated when each concentration of compound 1 was added, with the signal without compound 1 set to 100% and the signal without MYT1 protein set to 0%. IC ５０ The results are shown in Table 1. IC of 10 μM or less ５０ When the above expression is observed, it can be determined that the kinase activity of MYT1 protein is inhibited.

[0193] (6-3) Results As shown in Table 1, Compound 1 had an IC value of 10 μM or less in the binding assay for the ATP binding site of MYT1. ５０ This suggests that it binds to the ATP binding site of the MYT1 protein. In addition, in a MYT1 kinase activity inhibition test, it had an IC value of 10 μM or less. ５０ These results suggest that the compound is capable of inhibiting the kinase activity of MYT1 protein, i.e., is a MYT1 inhibitor.

[0194] Test Example 2: Test of combined cytotoxic activity of pemetrexed and compound 1 1. Experimental materials and methods (1) Cell line The cell line LU65 (provided by the JCRB Cell Bank) was used for the evaluation of the present invention. LU65 is a lung cancer cell line that has a truncated deletion mutation of S82* in the RB1 gene (see Non-Patent Document 22), resulting in decreased RB1 function. Cell culture was performed using RPMI-1640 medium (manufactured by SIGMA) containing 10% FBS (manufactured by SIGMA).

[0195] (2) Cytotoxicity test by pemetrexed when Compound 1 was added Pemetrexed (Tokyo Chemical Industry Co., Ltd.) and Compound 1 at various concentrations were diluted with DMSO, and 0.04 μL of the dilution series and DMSO were added to each well of a cell culture plate using an Echo 555 Liquid Handler (Beckman Coulter). 1,000 LU65 cells (40 μL) were added to each well, and the mixture was incubated at 37°C and 5% CO. ２The cells were cultured in an incubator for 7 days. The amount of intracellular ATP, a marker of cell viability, was measured and used to monitor cell number. After culture, 20 μL of CellTiter-Glo® 2.0 (Promega) was added to each well, and luminescence intensity was measured using a Multimode Plate Reader EnVision® Xcite (PerkinElmer). The luminescence of the DMSO-added wells minus the luminescence of the non-cell-seeded wells was set as 100%, and the viability under each condition was calculated by calculating the percentage of luminescence detected in each well minus the luminescence of the non-cell-seeded wells.

[0196] The cytotoxic activity under each condition was calculated by subtracting the viability at each combination of pemetrexed treatment concentration and Compound 1 treatment concentration from 100%. Furthermore, based on the cytotoxic activity of wells to which Compound 1 was not added at each pemetrexed concentration and the cytotoxic activity of wells to which Compound 1 was not added at each pemetrexed concentration, a Bliss score (see Non-Patent Document 23) based on Bliss independence, which serves as an index of the combined effect of each combination of pemetrexed concentration and Compound 1 concentration, was calculated, and the maximum value thereof and the concentrations of pemetrexed and Compound 1 at which the maximum value was obtained are listed in Table 2. The HSA score (see Non-Patent Document 23), which serves as an index of the combined effect different from Bliss independence, was also calculated, and the maximum value thereof and the concentrations of pemetrexed and Compound 1 at which the maximum value was obtained are listed in Table 2. It can be determined that a combined effect exists when both the maximum Bliss score and the maximum HSA score are 10% or more.

[0197] 2. Results As shown in Figure 1 and Table 2, in the pemetrexed cytotoxicity test when Compound 1 was added, the maximum Bliss score and maximum HSA score were both 10% or more, suggesting that Compound 1 inhibits the function of MYT1 in cells and exerts a combined effect with pemetrexed.

[0198] Effect of Additive Type on Solubility of Monohydrate of Hydrochloride of Compound 1 (Example 1-1-1) Monohydrate of hydrochloride of Compound 1 (1.2 mg) was added to FaSSIF (1.2 mL) kept at 37.0°C under 1 atm conditions and dissolved by shaking at 1500 rpm for 4 hours. After shaking, the mixture was centrifuged at 12000 rpm to obtain a supernatant, which was then filtered. The resulting filtrate was mixed 1:1 with a DMSO / EG solution (60:40 (v / v)) containing approximately 20 μg / mL of 21NE as an internal standard to prepare a measurement sample. The concentration of Compound 1 in the filtrate was measured by HPLC. The residue obtained after the test was measured by X-ray diffraction (XRD). The HPLC measurement conditions were as follows: Apparatus name: ACQUITY UPLC H-Class (trade name) Detector: ultraviolet absorption spectrophotometer Column: ACQUITY UPLC TM BEH C 18 Column (product name): Particle size: 1.7 μm, inner diameter 2.1 mm × length 50 mm Column temperature: Constant temperature around 40°C Detection wavelength: 250 nm Mobile phase A: 0.05% TFA / water Mobile phase B: 0.05% TFA / acetonitrile Gradient: The mixing ratio of mobile phases A and B was controlled as shown in Table 5. Injection volume: 5.0 μL Sample temperature: room temperature

[0199] The XRD measurement conditions were as follows: Measurement device (model): Empyrean (trade name, manufactured by Malvern Panalytical) Anticathode: Cu Tube voltage: 45 kV Tube current: 40 mA Step width: 0.026° Scan axis: 2θ Scan speed: 0.013° / sec Scan range: 3-25°

[0200] The XRD evaluation conditions were as follows: Measuring device (model): Empyrean (trade name, manufactured by Malvern Panalytical) Anticathode: Cu Tube voltage: 45 kV Tube current: 40 mA Step width: 0.026° Scan axis: 2θ Scan speed: 1.313° / sec Scan range: 3-25°

[0201] Example 1-1-2: Compound 1 hydrochloride monohydrate (1.2 mg) was added to FaSSIF (1.2 mL) containing SLS (0.5 mg / mL) kept at 37.0°C under 1 atm conditions, and dissolved by shaking at 1,500 rpm for 4 hours. After shaking, the mixture was centrifuged at 12,000 rpm to obtain a supernatant, which was then filtered. The resulting filtrate was mixed 1:1 with a DMSO / EG solution (60:40 (v / v)) containing approximately 20 μg / mL of 21NE as an internal standard to prepare a measurement sample. The concentration of Compound 1 in the filtrate was measured by HPLC (n=3). The HPLC measurement conditions were the same as in Example 1-1-1.

[0202] Examples 1-1-3 to 1-1-18 Measurements were carried out in the same manner as in Example 1-1-2, except that Additive 1 and Additive 2 in Table 6 were used instead of SLS. The additives used are as follows: Sucrose fatty acid ester (manufactured by Daiichi Kogyo Seiyaku Co., Ltd., trade name: DKesterSS) Poloxamer188: poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (manufactured by Merck Millipore, trade name: ParteckPLX188) HPMC: hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., trade name: HPMC TC5E) HPMCAS: hydroxypropyl methylcellulose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd., trade name: AQOAT AS-LG) HPMCP: hydroxypropyl methylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd., HPMCP55) MC: methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., trade name: METOLOSE SM-4VF) HPC: hydroxypropyl cellulose (manufactured by Nisso, trade name: HPC SL) PVA: polyvinyl alcohol (Merck Millipore, trade name: ParteckCOAT) Kollidon 30: Polyvinylpyrrolidone (trade name, manufactured by BASF) Kollidon VA64: Polyvinylpyrrolidone-vinylpyrrolidone-vinyl acetate copolymer (trade name, manufactured by BASF) EUDRAGIT L100: Methacrylic acid copolymer L (trade name, manufactured by Evonik) EUDRAGIT L100-55: Dry methacrylic acid copolymer LD (trade name, manufactured by Evonik) Soluplus: Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (trade name, manufactured by BASF)

[0203] The concentrations of Compound 1 measured by HPLC are shown in Table 6. In Table 6, "SD" stands for standard deviation.

[0204] As shown in Table 6, except for Examples 1-1-4 and 1-1-15, the monohydrate of the hydrochloride of Compound 1 exhibited high solubility.

[0205] Furthermore, in Examples 1-1-1, 1-1-4, and 1-1-18, the residues obtained after the above tests were measured by XRD. The results are shown in Figure 2. As shown in Figure 2, Example 1-1-4 suggested a transition in the crystalline form of the monohydrate of the hydrochloride of Compound 1, but Example 1-1-18 did not suggest a transition in the crystalline form of the monohydrate of the hydrochloride of Compound 1, and showed higher solubility than Example 1-1-5. It was found that Poloxamer 188, when used in combination with HPMC or the like, improves the solubility of the monohydrate of the hydrochloride of Compound 1.

[0206] Effect of the amount of additive added on the solubility of the monohydrate of hydrochloride of compound 1 (Example 1-2-1) The monohydrate of hydrochloride of compound 1 (152.4 mg) and SLS (13.3 mg) were weighed and mixed in a mortar, and the mixture was sieved through a sieve (mesh opening 500 μm) to prepare a mixed powder, which was then separated into 41.4 mg portions. The separated mixed powder was added to FaSSGF (40 mL) heated to 37.0 ° C. and stirred at 50 rpm for 30 minutes. Next, 5x concentrated FaSSIF (10 mL) was added, and aqueous sodium hydroxide solution was added to adjust the pH to 6.5. After a predetermined period of time had elapsed since preparation (5, 10, 15, 20, 25, 30, 45, 60, 120, and 240 minutes), the test solution was filtered, and the resulting filtrate was mixed 1:1 with a DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were as follows: Apparatus name: ACQUITY UPLC H-Class (trade name) Detector: ultraviolet absorption spectrophotometer Column: ACQUITY UPLC TM BEH C 18 Column (product name): Particle size: 1.7 μm, inner diameter 2.1 mm × length 50 mm Column temperature: constant temperature around 40°C Detection wavelength: 250 nm Mobile phase A: 0.05% TFA / water Mobile phase B: 0.05% TFA / acetonitrile Gradient: The mixing ratio of mobile phases A and B was controlled as shown in Table 7. Injection volume: 2.0 μL Sample temperature: room temperature

[0207] Examples 1-2-2 to 1-2-5 Except for changing the amount of SLS as shown in Table 8, the concentration of Compound 1 was calculated in the same manner as in Example 1-2-1.

[0208] The results are shown in Table 8 and Figure 3. As shown in Figure 3, the greater the amount of SLS added, the higher the solubility of the monohydrate of the hydrochloride of Compound 1 in FaSSIF.

[0209] (Example 1-2-6) Compound 1 hydrochloride monohydrate (45 mg), lactose hydrate (90 mg), and sucrose fatty acid ester (37.5 mg) were weighed and mixed in a mortar, and the mixture was sieved through a sieve (mesh opening 500 μm) to prepare a mixed powder, which was then separated into 57.5 mg portions. The separated mixed powder was added to FaSSIF (50 mL) heated to 37.0°C and stirred at 50 rpm. After a predetermined time had elapsed since stirring (5, 10, 15, 20, 25, 30, 45, 60, 120, and 240 minutes), the test solution was sampled and filtered. The resulting filtrate was mixed 1:1 with a DMSO / EG solution (60:40 (v / v)) containing approximately 20 μg / mL of 21NE as an internal standard to prepare a measurement sample. The concentration of Compound 1 in the filtrate was measured by HPLC. The HPLC measurement conditions were as follows: Device name: ACQUITY UPLC H-Class (trade name) Detector: Photodiode array detector Column: ACQUITY UPLC BEH Shield RP-18 Column (trade name), particle size: 1.7 μm, inner diameter 2.1 mm × length 50 mm Column temperature: constant temperature around 40°C Detection wavelength: 339 nm (compound 1) / 282 nm (internal standard substance) Mobile phase A: 0.05% TFA / water Mobile phase B: 0.05% TFA / acetonitrile Gradient: The mixing ratio of mobile phases A and B was controlled as shown in Table 9. Injection volume: 1.0 μL Sample temperature: constant temperature around 20°C

[0210] Examples 1-2-7 to 1-2-10 Measurements were carried out in the same manner as in Example 1-2-6, except that the amounts of sucrose fatty acid ester and lactose hydrate were changed as shown in Table 10, and the concentrations of Compound 1 were calculated.

[0211] The results are shown in Table 10 and Figure 4. As shown in Figure 4, the monohydrate of the hydrochloride of Compound 1 showed higher solubility in FaSSIF as the amount of sucrose fatty acid ester added increased.

[0212] Effect of Formulation of Composition Comprising Monohydrate of Hydrochloride of Compound 1 and Surfactant (Example 1-3-1) Monohydrate of hydrochloride of Compound 1 (112.5 mg) and SLS (84.4 mg) were weighed and mixed in a mortar, and the mixture was sieved through a sieve (mesh opening 500 μm) to prepare a mixed powder, which was then divided into 43.8 mg portions. The mixed powder was filled into HPMC capsules (size 1). The capsules filled with the mixed powder were added to FaSSIF (50 mL) heated to 37.0°C and stirred at 50 rpm. After a predetermined time had elapsed since stirring (15, 30, 60, 120, and 240 minutes), the test solution was filtered, and the resulting filtrate was mixed 1:1 with a DMSO / EG solution (60:40 (v / v)) containing approximately 20 μg / mL of 21NE as an internal standard substance to prepare a measurement sample. The concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 1-2-6.

[0213] Example 1-3-2 The concentration of Compound 1 was calculated in the same manner as in Example 1-3-1, except that the amount of SLS was changed as shown in Table 11 and no capsules were filled with SLS.

[0214] The results are shown in Table 11 and Figure 5. In the table, + indicates that the mixed powder was filled into a capsule, and - indicates that the mixed powder was not filled into a capsule.

[0215] Example 1-3-3: Compound 1 hydrochloride monohydrate (112.5 mg) and sucrose fatty acid ester (84.4 mg) were weighed and mixed in a mortar, and the mixture was sieved through a sieve (500 μm mesh) to prepare a mixed powder, which was then aliquoted into 43.8 mg portions. The mixed powder was filled into HPMC capsules (size 1). The filled capsules were added to FaSSIF (50 mL) heated to 37.0°C and stirred at 50 rpm. After a predetermined time had elapsed since stirring (15 minutes, 30 minutes, 60 minutes, 120 minutes, and 240 minutes), the test solution was filtered, and the resulting filtrate was mixed 1:1 with a DMSO / EG solution (60:40 (v / v)) containing approximately 20 μg / mL of 21NE as an internal standard to prepare a measurement sample. The concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 1-2-6.

[0216] Example 1-3-4 The concentration of Compound 1 was calculated in the same manner as in Example 1-3-3, except that the compound was not filled into capsules.

[0217] The results are shown in Table 12 and Figure 6. As shown in Figure 6, it was suggested that the dissolution rate of Compound 1 for FaSSIF in the capsules of Example 1-3-3 tended to be lower than the dissolution rate of the monohydrate of the hydrochloride of Compound 1 in Example 1-3-4.

[0218] Stability of Formulated Compound 1 Hydrochloride Monohydrate (Example 1-4-1) Compound 1 hydrochloride monohydrate (890.0 mg), SLS (667.5 mg), and HPMC (142.4 mg) were weighed and mixed in a mortar so that the content of Compound 1 hydrochloride monohydrate per capsule was 25 mg (set value: 25 mg), and the mixture was sieved through a sieve (mesh opening 500 μm) to prepare a mixed powder, which was then aliquoted into 47.8 mg portions. The mixed powder was filled into HPMC capsules (size 1). The filled capsules were placed in airtight glass vials and stored in a thermostatic chamber set at 40° C. for one month. The capsules after storage were dissolved in an acetonitrile / water mixture (50:50 (v / v), 100 mL) and filtered. The resulting filtrate was mixed with an acetonitrile / water mixture (50:50 (v / v)) at a ratio of 4:6 to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was measured by HPLC. From the measured concentration of Compound 1, the content of the monohydrate of hydrochloride of Compound 1 in the formulation was calculated (measured value), and the percentage (%) of this measured value relative to the set value was calculated. The HPLC measurement conditions were as follows: Device name: ACQUITY UPLC H-Class (trade name) Detector: Photodiode array detector Column: Inertsil ODS-HL (trade name), 2.1 mm ID × 50 mm, 1.9 μm (GL Sciences) Column temperature: Constant temperature around 35°C Detection wavelength: 325 nm Mobile phase A: 0.05% TFA / water Mobile phase B: 0.05% TFA / acetonitrile Gradient: The mixing ratio of mobile phases A and B was controlled as shown in Table 13. Injection volume: 1.0 μL Sample temperature: 10°C

[0219] Example 1-4-2 Except for changing the storage humidity as shown in Table 14, the ratio of the measured value to the set value of the content of Compound 1 was calculated in the same manner as in Example 1-4-1.

[0220] Comparative Example 1-4-1 In Comparative Example 1-4-1, the sample was treated in the same manner as in Example 1-4-1 without being stored in a thermostatic chamber.

[0221] The results are shown in Table 14. As shown in Table 14, no significant change was observed in the ratio of the measured content of Compound 1 to the set value for the capsules filled with a mixed powder consisting of the monohydrate of the hydrochloride of Compound 1, SLS, and HPMC, suggesting that the capsules have good stability under heated or heated and humidified conditions.

[0222] Effect of Solubilizing Agent (Example 2-1-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a glass vial to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (23.7 wt%), SLS (10.3 wt%), mannitol (26.6 wt%), microcrystalline cellulose (CEOLUS PH-101) (27.6 wt%), HPMC (4.1 wt%), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (1.0 wt%), and magnesium stearate (1.6 wt%). The obtained mixed powder was added to FaSSIF (60 mL) heated to 37.0°C and stirred with a stirrer. After a predetermined period of time had elapsed since stirring (60 minutes, 120 minutes, 180 minutes, and 240 minutes), the test solution was filtered, and the resulting filtrate was mixed 1:1 with a DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were as follows: Apparatus name: ACQUITY UPLC H-Class (trade name) Detector: ultraviolet absorption spectrophotometer Column: ACQUITY UPLC TM BEH C 18 Column (product name): Particle size: 1.7 μm, inner diameter 2.1 mm × length 50 mm Column temperature: constant temperature around 40°C Detection wavelength: 250 nm Mobile phase A: 0.05% TFA / water Mobile phase B: 0.05% TFA / acetonitrile Gradient: The mixing ratio of mobile phases A and B was controlled as shown in Table 15. Injection volume: 2.0 μL Sample temperature: constant temperature around 20°C

[0223] The residue obtained after the test was measured by XRD under the following conditions: Measurement device (model): Empyrean (trade name, manufactured by Malvern Panalytical) Anticathode: Cu Tube voltage: 45 kV Tube current: 40 mA Step width: 0.026° Scan axis: 2θ Scan rate: 0.0740° / sec Scan range: 3-25°

[0224] Example 2-1-2 The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a glass vial to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (23.7 wt%), SLS (10.3 wt%), mannitol (28.7 wt%), microcrystalline cellulose (29.7 wt%, trade name: Ceolus PH-101), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (1.0 wt%), and magnesium stearate (1.6 wt%). The obtained mixed powder was added to FaSSIF (60 mL) heated to 37.0°C and stirred with a stirrer. After the specified time had elapsed since stirring (60 minutes, 120 minutes, 180 minutes, and 240 minutes), the test solution was filtered, and the resulting filtrate was mixed 1:1 with a DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. In addition, the residue obtained after the test was measured by XRD. The HPLC measurement conditions and XRD measurement conditions were the same as those in Example 2-1-1.

[0225] The concentration of Compound 1 measured by HPLC is shown in Figure 7, and the XRD diffraction pattern is shown in Figure 8. As shown in Figure 7, the mixed powder of Example 2-1-1 (containing HPMC) showed improved solubility of the monohydrate of the hydrochloride of Compound 1 in FaSSIF after 120 to 240 minutes compared to the mixed powder of Example 2-1-2 (not containing HPMC). Furthermore, as shown in Figure 8, a new peak was observed in the mixed powder of Example 2-1-2, suggesting precipitation. On the other hand, no new peak was observed in the mixed powder of Example 2-1-1, suggesting no precipitation.

[0226] Effect of Disintegrant Type (Example 2-2-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 25 mL plastic tube to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (22.9 wt%), SLS (10.0 wt%), mannitol (28.6 wt%), microcrystalline cellulose (25.0 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), croscarmellose sodium (8.0 wt%), and light anhydrous silicic acid (1.0 wt%). The obtained mixed powder was dry granulated using a compression simulator (trade name: HB100, manufactured by Huxley Bertram) and dry sized using a small-scale hand mill (manufactured by Gerteis). Magnesium stearate (0.5 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added, and the mixture was mixed by inversion in a 25 mL plastic tube, and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 4.0 kN, tableting compression speed: 30.0 RPM, pre-compression pressure: 1.4 kN, main compression pressure: 7.0 kN

[0227] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring (15 minutes before pH adjustment), a test solution for measuring the concentration of Compound 1 was collected. Next, 5x FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC conditions were the same as in Example 2-1-1.

[0228] Example 2-2-2: Compound 1 hydrochloride monohydrate and each additive were mixed by inversion in a 25 mL plastic tube to obtain a mixed powder of Compound 1 hydrochloride monohydrate (22.9 wt%), SLS (10.0 wt%), mannitol (28.6 wt%), microcrystalline cellulose (25.0 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), crospovidone (8.0 wt%, trade name: Kollidon CL-SF, manufactured by BASF), and light anhydrous silicic acid (1.0 wt%). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (0.5 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added, and the mixture was mixed by inversion in a 25 mL plastic tube, and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 4.0 kN, tableting compression speed: 30.0 RPM, pre-compression pressure: 1.5 kN, main compression pressure: 6.5 kN

[0229] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0230] The results are shown in Figure 9. As shown in Figure 9, the dissolution properties of the tablets in FaSSIF were good regardless of whether croscarmellose sodium or crospovidone (trade name: Kollidon CL-SF, manufactured by BASF) was used as the disintegrant.

[0231] Effect of Disintegrant Amount (Example 2-3-1) Compound 1 hydrochloride monohydrate and each additive were mixed by inversion in a 25 mL plastic tube to obtain a mixed powder of Compound 1 hydrochloride monohydrate (23.7 wt%), SLS (10.3 wt%), mannitol (29.4 wt%), crystalline cellulose (25.9 wt%, trade name: Ceolus PH-101), HPMC (4.1 wt%), croscarmellose sodium (5.0 wt%), and light anhydrous silicic acid (1.0 wt%). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (0.5 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added. The mixture was mixed by inversion in a 25 mL plastic tube and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet production conditions were the same as in Example 2-2-1.

[0232] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous sodium hydroxide. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0233] Example 2-3-2: Compound 1 hydrochloride monohydrate and each additive were mixed by inversion in a 100 mL plastic tube to obtain a mixed powder of Compound 1 hydrochloride monohydrate (24.4 wt%), SLS (10.7 wt%), mannitol (30.3 wt%), crystalline cellulose (26.7 wt%, trade name: Ceolus PH-101), HPMC (4.3 wt%), croscarmellose sodium (2.0 wt%), and light anhydrous silicic acid (1.1 wt%). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (0.5 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added. The mixture was mixed by inversion in a 100 mL plastic tube and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 4.0 kN, Tableting compression speed: 30.0 RPM, pre-compression pressure: 2.0 kN, main compression pressure: 7.0 kN

[0234] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x concentration FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0235] The results are shown in Figure 10. As shown in Figure 10, the dissolution properties of FaSSIF were good even when the ratio of croscarmellose sodium in the mixed powder was changed to 2.0 wt%, 5.0 wt%, and 8.0 wt%.

[0236] Effect of Lubricant Amount (Example 2-4-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 25 mL plastic tube to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (23.7 wt%), SLS (10.3 wt%), mannitol (26.6 wt%), microcrystalline cellulose (27.6 wt%, trade name: Ceolus PH-101), HPMC (4.1 wt%), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (1.0 wt%), and magnesium stearate (0.5 wt%). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (1.0 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added, and the mixture was mixed by inversion in a 25 mL plastic tube, and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 7.0 kN, tableting compression speed: 30.0 RPM, pre-compression pressure: 1.4 kN, main compression pressure: 10.0 kN

[0237] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x concentration FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0238] The results are shown in Figure 11. As shown in Figure 11, the dissolution properties of FaSSIF were good even when the ratio of magnesium stearate in the mixed powder was changed to 0.5 wt% or 1.5 wt%.

[0239] When the ratio of magnesium stearate in the composition was 1.5 wt%, adhesion to the punch after tableting was further reduced. Figure 12(a) shows the state of adhesion to the punch when produced with 0.5 wt% magnesium stearate added, and Figure 12(b) shows the state of adhesion to the punch when produced with 1.5 wt% magnesium stearate added.

[0240] Effect of Formulation Content (Example 2-5-1) Compound 1 hydrochloride monohydrate and each additive were mixed by inversion in a 100 mL plastic tube to obtain a mixed powder of Compound 1 hydrochloride monohydrate (22.9 wt%), SLS (10.0 wt%), mannitol (28.6 wt%), microcrystalline cellulose (25.0 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), croscarmellose sodium (8.0 wt%), and light anhydrous silicic acid (1.0 wt%). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (0.5 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added, and the mixture was mixed by inversion in a 100 mL plastic tube. Tablets were compressed to a content of 60 mg using a compression simulator HB100 to obtain oval-shaped tablets (major axis: 13.90 mm, minor axis: 6.43 mm). The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 4.0 kN, tableting compression speed: 30.0 RPM, pre-compression pressure: 1.1 kN, main compression pressure: 13.0 kN

[0241] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 60 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0242] The tablets obtained in Example 2-2-1 were also tested under the same conditions as in Example 2-5-1.

[0243] The results are shown in Figure 13. As shown in Figure 13, no significant difference was observed in dissolution properties in FaSSIF between tablets containing 30 mg of Compound 1 per tablet and tablets containing 60 mg of Compound 1 per tablet.

[0244] Stability of Formulation (Example 2-6-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 100 mL plastic tube to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (23.7 wt%), SLS (10.3 wt%), mannitol (29.4 wt%), microcrystalline cellulose (25.9 wt%, trade name: Ceolus PH-101), HPMC (4.1 wt%), croscarmellose sodium (5.0 wt%), and light anhydrous silicic acid (1.0 wt%), so that the content per 1 tablet of Compound 1 was 30 mg (set value: 30 mg). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (0.5 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added, and the mixture was mixed by inversion in a 100 mL plastic tube, and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 4.0 kN, tableting compression speed: 30.0 RPM, pre-compression pressure: 1.2 kN, main compression pressure: 6.5 kN

[0245] HPMC (5.2 wt%), talc (0.7 wt%), titanium oxide (1.5 wt%), and purified water (92.6 wt%) were mixed. The resulting solution was coated onto tablets using a film coating machine (trade name: GTX-mini, manufactured by Powrex Corporation). The tablet coating conditions were as follows: spray air flow rate: 10 NL / min, spray air pressure: 0.6 MPa, supply air temperature: 65°C, supply air volume: 0.5 Nm ３ / min Liquid delivery speed: 1.5g / min Pan rotation speed: 15-18rpm

[0246] The obtained tablets were filled into airtight HDPE bottles, 15 tablets per bottle, and stored in a thermostatic chamber set at 40°C and 75% RH for one month. Samples packed in HDPE bottles with silica gel were also prepared and stored in the same manner. The stored tablets were added to an acetonitrile / water mixture (50:50 (v / v), 100 mL) and ultrasonicated for 15 minutes. After mixing, ultrasonication was continued for another 15 minutes. After confirming the state of dissolution, 5 mL of the supernatant was filtered through a 0.20 μm PTFE filter, and the concentration of Compound 1 in the remaining filtrate was measured by HPLC after discarding 4 mL of the initial solution. The content of Compound 1 was calculated from the measured concentration of Compound 1 (measured value), and the percentage (%) of this measured value relative to the set value was calculated. The HPLC conditions were as follows. The initial product of Example 2-6-1 was treated in the same manner except that it was not stored in a thermostatic chamber. Device name: ACQUITY UPLC H-Class (trade name) Detector: Photodiode array detector Column: Inertsil ODS-HL (trade name) Particle size: 1.9 μm, inner diameter 2.1 mm × length 50 mm Column temperature: Constant temperature around 40°C Detection wavelength: 250 nm Mobile phase A: 0.05% TFA / water Mobile phase B: 0.05% TFA / acetonitrile Gradient: The mixing ratio of mobile phases A and B was controlled as shown in Table 16. Injection volume: 3 μL Sample temperature: constant temperature around 10°C

[0247] The stored tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed after the adjustment (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was filtered, and the resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 1-2-1.

[0248] Example 2-6-2: The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 100 mL plastic tube to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (23.7 wt%), SLS (10.3 wt%), mannitol (29.4 wt%), microcrystalline cellulose (25.9 wt%, trade name: Ceolus PH-101), HPMC (4.1 wt%), croscarmellose sodium (5.0 wt%), and light anhydrous silicic acid (1.0 wt%), so that the content of Compound 1 per tablet was 30 mg (set value: 30 mg). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (0.5 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added, and the mixture was mixed by inversion in a 100 mL plastic tube, and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 4.0 kN, tableting compression speed: 30.0 RPM, pre-compression pressure: 1.2 kN, main compression pressure: 6.5 kN

[0249] HPMC (4.4 wt%), talc (0.7 wt%), titanium oxide (1.5 wt%), triethyl citrate (0.7 wt%), and purified water (92.6 wt%) were mixed. The resulting solution was coated onto tablets using a film coating machine (product name: GTX-mini). The tablet coating conditions were the same as in Example 2-6-1, except that the inlet air temperature was changed to 68°C and the liquid delivery rate was changed to 1.0 g / min.

[0250] The obtained tablets were filled into airtight HDPE bottles, 15 tablets per bottle, and stored in a thermostatic chamber set at 40°C and 75% RH for one month. Samples packed with silica gel in HDPE bottles were also prepared and stored in the same manner. The stored tablets were added to an acetonitrile / water mixture (50:50 (v / v), 100 mL) and subjected to ultrasonic treatment for 15 minutes. After mixing, ultrasonic treatment was performed for another 15 minutes. After confirming the state of dissolution, 5 mL of the supernatant was filtered through a 0.20 μm PTFE filter, and the concentration of Compound 1 in the remaining filtrate was measured by HPLC after discarding 4 mL of the initial solution. The content of Compound 1 was calculated from the measured concentration of Compound 1 (measured value), and the percentage (%) of this measured value relative to the set value was calculated. The HPLC measurement conditions were the same as in Example 2-6-1.

[0251] The stored tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x concentration FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate (unit: μg / mL) was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0252] (Example 2-6-3) Compound 1 and each additive were mixed by inversion in a 100 mL plastic tube to obtain a mixed powder of Compound 1 hydrochloride monohydrate (22.9 wt%), SLS (10.0 wt%), mannitol (28.6 wt%), crystalline cellulose (25.0 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), crospovidone (8.0 wt%, trade name: Kollidon CL-SF, manufactured by BASF), and light anhydrous silicic acid (1.0 wt%) so that the labeled amount of Compound 1 per tablet was 30 mg (set value: 30 mg). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (0.5 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added, and the mixture was mixed by inversion in a 100 mL plastic tube, and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 4.0 kN, tableting compression speed: 30.0 RPM, pre-compression pressure: 1.2 kN, main compression pressure: 7.0 kN

[0253] HPMC (5.2 wt%), talc (0.7 wt%), titanium oxide (1.5 wt%), and purified water (92.6 wt%) were mixed. The resulting solution was coated onto tablets using a film coating machine GTX-mini. The tablet coating conditions were the same as in Example 2-6-1.

[0254] The resulting tablets were filled into airtight HDPE bottles, 15 tablets per bottle, and stored in a thermostatic chamber set at 40°C and 75% RH for one month. Samples packed in HDPE bottles with silica gel were also prepared and stored in the same manner. The stored tablets were added to an acetonitrile / water mixture (50:50 (v / v), 100 mL) and subjected to ultrasonic treatment for 15 minutes. After mixing, ultrasonic treatment was performed for another 15 minutes. After confirming the state of dissolution, 5 mL of the supernatant was filtered through a 0.20 μm PTFE filter, and the concentration of Compound 1 in the filtrate was measured by HPLC using the remaining filtrate after discarding 4 mL of the initial solution. The content of the monohydrate of the hydrochloride of Compound 1 was calculated from the measured concentration of Compound 1 (measured value), and the percentage (%) of this measured value relative to the set value was calculated. The HPLC measurement conditions were the same as in Example 2-6-1.

[0255] The stored tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0256] The results are shown in Tables 17 to 19 and Figures 14 to 16. For any combination of tablet formulation and coating formulation, no significant change was observed in the ratio of the measured content of the monohydrate of hydrochloride of Compound 1 to the set value, and as shown in Figures 14 to 16, no significant change was observed in dissolution properties either, suggesting that the tablets have good stability under heated and humidified conditions.

[0257] Effect of Wet Manufacturing Process (Example 2-7-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 100 mL plastic tube to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (22.9 wt%), SLS (10.0 wt%), mannitol (27.6 wt%), microcrystalline cellulose (28.0 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (1.0 wt%), and magnesium stearate (0.5 wt%). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (1.0 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added, and the mixture was mixed by inversion in a 100 mL plastic tube, and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 5.0 kN, tableting compression speed: 20.0 RPM, pre-compression pressure: 1.0 kN, main compression pressure: 8.0 kN

[0258] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x concentration FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0259] Example 2-7-2 The monohydrate of the hydrochloride of Compound 1 and each additive were mixed in a mortar to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (22.9 wt%), SLS (10.0 wt%), mannitol (27.6 wt%), crystalline cellulose (28.0 wt%, trade name: Ceolus PH-101), croscarmellose sodium (5.0 wt%), and light anhydrous silicic acid (1.0 wt%). The resulting mixed powder was granulated with water containing HPC (4.0 wt%) and vacuum dried overnight. The resulting granulated powder was dry-sized using a sieve (mesh opening 850 μm), and then magnesium stearate (1.5 wt%) was triturated with a portion of the resulting sized powder, followed by addition of the remaining sized powder. The mixture was then mixed by inversion in a 25 mL plastic tube and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Tableting compression speed: 30.0 RPM Pre-compression pressure: 1.5 kN Main compression pressure: 5.0 kN

[0260] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x concentration FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0261] As shown in FIG. 17, when the dissolution profiles of the tablets obtained by the dry manufacturing method (Example 2-7-1) and the wet manufacturing method (Example 2-7-2) were compared, no decrease in concentration was observed in either case, and the dissolution properties were good, but the dissolution properties of the tablets obtained by the dry manufacturing method were superior.

[0262] Formulation without surfactant (Example 2-8-1) Compound 1 hydrochloride monohydrate and each additive were mixed by inversion in a 25 mL plastic tube to obtain a mixed powder of Compound 1 hydrochloride monohydrate (22.9 wt%), mannitol (37.6 wt%), crystalline cellulose (28.0 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (1.0 wt%), and magnesium stearate (0.5 wt%). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. Magnesium stearate (1.0 wt%) was triturated with a portion of the obtained sized powder, and the remaining sized powder was added. The mixture was mixed by inversion in a 25 mL plastic tube and compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 5.0 kN, Tableting compression speed: 30.0 RPM, pre-compression pressure: 1.5 kN, main compression pressure: 6.0 kN

[0263] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 1-2-1.

[0264] Example 2-8-2: Compound 1 hydrochloride monohydrate and each additive were mixed in a mortar to obtain a mixed powder of Compound 1 hydrochloride monohydrate (22.9 wt%), mannitol (34.3 wt%), crystalline cellulose (31.3 wt%, trade name: Ceolus PH-101), croscarmellose sodium (5.0 wt%), and light anhydrous silicic acid (1.0 wt%). The resulting mixed powder was granulated with water containing HPC (4.0 wt%) and vacuum dried overnight. The resulting granulated powder was dry-sized using a sieve (mesh opening 850 μm), and then magnesium stearate (1.5 wt%) was triturated with a portion of the resulting sized powder. The remaining sized powder was added, and the mixture was mixed by inversion in a 25 mL plastic tube. The mixture was compressed using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablet production conditions were as follows. Tableting compression speed: 30.0 RPM Pre-compression pressure: 1.5 kN Main compression pressure: 4.5 kN

[0265] The resulting tablets were added to FaSSGF (480 mL) heated to 37.0 ° C. so that the concentration was 90 mg (as the weight of Compound 1) per vessel, and the mixture was stirred for 30 minutes at 50 rpm. After 15 minutes of stirring, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x concentration FaSSIF (120 mL) was added to the FaSSGF containing the tablets, and the pH was adjusted to 6.5 with aqueous NaOH. After a predetermined time had passed (immediately after (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min), the test solution was collected and filtered. The resulting filtrate was mixed 1:1 with DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0266] As shown in Figure 18, in the dry manufacturing process, no decrease in concentration was observed in either the tablet containing SLS (Example 2-7-1) or the tablet not containing SLS (Example 2-8-1), and the dissolution properties were good. Compared to the tablet containing SLS (Example 2-7-1), the dissolution profile of the tablet not containing SLS (Example 2-8-1) was gentler, so the tablet containing SLS had better dissolution properties.

[0267] As shown in FIG. 19, in the wet process, the dissolution profiles of the tablet containing SLS (Example 2-7-2) and the tablet not containing SLS (Example 2-8-2) were almost the same.

[0268] Effect of Solubilizer on Capsules (Example 3-1-1) The monohydrate of the hydrochloride of Compound 1 and SLS were weighed and mixed in a mortar to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (82.1 wt%) and SLS (17.9 wt%). The mixed powder was sieved through a sieve (500 μm mesh) to prepare a mixed powder, which was then filled into HPMC capsules (size 1). Six capsules were added to FaSSGF (480 mL) heated to 37.0°C and stirred at 50 rpm for 30 minutes. After stirring for 15 minutes, a test solution for measuring the concentration of Compound 1 was collected. Next, 5x FaSSIF (120 mL) was added to the FaSSGF containing the capsules, and the pH was adjusted to 6.5 with aqueous NaOH. After the elapse of a predetermined time (immediately (0 min), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min, and 240 min) from the preparation, the test solution was sampled and filtered. The obtained filtrate was mixed with a DMSO / EG solution (60:40 (v / v)) at a ratio of 1:1 to prepare a measurement sample, and the concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as those in Example 2-1-1.

[0269] Examples 3-1-2 to 3-1-3 The concentrations of Compound 1 were calculated in the same manner as in Example 3-1-1, except that the contents of Compound 1 and SLS were changed as shown in Table 20.

[0270] The results are shown in Table 20 and Figure 20. As shown in Figure 20, even in capsules, the monohydrate of the hydrochloride of Compound 1 showed higher solubility as the ratio (wt %) of SLS to the mixed powder increased.

[0271] Stability of Capsules (Example 3-2-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (24.3 wt%), SLS (10.2 wt%), crystalline cellulose (61.4 wt%, trade name: Ceolus PH-101), and light anhydrous silicic acid (4.1 wt%) so that the content of the monohydrate of the hydrochloride of Compound 1 per capsule was 15 mg (set value: 15 mg). The obtained mixed powder was filled into hydroxypropyl methylcellulose capsules (size 1) using a capsule filling machine (trade name: Xcelodose600S, manufactured by LONZA Corporation) to obtain capsules.

[0272] The resulting capsules were filled in 40 capsules per bottle, an airtight container made of HDPE, and stored in a thermostatic chamber set at 40°C and 75% RH for one month. Ten stored capsules were dissolved in an acetonitrile / water mixture (50 / 50 (v / v), 500 mL), then mixed with an acetonitrile / water mixture (50:50 (v / v)) at a ratio of 1:10, filtered, and the concentration of Compound 1 in the filtrate was measured by HPLC. The content of Compound 1 was calculated from the measured concentration of Compound 1 (measured value), and the percentage (%) of the measured value relative to the set value was calculated. The HPLC measurement conditions were the same as in Example 1-4-1.

[0273] The resulting capsules were added to FaSSIF (600 mL) heated to 37.0°C so that the concentration per vessel was 90 mg (as the weight of Compound 1), and the mixture was stirred at 50 rpm. After a predetermined time had elapsed since stirring (5, 10, 15, 30, 45, 60, 120, and 240 minutes), the test solution was filtered, and the resulting filtrate was mixed 1:1 with a DMSO / EG solution (60:40 (v / v)) to prepare a measurement sample. The concentration of Compound 1 in the filtrate was calculated by HPLC. The HPLC measurement conditions were the same as in Example 2-1-1.

[0274] Comparative Example 3-2-1 In Comparative Example 3-2-1, the sample was treated in the same manner as in Example 3-2-1 without being stored in a thermostatic chamber.

[0275] The results are shown in Table 21 and Figure 21. As shown in Figure 21, no significant change was observed in the ratio of the measured value to the set value for the capsules, and no significant change was observed in the dissolution properties, suggesting that the capsules have good stability under heated and humidified conditions.

[0276] Effect of Lubricant Amount (Example 4-1-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 25 mL plastic tube to obtain a mixed powder of monohydrate of the hydrochloride of Compound 1 (22.9 wt%), SLS (10.0 wt%), mannitol (27.6 wt%), crystalline cellulose (23.0 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (1.0 wt%), and magnesium stearate (0.5 wt%) so that the content of Compound 1 per tablet was 60 mg (set value: 60 mg). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. The obtained sized powder and crystalline cellulose (5.0 wt%, trade name: Ceolus PH-101) were mixed by inversion in a 25 mL plastic tube, and then magnesium stearate (1.0 wt%) was triturated with a portion of the mixed powder of the obtained sized powder and crystalline cellulose, and the remaining mixed powder was added and mixed by inversion in a 25 mL plastic tube. Tablets were compressed using a compression simulator HB100 to obtain oval-shaped tablets (major axis: 12.15 mm, minor axis: 6.42 mm). The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 8.0 kN Tableting compression speed: 20.0 RPM, pre-compression pressure: 1.8 kN, main compression pressure: 11.9 kN

[0277] The maximum value of the pressure (ejection force) applied to the lower punch when ejecting the tablet from the die during tableting was obtained using a compression simulator HB100. The ejection force was measured 17 times in total, and the average value was calculated.

[0278] Example 4-1-2: Compound 1 hydrochloride monohydrate and each additive were mixed by inversion in a 25 mL plastic tube to obtain a mixed powder of Compound 1 hydrochloride monohydrate (22.9 wt%), SLS (10.0 wt%), mannitol (27.4 wt%), microcrystalline cellulose (23.2 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (1.0 wt%), and magnesium stearate (0.5 wt%), so that the content of Compound 1 per tablet was 60 mg (set value: 60 mg). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. The obtained sized powder and crystalline cellulose (4.5 wt%, trade name: Ceolus PH-101) were mixed by inversion in a 25 mL plastic tube, and then magnesium stearate (1.5 wt%) was triturated with a portion of the mixed powder of the obtained sized powder and crystalline cellulose, and the remaining mixed powder was added and mixed by inversion in a 25 mL plastic tube. Tablets were compressed using a compression simulator HB100 to obtain oval-shaped tablets (major axis: 12.15 mm, minor axis: 6.42 mm). The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 8.0 kN, tableting compression speed: 20.0 RPM, pre-compression pressure: 1.6 kN, main compression pressure: 11.9 kN

[0279] In the same manner as in Example 4-1-1, the ejection force during tablet production was measured. The ejection force was measured 10 times in total, and the average value was calculated.

[0280] The results are shown in Figure 22. The ejection force was 0.183 kN when the magnesium stearate ratio in the composition was 1.5 wt% (Example 4-1-1). On the other hand, the ejection force was 0.154 kN when the magnesium stearate ratio was 2.0 wt% (Example 4-1-2). Thus, a 0.5 wt% increase in the magnesium stearate ratio resulted in a 16.0% decrease in the ejection force. It has been reported that a decrease in ejection force is positively correlated with a decrease in adhesion to the punch, and these results suggest that increasing the magnesium stearate ratio in the composition to 2.0 wt% would further reduce adhesion to the punch.

[0281] Effect of Concomitant Use of Lubricant (Example 4-2-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 100 mL plastic tube to obtain a mixed powder of monohydrate of the hydrochloride of Compound 1 (19.9 wt%), SLS (8.7 wt%), mannitol (23.8 wt%), crystalline cellulose (20.0 wt%, trade name: Ceolus PH-101), HPMC (4.1 wt%), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (0.9 wt%), and magnesium stearate (0.4 wt%) so that the content of Compound 1 per tablet was 60 mg (set value: 60 mg). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. The obtained sized powder and crystalline cellulose (16.2 wt%, trade name: Ceolus UF-711) were mixed by inversion in a 25 mL plastic tube, and then magnesium stearate (1.0 wt%) was triturated with a portion of the mixed powder of the obtained sized powder and crystalline cellulose, and the remaining mixed powder was added and mixed by inversion in a 25 mL plastic tube. Tablets were compressed using a compression simulator HB100 to obtain oval-shaped tablets (major axis: 12.15 mm, minor axis: 6.42 mm). The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 8.0 kN, tableting compression speed: 20.0 RPM, pre-compression pressure: 1.5 kN, main compression pressure: 10.0 kN

[0282] The ejection force during tablet production was measured a total of nine times, and the average value was calculated.

[0283] Example 4-2-2: The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 100 mL plastic tube to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (19.9 wt%), SLS (8.7 wt%), mannitol (23.8 wt%), microcrystalline cellulose (20.0 wt%, trade name: Ceolus PH-101), HPMC (4.1 wt%), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (0.9 wt%), and magnesium stearate (0.4 wt%) so that the content of Compound 1 per tablet was 60 mg (set value: 60 mg). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. The resulting sized powder and crystalline cellulose (15.2 wt%, trade name: Ceolus UF-711) were mixed by inversion in a 25 mL plastic tube, and then magnesium stearate (1.0 wt%) and sodium stearyl fumarate (1.0 wt%) were individually triturated with a portion of the resulting mixed powder of sized powder and crystalline cellulose, and the remaining mixed powder was added and mixed by inversion in a 25 mL plastic tube. Tablets were compressed using a compression simulator HB100 to obtain oval-shaped tablets (major axis: 12.15 mm, minor axis: 6.42 mm). The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 8.0 kN, tableting compression speed: 20.0 RPM, pre-compression pressure: 1.5 kN, main compression pressure: 10.7 kN

[0284] The ejection force during tablet production was measured a total of eight times, and the average value was calculated.

[0285] Example 4-2-3: The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 100 mL plastic tube to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (19.9 wt%), SLS (8.7 wt%), mannitol (23.8 wt%), microcrystalline cellulose (20.0 wt%, trade name: Ceolus PH-101), HPMC (4.1 wt%), croscarmellose sodium (5.0 wt%), light anhydrous silicic acid (0.9 wt%), and magnesium stearate (0.4 wt%), so that the content of Compound 1 per tablet was 60 mg (set value: 60 mg). The obtained mixed powder was dry granulated using a compression simulator HB100 and dry sized using a small-scale hand mill. The obtained sized powder and crystalline cellulose (13.2 wt%, trade name: Ceolus UF-711) were mixed by inversion in a 25 mL plastic tube, and then magnesium stearate (1.0 wt%) and sodium stearyl fumarate (3.0 wt%) were individually triturated with a portion of the obtained mixed powder of sized powder and crystalline cellulose, and the remaining mixed powder was added and mixed by inversion in a 25 mL plastic tube. Tablets were compressed using a compression simulator HB100 to obtain oval-shaped tablets (major axis: 12.15 mm, minor axis: 6.42 mm). The tablet manufacturing conditions were as follows: Dry granulation compression speed: 2.0 RPM, compression pressure: 8.0 kN, tableting compression speed: 20.0 RPM, pre-compression pressure: 1.4 kN, main compression pressure: 11.5 kN

[0286] The ejection force during tablet production was measured seven times in total, and the average value was calculated.

[0287] The results are shown in Figure 23. In Example 4-2-1, which used magnesium stearate (1.5 wt%) as the lubricant, the ejection force was 0.199 kN. In Example 4-2-2, which used magnesium stearate (1.5 wt%) and sodium stearyl fumarate (1.0 wt%) as the lubricant, the ejection force was 0.182 kN. The combined use of sodium stearyl fumarate (1.0 wt%) reduced the ejection force by 8.4%. In Example 4-2-3, which used magnesium stearate (1.5 wt%) and sodium stearyl fumarate (3.0 wt%), the ejection force was 0.156 kN. The combined use of sodium stearyl fumarate (3.0 wt%) reduced the ejection force by 21.8%. These results suggest that the combined use of magnesium stearate and sodium stearyl fumarate is also effective in reducing adhesion to the punch.

[0288] (Example 4-3-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed in a 25 mL plastic tube by inversion to obtain a mixed powder of the monohydrate of the hydrochloride of Compound 1 (24.4 wt%), SLS (10.6 wt%), mannitol (29.4 wt%), crystalline cellulose (24.5 wt%, trade name: Ceolus PH-101), HPMC (4.3 wt%), croscarmellose sodium (5.3 wt%), light anhydrous silicic acid (1.1 wt%), and magnesium stearate (0.5 wt%) so that the content of Compound 1 per tablet was 30 mg (set value: 30 mg). The obtained mixed powder was tableted using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. The tablets were produced by direct compression without a granulation process, and the production conditions were as follows. Tableting compression speed: 20.0 RPM Pre-compression pressure: 1.4 kN Main compression pressure: 7.8 kN

[0289] The ejection force during tablet production was measured seven times in total, and the average value was calculated.

[0290] (Example 4-3-2) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed in a 25 mL plastic tube by inversion to obtain a mixed powder of 30 mg of Compound 1 per tablet (set value: 30 mg), monohydrate of the hydrochloride of Compound 1 (24.4 wt%), SLS (10.6 wt%), mannitol (29.4 wt%), crystalline cellulose (21.3 wt%, trade name: Ceolus PH-101), HPMC (4.3 wt%), croscarmellose sodium (5.3 wt%), light anhydrous silicic acid (1.1 wt%), magnesium stearate (0.5 wt%), and sodium stearyl fumarate (3.2 wt%). The obtained mixed powder was tableted using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. This tablet was produced by direct compression without a granulation process, and the production conditions were as follows. Tableting compression speed: 20.0 RPM Pre-compression pressure: 1.4 kN Main compression pressure: 8.1 kN

[0291] The ejection force during tablet production was measured seven times in total, and the average value was calculated.

[0292] The results are shown in Figure 24. In Example 4-3-1, which contained magnesium stearate (0.5 wt%) in the composition, the ejection force was 0.327 kN. On the other hand, in Example 4-3-2, which used magnesium stearate (0.5 wt%) in combination with sodium stearyl fumarate (3.2 wt%), the ejection force was 0.165 kN, a 49.6% decrease in ejection force. These results suggest that the use of sodium stearyl fumarate in combination with magnesium stearate can further suppress adhesion to punches during production.

[0293] (Example 4-4-1) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 10 L SUS container so that the content of Compound 1 per tablet was 30 mg (set value: 30 mg), and a mixed powder of Compound 1 hydrochloride monohydrate (23.1 wt%), SLS (10.1 wt%), mannitol (27.9 wt%), crystalline cellulose (28.3 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), croscarmellose sodium (5.1 wt%), light anhydrous silicic acid (1.0 wt%), and magnesium stearate (0.5 wt%) was obtained. The obtained mixed powder was tableted using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. This tablet was produced by direct compression without a granulation process, and the production conditions were as follows. Tableting compression speed: 20.0 RPM Pre-compression pressure: 1.4 kN Main compression pressure: 8.1 kN

[0294] The ejection force during tablet production was measured. The ejection force was measured a total of 11 times, and the average value was calculated.

[0295] (Example 4-4-2) The monohydrate of the hydrochloride of Compound 1 and each additive were mixed by inversion in a 25 mL plastic tube so that the content of Compound 1 per tablet was 30 mg (set value: 30 mg), and a mixed powder of Compound 1 hydrochloride monohydrate (23.1 wt%), SLS (10.1 wt%), mannitol (22.8 wt%), crystalline cellulose (28.3 wt%, trade name: Ceolus PH-101), HPMC (4.0 wt%), croscarmellose sodium (5.1 wt%), light anhydrous silicic acid (1.0 wt%), magnesium stearate (0.5 wt%), and hydrogenated castor oil (5.1 wt%) was obtained. The obtained mixed powder was tableted using a compression simulator HB100 to obtain tablets with a diameter of 7.00 mm. This tablet was produced by direct compression without a granulation process, and the production conditions were as follows. Tableting compression speed: 20.0 RPM Pre-compression pressure: 1.6 kN Main compression pressure: 7.8 kN

[0296] The ejection force during tablet production was measured 20 times in total, and the average value was calculated.

[0297] The results are shown in Figure 25. In Example 4-4-1, which contained magnesium stearate (0.5 wt%) in the composition, the ejection force was 0.354 kN. On the other hand, in Example 4-4-2, which used hydrogenated castor oil (5.1 wt%) in combination with magnesium stearate (0.5 wt%), the ejection force was 0.237 kN, a 33.2% decrease in ejection force. These results suggest that the use of hydrogenated castor oil in combination with magnesium stearate can further suppress adhesion to the punch during production.

Claims

1. A composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a solubilizing agent:

2. The composition of claim 1, wherein the solubilizing agent is a surfactant or a polymer, and the polymer is not poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

3. The composition according to claim 1 or 2, wherein the solubilizing agent is a surfactant.

4. The composition according to any one of claims 1 to 3, wherein the content of the solubilizing agent is 0.1 to 250.0 wt % based on the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition.

5. A composition comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a disintegrant.

6. The composition according to claim 5, wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, starch, pregelatinized starch, agar, gelatin powder, calcium carbonate, sodium chloride, sodium bicarbonate, calcium citrate, anhydrous silicic acid, dextrin, pectin, carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate.

7. The composition of claim 5 or 6, wherein the disintegrant is croscarmellose sodium or crospovidone.

8. The composition according to any one of claims 5 to 7, wherein the content of the disintegrant is 0.1 to 80.0 wt % based on the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition.

9. A composition comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a lubricant.

10. The composition according to claim 9, wherein the lubricant is at least one selected from the group consisting of stearates, light anhydrous silicic acid, hydrogenated oils, sodium stearyl fumarate, shellac, talc, carnauba wax, and paraffin.

11. The composition of claim 9 or 10, wherein the lubricant is a stearate.

12. The composition according to any one of claims 9 to 11, wherein the content of the lubricant is 0.1 to 50.0 wt % based on the weight of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt contained in the composition.

13. The composition according to any one of claims 1 to 12, which is in solid form.

14. The composition according to any one of claims 1 to 13, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, is a monohydrate of the hydrochloride salt of the compound represented by formula (1).

15. A method for producing the composition according to any one of claims 1 to 14, comprising the step of mixing the compound represented by formula (1), the salt, or the solvate with at least one selected from the group consisting of a solubilizing agent, a disintegrant, and a lubricant.

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