A formulation with excellent dissolution and tableting properties.

Abstract

The present invention provides an oral solid dosage form containing 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide as the active ingredient, which has good dissolution properties and storage stability. [Solution] An oral solid dosage form is provided, comprising hydroxypropyl cellulose as a binder at a concentration of 4.0 to 6.0% by weight per 100% by weight of the formulation, and stearyl sodium fumarate as a lubricant at a concentration of 2.0 to 10.0% by weight.

Description

[Technical Field]

[0001] This disclosure relates to an oral solid dosage form in which 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter also referred to as "the compound") or a pharmaceutically acceptable salt thereof, or its hydrate or solvate (hereinafter, the compound to the solvate are also referred to as "the drug," "the drug," or "the drug of this disclosure") is the active ingredient, and which has good dissolution and storage stability, and furthermore, when manufactured as a tablet, tableting problems are suppressed. [Background technology]

[0002] In clinical development planning, obtaining information on dosage and response is crucial. According to Non-Patent Literature 1, the purpose of dose-response information is to collect necessary information at each stage throughout the entire process, from preclinical to clinical development, and to utilize this useful information in subsequent clinical trials and post-marketing use. In other words, it is important to understand the relationship between dosage, blood concentration, and clinical response (efficacy and safety), and to identify the appropriate starting dose for a population or individual patient, the best way to adjust the dose to suit the needs of a specific patient, and the dose at which further increases are not expected to provide any further benefit, or the dose at which unacceptable side effects are likely to occur, and to utilize this information in the next stage. Furthermore, since the dose may change during clinical development, it is preferable to have oral solid dosage forms that cover a wide range of doses, from low to high, for obtaining such information.

[0003] When solid dosage forms are administered orally, for them to exert their effects, the drug must dissolve through processes of disintegration, dispersion, and dissolution and reach the absorption site. Since this process greatly affects drug absorption, it is desirable to design the formulation to maintain stable and good dissolution in order to exert and maintain the pharmacological effect.

[0004] Patent Document 1 discloses formulations of this compound, but does not disclose examples showing specific components, formulations, and manufacturing methods. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] WO2020 / 045334 [Non-patent literature]

[0006] [Non-Patent Document 1] Guidelines for examining dose-response relationships necessary for the approval of new drugs (ICH E4) [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The objective of this disclosure is to provide an oral solid dosage form of the drug with good dissolution properties and storage stability, and furthermore, to provide an oral solid dosage form in which tablet compression problems are suppressed when manufactured as tablets. [Means for solving the problem]

[0008] When preparing this drug as an oral solid dosage form, it became clear that tableting problems occurred during the tablet manufacturing process (i.e., the tableting process), such as the adhesion of the composition containing this drug to the surface of the punch (so-called sticking) and the peeling of the surface (so-called capping). Generally, the inclusion of binders and lubricants tends to improve tableting problems in the tableting process, but it is also known that increasing the amount of binders and lubricants beyond the appropriate level can delay the dissolution rate of the compound and reduce the moldability of the tablets (reduction in hardness). However, after diligent research by the present disclosers, surprisingly, by using binders and lubricants in proportions higher than those of the usual formulation, problems such as delayed dissolution and reduced hardness were not observed, and it was possible to improve fluidity and eliminate tableting problems.

[0009] The Disclosers, after diligent research, have found that by incorporating both a lubricant and a binder in higher concentrations than those typically used, it is possible to provide oral solid dosage forms with good dissolution and storage stability. Specifically, they found that even when tablets were manufactured using high concentrations of hydroxypropyl cellulose as a binder and sodium stearyl fumarate as a lubricant, dissolution delay and hardness reduction did not occur, tableting problems were suppressed, good dissolution was maintained, and excellent storage stability was achieved, leading to the completion of this disclosure.

[0010] In other words, this disclosure provides the following items:

[0011] [Section 1] (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate (2) A binder in an amount of 4.0 to 6.0% by weight per 100% by weight of the formulation, (3) 2.0 to 10.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form containing [a specific ingredient / material].

[0012] [Section 2] The oral solid preparation according to item 1, wherein the content of the binder is 5.0 to 6.0% by weight relative to 100% by weight of the preparation.

[0013] [Section 3] The oral solid dosage form according to claim 1 or 2, wherein the binder is a water-soluble polymer binder.

[0014] [Section 4] The oral solid preparation according to claim 3, wherein the water-soluble polymer binder is hydroxypropyl cellulose or polyvinyl alcohol.

[0015] [Item 5] The oral solid preparation according to item 3, wherein the water-soluble polymer binder is hydroxypropyl cellulose.

[0016] [Item 6] The oral solid preparation according to any one of items 1 to 5, wherein the content of the lubricant is 2.0 to 6.0% by weight based on 100% by weight of the preparation.

[0017] [Item 7] The oral solid preparation according to any one of items 1 to 5, wherein the content of the lubricant is 4.0 to 6.0% by weight based on 100% by weight of the preparation.

[0018] [Item 8] The oral solid preparation according to any one of items 1 to 7, wherein the lubricant is sodium stearyl fumarate.

[0019] [Item 9] The oral solid preparation according to any one of items 1 to 8, further comprising an excipient.

[0020] [Item 10] The oral solid preparation according to item 9, wherein the excipient is a hydrophilic excipient.

[0021] [Item 11] The oral solid preparation according to item 10, wherein the hydrophilic excipient is one or a mixture of two or more selected from sugar alcohols, pregelatinized starches, lactose hydrates, and crystalline cellulose.

[0022] [Item 12] The oral solid preparation according to item 10, wherein the hydrophilic excipient is one or a mixture of two or more selected from sugar alcohols, pregelatinized starches, and crystalline cellulose.

[0023] [Item 13] The oral solid preparation according to item 10, wherein the hydrophilic excipient is one or a mixture of two or more selected from sugar alcohols and pregelatinized starches.

[0024] [Section 14] The oral solid preparation according to claim 10, wherein the hydrophilic excipient is a mixture of sugar alcohols and pregelatinized starches.

[0025] [Section 15] The oral solid preparation according to any one of claims 11 to 14, wherein the pregelatinized starches are partially pregelatinized starches.

[0026] [Section 16] The oral solid preparation according to any one of claims 11 to 15, wherein the sugar alcohol is D-mannitol.

[0027] [Section 17] An oral solid dosage form according to any one of items 1 to 16, further comprising a disintegrant.

[0028] [Section 18] The oral solid preparation according to item 17, wherein the content of the disintegrant is 0.5 to 50.0% by weight relative to 100% by weight of the preparation.

[0029] [Section 19] The oral solid preparation according to item 17, wherein the content of the disintegrant is 0.5 to 30.0% by weight relative to 100% by weight of the preparation.

[0030] [Section 20] The oral solid preparation according to item 17, wherein the content of the disintegrant is 0.5 to 20.0% by weight relative to 100% by weight of the preparation.

[0031] [Section 21] The oral solid dosage form according to any one of claims 17 to 20, wherein the disintegrant is one or a mixture of two or more selected from croscarmellose sodium, sodium starch glycolate, and crospovidone.

[0032] [Section 22] The oral solid dosage form according to any one of claims 17 to 20, wherein the disintegrant is one or a mixture of two or more selected from croscarmellose sodium and sodium starch glycolate.

[0033] [Section 23] The oral solid preparation according to any one of claims 17 to 20, wherein the disintegrant is croscarmellose sodium.

[0034] [Section 24] An oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 0.5 to 70% by weight based on 100% by weight of the preparation.

[0035] [Section 25] An oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 10 to 50% by weight based on 100% by weight of the preparation.

[0036] [Section 26] An oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 15 to 40% by weight based on 100% by weight of the preparation.

[0037] [Section 27] An oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 15 to 38% by weight based on 100% by weight of the preparation.

[0038] [Section 28] An oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 20 to 38% by weight based on 100% by weight of the preparation.

[0039] [Section 29] An oral solid dosage form manufactured using a fluid bed granulation method, as described in any one of items 1 to 28.

[0040] [Section 30] An oral solid dosage form according to any one of items 1 to 29, wherein the dosage form is film-coated with a coating agent.

[0041] [Section 31] An oral solid dosage form according to any one of items 1 to 30, for the treatment and / or prevention of tumors. [Effects of the Invention]

[0042] The oral solid dosage form of this disclosure can be provided with good dissolution and storage stability by incorporating higher concentrations of binders and lubricants than those normally used. Furthermore, by using high concentrations of binders and lubricants, tableting problems can be suppressed, and tablets with good dissolution and excellent storage stability can be provided. [Modes for carrying out the invention]

[0043] The following provides further details about this disclosure. The embodiments provided below are provided for a better understanding of this disclosure, and the scope of this disclosure is not limited to what is described below. The embodiments below can also be used individually or in combination.

[0044] In this disclosure, "average particle size" means the cumulative 50% particle size D50 in volume-based measurement of powder particles. Such average particle size is measured volume-based using a laser diffraction particle size distribution analyzer (e.g., Particle Viewer from Powrec, or SALD-3000J from Shimadzu Corporation, or HELOS & RODOS from Sympatec).

[0045] In this disclosure, "tableting defect" means phenomena such as the adhesion of the compound to the surface of the punch (sticking) and the peeling of the surface (capping) during the tablet manufacturing process (i.e., the tableting process), and the friction between the powder used for tableting and the metal surface, causing scratches on the side of the tablet (die friction).

[0046] In this disclosure, "content" means the amount or content (wt / wt) when the total amount of the formulation is considered to be 100% by weight, unless otherwise specified. Weight percent is also expressed as wt%.

[0047] In this disclosure, "excellent storage stability" means that the formulation characteristics indicate a small increase in the amount of related substances in the purity test of the storage stability test, and that good dissolution is maintained in the dissolution test after storage.

[0048] "Storage" refers to keeping a manufactured preparation in an appropriate container, storing it, or keeping it in storage. During storage, the container may be sealed or open, and may or may not be protected from light. Examples of storage include storage at room temperature, room temperature, cool place storage, refrigerated storage, or frozen storage. Suitable storage temperatures include, but are not limited to, standard temperature: 20°C, room temperature: 15-25°C, ambient temperature: 1-30°C, lukewarm temperature: 30-40°C, cool place: 1-15°C, refrigerated: 2-6°C, and frozen: approximately -20°C to -18°C. The relative humidity (%RH) during storage may be anywhere from 0 to 100%RH, with 40-60%RH being preferred, but is not limited to these ranges. Suitable storage periods include, but are not limited to, several hours, several days, several weeks, several months, or several years. The above storage parameters may be appropriately selected depending on the properties of the preparation and the storage conditions. A "storage stability test" is a stability test to confirm whether the quality of a manufactured pharmaceutical product is maintained. It is conducted using storage conditions that accelerate chemical or physical changes in the product. The test results can be used to evaluate the chemical effects of long-term storage under specified storage conditions. They can also be used to evaluate the effects of short-term deviations from storage conditions that may occur during transport. Depending on the temperature / relative temperature, there are various types of tests, such as long-term tests (e.g., 25°C / 60%RH), accelerated tests (e.g., 40°C / 75%RH), and harsh tests (e.g., 50°C / 85%RH). The accelerated or harsh tests described herein are performed by setting the conditions of a constant temperature and humidity chamber to a higher temperature / higher relative humidity (e.g., 40°C / 75%RH or 50°C / 85%RH, respectively), placing the prepared solid dosage form in an appropriate container (e.g., an HDPE bottle (material: high-density polyethylene (HDPE), or a brown screw-cap test tube (material: glass)), and storing it in the constant temperature and humidity chamber for a set period (e.g., 1, 3, or 6 months, or 2 or 4 weeks, respectively), either open or closed. In storage stability tests, keeping the amount of related substances below a specified level is necessary to provide patients with a formulation of superior quality. The specified level of related substances is approximately 3.0% or less in total related substances.

[0049] In this disclosure, "good dissolution performance" means, for example, that when the dissolution test of the formulation is performed under the following dissolution test conditions in accordance with the dissolution test paddle method of the 18th edition of the Japanese Pharmacopoeia, the formulation shows a dissolution rate of 80% or more, preferably 85% or more, at the 15-minute mark. Another aspect of "good dissolution" means exhibiting an elution rate of 70% or more, preferably 80% or more, and more preferably 85% or more at 10 minutes. Yet another aspect of "good dissolution" means exhibiting an elution rate of 80% or more, preferably 85% or more, at 5 minutes. Test solution: 0.1 mol / L hydrochloric acid reagent Paddle rotation speed: 50 rpm Test solution: 900 mL Test solution temperature: 37±0.5℃

[0050] [1] Oral solid dosage form An "oral solid dosage form" refers to a solid preparation of a specific shape that is administered orally. Solid dosage forms include tablets, capsules, granules, fine granules, pills, and powders.

[0051] The oral solid dosage forms described herein refer particularly to those formulated as tablets, capsules, granules, or fine granules. Preferred examples of oral solid dosage forms include tablets or capsules. More preferred examples of oral solid dosage forms include tablets. Oral solid dosage forms (e.g., tablets) in this disclosure may be film-coated with a coating agent for purposes such as facilitating administration or preventing the degradation of the active ingredient. In such cases, the oral solid dosage forms in this disclosure can be said to be film-coated tablets. Film-coated tablets are typically tablets formulated by film-coating an uncoated tablet with a suitable coating agent such as a polymer compound.

[0052] The oral solid dosage forms of the present disclosure comprise (1) a drug, (2) a binder, and (3) a lubricant, and may further optionally contain (4) excipients, (5) disintegrants, and other (6) additives, to the extent that they do not affect the formulation properties of the present disclosure. In the case of tablets, the forms include uncoated tablets, film-coated tablets (sometimes referred to as FC tablets in this specification) in which a film coating is applied to the surface of an uncoated tablet, and sugar-coated tablets in which a sugar coating is applied to the surface of an uncoated tablet, with uncoated tablets or film-coated tablets being preferred.

[0053] (1) Drugs In this disclosure, “drug” means the active ingredient of this disclosure, 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (the compound) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, the compound having the following structure. TIFF2026071393000001.tif4161 Furthermore, in "the compound or its pharmaceutically acceptable salt, or its hydrate or solvate," "its hydrate or solvate" refers to the hydrate or solvate of the compound, and the hydrate or solvate of a pharmaceutically acceptable salt of the compound.

[0054] In this disclosure, "pharmaceutically acceptable salts" include, but are not limited to, hydrochloride, citrate, fumarate, maleate, phosphate, succinate, sulfate, tartrate, besylate, and bromate.

[0055] "The tartrate of this compound" refers to 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide 1L(+)-tartrate. In this disclosure, "hydrate" refers to a solid state in which the molecules of the compound contain water molecules in a certain proportion, and "solvate" refers to a state in which the water molecules are organic solvent molecules. The organic solvents that can form solvates in this disclosure can be appropriately selected depending on the type and properties of the substance, and examples include alcohols such as ethanol and propanol, and common solvents such as acetone and ethyl acetate. The number of solvent molecules in the hydrate and solvate can be appropriately selected depending on the stability of the solvate, etc.

[0056] The drug content of the present disclosure is typically 0.1 to 96% by weight per 100% by weight of the formulation, with a preferred example being 0.5 to 70% by weight, more preferred examples being 5 to 60% by weight, 5 to 50% by weight, 10 to 60% by weight, 10 to 50% by weight, 15 to 60% by weight, 15 to 50% by weight, 10 to 40% by weight, 15 to 40% by weight, 20 to 40% by weight, 20 to 38% by weight, 15 to 38% by weight, 15 to 36% by weight, and a still preferred example being 20 to 30% by weight.

[0057] The drug may be ground to a desired particle size as needed during formulation. The average particle size of the drug is typically 0.1 to 100 μm, preferably 0.1 to 80 μm, more preferably 0.1 to 50 μm, and even more preferably 1 to 20 μm. The average particle size of the drug as a raw material may be within the above range and may change during the manufacturing process.

[0058] (2) Binder A "binder" refers to a component used to provide binding force to powders and to create and maintain the shape of a formulation. In this disclosure, a water-soluble polymer binder is preferred. While not particularly limited, examples of water-soluble polymer binders include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, polyethylene glycol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, vinyl acetate / vinylpyrrolidone copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer, pregelatinized starches, dextrin, dextran, pullulan, alginic acid, gelatin, and pectin. More preferred examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinyl alcohol, and even more preferred examples include hydroxypropylcellulose. One or more of the above-mentioned water-soluble polymer binders can be used simultaneously. In the case of hydroxypropylcellulose, a typical binder, it is generally used in formulations of 2-3%.

[0059] Using hydroxypropylcellulose as a water-soluble polymer binder allows for smooth preparation (i.e., granulation) of drug-containing granules during formulation, and can yield formulations with excellent handling properties and good disintegration characteristics.

[0060] The viscosity of the above-mentioned hydroxypropyl cellulose is not particularly limited, but when prepared as a 2% aqueous solution at 20°C, it has a viscosity of 2 to 400 mPa·s, preferably 2 to 10 mPa·s.

[0061] The binder content is typically 4.0 to 20% by weight per 100% by weight of the formulation, with a preferred example being 4.0 to 10% by weight, more preferred examples being 4.0 to 6.0% by weight, 4.5 to 6.0% by weight, 5.0 to 6.0% by weight, 5.5 to 6.0% by weight, 4.0 to 5.5% by weight, 4.5 to 5.5% by weight, 5.0 to 5.5% by weight, 4.0 to 5.0% by weight, and even more preferred examples being 5.0 to 5.5% by weight and 5.0 to 6.0% by weight. The binder of this disclosure can be dissolved in a solvent such as water and granulated while being sprayed. Furthermore, the binder can be charged together with other components and granulated while spraying a solvent such as water.

[0062] (3) Lubricants A "lubricant" is an ingredient added during the manufacturing process of capsules and tablets to improve the fluidity and filling properties of powders, and to prevent adhesion, when filling capsules or compressing tablets. In the case of tablets, the lubricant may be mixed with other ingredients before tableting, or it may be sprayed onto the mortar and pestle during tableting. The lubricant is not particularly limited, but examples include magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, silica, or hydrogenated vegetable oil. More preferred examples include magnesium stearate and sodium stearyl fumarate, and even more preferred examples include sodium stearyl fumarate. One or more of the above lubricants can be used simultaneously. Using sodium stearyl fumarate as a lubricant can suppress tableting problems during tableting, and can result in a formulation with excellent handling and good disintegration properties. The lubricant is generally included in a concentration of 1% or less, and at most up to about 2%. A commonly used lubricant is magnesium stearate. The lubricant content is typically 0.1 to 20% by weight per 100% by weight of the formulation, with a preferred example being 2.0 to 10% by weight, more preferred examples being 4.0 to 10% by weight, 5.0 to 10% by weight, 2.0 to 6.0% by weight, 2.5 to 6.0% by weight, 3.0 to 6.0% by weight, 3.5 to 6.0% by weight, 4.5 to 6.0% by weight, and 5.0 to 6.0% by weight, with an even more preferred example being 4.0 to 6.0% by weight.

[0063] (4) Excipients An "excipient" is an ingredient added to a dosage form when the main ingredient alone is insufficient to obtain sufficient volume. It is used to create the shape of the formulation, increase its volume, or dilute it to make it easier to handle. Furthermore, it not only increases the volume but also improves the mixability of powders, enhances the granulation properties when forming particles in granules, improves the filling, adhesion, and fluidity of tablets when compressing them into a mortar, and improves the filling properties of capsules.

[0064] Examples of "excipients" include hydrophilic excipients and non-hydrophilic excipients, with hydrophilic excipients being preferred. As hydrophilic excipients, hydrophilic excipients commonly used in formulation can be used, and preferred examples include sugars, crystalline cellulose, or sugar alcohols. The type of sugar or sugar alcohol used here is not particularly limited, but examples include pregelatinized starches, D-mannitol, erythritol, xylitol, maltitol, sorbitol, lactose, sucrose, or tolhalose. Preferred examples include D-mannitol, erythritol, lactose, or tolhalose. More preferred examples include pregelatinized starches, D-mannitol, or lactose. Most preferred examples include pregelatinized starches and D-mannitol. The hydrophilic excipient may be one or more selected from the above-mentioned options.

[0065] The excipient content is typically 0.1 to 90% by weight per 100% by weight of the formulation, with a preferred example being 10 to 90% by weight, a more preferred example being 30 to 80% by weight, and an even more preferred example being 40 to 70% by weight.

[0066] The D-mannitol content is typically 0.1 to 90% by weight per 100% by weight of the formulation, with a preferred example being 1 to 80% by weight, and a more preferred example being 30 to 60% by weight.

[0067] Specific examples of "pregelatinized starches" include "pregelatinized starch" or "partly pregelatinized starch" as defined in the Pharmaceutical Additives Standards, as well as "pregelatinized starch" in the USP / NF and "starch, pregelatinised" in the Ph.Eur. A preferred example of "pregelatinized starches" is "partially pregelatinized starch." Specific examples of commercially available pregelatinized or partially pregelatinized starch include PC-10 (product name, distributor: Asahi Kasei Corporation), SWELSTAR (product name, distributor: Asahi Kasei Corporation), Starch 1500 and Starch 1500G (product name, distributor: Karakon), or LYCATAB C (product name, distributor: Roquette), but are not limited to these. Any product may be used as long as its components are pregelatinized or partially pregelatinized starch and its purity and other specifications meet the standards of those skilled in the art. Examples of raw materials for pregelatinized starch include various starches such as corn starch, potato starch, wheat starch, rice starch, and tapioca starch.

[0068] The pregelatinized starch content is typically 0.1 to 50% by weight per 100% by weight of the preparation, with a preferred example being 1 to 40% by weight, and a more preferred example being 10 to 30% by weight.

[0069] (5) Disintegrant A "disintegrant" refers to an ingredient added to solid dosage forms, such as tablets or granules, for the purpose of disintegrating and dispersing them into particles. The "disintegrant" is not particularly limited, but examples include corn starch, croscarmellose sodium, sodium starch glycolate (or carboxymethyl starch sodium), low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carboxymethyl ethyl cellulose, and crospovidone. Preferred examples include croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, and crospovidone. More preferred examples include croscarmellose sodium, sodium starch glycolate, and crospovidone. A further preferred example is croscarmellose sodium. The disintegrant may be one selected from the above or a combination of two or more of them.

[0070] The disintegrant content is typically 0.1 to 50.0% by weight per 100% by weight of the formulation, with preferred examples being 0.5 to 50.0% by weight and 0.5 to 30.0% by weight, more preferred examples being 0.5 to 20% by weight, 0.5 to 30.0% by weight, 1.0 to 30.0% by weight and 1.0 to 20.0% by weight, and even more preferred examples being 0.5 to 20.0% by weight, 2.0 to 10.0% by weight, 1.0 to 10.0% by weight and 2.0 to 5.0% by weight.

[0071] (6) Additives "Additives" refer to substances other than the active ingredients contained in a pharmaceutical preparation that are used for purposes such as enhancing the usefulness of the active ingredients and the preparation, facilitating formulation, stabilizing quality, or improving usability.

[0072] The formulations of this disclosure may contain, as necessary, non-toxic and inert additives commonly used in the pharmaceutical field, provided that they do not affect the action of the drug of this disclosure. These additives include those commonly used in oral formulations that do not affect the therapeutic effect of the drug of this disclosure. Examples of additives include, but are not limited to, stabilizers, flavoring agents, sweeteners, odorants, fragrances, antioxidants, antistatic agents, fluidizing agents, colorants, plasticizers, anti-flocculation agents, and glazing agents. The amount of additives can be set arbitrarily, but is typically 0.001 to 10% by weight per 100% by weight of the formulation, preferably 0.005 to 10% by weight, and more preferably 0.01 to 5% by weight. Another preferred embodiment is a formulation that does not contain additives.

[0073] A "coating agent" is a component used to cover the surface of a pharmaceutical product. It is used to prevent contact with water, air, and light, to mask odors and bitter tastes, to impart pharmaceutical properties such as sustained release or enteric coating, or to enhance the product's appearance and thus increase its market value. The coating agent is not particularly limited, but examples include, but is not limited to, combinations of a base material such as hypromellose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer, etc., with a plasticizer such as polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, glycerin fatty acid ester, etc. Additives such as titanium dioxide, iron oxide, talc, and colorants may also be added. Mixtures of these additives may also be used, such as OPADRY.

[0074] "Coloring agents" refer to ingredients used for identifying capsules or tablets, protecting the contents of pharmaceuticals from light, or adding commercial value. While not particularly limited, coloring agents include, for example, tar dyes, lake dyes, yellow ferric oxide, ferric oxide, or titanium dioxide. Furthermore, after film coating, carnauba wax, talc, etc., may be added as glossing agents.

[0075] The preparation of the oral formulations of this disclosure varies depending on the desired dosage form, but the desired dosage form can be obtained by conventional methods. (1) Preparation of aqueous solution of binder: The binder is dissolved in purified water. The amount of binder is selected from, for example, 1 to 20% by weight relative to the amount of purified water, preferably from 2 to 8% by weight.

[0076] (2) Preparation of drug-containing granules of the present disclosure: The drug, water-soluble excipient, and disintegrant of this disclosure are charged into a granulator, and the binder prepared in step (1) above is sprayed onto the granulator while granulation is performed. Alternatively, the drug, water-soluble excipient, disintegrant, and binder of this disclosure can be charged into a granulator while granulation is performed while spraying a solvent such as water onto the granulator. Examples of granulation equipment include fluid bed granulation, high-share granulation, roto fluid bed granulation, and twin-screw continuous granulation. However, the equipment is not limited to these.

[0077] (3) Drying of the granules: The above granulated material is dried under reduced pressure or atmospheric pressure. This drying is carried out so that the loss on drying, as measured by an infrared moisture meter, is, for example, 4% by weight or less, preferably 2% by weight or less.

[0078] (4) Formulation of lubricant: Add a lubricant to the dried granules as described in (3) above and mix. Mixing is performed using a mixer classified as a diffusion mixer (Tumble), for example. Specifically, this includes tumble blenders, V blenders, double cone blenders, bin tumblers, etc. However, it is not limited to these.

[0079] (5) Tablet compression: Tablets are prepared by compressing the above mixture into tablets. Examples of tablet presses include tablet presses. The compression pressure is set by selecting the tablet hardness from a range such as 20 to 250 N.

[0080] (6) Apply a film coating as desired: The above tablets may be film-coated as needed. Examples of coating devices include those classified as coating pans. A preferred example is a device classified as a perforated coating system.

[0081] (7) Drying: The tablets obtained as described above are dried. Drying is carried out under reduced pressure or atmospheric pressure, so that the loss on drying, as measured by an infrared moisture meter, is, for example, 4% by weight or less, preferably 2% by weight or less.

[0082] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 4.0 to 6.0% by weight per 100% by weight of the formulation, (3) 2.0 to 10.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0083] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 5.0 to 6.0% by weight per 100% by weight of the formulation, (3) 4.0 to 6.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0084] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 4.5 to 6.0% by weight per 100% by weight of the formulation, (3) 2.0 to 10.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0085] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 4.0 to 6.0% by weight per 100% by weight of the formulation, (3) 4.0 to 10.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0086] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 4.5 to 6.0% by weight per 100% by weight of the formulation, (3) 4.0 to 10.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0087] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 5.0 to 5.5% by weight per 100% by weight of the formulation, (3) 4.0 to 10.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0088] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 5.0 to 6.0% by weight per 100% by weight of the formulation, (3) 4.0 to 10.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0089] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 5.0 to 5.5% by weight per 100% by weight of the formulation, (3) 2.0 to 10.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0090] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 4.5 to 6.0% by weight per 100% by weight of the formulation, (3) 2.0 to 6.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0091] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 4.5 to 6.0% by weight per 100% by weight of the formulation, (3) 4.0 to 6.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0092] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) A binder in an amount of 5.0 to 5.5% by weight per 100% by weight of the formulation, (3) 2.0 to 6.0% by weight of a lubricant per 100% by weight of the preparation An oral solid dosage form is provided which contains (4) an excipient, (5) a disintegrant, and / or (6) an additive, as needed.

[0093] In one embodiment of this disclosure, (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 5.0 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the preparation, (3) 4.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) Croscarmellose sodium An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0094] In one embodiment of this disclosure, (1) 15 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 5.0 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0095] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 5.0 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0096] In one embodiment of this disclosure, (1) 15 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.5 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0097] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.0 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 2.0 to 10.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0098] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.0 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 10.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0099] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.5 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 2.0 to 10.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0100] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.5 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 10.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0101] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.5 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 2.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0102] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.5 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0103] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 5.0 to 5.5% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 2.0 to 10.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0104] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 5.0 to 5.5% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 10.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0105] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 5.0 to 5.5% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 2.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0106] In one embodiment of this disclosure, (1) 20 to 38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 5.0 to 5.5% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0107] In one embodiment of this disclosure, (1) 20 to 30% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.5 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 2.0 to 10.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0108] In one embodiment of this disclosure, (1) 20 to 30% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.5 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 10.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0109] In one embodiment of this disclosure, (1) 20 to 30% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 4.5 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0110] In one embodiment of this disclosure, (1) 20 to 30% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, (2) 5.0 to 6.0% by weight of hydroxypropyl cellulose per 100% by weight of the formulation, (3) 4.0 to 6.0% by weight of sodium stearyl fumarate per 100% by weight of the preparation (4) A mixture of partially pregelatinized starch and D-mannitol, and (5) 0.5 to 20.0% by weight of croscarmellose sodium per 100% by weight of the preparation An oral solid dosage form is provided which contains (6) an additive, and which may further contain (6) an additive as needed.

[0111] [2] Pharmaceutical uses of oral solid dosage forms The drugs disclosed herein exert their anticancer effects by inhibiting the binding of menin to MLL (mixed lineage leukemia) fusion proteins, which are fused with representative fusion partner genes such as AF4 and AF9 that cause MLL leukemia, and are effective as antitumor agents. Therefore, this disclosure relates to pharmaceutical compositions, therapeutic agents and / or prophylactic agents for treating cancer, preferably oral solid dosage forms, comprising the drugs disclosed herein.

[0112] In this disclosure, "prevention" refers to the act of administering the drug disclosed, which is the active ingredient, to a healthy person who has not developed a disease or is in good health at the time of administration. A "preventive agent" is administered to such a healthy person and is intended, for example, to prevent the onset of a disease. It is expected to be particularly appropriate for people who have previously experienced symptoms of the disease or who are considered to be at increased risk of developing the disease. "Treatment" refers to the act of administering the drug disclosed, which is the active ingredient, to a person (patient) who has been diagnosed by a physician with a disease. A "therapeutic agent" is administered to such a patient and is intended, for example, to alleviate the disease or symptoms, prevent the disease or symptoms from worsening, or return to the state before the onset of the disease. Furthermore, even if the purpose of administration is to prevent the worsening of a disease or symptoms, if it is administered to a patient, it is considered a therapeutic act.

[0113] In this disclosure, “cancer” and “tumor” are synonymous and both refer to malignant tumors, including carcinoma, sarcoma and hematological malignancies. Specific examples of “cancer” or “tumor” include, for example, acute leukemia (including MLL acute leukemia, MLL partial tandem overlapping acute leukemia, NPM mutation acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, Examples of tumors include small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumors, testicular germ cell tumors, ovarian germ cell tumors, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, and skin cancer. Furthermore, the above tumors may be accompanied by increased expression or mutations of specific genes. Examples of tumors accompanied by increased gene expression include tumors with high expression of the HOXa gene group and tumors with high expression of the MEIS gene group. Examples of tumors accompanied by gene mutations include tumors with gain-of-function mutations in p53.

[0114] The drugs disclosed herein may be used in combination with "combination agents" for the purpose of enhancing their effects. Examples of "combination agents" include antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-coordinate compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine / threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, and other antitumor agents. Specific examples of "concomitant drugs" include, for example, azacitidine, vorinostat, decitabine, romidepsin, idarubicin, daunorubicin, doxorubicin, enocitabine, cytarabine, mitoxantrone, thioguanine, etoposide, ifosfamide, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, ranimustine, all-trans retinoic acid, tamibarotene, cisplatin, carboplatin, oxaliplatin, irinotecan, bleomycin, mitomycin C, methotrexate, paclitaxel, docetaxel, gemcitabine, tamoxifen, thiotepa, tegafur, fluorouracil, and everolim. S, Temsirolimus, Gefitinib, Erlotinib, Imatinib, Crizotinib, Osimertinib, Afatinib, Dasatinib, Bosutinib, Vandetanib, Sunitinib, Axitinib, Pazopanib, Lenvatinib, Lapatinib, Nilotinib, Ibrutinib, Ceritinib, Alectinib, Tofacitinib, Baricitinib, Ruxolitinib, Ora Examples include parib, sorafenib, vemurafenib, dabrafenib, trametinib, palbociclib, bortezomib, carfilzomib, rituximab, cetuximab, trastuzumab, bevacizumab, panitumumab, nivolumab, atezolizumab, mogamulizumab, alemtuzumab, ofatumumab, ipilimumab, ramucirumab, brentuximab, vedotin, gemtuzumab, ozogamicin, inotuzumab, and ozogamicin.

[0115] The timing of administration of the drug disclosed herein and the concomitant drug is not limited; they may be administered simultaneously to the target patient, or at appropriate intervals. Furthermore, the drug disclosed herein and the concomitant drug may be administered as a combination preparation, or the concomitant drug may be administered as a separate formulation from the drug disclosed herein, or via a different route of administration. The dosage of the concomitant drug can be appropriately selected based on clinically used doses. The mixing ratio of the drug disclosed herein and the concomitant drug can be appropriately selected depending on the target patient, route of administration, target disease, symptoms, combination, etc.

[0116] The compound, its pharmaceutically acceptable salt, or its hydrate or solvate may be administered orally or parenterally, but oral administration is preferred. The dosage varies depending on the method of administration, the patient's symptoms and age, etc., but is usually in the range of 0.01 to 30 mg / kg / day, preferably 0.05 to 20 mg / kg / day, and more preferably 0.1 to 10 mg / kg / day. Another preferred mode of dosage is usually in the range of 0.01 mg to 1600 mg / day, preferably 0.1 mg to 1200 mg / day, more preferably 0.5 mg to 1000 mg / day, even more preferably 1 mg to 800 mg / day, and most preferably 5 mg to 600 mg / day. The number of doses per day may be once or several times a day, for example, 1, 2, or 3 doses each time. [Examples]

[0117] Examples of the present disclosure are given below, but these examples are for illustrative purposes only and do not limit the present disclosure in any way. Furthermore, the present disclosure may be modified without departing from the scope of the present disclosure. Note that the compound names shown in the following examples, test examples and comparative examples do not necessarily follow IUPAC nomenclature.

[0118] In this example, test example, and comparative example, unless otherwise specified, percentages in solution refer to (wt%), and percentages in particles refer to weight %.

[0119] In this example, test example, and comparative example, the following additives were used unless otherwise specified. Hydroxypropyl cellulose (HPC-L (6 - 10 mPa·s 注1) )): Nippon Soda Co., Ltd. Polyvinyl alcohol (Gosenol TM EG-05P (4.5 - 6.1 mm 2 / s 注2) )) Hypromellose (TC-5 TM R (6 mPa·s 注1) )): Shin-Etsu Chemical Co., Ltd. Partially pregelatinized starch (PCS TM PC-10): Asahi Kasei Chemicals Corporation Croscarmellose sodium (Ac-Di-Sol TM ): DuPont Crospovidone (Kollidon TM CL): BASF Sodium starch glycolate (Primojel TM ): DFE Pharma Mannitol (PEARLITOL 50C): Roquette Sodium stearyl fumarate (PRUV TM ): JRS PHARMA GmbH & Co. KG Carnauba wax (Polishing wax 105): Nippon Wax Co., Ltd. Yellow ferric oxide S: Kisei Kasei Co., Ltd. Ferric oxide S: Kisei Kasei Co., Ltd. In addition, the OPADRY used in this example is a film coating agent that does not affect dissolution. Note 1) Manufacturer catalog value at 20°C, 2% solution. Note 2) Manufacturer catalog value at 20°C, 4% solution.

[0120] Example 1: A tablet containing the tartrate salt of this compound (1) A. Prescription of tablets containing the tartrate of this compound Granules, mixed powder, and tablets with the composition shown in Table 1-1 were manufactured. TIFF2026071393000002.tif68156

[0121] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (1) 2850g of purified water was placed in a stainless steel beaker, and 150g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (1).

[0122] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 1-2 and the manufacturing conditions listed in Table 1-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 1-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the 5 wt% hydroxypropyl cellulose solution (1) listed in Table 1-2 was sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000003.tif48155 TIFF2026071393000004.tif63155

[0123] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 1-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 1-4, were placed into a plastic bag, followed by the addition of stearyl sodium fumarate, according to the amounts listed in Table 1-4, and the bag was mixed (50 rotations vertically, 50 rotations horizontally, for a total of 100 rotations). TIFF2026071393000005.tif29155

[0124] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 50 mg of the tartrate salt of this compound were produced by compressing them using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 1-5. TIFF2026071393000006.tif34155

[0125] (5) Preparation of film coating solution (1) 540.0g of purified water was placed in a stainless steel tank, and 60.0g of a coating component mixture consisting of hypromellose, titanium dioxide, propylene glycol, yellow ferric oxide, and ferric oxide was gradually added while stirring to disperse and dissolve the mixture. This solution was passed through a 108μm mesh screen to obtain film coating solution (1).

[0126] (6) Manufacturing of film-coated tablets containing the tartrate of this compound Film-coated tablets containing the tartrate salt of this compound were manufactured under the conditions described in Table 1-6. First, 231.16 g of uncoated tablets were placed in a coating machine (HC-LABO type, manufactured by Freund Industrial Co., Ltd.), and the coating pan was heated under the conditions in Table 1-6 until the exhaust temperature reached 45°C while the coating pan was rotated in an inching motion. Next, while rotating the coating pan at 20 rpm, film coating solution (1) was sprayed under the conditions in Table 1-6 until the film coating amount reached approximately 3.8 mg. After that, the coating pan was dried while rotating at 12 rpm until the exhaust temperature reached 50°C. After removing the tablets, polishing wax 105 was added, the mixture was bagged and polished. TIFF2026071393000007.tif68155

[0127] Example 2: Tablets containing the tartrate salt of this compound (2) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 2-1. TIFF2026071393000008.tif68156

[0128] B. Manufacturing method (1) Preparation of a 5 wt% hydroxypropyl cellulose solution (2) 1900g of purified water was placed in a stainless steel beaker, and 100g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (2).

[0129] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 2-2 and the manufacturing conditions listed in Table 2-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 2-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, while fluidized, the amount of 5.5 wt% hydroxypropyl cellulose solution (2) listed in Table 2-2 was sprayed onto the mixture. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000009.tif48155 TIFF2026071393000010.tif63155

[0130] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 2-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 2-4, were placed into a plastic bag, followed by the addition of stearyl sodium fumarate, according to the amounts listed in Table 2-4, and the bag was mixed (50 rotations vertically, 50 rotations horizontally, for a total of 100 rotations). TIFF2026071393000011.tif29155

[0131] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 50 mg of the tartrate salt of this compound were produced by compressing them using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 2-5. TIFF2026071393000012.tif34155

[0132] Example 3: Tablets containing the tartrate salt of this compound (3) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 3-1. TIFF2026071393000013.tif68156

[0133] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (3) 2850g of purified water was placed in a stainless steel beaker, and 150g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (3).

[0134] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 3-2 and the manufacturing conditions listed in Table 3-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 3-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the amounts of 5 wt% hydroxypropyl cellulose solution (3) listed in Table 3-2 were sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000014.tif48156 TIFF2026071393000015.tif63155

[0135] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 3-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 3-4, were placed in a 10L V-type container. Subsequently, the amount of sodium stearyl fumarate, according to the amounts listed in Table 3-4, was added, and the mixture was mixed for 10 minutes at 40 rpm using a mixer (S-5 type, manufactured by Tsutsui Chemical Instruments Co., Ltd.). TIFF2026071393000016.tif29155

[0136] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 25 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 3-5. TIFF2026071393000017.tif34155

[0137] (5) Preparation of film coating solution (2) 1800.00 g of purified water was weighed out. 0.32 g of yellow ferric oxide and 0.16 g of ferric oxide were added to a portion of the purified water and dispersed using a Robomix (TK Homomixer MARK2.5 type). 199.52 g of a coating component mixture consisting of hypromellose, titanium dioxide, and propylene glycol was gradually added to a portion of the purified water while stirring, and dispersed and dissolved. A solution containing dispersed dye was added to this solution. Finally, this solution was passed through a 108 μm mesh screen to obtain film coating solution (2).

[0138] (6) Manufacturing of film-coated tablets containing the tartrate of this compound Film-coated tablets containing the tartrate of this compound were manufactured under the conditions described in Table 3-6. First, 400.00 g of uncoated tablets were placed in a coating machine (HC-LABO type, manufactured by Freund Industrial Co., Ltd.), and the coating pan was heated under the conditions in Table 3-6 until the exhaust temperature reached 45°C while the coating pan was rotated in an inching motion. Next, the coating pan was rotated at 20 rpm while film coating solution (2) was sprayed under the conditions in Table 3-6 until the film coating amount reached approximately 2.4 mg. After that, the coating pan was rotated at 12 rpm and dried until the exhaust temperature reached 50°C. After removing the tablets, polishing wax 105 was added, the mixture was bagged and polished. TIFF2026071393000018.tif68155

[0139] Example 4: Tablets containing the tartrate salt of the compound (4) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 4-1. TIFF2026071393000019.tif68156

[0140] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (4) 2850g of purified water was placed in a stainless steel beaker, and 150g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (4).

[0141] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 4-2 and the manufacturing conditions listed in Table 4-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 4-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the 5 wt% hydroxypropyl cellulose solution (4) listed in Table 4-2 was sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000020.tif48155 TIFF2026071393000021.tif63155

[0142] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 4-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 4-4, were placed in a 10L V-type container. Subsequently, the amount of sodium stearyl fumarate, according to the amounts listed in Table 4-4, was added, and the mixture was mixed at 40 rpm for 10 minutes using a mixer (S-5 type, manufactured by Tsutsui Chemical Instruments Co., Ltd.). TIFF2026071393000022.tif29155

[0143] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 50 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 4-5. TIFF2026071393000023.tif34155

[0144] (5) Preparation of film coating solution (3) 900.00 g of purified water was weighed out. 0.24 g of yellow iron(III) oxide was added to a portion of the purified water and dispersed using a Robomix (TK Homomixer MARK2.5). 99.76 g of a coating component mixture consisting of hypromellose, titanium dioxide, and propylene glycol was gradually added to a portion of the purified water while stirring, and dispersed and dissolved. A solution containing dispersed dye was added to this solution. Finally, this solution was passed through a 108 μm mesh screen to obtain film coating solution (3).

[0145] (6) Manufacturing of film-coated tablets containing the tartrate of this compound Film-coated tablets containing the tartrate salt of this compound were manufactured under the conditions described in Table 4-6. First, 367.43 g of uncoated tablets were placed in a coating machine (HC-LABO type, manufactured by Freund Industrial Co., Ltd.), and the coating pan was heated under the conditions in Table 4-6 until the exhaust temperature reached 45°C while the coating pan was rotated in an inching motion. Next, the coating pan was rotated at 20 rpm, and film coating (3) was sprayed under the conditions in Table 4-6 until the film thickness reached approximately 3.8 mg. After that, the coating pan was rotated at 12 rpm and dried until the exhaust temperature reached 50°C. After removing the tablets, polishing wax 105 was added, the mixture was bagged, and polished. TIFF2026071393000024.tif68155

[0146] Example 5: Tablets containing the tartrate salt of the compound (5) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 5-1. TIFF2026071393000025.tif68156

[0147] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (5) 2850g of purified water was placed in a stainless steel beaker, and 150g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (5).

[0148] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 5-2 and the manufacturing conditions listed in Table 5-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 5-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidizing until the exhaust temperature reached 40°C. Next, the amounts of 5 wt% hydroxypropyl cellulose solution (5) listed in Table 5-2 were sprayed while fluidizing. After that, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000026.tif48156 TIFF2026071393000027.tif63155

[0149] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 5-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 5-4, were placed in a 10L V-type container. Subsequently, the amount of sodium stearyl fumarate, according to the amounts listed in Table 5-4, was added, and the mixture was mixed at 40 rpm for 10 minutes using a mixer (S-5 type, manufactured by Tsutsui Chemical Instruments Co., Ltd.). TIFF2026071393000028.tif29155

[0150] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 125 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 5-5. TIFF2026071393000029.tif34155

[0151] (5) Preparation of film coating solution (4) 900.00 g of purified water was weighed out. 0.24 g of ferric oxide was added to a portion of the purified water and dispersed using a Robomix (TK Homomixer MARK2.5 type). 99.76 g of a coating component mixture consisting of hypromellose, titanium dioxide, and propylene glycol was gradually added to a portion of the purified water while stirring, and dispersed and dissolved. A solution containing dispersed dye was added to this solution. Finally, this solution was passed through a 108 μm mesh screen to obtain the film coating solution (4).

[0152] (6) Manufacturing of film-coated tablets containing the tartrate of this compound Film-coated tablets containing the tartrate salt of this compound were manufactured under the conditions described in Table 5-6. First, 366.80 g of uncoated tablets were placed in a coating machine (HC-LABO type, manufactured by Freund Industrial Co., Ltd.), and the coating pan was heated under the conditions in Table 5-6 until the exhaust temperature reached 45°C while the coating pan was rotated in an increment. Next, the coating pan was rotated at 20 rpm, and film coating (4) was sprayed under the conditions in Table 1-6 until the film thickness reached approximately 6.0 mg. After that, the coating pan was rotated at 12 rpm and dried until the exhaust temperature reached 50°C. After removing the tablets, polishing wax 105 was added, the mixture was bagged, and polished. TIFF2026071393000030.tif68155

[0153] Example 6: Tablets containing the tartrate salt of this compound (6) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 6-1. TIFF2026071393000031.tif68156

[0154] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (6) 2850g of purified water was placed in a stainless steel beaker, and 150g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (6).

[0155] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 6-2 and the manufacturing conditions listed in Table 6-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 6-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the amount of 5 wt% hydroxypropyl cellulose solution (6) listed in Table 6-2 was sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000032.tif48155 TIFF2026071393000033.tif63155

[0156] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 6-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 6-4, were placed in a 10L V-type container. Subsequently, stearyl sodium fumarate, according to the amounts listed in Table 6-4, was added, and the mixture was mixed at 40 rpm for 10 minutes using a mixer (S-5 type, manufactured by Tsutsui Chemical Instruments Co., Ltd.). TIFF2026071393000034.tif29155

[0157] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 50 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 6-5. TIFF2026071393000035.tif34155

[0158] Example 7: Tablets containing the tartrate salt of this compound (7) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 7-1. TIFF2026071393000036.tif68156

[0159] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (7) 2850g of purified water was placed in a stainless steel beaker, and 150g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (7).

[0160] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 7-2 and the manufacturing conditions listed in Table 7-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 7-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the amounts of 5 wt% hydroxypropyl cellulose solution (7) listed in Table 7-2 were sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000037.tif48155 TIFF2026071393000038.tif63155

[0161] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 7-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 7-4, were placed in a 10L V-type container. Subsequently, stearyl sodium fumarate, according to the amounts listed in Table 7-4, was added, and the mixture was mixed for 10 minutes at 40 rpm using a mixer (S-5 type, manufactured by Tsutsui Chemical Instruments Co., Ltd.). TIFF2026071393000039.tif29155

[0162] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 50 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 7-5. TIFF2026071393000040.tif34155

[0163] Example 8: Tablets containing the tartrate salt of this compound (8) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 8-1. TIFF2026071393000041.tif68156

[0164] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (8) 2850g of purified water was placed in a stainless steel beaker, and 150g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (8).

[0165] (2) Preparation of granular granules containing the tartrate of this compound Granular particles containing the tartrate of this compound were produced under the charged amounts described in Table 8-2 and the production conditions described in Table 8-3. First, the tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium in the charged amounts described in Table 8-2 were put into a fluidized bed granulator dryer (manufactured by Powrex Corporation, Multiplex MP-01 type), and mixed while being fluidized until the exhaust temperature reached 40°C. Subsequently, a 5 wt% hydroxypropyl cellulose solution (8) in the charged amount described in Table 8-2 was sprayed while being fluidized. Then, after drying while being fluidized until the exhaust temperature reached 45°C, it was taken out from the container. Further, the taken-out granules were passed through a sieve with a mesh opening of 710 μm to obtain granular particles containing the tartrate of this compound. TIFF2026071393000042.tif48155 TIFF2026071393000043.tif63155

[0166] (3) Production of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate of this compound was produced with the charged amounts described in Table 8-4. Granular particles containing the tartrate of this compound in the charged amount described in Table 8-4 were put into a 10 L V-type container, and subsequently, sodium stearyl fumarate in the charged amount described in Table 8-4 was added, and mixed at 40 rpm for 10 minutes using a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd., S-5 type). TIFF2026071393000044.tif29155

[0167] (4) Production of tablets containing the tartrate of this compound Tablets were produced under the conditions of Table 8-5 using a rotary tablet press (manufactured by Kikusui Seisakusho, VELC) so that 25 mg of the tartrate of this compound was contained in one tablet. TIFF2026071393000045.tif34155

[0168] (5) Preparation of film coating solution (5) 1800.00 g of purified water was weighed. 0.32 g of yellow ferric oxide and 0.16 g of ferric oxide were added to a part of the purified water and dispersed with a Robomix (T.K. Homomixer MARK2.5 type). While stirring, 199.52 g of a coating component mixture composed of hypromellose, titanium oxide, and propylene glycol was gradually added to a part of the purified water and dispersed and dissolved. A solution in which a pigment was dispersed was added to this solution. Finally, this liquid was passed through a screen with a mesh opening of 108 μm to obtain a film coating solution (5).

[0169] (6) Production of film-coated tablets containing the tartrate of this compound Film-coated tablets containing the tartrate of this compound were produced under the conditions described in Table 8-6. First, 400.06 g of core tablets were put into a coating machine (manufactured by Freund Industry Co., Ltd., HC-LABO type), and while the coating pan was rotated in jog mode, it was heated until the exhaust temperature reached 45 °C under the conditions of Table 8-6. Subsequently, while the coating pan was rotated at 20 rpm, the film coating solution (5) was sprayed under the conditions of Table 8-6, and film coating was performed until the coating amount reached approximately 2.4 mg. Thereafter, while the coating pan was rotated at 12 rpm, it was dried until the exhaust temperature reached 50 °C. After taking out the tablets, 105 polishing wax was added, followed by bag mixing and glazing. TIFF2026071393000046.tif68155

[0170] Example 9: Tablets containing the tartrate salt of this compound (9) A. Prescription of core tablets containing the tartrate of this compound Granules, mixed powder, and core tablets having the composition shown in Table 9-1 were produced. TIFF2026071393000047.tif68156

[0171] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (9) 3325g of purified water was placed in a stainless steel beaker, and 175g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (9).

[0172] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 9-2 and the manufacturing conditions listed in Table 9-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 9-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the amount of 5 wt% hydroxypropyl cellulose solution (9) listed in Table 9-2 was sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000048.tif48155 TIFF2026071393000049.tif63155

[0173] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 9-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 9-4, were placed into a plastic bag, followed by the addition of stearyl sodium fumarate, according to the amounts listed in Table 9-4, and the bag was mixed (50 rotations vertically, 50 rotations horizontally, for a total of 100 rotations). TIFF2026071393000050.tif29155

[0174] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 125 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 9-5. TIFF2026071393000051.tif34155

[0175] Example 10: Tablets containing the tartrate salt of this compound (10) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 10-1. TIFF2026071393000052.tif68156

[0176] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (10) 24624g of purified water was placed in a stainless steel beaker, and 1296g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (10).

[0177] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 10-2 and the manufacturing conditions listed in Table 10-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 10-2 were placed in a fluidized bed granulator (NFLF-30SJC model, manufactured by Freund Industrial Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the 5 wt% hydroxypropyl cellulose solution (10) listed in Table 10-2 was sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a cormill for dry sizing to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000053.tif48155 TIFF2026071393000054.tif51155

[0178] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate of this compound was produced with the charged amounts described in Table 10-4. Granules containing the tartrate of this compound with the charged amounts described in Table 10-4 were put into a 110L hopper bin, and then sodium stearyl fumarate with the charged amounts described in Table 10-4 was added. They were mixed at 20 rpm for 15 minutes using a mixer (manufactured by Yamazaki Metal Industry Co., Ltd., model MB02-001). TIFF2026071393000055.tif29155

[0179] (4) Manufacture of tablets containing the tartrate of this compound Tablets were manufactured under the conditions of Table 10-5 using a rotary tablet press (manufactured by Kikusui Seisakusho Co., Ltd., model AQUARIUS3-A) so that each tablet contained 125 mg of the tartrate of this compound. TIFF2026071393000056.tif34155

[0180] (5) Preparation of film coating solution (6) 10800 g of purified water was weighed. 9.6 g of yellow ferric oxide and 4.8 g of ferric oxide were put into a part of the purified water and dispersed using Robomix (T.K. Homojetter O type, Homomixer MARKII40 type). While stirring, 1185.6 g of a coating component mixture consisting of hypromellose, titanium oxide, and propylene glycol was gradually put into a part of the purified water and dispersed and dissolved. A solution in which the pigment was dispersed was added to this solution. Finally, this solution was passed through a screen with a mesh size of 108 μm to obtain the film coating solution (6).

[0181] (6) Manufacture of film-coated tablets containing the tartrate of this compound Film-coated tablets containing the tartrate of this compound were manufactured under the conditions described in Table 10-6. The uncoated tablets to be used for film coating were placed in a coating machine (Freund Industrial Co., Ltd., AQC-80 model), and the coating pan was heated under the conditions in Table 10-6 until the exhaust temperature reached 50°C while the coating pan was rotated in short increments. Subsequently, the coating pan was rotated at 10 rpm while the film coating solution (6) was sprayed under the conditions in Table 10-6 until the film coating amount reached approximately 7.5 mg. After that, the coating pan was dried while rotating intermittently at 4.0 rpm until the exhaust temperature reached 60°C. After drying was complete, polishing wax 105 was added to the tablets to produce film-coated tablets. TIFF2026071393000057.tif63155

[0182] Example 11: Tablets containing the tartrate salt of this compound (11) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 11-1. TIFF2026071393000058.tif68156

[0183] B. Manufacturing method (1) Preparation of 5 wt% polyvinyl alcohol solution (1) Approximately 500g of purified water was placed in a stainless steel beaker, and 100g of EG-05P was gradually added and dispersed. Approximately 1500g of purified water was heated to 80°C and added to the dispersed solution, where it was dissolved. After standing overnight, the mixture was stirred again, and the weight was corrected to account for the evaporated purified water, so that a total of 2000g of 5wt% polyvinyl alcohol solution (1) was prepared.

[0184] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 11-2 and the manufacturing conditions listed in Table 11-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 11-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the amounts of 5 wt% polyvinyl alcohol solution (1) listed in Table 11-2 were sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000059.tif48155 TIFF2026071393000060.tif63155

[0185] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 11-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 11-4, were placed in a 10L V-type container. Subsequently, stearyl sodium fumarate, according to the amounts listed in Table 11-4, was added, and the mixture was mixed at 40 rpm for 10 minutes using a mixer (S-5 type, manufactured by Tsutsui Chemical Instruments Co., Ltd.). TIFF2026071393000061.tif29155

[0186] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 25 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 11-5. TIFF2026071393000062.tif34155

[0187] Example 12: Tablets containing the tartrate salt of this compound (12) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 12-1. TIFF2026071393000063.tif66156

[0188] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (11) 2375g of purified water was placed in a stainless steel beaker, and 125g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (11).

[0189] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 12-2 and the manufacturing conditions listed in Table 12-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and crospovidone listed in Table 12-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the amounts of 5 wt% hydroxypropyl cellulose solution (11) listed in Table 12-2 were sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000064.tif48155 TIFF2026071393000065.tif63155

[0190] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 12-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 12-4, were placed in a 10L V-type container. Subsequently, stearyl sodium fumarate, according to the amounts listed in Table 12-4, was added, and the mixture was mixed at 40 rpm for 10 minutes using a mixer (S-5 type, manufactured by Tsutsui Chemical Instruments Co., Ltd.). TIFF2026071393000066.tif29155

[0191] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions shown in Table 12-5, with each tablet containing 25 mg of the tartrate salt of this compound. TIFF2026071393000067.tif34155

[0192] Example 13: Tablets containing the tartrate salt of this compound (13) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 13-1. TIFF2026071393000068.tif68156

[0193] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (12) 2375g of purified water was placed in a stainless steel beaker, and 125g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (12).

[0194] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 13-2 and the manufacturing conditions listed in Table 13-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and sodium starch glycolate listed in Table 13-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the amounts of 5 wt% hydroxypropyl cellulose solution (12) listed in Table 13-2 were sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000069.tif48155 TIFF2026071393000070.tif63155

[0195] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 13-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 13-4, were placed in a 10L V-type container. Subsequently, the amount of stearyl sodium fumarate, according to the amounts listed in Table 13-4, was added, and the mixture was mixed at 40 rpm for 10 minutes using a mixer (S-5 type, manufactured by Tsutsui Rikagakukikai Co., Ltd.). TIFF2026071393000071.tif29155

[0196] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 25 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 13-5. TIFF2026071393000072.tif34155

[0197] Example 14: Tablets containing the tartrate salt of this compound (14) In this example, the following partially pregelatinized starch products were used. STARCH1500 TM :Colorcon A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 14-1. TIFF2026071393000073.tif68155

[0198] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (13) 2375g of purified water was placed in a stainless steel beaker, and 125g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (13).

[0199] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 14-2 and the manufacturing conditions listed in Table 14-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 14-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the amounts of 5 wt% hydroxypropyl cellulose solution (13) listed in Table 14-2 were sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000074.tif48156 TIFF2026071393000075.tif63155

[0200] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 14-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 14-4, were placed in a 10L V-type container. Subsequently, the amount of sodium stearyl fumarate, according to the amounts listed in Table 14-4, was added, and the mixture was mixed at 40 rpm for 10 minutes using a mixer (S-5 type, manufactured by Tsutsui Rikagakukikai Co., Ltd.). TIFF2026071393000076.tif29155

[0201] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 25 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 14-5. TIFF2026071393000077.tif34155

[0202] Comparative Example 1: Tablets containing the tartrate salt of the compound (15) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 15-1. TIFF2026071393000078.tif68155

[0203] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (14) 684 g of purified water was placed in a stainless steel beaker, and 36 g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5 wt% hydroxypropyl cellulose solution (14).

[0204] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 15-2 and the manufacturing conditions listed in Table 15-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 15-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the 5 wt% hydroxypropyl cellulose solution (14) listed in Table 15-2 was sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000079.tif47155 TIFF2026071393000080.tif62155

[0205] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 15-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 15-4, were placed into a plastic bag, followed by the addition of stearyl sodium fumarate, according to the amounts listed in Table 15-4, and the bag was mixed (50 rotations vertically, 50 rotations horizontally, for a total of 100 rotations). TIFF2026071393000081.tif29155

[0206] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 50 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 15-5. TIFF2026071393000082.tif34155

[0207] Comparative Example 2: Tablets containing the tartrate salt of the compound (16) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 16-1. TIFF2026071393000083.tif68155

[0208] B. Manufacturing method (1) Preparation of 5 wt% hydroxypropyl cellulose solution (15) 684g of purified water was placed in a stainless steel beaker, and 36g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (15).

[0209] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 16-2 and the manufacturing conditions listed in Table 16-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 16-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the amounts of 5 wt% hydroxypropyl cellulose solution (15) listed in Table 16-2 were sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000084.tif48156 TIFF2026071393000085.tif63155

[0210] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 16-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 16-4, were placed into a plastic bag, followed by the addition of magnesium stearate, according to the amounts listed in Table 16-4, and the bag was mixed (50 rotations vertically, 50 rotations horizontally, for a total of 100 rotations). TIFF2026071393000086.tif29155

[0211] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 50 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 16-5. TIFF2026071393000087.tif34155

[0212] Comparative Example 3: Tablets containing the tartrate salt of the compound (17) A. Prescription of uncoated tablets containing the tartrate salt of this compound. Granulated granules, mixed powders, and uncoated tablets were manufactured with the compositions shown in Table 17-1. TIFF2026071393000088.tif68156

[0213] B. Manufacturing method (1) Preparation of 5 wt% hypromellose solution (1) 1900g of purified water was placed in a stainless steel beaker, and 100g of HPC-L was gradually added while stirring to dissolve it. After standing overnight, the mixture was stirred again to prepare a 5wt% hypromellose solution (1).

[0214] (2) Preparation of granular granules containing the tartrate of this compound Granulated granules containing the tartrate of this compound were produced using the amounts listed in Table 17-2 and the manufacturing conditions listed in Table 17-3. First, the amounts of tartrate of this compound, D-mannitol, partially pregelatinized starch, and croscarmellose sodium listed in Table 17-2 were placed in a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) and mixed while fluidized until the exhaust temperature reached 40°C. Next, the 5 wt% hypromellose solution (1) listed in Table 17-2 was sprayed while fluidized. After that, the mixture was dried while fluidized until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then passed through a sieve with a mesh size of 710 μm to obtain granulated granules containing the tartrate of this compound. TIFF2026071393000089.tif48155 TIFF2026071393000090.tif63155

[0215] (3) Preparation of a mixed powder containing the tartrate of this compound A mixed powder containing the tartrate salt of this compound was prepared using the amounts listed in Table 17-4. Granulated granules containing the tartrate salt of this compound, according to the amounts listed in Table 17-4, were placed in a 10L V-type container. Subsequently, stearyl sodium fumarate, according to the amounts listed in Table 17-4, was added, and the mixture was mixed at 40 rpm for 10 minutes using a mixer (S-5 type, manufactured by Tsutsui Chemical Instruments Co., Ltd.). TIFF2026071393000091.tif29155

[0216] (4) Manufacturing of uncoated tablets containing the tartrate of this compound Tablets containing 25 mg of the tartrate salt of this compound were produced using a rotary tablet press (VELC, manufactured by Kikusui Seisakusho) under the conditions shown in Table 17-5. TIFF2026071393000092.tif34155

[0217] The formulations obtained by the method described above were evaluated for quality using the following method. Test Example 1: Evaluation of tablet compressibility and measurement of the shape, hardness, and abrasion of uncoated tablets. For Examples 1-14 and Comparative Examples 1-2, the tablet compressibility was evaluated, and the thickness, hardness, and abrasion of the uncoated tablets were measured. The thickness of the uncoated tablets was measured using a special digital thickness gauge 547-301, and the hardness was measured using a tablet breaking strength meter TH-203MP manufactured by Toyama Sangyo Co., Ltd., with the average value of 5 or 10 tablets recorded. The abrasion of the tablets was measured according to the test method described in the Japanese Pharmacopoeia, using a FRIABILATOR TFT-1200 manufactured by Toyama Sangyo Co., Ltd. The measurement results are shown in Table 18. TIFF2026071393000093.tif161156 Table 18 shows that Examples 1-14 exhibited good tablet properties, hardness, and abrasion resistance. Comparative Example 1, which contained 2% binder and 2% lubricant, experienced sticking, resulting in poor tablet properties and low hardness of the uncoated tablet. In Comparative Example 2, which used 1% magnesium stearate as a lubricant, not only did sticking occur but die friction was also observed, and the hardness was even lower than in Comparative Example 1, making continuous tableting difficult. It became clear that by using 4% or more binder and 2% or more lubricant, it is possible to produce tablets that exhibit significantly superior tablet properties and high hardness.

[0218] Test Example 2: Dissolution Test For Examples 1-14 and Comparative Example 3, dissolution tests were performed under the following conditions, in accordance with the dissolution test method of the General Test Methods of the Japanese Pharmacopoeia. <Dissolution Test Conditions> Method: Dissolution test method (paddle method) according to the general test methods of the Japanese Pharmacopoeia Rotation speed: 50 rpm Test solution volume: 900 mL Test solution temperature: 37℃±0.5℃ Test solution: 0.1N HCl <Preparation of sample solution> A tablet was placed in a test apparatus containing 900 mL of test solution. At 5, 10, and 15 minutes after the start of the test, 10 mL of the test solution was taken using a 10 mL syringe and slowly filtered using a membrane filter with a pore size of 0.45 μm or less. The initial filtrate of 2 mL or more was removed and used as the sample solution. <Preparation of standard solutions> 50.00 mg of the tartrate salt of this compound was weighed into a 300 mL volumetric flask and dissolved using the elution test solution. This solution was then weighed into a 30 mL volumetric flask to a volumetric volumetric flask to a volumetric volumetric flask and dissolved using the elution test solution. This was used as the mother liquor for the standard solution. This mother liquor was used to dilute each sample according to its dosage, and these dilutions were used as standard solutions. <High-performance liquid chromatography analysis conditions 1> Analysis condition 1 was used in the tests of Example 1 and Example 2. High-performance liquid chromatography system: Shimadzu Corporation UFLC-XR Detection wavelength: 260 nm Column: Waters Xselect CSH C18 150mm x 4.6mm ID, particle size 3.5μm Mobile phase: Water / methanol / perchloric acid mixture (1000 / 1000 / 1) Analysis time: 5 minutes Flow rate: 0.8mL / min Column temperature: 40℃ Injection volume: 5μL Sample cooler temperature: 5℃ Syringe washing solution: Methanol / water mixture (1 / 1) <High-performance liquid chromatography analysis conditions 2> Analytical condition 2 was used in the tests of Examples 3-14 and Comparative Example 3. High-performance liquid chromatography system: Shimadzu Corporation UFLC-XR Detection wavelength: 260 nm Column: Waters Xselect CSH C18 150mm x 4.6mm ID, particle size 3.5μm Mobile phase: Water / methanol / perchloric acid mixture (1000 / 1000 / 3) Analysis time: 5 minutes Flow rate: 0.8mL / min Column temperature: 40℃ Injection volume: 5μL Sample cooler temperature: 25℃ Syringe washing solution: Methanol / water mixture (1 / 1)

[0219] The dissolution test results are shown in Table 19. TIFF2026071393000094.tif141153 As shown in Table 19, the uncoated tablets or FC tablets of the present invention dissolve rapidly, and high absorption in the body is expected. Furthermore, although there was a slight difference in the initial stage of dissolution depending on whether or not film coating was present, there was almost no difference in the dissolution rate at 15 minutes, indicating that it did not affect dissolution performance. Despite using relatively large amounts of binders and lubricants, we were able to manufacture tablets that dissolve rapidly and exhibit good dissolution performance.

[0220] Test Example 3: Storage Stability Test (Purity Test) The constant temperature and humidity chamber was set to 40°C / 75%RH or 50°C / 85%RH. The tablets prepared in Examples 1-14 were placed in HDPE bottles or brown screw-cap test tubes (material: glass), and stored in the constant temperature and humidity chamber for a predetermined period in an open state. After that, a purity test was performed and the amount of related substances was evaluated. Test condition 1 Test condition 1 was used in the tests of Example 1 and Example 2. Detector: UV absorbance spectrophotometer (measurement wavelength 220 nm) Column: Waters Xselect CSH C18 150mm x 4.6mm ID, particle size 3.5μm Column temperature: Constant temperature around 40°C Mobile phase A: Water / perchloric acid mixture (10000:1) Mobile phase B: methanol Elution method: Gradient method Flow rate: 0.8mL / min Area measurement range: 50 minutes after injection Sample cooler temperature: 5℃ Dissolving solvent: Water / methanol / perchloric acid mixture (1000 / 1000 / 1) Syringe washing solution: Methanol / water mixture (1 / 1) Test condition 2 Test condition 2 was used in the tests of Examples 3 to 14. Detector: UV absorbance spectrophotometer (measurement wavelength 220 nm) Column: Waters Xselect CSH C18 150mm x 4.6mm ID, particle size 3.5μm Column temperature: Constant temperature around 40°C Mobile phase A: Water / perchloric acid mixture (10000:1) Mobile phase B: methanol Elution method: Gradient method Flow rate: 0.8mL / min Area measurement range: 60 minutes after injection Sample cooler temperature: 25℃ Dissolving solvent: Water / methanol / perchloric acid mixture (1000 / 1000 / 3) Syringe washing solution: Methanol / water mixture (1 / 1)

[0221] Based on the peak area values ​​obtained from liquid chromatography, the amount of related substances relative to the compound was calculated. The total amount of the detected related substances is shown in Tables 20-1 and 20-2. TIFF2026071393000095.tif102153 TIFF2026071393000096.tif100153 As shown in Tables 20-1 and 20-2, the tablets of the present invention showed no increase in related substances during the storage stability test, demonstrating good storage stability.

[0222] Test Example 4: Storage Stability Test (Leaching Test) The constant temperature and humidity chamber was set to 40°C / 75%RH, and the uncoated tablets or FC tablets prepared in Examples 1 to 14 were placed in HDPE bottles. After being stored in the constant temperature and humidity chamber for a specified period in an open state, a dissolution test was performed according to the dissolution test method of the Japanese Pharmacopoeia, under the conditions described in Test Example 2.

[0223] The dissolution test results are shown in Tables 21-1 and 21-2. TIFF2026071393000097.tif113153 TIFF2026071393000098.tif119153 As shown in Tables 21-1 and 21-2, the uncoated tablets or FC tablets of the present invention dissolve rapidly, and high absorption in the body is expected. Furthermore, although there was a slight difference in the initial stage of dissolution depending on whether or not film coating was present, there was almost no difference in the dissolution rate at 15 minutes, indicating that it did not affect dissolution performance. Despite using relatively large amounts of binders and lubricants, we were able to manufacture tablets that dissolve rapidly and exhibit good dissolution performance.

[0224] Based on the results described above, it has become clear that the formulation of this disclosure has good dissolution properties and storage stability, and furthermore, when provided as tablets, it suppresses tableting problems. As described above, while the present disclosure has been illustrated using preferred embodiments, it should be understood that the scope of this disclosure should be interpreted solely by the claims. Patents, patent applications and other documents cited herein should be incorporated herein by reference as if their contents were specifically described herein. [Industrial applicability]

[0225] This disclosure makes it possible to provide an oral solid dosage form that contains (i) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, as an active ingredient, and has a high content of (ii) a binder and (iii) a lubricant, thereby suppressing tableting problems and providing excellent dissolution properties.

Claims

1. (1) 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate (2) A binder in an amount of 4.0 to 6.0% by weight per 100% by weight of the formulation, (3) A lubricant in an amount of 2.0 to 10.0% by weight per 100% by weight of the preparation. An oral solid dosage form containing [a specific ingredient / material].

2. The oral solid preparation according to claim 1, wherein the content of the binder is 5.0 to 6.0% by weight relative to 100% by weight of the preparation.

3. The oral solid dosage form according to claim 1 or 2, wherein the binder is a water-soluble polymer binder.

4. The oral solid preparation according to claim 3, wherein the water-soluble polymer binder is hydroxypropyl cellulose or polyvinyl alcohol.

5. The oral solid preparation according to claim 3, wherein the water-soluble polymer binder is hydroxypropylcellulose.

6. The oral solid preparation according to any one of claims 1 to 5, wherein the content of the lubricant is 2.0 to 6.0% by weight relative to 100% by weight of the preparation.

7. The oral solid preparation according to any one of claims 1 to 5, wherein the content of the lubricant is 4.0 to 6.0% by weight based on 100% by weight of the preparation.

8. The oral solid preparation according to any one of claims 1 to 7, wherein the lubricant is sodium stearyl fumarate.

9. An oral solid preparation according to any one of claims 1 to 8, further comprising an excipient.

10. The oral solid preparation according to claim 9, wherein the excipient is a hydrophilic excipient.

11. The oral solid preparation according to claim 10, wherein the hydrophilic excipient is one or more selected from sugar alcohols, pregelatinized starches, lactose monohydrate, and crystalline cellulose.

12. The oral solid preparation according to claim 10, wherein the hydrophilic excipient is one or more mixtures selected from sugar alcohols, pregelatinized starches, and crystalline cellulose.

13. The oral solid preparation according to claim 10, wherein the hydrophilic excipient is a mixture of one or more selected from sugar alcohols and pregelatinized starches.

14. The oral solid preparation according to claim 10, wherein the hydrophilic excipient is a mixture of sugar alcohols and pregelatinized starches.

15. The oral solid preparation according to any one of claims 11 to 14, wherein the pregelatinized starches are partially pregelatinized starches.

16. The oral solid preparation according to any one of claims 11 to 15, wherein the sugar alcohol is D-mannitol.

17. An oral solid preparation according to any one of claims 1 to 16, further comprising a disintegrant.

18. The oral solid preparation according to claim 17, wherein the content of the disintegrant is 0.5 to 50.0% by weight relative to 100% by weight of the preparation.

19. The oral solid preparation according to claim 17, wherein the content of the disintegrant is 0.5 to 30.0% by weight relative to 100% by weight of the preparation.

20. The oral solid preparation according to claim 17, wherein the content of the disintegrant is 0.5 to 20.0% by weight relative to 100% by weight of the preparation.

21. The oral solid preparation according to any one of claims 17 to 20, wherein the disintegrant is one or a mixture of two or more selected from croscarmellose sodium, sodium starch glycolate, and crospovidone.

22. The oral solid preparation according to any one of claims 17 to 20, wherein the disintegrant is one or a mixture of two or more selected from croscarmellose sodium and sodium starch glycolate.

23. The oral solid preparation according to any one of claims 17 to 20, wherein the disintegrant is croscarmellose sodium.

24. The oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 0.5 to 70% by weight with respect to 100% by weight of the preparation.

25. The oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 10 to 50% by weight with respect to 100% by weight of the preparation.

26. The oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 15 to 40% by weight based on 100% by weight of the preparation.

27. The oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 15 to 38% by weight with respect to 100% by weight of the preparation.

28. The oral solid preparation according to any one of claims 1 to 23, wherein the content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is 20 to 38% by weight with respect to 100% by weight of the preparation.

29. An oral solid dosage form according to any one of claims 1 to 28, manufactured using a fluid bed granulation method.

30. An oral solid dosage form according to any one of claims 1 to 29, wherein the dosage form is film-coated with a coating agent.

31. An oral solid preparation according to any one of claims 1 to 30 for the treatment and / or prevention of tumors.

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