Pharmaceutical composition containing pimitespib

Abstract

Provided is a pharmaceutical composition containing compound 1 and having excellent disintegrability and bioavailability.　This pharmaceutical composition contains crystalline cellulose and a granulated substance containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and has a disintegration time of 360 seconds or less in a coated tablet state.

Description

Pharmaceutical compositions containing pimitespib

[0001] The present invention relates to a pharmaceutical composition, particularly a pharmaceutical composition for oral administration, containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (hereinafter also referred to as "Compound 1") or a pharmaceutically acceptable salt thereof and crystalline cellulose, and a method for producing the same.

[0002] A group of proteins called molecular chaperones have multiple functions, such as promoting and maintaining the formation of functional structures of other proteins, promoting correct association, inhibiting unnecessary aggregation, protecting from degradation, and promoting secretion. HSP90 is a molecular chaperone that is abundant, accounting for approximately 1-2% of all soluble proteins in cells, but unlike other chaperone proteins, it is not required for the biosynthesis of most polypeptides (Non-Patent Document 1). Known major client proteins that interact with HSP90 and control its structural formation and stability include signal transduction-related factors (e.g., ERBB1 / EGFR, ERBB2 / HER2, MET, IGF1R, KDR / VEGFR, FLT3, ZAP70, KIT, CHUK / IKK, BRAF, RAF1, SRC, AKT), cell cycle regulatory factors (e.g., CDK4, CDK6, Cyclin D, PLK1, BIRC5), and transcription regulatory factors (e.g., HIF-1α, p53, androgen receptor, estrogen receptor, progesterone receptor) (Non-Patent Documents 2 and 3). HSP90 is deeply involved in cell proliferation and survival by maintaining the normal function of these proteins. Furthermore, mutant or chimeric factors (e.g., BCR-ABL, NPM-ALK) that cause canceration or aggravation of cancer require HSP90 for their normal function, demonstrating the importance of HSP90 in processes such as canceration, survival, proliferation, aggravation, and metastasis (Non-Patent Document 2).

[0003] Currently, several HSP90 inhibitors have been reported as antitumor agents, and Patent Document 1 discloses Compound 1, which has excellent HSP90 inhibitory activity and exhibits antitumor activity. Patent Documents 2 to 6 disclose uses of Compound 1 and its use in combination with other anticancer agents. Patent Document 7 discloses crystalline polymorphs of Compound 1.

[0004] Generally, pharmaceutical compositions for oral administration are required to have not only stability of the active ingredient but also excellent disintegrability and bioavailability upon oral administration. However, since there are a wide variety of means for solving the above problems depending on the structure and properties of the active ingredient, the type of formulation, etc., it is not easy to find an optimal formulation having excellent disintegrability and bioavailability.

[0005] International Publication No. WO 2011 / 004610, International Publication No. WO 2015 / 046498, International Publication No. WO 2019 / 004417, International Publication No. WO 2019 / 054465, International Publication No. WO 2019 / 220512, International Publication No. WO 2019 / 221086, International Publication No. WO 2016 / 181990

[0006] Nat. Rev. Cancer, 5:761-772 (2005) TRENDS Mol. Med. , 10:283-290 (2004) Clin Can Res 15, 9-14 (2009)

[0007] Compound 1 is a compound having excellent HSP90 inhibitory activity and antitumor activity. Therefore, the present invention relates to providing a pharmaceutical composition containing Compound 1, which has excellent disintegrability and bioavailability.

[0008] The present inventors have investigated various manufacturing methods for pharmaceutical compositions containing Compound 1 or a pharmaceutically acceptable salt thereof, and have also added various compounds to conduct various studies on the disintegration and bioavailability of Compound 1 or a pharmaceutically acceptable salt thereof, and have found that when Compound 1 is subjected to direct compression, it is prone to tableting problems such as sticking, which is thought to be attributable to the properties of Compound 1. As a result of further investigation, they have found that a pharmaceutical composition having excellent disintegration and bioavailability can be obtained by granulating Compound 1 or a pharmaceutically acceptable salt thereof, adding a predetermined crystalline cellulose to the granules, and then tableting the granules.

[0009] That is, the present invention relates to the following [1] to

[17] : [1] A pharmaceutical composition comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, the pharmaceutical composition having a disintegration time of 360 seconds or less in the form of a coated tablet. [2] A pharmaceutical composition obtained by mixing a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof with 20.0 to 55.0% by mass of crystalline cellulose, wherein the L / D ratio of the crystalline cellulose before mixing is 1.00 to 4.00 and / or the bulk density is 0.20 to 0.50 g / cm ３[3] A pharmaceutical composition comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and 20.0 to 55.0% by mass of a crystalline cellulose selected from the group consisting of Ceolus PH-102, PH-302, KG-802, and UF-711. [4] The pharmaceutical composition according to [2] or [3], wherein the content of the crystalline cellulose is 30.0 to 55.0% by mass. [5] The pharmaceutical composition according to any one of [2] to [4], which has a disintegration time of 180 seconds or less in the uncoated state, or a disintegration time of 360 seconds or less in the coated state. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the additives added to the granules other than microcrystalline cellulose are only additives selected from the group consisting of binders, lubricants, flow agents, colorants, flavoring agents, taste-correcting agents, sweeteners, glossing agents, and plasticizers. [7] The pharmaceutical composition according to any one of [1] to [5], wherein the additives added to the granules other than microcrystalline cellulose are only additives selected from the group consisting of lubricants. [8] The pharmaceutical composition according to any one of [1] to [7], comprising 18.0 to 40.0% by mass of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof. [9] The pharmaceutical composition according to any one of [1] to [8], wherein the granules are produced by a wet granulation method.

[10] The pharmaceutical composition according to any one of [1] to [9], wherein the average particle size (d50) of the granules is 50 to 400 μm.

[11] The pharmaceutical composition according to any one of [1] to

[10] , wherein the granules are in the form of a solid formulation, preferably a solid formulation for oral administration.

[12] The pharmaceutical composition according to

[11] , wherein the granules are in the form of a tablet.

[13] The pharmaceutical composition according to

[12] , wherein the granules have a diameter of 6.5 to 9.5 mm.

[14] A coating composition obtained by coating the pharmaceutical composition according to any one of [1] to

[13] .

[15] A process for granulating a powder containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof using a binding liquid; and producing a granule having an L / D ratio of 1.00 to 4.00 and / or a bulk density of 0.20 to 0.50 g / cm with respect to the granules obtained in the process. ３

[16] A method for producing the pharmaceutical composition according to

[15] , wherein the granulation method is fluidized bed granulation.

[17] A pharmaceutical composition produced by the method according to

[15] or

[16] .

[0010] The present invention also relates to the following items

[18] to

[54] .

[18] The pharmaceutical composition according to any one of items [1] to

[13] or the coating composition according to item

[14] , which is used for treating a tumor.

[19] Use of a pharmaceutical composition comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, the pharmaceutical composition having a disintegration time of 360 seconds or less in the form of a coated tablet, for the manufacture of a medicament for treating a tumor.

[20] A pharmaceutical composition for the manufacture of a medicament for treating a tumor, obtained by mixing a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof with 20.0 to 55.0% by mass of crystalline cellulose, wherein the L / D ratio of the crystalline cellulose before mixing is 1.00 to 4.00 and / or the bulk density is 0.20 to 0.50 g / cm. ３

[21] Use of a pharmaceutical composition comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and 20.0 to 55.0% by mass of a crystalline cellulose selected from the group consisting of Ceolus PH-102, PH-302, KG-802, and UF-711, for the manufacture of a medicament for treating a tumor.

[22] The use according to

[20] or

[21] , wherein the content of the crystalline cellulose in the pharmaceutical composition is 30.0 to 55.0% by mass.

[23] The use according to any one of

[20] to

[22] , wherein the pharmaceutical composition has a disintegration time of 180 seconds or less in the uncoated tablet state, or 360 seconds or less in the coated tablet state.

[24] The use according to any one of

[19] to

[23] , wherein the pharmaceutical composition contains 18.0 to 40.0 mass% of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof.

[25] The use according to any one of

[19] to

[24] , wherein the granules are produced by a wet granulation method.

[26] The use according to any one of

[19] to

[25] , wherein the average particle size (d50) of the granules is 50 to 400 μm.

[27] The use according to any one of

[19] to

[26] , wherein the pharmaceutical composition is a solid formulation, preferably a solid formulation for oral administration.

[28] The use according to any one of

[19] to

[27] , wherein the pharmaceutical composition is a tablet.

[29] The use according to

[28] , wherein the tablet has a diameter of 6.5 to 9.5 mm.

[30] The use according to any one of

[19] to

[29] , wherein the pharmaceutical composition is a coating composition obtained by coating a pharmaceutical composition.

[31] A pharmaceutical composition for use in treating a tumor, comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and crystalline cellulose, the pharmaceutical composition having a disintegration time of 360 seconds or less in the form of a coated tablet.

[32] A pharmaceutical composition for use in treating a tumor, obtained by mixing a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof with 20.0 to 55.0% by mass of crystalline cellulose, wherein the L / D ratio of the crystalline cellulose before mixing is 1.00 to 4.00 and / or the bulk density is 0.20 to 0.50 g / cm. ３

[33] A pharmaceutical composition for use in treating a tumor, comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and 20.0 to 55.0% by mass of a crystalline cellulose selected from the group consisting of Ceolus PH-102, PH-302, KG-802, and UF-711.

[34] The pharmaceutical composition according to

[32] or

[33] , wherein the content of the crystalline cellulose is 30.0 to 55.0% by mass.

[35] The pharmaceutical composition according to any of

[32] to

[34] , which has a disintegration time of 180 seconds or less in the uncoated state, or a disintegration time of 360 seconds or less in the coated state.

[36] The pharmaceutical composition according to any one of

[31] to

[35] , which contains 18.0 to 40.0% by mass of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof.

[37] The pharmaceutical composition according to any one of

[31] to

[36] , wherein the granule is produced by a wet granulation method.

[38] The pharmaceutical composition according to any one of

[31] to

[37] , wherein the average particle size (d50) of the granule is 50 to 400 μm.

[39] The pharmaceutical composition according to any one of

[31] to

[38] , which is a solid formulation, preferably a solid formulation for oral administration.

[40] The pharmaceutical composition according to any one of

[31] to

[39] , which is a tablet.

[41] The pharmaceutical composition according to

[40] , which has a diameter of 6.5 to 9.5 mm.

[42] The pharmaceutical composition according to any one of

[31] to

[41] , which is a coating composition obtained by coating a pharmaceutical composition.

[43] A method for treating a tumor, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, the pharmaceutical composition having a disintegration time of 360 seconds or less in the form of a coated tablet.

[44] A method for treating a tumor, comprising administering to a subject in need thereof a pharmaceutical composition obtained by mixing a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof with 20.0 to 55.0% by mass of crystalline cellulose, wherein the L / D ratio of the crystalline cellulose before mixing is 1.00 to 4.00 and / or the bulk density is 0.20 to 0.50 g / cm. ３

[45] A method for treating a tumor, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and 20.0 to 55.0% by mass of a crystalline cellulose selected from the group consisting of Ceolus PH-102, PH-302, KG-802, and UF-711.

[46] The method according to

[44] or

[45] , wherein the content of the crystalline cellulose in the pharmaceutical composition is 30.0 to 55.0% by mass.

[47] The method according to any one of

[44] to

[46] , wherein the pharmaceutical composition has a disintegration time of 180 seconds or less in the uncoated tablet state, or 360 seconds or less in the coated tablet state.

[48] The method according to any one of

[43] to

[47] , wherein the pharmaceutical composition contains 18.0 to 40.0 mass% of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof.

[49] The method according to any one of

[43] to

[48] , wherein the granules are produced by a wet granulation method.

[50] The method according to any one of

[43] to

[49] , wherein the average particle size (d50) of the granules is 50 to 400 μm.

[51] The method according to any one of

[43] to

[50] , wherein the pharmaceutical composition is a solid formulation, preferably a solid formulation for oral administration.

[52] The method according to any one of

[43] to

[51] , wherein the pharmaceutical composition is a tablet.

[53] The method according to

[52] , wherein the tablet has a diameter of 6.5 to 9.5 mm.

[54] The method according to any one of

[43] to

[53] , wherein the pharmaceutical composition is a coating composition obtained by coating a pharmaceutical composition.

[0011] According to the present invention, it is possible to provide a pharmaceutical composition containing Compound 1 or a pharmaceutically acceptable salt thereof, which has excellent disintegrability and bioavailability and is free from tableting problems such as sticking.

[0012] 1 shows the results of measuring the bulk density and major axis / minor axis ratio of various crystalline celluloses. 2 shows the results of an absorption experiment in dogs.

[0013] The pharmaceutical composition and its manufacturing method according to the present invention will be described below. However, the pharmaceutical composition and its manufacturing method according to the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0014] [Pharmaceutical Composition] The pharmaceutical composition of the present invention is a pharmaceutical composition comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (Compound 1) or a pharmaceutically acceptable salt thereof, and a specific crystalline cellulose. In the present invention, 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide, also known as pimitespib, is a compound having the following structure:

[0015]

[0016] Compound 1 or a pharmaceutically acceptable salt thereof is a known compound, and can be synthesized, for example, according to the method described in Patent Document 1 (WO 2011 / 004610).

[0017] When Compound 1 exists as isomers such as optical isomers, stereoisomers, rotamers, and tautomers, unless otherwise specified, all isomers and mixtures thereof are encompassed by Compound 1. Furthermore, Compound 1 or a pharmaceutically acceptable salt thereof may be a solvate (e.g., a hydrate) or a non-solvate, and in the present invention, both are encompassed by "Compound 1 or a pharmaceutically acceptable salt thereof."

[0018] "Pharmaceutically acceptable salts" refers to salts having the desired pharmacological activity of a compound, prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Examples of pharmaceutically acceptable salts of Compound 1 include, but are not limited to, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid, salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium and magnesium, and salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts.

[0019] Direct compression is the simplest tableting method, but when Compound 1 was tableted using this method, tableting problems likely due to the properties of Compound 1 occurred. As a solution, granulation followed by tableting was investigated. Because the properties of each compound differ, it is difficult to determine which method can be implemented for each compound, and it is not easy to find the optimal tableting method. However, by granulating Compound 1 or a pharmaceutically acceptable salt thereof, adding a specific crystalline cellulose to the granules, and then tableting, the above-mentioned problems were overcome, as shown in the examples below, and tablets with excellent disintegrability were provided. In the present invention, the granules containing Compound 1 or a pharmaceutically acceptable salt thereof are not particularly limited and may be wet granulated or dry granulated. Since dry granulation does not use a binder, it has the advantage of being able to granulate water-labile drugs, but the tablets tend to be large. Therefore, from the perspective of producing tablets as small as possible, it is preferable that the granules containing Compound 1 or a pharmaceutically acceptable salt thereof be wet granulated.

[0020] The granules containing Compound 1 or a pharmaceutically acceptable salt thereof of the present invention may contain active ingredients other than Compound 1 or a pharmaceutically acceptable salt thereof, or additives commonly used in pharmaceutical formulations, as long as the effects of the present invention are achieved. Preferably, the granules contain only Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient. The content of the additives can be appropriately determined within a range that does not impair the object of the present invention. Examples of additives contained in the granules include excipients, binders, disintegrants, fluidizers, solubilizers, etc. Examples of excipients used in the granules include sugar alcohols such as D-mannitol, erythritol, D-sorbitol, and xylitol, trehalose hydrate, β-cyclodextrin, corn starch, sucrose, lactose, crystalline cellulose, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc. Among these, lactose, D-mannitol, crystalline cellulose, corn starch, or a combination thereof is preferred, and lactose, corn starch, or a combination thereof is more preferred. Examples of binders in the granules include hydroxypropyl cellulose, hypromellose, povidone, polyvinyl alcohol, etc. Among these, hydroxypropyl cellulose, povidone, or a combination thereof is preferred, and hydroxypropyl cellulose is more preferred.

[0021] A preferred embodiment of the granules of the present invention containing Compound 1 or a pharmaceutically acceptable salt thereof is a granule containing Compound 1 or a pharmaceutically acceptable salt thereof and one or more additives selected from lactose, D-mannitol, crystalline cellulose, corn starch, hydroxypropyl cellulose, and povidone, more preferably a granule containing Compound 1 or a pharmaceutically acceptable salt thereof and one or more additives selected from lactose, corn starch, and hydroxypropyl cellulose, and particularly preferably a granule containing Compound 1 or a pharmaceutically acceptable salt thereof, lactose, corn starch, and hydroxypropyl cellulose. Another preferred embodiment of the granules containing Compound 1 or a pharmaceutically acceptable salt thereof of the present invention is a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient and containing one or more additives selected from lactose, D-mannitol, crystalline cellulose, corn starch, hydroxypropyl cellulose, and povidone, more preferably a granule consisting of Compound 1 or a pharmaceutically acceptable salt thereof and one or more additives selected from lactose, D-mannitol, crystalline cellulose, corn starch, hydroxypropyl cellulose, and povidone, more preferably a granule consisting of Compound 1 or a pharmaceutically acceptable salt thereof and one or more additives selected from lactose, corn starch, and hydroxypropyl cellulose, and particularly preferably a granule consisting of Compound 1 or a pharmaceutically acceptable salt thereof, lactose, corn starch, and hydroxypropyl cellulose.

[0022] In the pharmaceutical composition of the present invention, the content of Compound 1 or a pharmaceutically acceptable salt thereof is preferably 18.0 to 40.0% by mass, more preferably 20.0 to 32.0% by mass, more preferably 20.0 to 29.0% by mass, even more preferably 26.0 to 29.0% by mass, particularly preferably 26.0 to 27.0% by mass, and most preferably 26.7% by mass, based on 100.0% by mass of the total amount of the pharmaceutical composition, in terms of dissolution property, stability, absorbability, ease of operation in mass production, and the like.

[0023] The average particle size of the granules containing Compound 1 or a pharmaceutically acceptable salt thereof in the present invention is not particularly limited as long as the effects of the present invention are achieved. However, if the average particle size is too small, it may affect the properties of the tablet and may cause tableting problems such as sticking, and if the average particle size is too large, it may cause variations in the content of the tablet. A preferred average particle size is the median size (particle size at which the cumulative frequency is 50%: d ５０ ) is 50 to 400 μm, more preferably 50 to 300 μm, more preferably 50 to 250 μm, more preferably 50 to 200 μm, more preferably 60 to 180 μm, more preferably 60 to 150 μm, and particularly preferably 80 to 120 μm. The median diameter of the granulated product can be measured by known measuring means, for example, by a sieving method or a laser diffraction particle size distribution measurement method (wet or dry).

[0024] As described in the Examples below, lactose, crystalline cellulose, and D-mannitol, which are excipients commonly used in pharmaceutical formulations, were compared as excipients to be added in addition to granules containing Compound 1 or a pharmaceutically acceptable salt thereof, and it was found that a specific crystalline cellulose was preferable from the viewpoints of tablet hardness, moldability, and disintegration. In particular, its disintegration property was excellent. Therefore, in the pharmaceutical composition of the present invention, crystalline cellulose is included as an excipient to be added in addition to the granules.

[0025] In the present invention, the crystalline cellulose added outside the granules preferably has a bulk density of 0.20 to 0.50 g / cm ３ The bulk density of the crystalline cellulose is 0.20 to 0.44 g / cm from the viewpoint of disintegration. ３ More preferably, it is 0.25 to 0.44 g / cm ３ Particularly preferred is a bulk density of 0.20 to 0.50 g / cm ３As the crystalline cellulose, commercially available products can be used, specifically Ceolus (registered trademark) PH-102, PH-302, KG-802, UF-711 (all manufactured by Asahi Kasei Corporation), etc. are usable. As the type of crystalline cellulose, Ceolus PH-102, PH-302, KG-802, and UF-711 are preferred, Ceolus PH-102 and PH-302 are more preferred, and Ceolus PH-102 is particularly preferred. The term "bulk density" refers to the density when a container of a certain volume is filled to the brim with powder and the internal volume is taken as the volume, and can be measured by the bulk density and tap density measurement method specified in the Japanese Pharmacopoeia. Measurement of bulk density can vary somewhat depending on the measurement conditions, such as humidity during measurement. Therefore, the numerical value should not be interpreted strictly. Therefore, in this specification, the numerical value of bulk density is ±0.08 g / cm. ３ There may be a measurement error within a certain range.

[0026] In the present invention, the "L / D ratio" refers to the ratio of the major axis to the minor axis of a crystalline cellulose particle. For example, the L / D ratio can be determined by measuring the major axis and minor axis of 50 particles using an electron microscope (VHX-D500, manufactured by Keyence Corporation) and calculating the ratio of the average values. In this specification, the numerical values ​​of the L / D ratio may have a measurement error within a range of about ±5%.

[0027] In the present invention, the crystalline cellulose added outside the granules is preferably crystalline cellulose having an L / D ratio of 1.00 to 4.00. From the viewpoint of disintegration property, the L / D ratio of the crystalline cellulose is more preferably 1.00 to 3.50, more preferably 1.50 to 3.50, more preferably 1.62 to 3.50, and particularly preferably 1.62 to 3.15. As the crystalline cellulose having an L / D ratio of 1.00 to 4.00, commercially available products can be used, specifically Ceolus (registered trademark) PH-102, PH-302, KG-802, UF-711 (all manufactured by Asahi Kasei Corporation), etc. As the type of crystalline cellulose, Ceolus PH-102, PH-302, KG-802, and UF-711 are preferred, Ceolus PH-102 and PH-302 are more preferred, and Ceolus PH-102 is particularly preferred.

[0028] In the pharmaceutical composition of the present invention, the content of microcrystalline cellulose added outside the granules is preferably 20.0 to 55.0% by mass, more preferably 30.0 to 55.0% by mass, even more preferably 35.0 to 55.0% by mass, even more preferably 35.0 to 36.0% by mass, and particularly preferably 35.2% by mass, based on 100.0% by mass of the total amount of the pharmaceutical composition, from the viewpoint of disintegrability.

[0029] The pharmaceutical composition of the present invention may contain additives other than microcrystalline cellulose that are commonly used in pharmaceutical formulations, as long as they achieve the effects of the present invention. The additives added in addition to the granules other than microcrystalline cellulose are not particularly limited as long as they are commonly used in pharmaceutical formulations, and examples thereof include excipients other than microcrystalline cellulose, binders, disintegrants, lubricants, flow agents, colorants, flavoring agents, flavoring agents, sweeteners, glossing agents, plasticizers, etc. Here, examples of excipients and binders include those described above. Examples of disintegrants include low-substituted hydroxypropyl cellulose, carmellose, corn starch, carmellose sodium, croscarmellose sodium, carmellose calcium, partially pregelatinized starch, crospovidone, etc. Among these, croscarmellose sodium, carmellose calcium, partially pregelatinized starch, crospovidone, or a combination thereof is preferred, with croscarmellose sodium being particularly preferred. Examples of lubricants include hydrogenated oils, sucrose fatty acid esters, sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, and stearic acid. Of these, magnesium stearate, stearic acid, or a combination thereof is preferred, with magnesium stearate being particularly preferred. Examples of colorants include food yellow No. 5, food blue No. 2, food lake color, iron sesquioxide, yellow iron sesquioxide, and titanium oxide. Of these, titanium oxide is preferred. Examples of flow agents include light anhydrous silicic acid, hydrated silicon dioxide, talc, and magnesium stearate.A preferred embodiment of the additives other than crystalline cellulose that are added outside the granules in the pharmaceutical composition of the present invention is that they do not contain any excipients other than crystalline cellulose (i.e., the only excipient added outside the granules is crystalline cellulose), specifically, that they contain only additives selected from the group consisting of binders, disintegrants, lubricants, flow agents, colorants, flavorings, corrigents, sweeteners, glazing agents, and plasticizers, and more preferably, they do not contain any excipients or disintegrants other than crystalline cellulose, specifically, they contain only additives selected from the group consisting of binders, lubricants, flow agents, colorants, flavorings, corrigents, sweeteners, glazing agents, and plasticizers, and particularly preferably, they contain only lubricants.

[0030] The pharmaceutical composition of the present invention can take various forms, but is preferably in the form of a solid preparation, and more preferably in the form of a solid preparation for oral administration. Examples of solid preparations include tablets (including plain tablets, orally disintegrating tablets, chewable tablets, etc.), capsules (including soft capsules, hard capsules, etc.), granules, powders, and pills, and tablets are preferred, and plain tablets are particularly preferred.

[0031] The pharmaceutical composition of the present invention is intended for use as an antitumor agent and is a highly active substance. From the standpoint of hazard prevention and ease of administration, it is preferable to form a coated composition by applying a coating to the surface of the pharmaceutical composition of the present invention. The coating is not particularly limited as long as it prevents the active ingredient in the uncoated tablet from being exposed on the surface, and includes film coating and sugar coating, etc., with film coating being preferred. An uncoated tablet refers to a tablet that has not been coated on its surface after compression, while a coated tablet refers to a tablet that has been coated on its surface. Examples of coating bases include hypromellose, ethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, sucrose, etc. Among these, hypromellose, polyethylene glycol, or a combination thereof are preferred. Furthermore, a coating additive may be used for the coating. Examples of coating additives include a light-blocking agent, a fluidizing agent, a colorant, a flavoring agent, a plasticizer, etc.

[0032] Since Compound 1 has excellent HSP90 inhibitory activity and antitumor activity, the pharmaceutical composition of the present invention is useful as a pharmaceutical composition for preventing or treating tumors. The tumor is a tumor against which Compound 1 or a pharmaceutically acceptable salt thereof exhibits an antitumor effect, more preferably a malignant tumor in which HSP90 is involved. Specific examples of the tumor include head and neck cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder / bile duct cancer, etc.), pancreatic cancer, small intestine cancer, large intestine cancer (colorectal cancer, colon cancer, rectal cancer, etc.), gastrointestinal stromal tumor, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer), breast cancer, ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.), kidney cancer, bladder cancer, prostate cancer, skin cancer, etc.

[0033] The size of pharmaceutical compositions for oral administration is a major problem for elderly people with impaired swallowing function, and providing small, easy-to-take formulations can contribute to improving compliance in elderly people. On the other hand, to achieve excellent disintegrability and tablet hardness, it is necessary to add sufficient excipients, binders, disintegrants, lubricants, etc. depending on the characteristics of the active ingredient. Therefore, it is difficult to achieve excellent disintegrability and tablet hardness while miniaturizing tablets. Generally, a diameter of 10 mm requires consideration of the subject's swallowing function, and a diameter of 6 mm is considered too small for elderly people to handle ( Journal of the Japanese Geriatrics Society, Vol. 44, No. 5, pp. 627-633 (2007:9)). Based on the above, the diameter of the pharmaceutical composition of the present invention is preferably 6.5 to 9.5 mm, more preferably 7.0 to 9.0 mm, and particularly preferably 7.0 to 8.0 mm, from the standpoints of ease of administration and ease of gripping. In the present invention, "diameter" refers to the general diameter in the case of round tablets, and the major axis in the case of oval or other elliptical shapes. The diameter of the tablet can be measured by a commonly known measuring method.

[0034] Furthermore, the disintegration time of the pharmaceutical composition of the present invention is preferably within 180 seconds, more preferably within 120 seconds, for uncoated tablets. It is preferably within 360 seconds, more preferably within 300 seconds, for coated tablets. As will be described in the Examples below, such excellent disintegration time can be achieved by incorporating a specific amount of a specific crystalline cellulose in addition to the granules of the present invention. The "disintegration time" can be measured, for example, by the disintegration test method specified in the Japanese Pharmacopoeia. Depending on the dosage form being measured, it can also be measured by the disintegration test method for tablets or coating agents specified in the Japanese Pharmacopoeia. More specifically, it can be measured using a disintegration tester, with the test liquid being water (37±2°C) and no disc, as the time from when the tablet is placed in the tester to when it completely disintegrates. A preferred embodiment of the disintegration time of the pharmaceutical composition of the present invention is that the disintegration time measured by the disintegration test method specified in the Japanese Pharmacopoeia is preferably within 180 seconds, more preferably within 120 seconds, for uncoated tablets. The disintegration time measured by the disintegration test method specified in the Japanese Pharmacopoeia is preferably within 360 seconds, more preferably within 300 seconds, for coated tablets. In another preferred embodiment of the disintegration time of the pharmaceutical composition of the present invention, the disintegration time measured using a disintegration tester with a test liquid of water (37±2°C) and no disk as the time from when the tablet is placed into the tester to when the tablet completely disintegrates is preferably within 180 seconds, more preferably within 120 seconds, in the form of an uncoated tablet. The disintegration time measured using a disintegration tester with a test liquid of water (37±2°C) and no disk as the time from when the tablet is placed into the tester to when the tablet completely disintegrates is preferably within 360 seconds, more preferably within 300 seconds, in the form of a coated tablet.

[0035] Furthermore, from the viewpoint of moldability and the possibility of defects during transportation, the hardness of the pharmaceutical composition of the present invention is 50 N or more, preferably 60 N or more, more preferably 70 N or more, and even more preferably 80 N or more. "Hardness" is a standard known in the pharmaceutical field, and in the case of tablets, for example, it can be measured using a tablet hardness tester (e.g., PC-30, manufactured by Okada Seiko Co., Ltd., 8M, Schleuniger) by clamping the tablet from the side with the device and gradually applying pressure, and the load (N) at the time the tablet breaks can be measured.

[0036] The pharmaceutical composition of the present invention has excellent disintegrability, and therefore exhibits sufficient bioavailability in the patient's body to exert its medicinal effects. Here, "bioavailability" is an index indicating how much of an administered drug circulates throughout the body, and refers to the proportion of Compound 1 circulating throughout the body from a pharmaceutical composition containing orally administered Compound 1. Bioavailability can be measured, for example, by absorbability in dog pharmacokinetics, as shown in the Examples below.

[0037] A preferred embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a granule containing Compound 1 or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, which has a disintegration time of 360 seconds or less in the form of a coated tablet; more preferably, a pharmaceutical composition comprising a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and microcrystalline cellulose, but containing no excipients other than microcrystalline cellulose as additives other than microcrystalline cellulose added outside the granules, which has a disintegration time of 360 seconds or less in the form of a coated tablet; more preferably, a pharmaceutical composition comprising a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and containing one or more additives selected from lactose, D-mannitol, microcrystalline cellulose, corn starch, hydroxypropyl cellulose, and povidone, and microcrystalline cellulose, but containing no excipients other than microcrystalline cellulose as additives other than microcrystalline cellulose added outside the granules, which has a disintegration time of 360 seconds or less in the form of a coated tablet; Particularly preferred is a pharmaceutical composition comprising a granule of Compound 1 or a pharmaceutically acceptable salt thereof, lactose, corn starch, and hydroxypropyl cellulose, crystalline cellulose, and a lubricant, which has a disintegration time of 360 seconds or less in the form of a coated tablet.

[0038] A preferred embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a granule containing Compound 1 or a pharmaceutically acceptable salt thereof and crystalline cellulose, wherein the disintegration time of the coated tablet, as measured by the disintegration test method specified in the Japanese Pharmacopoeia, is 360 seconds or less; more preferred is a pharmaceutical composition comprising a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient and crystalline cellulose, and containing no excipients other than crystalline cellulose as additives other than crystalline cellulose added outside the granules, wherein the disintegration time of the coated tablet, as measured by the disintegration test method specified in the Japanese Pharmacopoeia, is 360 seconds or less; more preferred is a pharmaceutical composition comprising a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient and one or more additives selected from lactose, D-mannitol, crystalline cellulose, corn starch, hydroxypropyl cellulose, and povidone, and crystalline cellulose, and containing no excipients other than crystalline cellulose as additives other than crystalline cellulose added outside the granules, wherein the disintegration time of the coated tablet, as measured by the disintegration test method specified in the Japanese Pharmacopoeia, is 360 seconds or less; Particularly preferred is a pharmaceutical composition comprising a granule of Compound 1 or a pharmaceutically acceptable salt thereof, lactose, corn starch, and hydroxypropyl cellulose, and crystalline cellulose and a lubricant, wherein the disintegration time of the coated tablet is within 360 seconds as measured by the disintegration test method specified in the Japanese Pharmacopoeia.

[0039] A preferred embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a granule containing Compound 1 or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, wherein the disintegration time measured using a disintegration tester in a test liquid of water (37±2°C) without a disk as the time from when the tablet is put into the tester to when it completely disintegrates is within 360 seconds in the form of a coated tablet; and more preferably a pharmaceutical composition comprising a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient and microcrystalline cellulose, and wherein the disintegration time measured using a disintegration tester in a test liquid of water (37±2°C) without a disk as the time from when the tablet is put into the tester to when it completely disintegrates is within 360 seconds in the form of a coated tablet. More preferably, it is a pharmaceutical composition comprising only Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, and one or more additives selected from lactose, D-mannitol, microcrystalline cellulose, corn starch, hydroxypropyl cellulose, and povidone, and microcrystalline cellulose, but no excipients other than microcrystalline cellulose as additives other than microcrystalline cellulose added outside the granules, wherein the disintegration time measured in a disintegration tester using water (37±2°C) in the absence of a disc as the time from introduction into the tester to complete disintegration of the tablet is within 360 seconds in the state of a coated tablet; and particularly preferably, it is a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, lactose, corn starch, and hydroxypropyl cellulose, and microcrystalline cellulose and a lubricant, wherein the disintegration time measured in a disintegration tester using water (37±2°C) in the absence of a disc as the time from introduction into the tester to complete disintegration of the tablet is within 360 seconds in the state of a coated tablet.

[0040] Another preferred embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition obtained by mixing a granule containing Compound 1 or a pharmaceutically acceptable salt thereof with 20.0 to 55.0% by mass of crystalline cellulose, wherein the L / D ratio of the crystalline cellulose before mixing is 1.00 to 4.00 and / or the bulk density is 0.20 to 0.50 g / cm ３ and more preferably, a pharmaceutical composition obtained by mixing a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient with 20.0 to 55.0% by mass of crystalline cellulose, wherein the L / D ratio of the crystalline cellulose before mixing is 1.00 to 4.00 and / or the bulk density is 0.20 to 0.50 g / cm. ３ and does not contain any excipients other than crystalline cellulose as additives other than crystalline cellulose added outside the granules, more preferably a pharmaceutical composition obtained by mixing a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient and containing one or more additives selected from lactose, D-mannitol, crystalline cellulose, corn starch, hydroxypropyl cellulose, and povidone with 20.0 to 55.0% by mass of crystalline cellulose, wherein the L / D ratio of the crystalline cellulose before mixing is 1.00 to 4.00 and / or the bulk density is 0.20 to 0.50 g / cm ３ and does not contain any excipient other than crystalline cellulose as an additive other than crystalline cellulose added outside the granules, and particularly preferably a pharmaceutical composition obtained by mixing only a granule consisting of Compound 1 or a pharmaceutically acceptable salt thereof, lactose, corn starch, and hydroxypropyl cellulose with 20.0 to 55.0% by mass of crystalline cellulose and a lubricant, wherein the L / D ratio of the crystalline cellulose before mixing is 1.00 to 4.00 and / or the bulk density is 0.20 to 0.50 g / cm ３ The pharmaceutical composition is

[0041] Another preferred embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a granule containing Compound 1 or a pharmaceutically acceptable salt thereof and 20.0 to 55.0% by mass of one or more crystalline celluloses selected from the group consisting of Ceolus PH-102, PH-302, KG-802 and UF-711, more preferably a pharmaceutical composition comprising a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient and 20.0 to 55.0% by mass of one or more crystalline celluloses selected from the group consisting of Ceolus PH-102, PH-302, KG-802 and UF-711, which does not contain any excipients other than crystalline cellulose as additives other than crystalline cellulose added outside the granules, More preferably, the pharmaceutical composition comprises a granule containing only Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, and containing one or more additives selected from lactose, D-mannitol, crystalline cellulose, corn starch, hydroxypropyl cellulose, and povidone, and 20.0 to 55.0% by mass of one or more crystalline celluloses selected from the group consisting of Ceolus PH-102, PH-302, KG-802, and UF-711, and the pharmaceutical composition does not contain any excipient other than crystalline cellulose as an additive other than crystalline cellulose added outside the granule. Particularly preferred is a pharmaceutical composition comprising a granule consisting of Compound 1 or a pharmaceutically acceptable salt thereof, lactose, corn starch, and hydroxypropyl cellulose, and 20.0 to 55.0% by mass of one or more crystalline celluloses selected from the group consisting of Ceolus PH-102, PH-302, KG-802, and UF-711, and a lubricant.

[0042] [Method for Producing Pharmaceutical Composition] The pharmaceutical composition of the present invention can be preferably obtained by a production method comprising the steps of granulating a powder containing Compound 1 or a pharmaceutically acceptable salt thereof using a binder liquid, and mixing the granulated product obtained in the previous step with microcrystalline cellulose so that the content of the microcrystalline cellulose in the pharmaceutical composition is 20.0 to 55.0% by mass. The powder containing Compound 1 or a pharmaceutically acceptable salt thereof may contain active ingredients other than Compound 1 or a pharmaceutically acceptable salt thereof, as well as additives commonly used in pharmaceutical formulations as described above. Granulation methods used in the present invention include, for example, wet granulation methods such as fluidized bed granulation, agitation granulation, tumbling fluidized bed granulation, extrusion granulation, spray granulation, and crushing granulation. Of these, fluidized bed granulation is preferred. The binder liquid used in granulation is preferably a solution prepared by dissolving or dispersing the aforementioned binder in water. After granulation, the resulting granules may be dried, or the particle size of the granules may be adjusted using a sizer or the like.

[0043] Next, the obtained granules are mixed with crystalline cellulose. The crystalline cellulose is as described above. The mixing ratio of the granules and crystalline cellulose is such that the content of crystalline cellulose in the pharmaceutical composition is 20.0 to 55.0% by mass, preferably 30.0 to 55.0% by mass, more preferably 35.0 to 55.0% by mass, even more preferably 35.0 to 36.0% by mass, and particularly preferably 35.2% by mass, based on 100.0% by mass of the total pharmaceutical composition. Furthermore, the content of Compound 1 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is preferably 18.0 to 40.0% by mass, more preferably 20.0 to 32.0% by mass, even more preferably 20.0 to 29.0% by mass, even more preferably 26.0 to 29.0% by mass, particularly preferably 26.0 to 27.0% by mass, and most preferably 26.7% by mass, based on 100.0% by mass of the total pharmaceutical composition.

[0044] In this manner, a pharmaceutical composition containing granules containing Compound 1 or a pharmaceutically acceptable salt thereof and 20.0 to 55.0% by mass of crystalline cellulose can be obtained. The pharmaceutical composition can also be administered as granules, powder, or the like. Furthermore, when the pharmaceutical composition is formulated as a tablet, it can be produced, for example, by mixing the granules with crystalline cellulose and then tableting. Tableting is performed using a known tablet press, with appropriate adjustment of the tableting pressure and other factors so that the resulting tablets have appropriate hardness and can rapidly disintegrate as a pharmaceutical composition. Examples of tablet presses that can be used include rotary tablet presses, single-punch tablet presses, and hydraulic presses. Furthermore, the pharmaceutical composition may be coated, if necessary. The coating base and coating additives are as described above.

[0045] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0046] The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.

[0047] Reference Example 1: Production of granulated product 2000 g of pimitespib (manufactured by Alps Pharmaceutical Co., Ltd.), 1925 g of lactose hydrate (Lactochem fine powder, manufactured by DMV Fonterra Excipients GmbH & Co. KG), and 750 g of corn starch (Nisshoku Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) were charged into a fluidized bed granulator "FLC-3N-5" (manufactured by Freund Corporation), and fluidized bed granulation was carried out using 1500 g of a binding solution prepared by dissolving 300 g of hydroxypropyl cellulose (HPC SSL, manufactured by Nippon Soda Co., Ltd.) in 2700 g of purified water. The mixture was sieved (mesh opening: 600 μm) to obtain granulated product.

[0048] Reference Example 2: Production of Tablet I 100 g of pimitespib (manufactured by Alps Pharmaceutical Co., Ltd.), 96.25 g of lactose hydrate (Lactochem fine powder, manufactured by DMV Fonterra Excipients GmbH & Co. KG), and 37.5 g of corn starch (Nisshoku Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) were charged into a fluidized bed granulator "FL-LABO" (manufactured by Freund Corporation), and fluidized bed granulation was carried out using 75 g of a binding solution prepared by dissolving 30 g of hydroxypropyl cellulose (HPC SSL, manufactured by Nippon Soda Co., Ltd.) in 270 g of purified water. The granules were sized using a sieve (mesh opening: 600 μm) to obtain a granulated product. To 193 g of the obtained granules, 6 g of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC Health and Nutrition) and 1 g of magnesium stearate (special product, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tablet press "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) at a compression force of 5 kN to obtain tablets with a diameter of 6 mm and a mass of 100 mg.

[0049] Reference Example 3: Production of Tablet B To 1.93 g of the granules obtained in Reference Example 1, 1 g of lactose hydrate (Supertab 11SD, manufactured by DMV Fonterra Excipients GmbH & Co. KG), 0.06 g of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC Health and Nutrition), and 0.01 g of magnesium stearate (special product, vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was tableted using a hydraulic press (manufactured by Riken Seiki Co., Ltd.) at a compression force of 0.75 ton to obtain tablets with a diameter of 7 mm and a mass of 150 mg.

[0050] Reference Example 4: Production of tablet C To 1.93 g of the granules obtained in Reference Example 1, 1 g of crystalline cellulose (Ceolus KG-802, manufactured by Asahi Kasei Corporation), 0.06 g of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC Health and Nutrition), and 0.01 g of magnesium stearate (special product, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was tableted using a precision universal testing machine Autograph (manufactured by Shimadzu Corporation) at a compression force of 2 kN to obtain tablets with a diameter of 7 mm and a mass of 150 mg.

[0051] Reference Example 5: Production of tablet D To 1.93 g of the granules obtained in Reference Example 1, 1 g of D-mannitol (Pearlitol 100SD, Roquette), 0.06 g of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC Health and Nutrition), and 0.01 g of magnesium stearate (special product, plant-based, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was tableted using a precision universal testing machine Autograph (manufactured by Shimadzu Corporation) at a compression force of 3.5 kN to obtain tablets with a diameter of 7 mm and a mass of 150 mg.

[0052] Test Example 1: Measurement of hardness and disintegration time For the tablets produced in Reference Example 2, the hardness in the diametric direction was measured using a tablet hardness tester (8M, Schleuniger), and the hardness (N) was calculated from the average value of five tablets. The disintegration time was measured using a disintegration tester (NT-4H(P), manufactured by Toyama Sangyo Co., Ltd.) under the conditions of test liquid: water (37±2°C) and no disc, and the time from when the tablet was placed in the tester to when it completely disintegrated. For the tablets produced in Reference Example 3, the hardness in the diametric direction was measured using a tablet hardness tester (8M, Schleuniger), and the hardness (N) was calculated from the average value of three tablets. The disintegration time was measured using a disintegration tester (NT-4H, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of test liquid: water (37±2°C) and no disc, and the time from when the tablet was placed in the tester to when it completely disintegrated. For the tablets produced in Reference Examples 4 and 5, the hardness in the diameter direction was measured using a tablet hardness tester (PC-30, manufactured by Okada Seiko Co., Ltd.), and the hardness (N) was calculated from the average value of three tablets. The disintegration time was measured using a disintegration tester (NT-4H, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of test liquid: water (37±2°C) and no disk, and the time from when the tablet was placed into the tester until it completely disintegrated. The results are shown in Table 1.

[0053]

[0054] From Table 1, when the disintegration behavior was observed, it was found that in Reference Example 2, the tablet gradually disintegrated from the periphery, and it was thought that water was not guided into the interior of the tablet, whereas in Reference Examples 3, 4, and 5, it was confirmed that the tablets disintegrated into several pieces in the disintegration tester, and it was found that the disintegration time and disintegration behavior could be improved by adding a sufficient amount of excipient between the granules. The formulation was optimized based on Reference Example 4, in which a further improvement in disintegration time was observed.

[0055] Example 1 Production of Tablet A To 96.5 g of the granules obtained in Reference Example 1, 52.75 g of crystalline cellulose (Ceolus PH-102, manufactured by Asahi Kasei Corporation) and 0.75 g of magnesium stearate (special product, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tablet press "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a tableting pressure of 4 kN, each tablet containing 40 mg of pimitespib and 52.75 mg of crystalline cellulose (Ceolus PH-102). The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 28.8 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 3.6 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 3.6 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 324 g of purified water, to give a coating solution of 150 mg per tablet, 3.6 mg of hypromellose, 0.45 mg of macrogol 6000, and 0.45 mg of titanium oxide, to give coated tablets with a diameter of 7.5 mm and a mass of 154.5 mg.

[0056] Example 2 Production of Tablet B To 96.5 g of the granules obtained in Reference Example 1, 52.75 g of crystalline cellulose (Ceolus PH-302, manufactured by Asahi Kasei Corporation) and 0.75 g of magnesium stearate (special product, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tableting machine "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a tableting pressure of 5 kN, each tablet containing 40 mg of pimitespib and 52.75 mg of crystalline cellulose (Ceolus PH-302). The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 64.8 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 8.1 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 8.1 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 729 g of purified water, to give a coating solution of 150 mg per tablet, 3.6 mg of hypromellose, 0.45 mg of macrogol 6000, and 0.45 mg of titanium oxide, to give coated tablets having a diameter of 7.5 mm and a mass of 154.5 mg.

[0057] Example 3 Production of Tablet C To 96.5 g of the granules obtained in Reference Example 1, 52.75 g of crystalline cellulose (Ceolus KG-802, manufactured by Asahi Kasei Corporation) and 0.75 g of magnesium stearate (special product, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tableting machine "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a tableting pressure of 3 kN, each tablet containing 40 mg of pimitespib and 52.75 mg of crystalline cellulose (Ceolus KG-802). The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 28.8 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 3.6 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 3.6 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 324 g of purified water, to give a coating solution of 150 mg per tablet, 3.6 mg of hypromellose, 0.45 mg of macrogol 6000, and 0.45 mg of titanium oxide, to give coated tablets with a diameter of 7.5 mm and a mass of 154.5 mg.

[0058] Example 4 Production of Tablet D To 96.5 g of the granules obtained in Reference Example 1, 52.75 g of crystalline cellulose (Ceolus UF-711, manufactured by Asahi Kasei Corporation) and 0.75 g of magnesium stearate (special product, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tableting machine "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a tableting pressure of 3.5 kN, each tablet containing 40 mg of pimitespib and 52.75 mg of crystalline cellulose (Ceolus UF-711). The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 28.8 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 3.6 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 3.6 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 324 g of purified water, to give a coating solution of 150 mg per tablet, 3.6 mg of hypromellose, 0.45 mg of macrogol 6000, and 0.45 mg of titanium oxide, to give coated tablets with a diameter of 7.5 mm and a mass of 154.5 mg.

[0059] Comparative Example 1: Production of tablet a To 96.5 g of the granules obtained in Reference Example 1, 52.75 g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Corporation) and 0.75 g of magnesium stearate (special product, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tableting machine "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a tableting pressure of 3 kN, each tablet containing 40 mg of pimitespib and 52.75 mg of crystalline cellulose (Ceolus KG-1000). The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 28.8 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 3.6 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 3.6 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 324 g of purified water, to give a coating solution of 150 mg per tablet, 3.6 mg of hypromellose, 0.45 mg of macrogol 6000, and 0.45 mg of titanium oxide, to give coated tablets with a diameter of 7.5 mm and a mass of 154.5 mg.

[0060] Comparative Example 2: Production of tablet b To 125.45 g of the granules obtained in Reference Example 1, 0.62 g of magnesium stearate (specially made, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) was added and thoroughly mixed, and the mixture was compressed into tablets with a mass of 96.98 mg and 40 mg of pimitespib per tablet at a compression pressure of 4 kN using a rotary tableting machine "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets. The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 23.3 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 2.9 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 2.9 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 261.8 g of purified water, to give a weight of 96.98 mg per tablet, 2.33 mg of hypromellose, 0.29 mg of macrogol 6000, and 0.29 mg of titanium oxide, to give coated tablets with a diameter of 6 mm and a weight of 99.89 mg.

[0061] Example 5 Production of Tablet E To 96.5 g of the granules obtained in Reference Example 1, 27.88 g of crystalline cellulose (Ceolus PH-102, manufactured by Asahi Kasei Corporation) and 0.63 g of magnesium stearate (special product, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tableting machine "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a tableting pressure of 4 kN, each tablet containing 40 mg of pimitespib and 27.875 mg of crystalline cellulose (Ceolus PH-102). The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 64.8 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 8.1 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 8.1 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 729 g of purified water, to give a weight of 125 mg per tablet, 3 mg of hypromellose, 0.375 mg of macrogol 6000, and 0.375 mg of titanium oxide, to give coated tablets with a diameter of 7 mm and a weight of 128.75 mg.

[0062] Example 6 Production of Tablet F To 96.5 g of the granules obtained in Reference Example 1, 42.8 g of crystalline cellulose (Ceolus PH-102, manufactured by Asahi Kasei Corporation) and 0.7 g of magnesium stearate (special product, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tableting machine "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a tableting pressure of 4.5 kN, each tablet containing 40 mg of pimitespib and 42.8 mg of crystalline cellulose (Ceolus PH-102). The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 64.8 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 8.1 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 8.1 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 729 g of purified water, to give a weight of 140 mg per tablet, 3.36 mg of hypromellose, 0.42 mg of macrogol 6000, and 0.42 mg of titanium oxide, to give coated tablets having a diameter of 7.5 mm and a weight of 144.2 mg.

[0063] Example 7 Production of Tablet G To 96.5 g of the granules obtained in Reference Example 1, 102.5 g of crystalline cellulose (Ceolus PH-102, manufactured by Asahi Kasei Corporation) and 1 g of magnesium stearate (special product, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tableting machine "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a tableting pressure of 3.5 kN, each tablet containing 40 mg of pimitespib and 102.5 mg of crystalline cellulose (Ceolus PH-102). The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 64.8 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 8.1 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 8.1 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 729 g of purified water, to give a coating solution of 200 mg per tablet, 4.8 mg of hypromellose, 0.6 mg of macrogol 6000, and 0.6 mg of titanium oxide, to give coated tablets with a diameter of 8 mm and a mass of 206 mg.

[0064] Comparative Example 3: Production of tablet c To 96.5 g of the granules obtained in Reference Example 1, 301.5 g of crystalline cellulose (Ceolus PH-102, manufactured by Asahi Kasei Corporation) and 2 g of magnesium stearate (special product, vegetable-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tablet press "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a tableting pressure of 3.5 kN, each tablet containing 400 mg of pimitespib and 301.5 mg of crystalline cellulose (Ceolus PH-102). The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 64.8 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 8.1 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 8.1 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 729 g of purified water, to give a coating solution of 400 mg per tablet, 9.6 mg of hypromellose, 1.2 mg of macrogol 6000, and 1.2 mg of titanium oxide, to give coated tablets having a diameter of 10 mm and a mass of 412 mg.

[0065] Test Example 2: Measurement of disintegration time For the tablets produced in Examples 1 to 7 and Comparative Examples 1 to 3, a disintegration tester (NT-4H, NT-4H(P), manufactured by Toyama Sangyo Co., Ltd.) was used to measure the time from when the tablet was placed into the tester until it completely disintegrated, under the conditions of test liquid: water (37±2°C) and no disk. The results are shown in Tables 2 and 3.

[0066]

[0067]

[0068] The disintegration times of crystalline cellulose with different physical properties were evaluated for coated tablets prepared by coating the uncoated tablets in Table 2 (Examples 1 to 4 and Comparative Example 1). The disintegration times of the coated tablets in Examples 1 and 2 were confirmed to be 3 minutes or less, and those of the coated tablets in Examples 3 and 4 to be 5 minutes or less, while the disintegration time of the coated tablet in Comparative Example 1 was found to require 15 minutes or more. The disintegration times of the coated tablets in Examples 1 and 2 were the most improved, but when the tableting pressure during tableting was confirmed, it was found that the tableting pressure in Example 1 was approximately 4 kN and that in Example 2 was 5 kN. Therefore, from the perspective of moldability, the amount of crystalline cellulose added was evaluated based on Example 1. The disintegration times of the uncoated tablets in Table 3 (Examples 1, 5 to 7, Comparative Examples 2 and 3) were evaluated. It was found that the disintegration time decreased depending on the amount of crystalline cellulose added in Examples 1, 5 to 7, and Comparative Example 2, but that the disintegration time was delayed when the amount of crystalline cellulose added increased, as in Comparative Example 3. The disintegration times of the uncoated tablets and the coated tablets showed the same tendency. A desirable amount of crystalline cellulose was considered to be 27.875 to 102.5 mg. While the addition of a disintegrant is usually considered as the first choice for improving disintegration, it was surprising that a composition with excellent disintegration properties could be obtained simply by adding crystalline cellulose and adjusting the amount added, without the need for a separate disintegrant. Furthermore, the sizes of the coated tablets in Examples 1, 5 to 7 and Comparative Examples 2 and 3 were compared. The results showed that the coated tablets in Comparative Example 3 were 10 mm, while the coated tablets in Examples 1, 5 to 7 were all small, measuring 8 mm or less. Tablets with a size of 7 to 8 mm are considered to be small, easy to take, and promote good compliance. The coated tablets in Examples 1, 5 to 7 were 7 to 8 mm, and are expected to be tablets with good compliance. Furthermore, no tableting problems, such as sticking, were observed in the tablets of the present invention.

[0069] Test Example 3: Measurement of bulk density and major axis / minor axis ratio For crystalline cellulose (Ceolus PH-102, PH-302, KG-802, UF-711, KG-1000, manufactured by Asahi Kasei Corporation), the bulk density was determined according to the bulk density and tap density measurement method specified in the Japanese Pharmacopoeia using a powder tester (PT-R, manufactured by Hosokawa Micron Corporation). In addition, the major axis / minor axis ratio was determined by measuring the major axis and minor axis of 50 particles using an electron microscope (VHX-D500, manufactured by Keyence Corporation). The results are shown in FIG. 1.

[0070] [Example 8: Production of Tablet H] 3,000 g of pimitespib (manufactured by Alps Pharmaceutical Co., Ltd.), 2,887.5 g of lactose hydrate (Lactochem fine powder, manufactured by DMV Fonterra Excipients GmbH & Co. KG), and 1,125 g of corn starch (Nisshoku Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) were charged into a fluidized bed granulator "FLC-3N-5" (manufactured by Freund Corporation), and fluidized bed granulation was carried out using 2,250 g of a binding solution prepared by dissolving 400 g of hydroxypropyl cellulose (HPC SSL, manufactured by Nippon Soda Co., Ltd.) in 3,600 g of purified water. A granulator "QC-U10" (manufactured by Powrex Corporation) was used at an impeller speed of 400 min －１To 144.75 g of the obtained granules, 79.125 g of crystalline cellulose (Ceolus PH-102, manufactured by Asahi Kasei Corporation) and 1.125 g of magnesium stearate (special product, vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets using a rotary tablet press "VELAG" (manufactured by Kikusui Seisakusho Co., Ltd.) with a mass of 150 mg per tablet, 40 mg of pimitespib, and 52.75 mg of crystalline cellulose (Ceolus PH-102), and a hardness of 70 N. The compressed tablet was placed in a coating machine "HC-FZ-LABO" (manufactured by Freund Corporation) and coated with a coating solution prepared by dissolving 40 g of hypromellose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 5 g of macrogol 6000 (macrogol 6000P, manufactured by NOF Corporation), and 5 g of titanium oxide (titanium oxide NA63, manufactured by Toho Titanium Co., Ltd.) in 450 g of purified water, to give a weight of 154.5 mg per tablet, 3.6 mg of hypromellose, 0.45 mg of macrogol 6000, and 0.45 mg of titanium oxide, to give coated tablets with a diameter of 7 mm and a weight of 154.5 mg.

[0071] Comparative Example 4: Production of Tablet d 3,000 g of pimitespib (manufactured by Alps Pharmaceutical Co., Ltd.), 2,887.5 g of lactose hydrate (Lactochem fine powder, manufactured by DMV Fonterra Excipients GmbH & Co. KG), and 1,125 g of corn starch (Nisshoku Pharmacopoeia Corn Starch, manufactured by Nihon Shokuhin Kako Co., Ltd.) were charged into a fluidized bed granulator "FLC-3N-5" (manufactured by Freund Corporation), and fluidized bed granulation was carried out using 2,250 g of a binding solution prepared by dissolving 450 g of hydroxypropyl cellulose (HPC SSL, manufactured by Nippon Soda Co., Ltd.) in 4,050 g of purified water. A granulator "QC-U10" (manufactured by Powrex Corporation) was used at an impeller speed of 400 min －１To 5795.15 g of the granules, 180.16 g of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC Health and Nutrition) and 30.03 g of magnesium stearate (special product, vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were added and thoroughly mixed, and the mixture was compressed into tablets with a mass of 100 mg per tablet, containing 40 mg of pimitespib and 3 mg of croscarmellose sodium, and a hardness of 60 N, using a rotary tablet press "AQUARIUS C-H" (manufactured by Kikusui Seisakusho Co., Ltd.). The compressed tablet was placed in a coating machine "PRC-10GTX" (Powrex Corporation) and coated with a coating solution prepared by dissolving 360 g of hypromellose (TC-5R, Shin-Etsu Chemical Co., Ltd.), 45 g of macrogol 6000 (Macrogol 6000P, NOF Corporation), and 45 g of titanium oxide (Titanium oxide NA63, Toho Titanium Co., Ltd.) in 4050 g of purified water, to give a weight of 103 mg per tablet, 2.4 mg of hypromellose, 0.3 mg of macrogol 6000, and 0.3 mg of titanium oxide, yielding coated tablets with a diameter of 6 mm and a weight of 103 mg. The compositions of the coated tablets of Example 8 and Comparative Example 4 are shown in Table 4.

[0072]

[0073] Test Example 4: Absorption experiment in dogs Two coated tablets prepared in Example 8 and Comparative Example 4 were administered to beagle dogs (Kitayama Labes Co., Ltd., six male dogs, approximately 9 to 11 kg, 39 to 44 months old, fasted; 30 minutes before administration, 20 μg / 0.04 mL / kg of atropine sulfate intravenous injection was administered intravenously, and 10 μg / 0.1 mL / kg of pentagastrin intramuscular injection was administered intramuscularly. Thereafter, the same amount of pentagastrin intramuscular injection was administered twice at 45-minute intervals). Two tablets per dog were administered together with 50 mL of water (80 mg / body). Blood samples were taken at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and approximately 1 mL of blood was collected from the forearm vein using a heparinized syringe and needle (21G). The collected blood was centrifuged (12,000 rpm, 5°C, 3 minutes), and 50 μL of the resulting plasma was placed in a polypropylene microtube. 50 μL of acetonitrile and 100 μL of internal standard solution were added and mixed using a vortex mixer. After centrifugation (20,400 g, 5°C, 1 minute), 100 μL of the supernatant was placed in a polypropylene autosampler tube, and 200 μL of water was added and mixed using a vortex mixer. The resulting sample was quantified using a high-performance liquid chromatograph / mass spectrometer (AB Sciex Corporation), and the Tmax, Cmax, and AUC values ​​were calculated. <Liquid chromatography measurement conditions> Apparatus: High-performance liquid chromatograph / mass spectrometer (AB Sciex Corporation) Column: Imtakt Unison uk-c18 (2.0 mm i.d. × 50 mm, 3 μm) Column temperature: 40°C Mobile phase A: 10 mmol / L ammonium formate solution Mobile phase B: acetonitrile Mobile phase delivery: Mobile phase A and mobile phase B were delivered from a pump at a mixing ratio of 67:33 or 65:35. Flow rate: 0.3 mL / min MS / MS measurement conditions Ionization source: Electrospray ionization (esi)-positive Scan mode: Multiple reaction monitoring (MRM)

[0074] An absorption experiment was conducted using beagle dogs (6 males, approximately 9 to 11 kg, 39 to 44 months old) for the coated tablets in Table 4 (Example 8 and Comparative Example 4). The relative BA of Example 8 was 146% of that of Comparative Example 4, demonstrating that the use of crystalline cellulose instead of a disintegrant improved absorbability (FIG. 2, Table 5).

[0075]

Claims

1. A pharmaceutical composition comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and crystalline cellulose, said pharmaceutical composition having a disintegration time of 360 seconds or less in the form of a coated tablet.

2. A pharmaceutical composition obtained by mixing a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof with 20.0 to 55.0% by mass of crystalline cellulose, wherein the L / D ratio of the crystalline cellulose before mixing is 1.00 to 4.00 and / or the bulk density is 0.20 to 0.50 g / cm. ３ A pharmaceutical composition comprising:

3. A pharmaceutical composition comprising a granule containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof, and 20.0 to 55.0% by mass of a crystalline cellulose selected from the group consisting of Ceolus (registered trademark) PH-102, PH-302, KG-802, and UF-711.

4. 4. The pharmaceutical composition according to claim 2, wherein the content of the crystalline cellulose is 30.0 to 55.0% by mass.

5. 4. The pharmaceutical composition according to claim 2 or 3, which has a disintegration time of 180 seconds or less in the form of an uncoated tablet, or 360 seconds or less in the form of a coated tablet.

6. The pharmaceutical composition according to any one of claims 1 to 3, comprising 18.0 to 40.0% by mass of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the granules are produced by a wet granulation method.

8. The pharmaceutical composition according to any one of claims 1 to 3, wherein the average particle size (d50) of the granules is 50 to 400 µm.

9. The pharmaceutical composition according to any one of claims 1 to 3, which is a solid formulation.

10. 10. The pharmaceutical composition of claim 9, which is a tablet.

11. The pharmaceutical composition of claim 10, having a diameter of 6.5 to 9.5 mm.

12. A coating composition obtained by coating the pharmaceutical composition according to any one of claims 1 to 3.

13. A step of granulating a powder containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof using a binding liquid; and a method of preparing a granulated product having an L / D ratio of 1.00 to 4.00 and / or a bulk density of 0.20 to 0.50 g / cm3. ３ and mixing the crystalline cellulose represented by the formula (I) with the pharmaceutical composition so that the content of the crystalline cellulose is 20.0 to 55.0% by mass.

14. The method for producing a pharmaceutical composition according to claim 13, wherein the granulation method is a fluidized bed granulation method.

15. A pharmaceutical composition produced by the method of claim 13 or 14.