Preparation having excellent dissolution and tabletability

Abstract

The present invention relates to an oral solid preparation which has, as an active ingredient, 5-fluoro-2-[(4-{7-[(1S, 3S, 4R)-5-methylene-2-azabicyclo [2.2. 2] octane-3-carbonyl]-2, 7-diazaspiro [3.5] nonane-2-yl} pyrimidin-5-yl) oxy]-N, N-bis (propan-2-yl) benzamide, and which has good dissolution properties and storage stability.

Description

Technical Field

[0001] This disclosure relates to an oral solid dosage form with 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propane-2-yl)benzamide (hereinafter also referred to as "the Compound") or a pharmaceutically acceptable salt thereof, or a hydrate or solvation thereof (hereinafter, the Compound to the solvation are referred to as "the Drug", "the Drug" or "the Drug of this Disclosure") as the active ingredient, exhibiting good dissolution and storage stability, and thus exhibiting suppressed tableting obstacles when formulated into tablets. Background Technology

[0002] In clinical development programs, obtaining information about dosage and its response is crucial. According to Non-Patent Literature 1, the aim regarding dose-response is to collect the necessary information at each stage throughout the entire process from preclinical to clinical development, and to utilize this beneficial information in subsequent clinical trials and post-market use. Specifically, it is important to understand the relationship between dosage, blood drug concentration, and clinical response (efficacy and safety), to identify suitable starting doses for populations or individual patients, the optimal methods for adjusting dosages according to the needs of specific patients, and doses where increasing the dose will not yield further benefit or where increasing the dose is expected to cause intolerable side effects, and to utilize these in subsequent stages. Furthermore, since dosages may change during clinical development, it is preferable to obtain in advance an oral solid dosage form corresponding to a broad dose range from low to high doses for acquiring this information.

[0003] In order to exert its effect, oral solid dosage forms need to undergo a process of disintegration, dispersion and dissolution so that the dissolved drug can reach the absorption site. Since this process has a great influence on the absorption of the drug, in order to exert and maintain the pharmacological effect, it is desirable to design the formulation in a way that can stably maintain good dissolution.

[0004] Patent document 1 discloses a formulation of this compound, but does not disclose examples of specific components, formulations, and preparation methods.

[0005] Existing technical documents Patent documents Patent Document 1: WO2020 / 045334 Non-patent literature Non-patent document 1: Guidelines for the study of dose-response relationships required for approval of new drugs (Guidelines for the recognition of necessary dose-response relationships for new medical drugs) (ICH E4). Summary of the Invention

[0006] The problem that the invention aims to solve The subject of this disclosure is to provide an oral solid dosage form with good dissolution and storage stability for the drug, and further, when manufactured as a tablet, to provide an oral solid dosage form in which tableting obstacles are suppressed.

[0007] Methods for solving problems When formulating this drug into an oral solid dosage form, it was found that during the tablet manufacturing process (i.e., the tableting process), tableting obstacles such as the adhesion of the composition containing this drug to the surface of the punch (so-called punch sticking) and surface peeling (so-called top cracking) occurred. While it is generally known that incorporating binders and lubricants tends to improve tableting obstacles during the tableting process, increasing the amount of binders and lubricants to an appropriate level or more can cause delayed dissolution of the compound and reduced tablet forming ability (reduced hardness). However, the present inventors conducted in-depth research and surprisingly found that by using binders and lubricants in proportions higher than those in conventional formulations, no problems such as delayed dissolution or reduced hardness were observed, and the flowability was improved, eliminating tableting obstacles.

[0008] The authors conducted in-depth research and discovered that by combining lubricants and binders at high concentrations (above the conventional usage ratio), oral solid dosage forms with excellent dissolution and storage stability can be provided. Specifically, they found that even when tablets are manufactured by combining hydroxypropyl cellulose (as a binder) and sodium stearate fumarate (as a lubricant) at high concentrations, there is no delay in dissolution, no decrease in hardness, no suppression of tableting obstacles, good dissolution is maintained, and excellent storage stability is achieved, thus completing this disclosure.

[0009] That is, this disclosure provides the following items.

[0010] [Project 1] Oral solid dosage forms containing: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvation thereof, (2) The adhesive, at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation, and (3) A lubricant comprising 2.0 to 10.0% by weight of 100% of the formulation.

[0011] [Project 2] According to the oral solid dosage form of Project 1, the content of the aforementioned binder is 5.0 to 6.0% by weight relative to 100% by weight of the aforementioned dosage form.

[0012] [Project 3] According to Project 1 or 2, the oral solid dosage form wherein the aforementioned binder is a water-soluble polymeric binder.

[0013] [Project 4] According to the oral solid dosage form described in Project 3, the aforementioned water-soluble polymeric binder is hydroxypropyl cellulose or polyvinyl alcohol.

[0014] [Project 5] According to Project 3, the oral solid dosage form wherein the aforementioned water-soluble polymeric binder is hydroxypropyl cellulose.

[0015] [Project 6] The oral solid dosage form according to any one of items 1 to 5, wherein the content of the aforementioned lubricant is 2.0 to 6.0% by weight relative to 100% by weight of the aforementioned dosage form.

[0016] [Project 7] The oral solid dosage form according to any one of items 1 to 5, wherein the content of the aforementioned lubricant is 4.0 to 6.0% by weight relative to 100% by weight of the aforementioned dosage form.

[0017] [Project 8] According to the oral solid dosage forms described in items 1 to 7, the aforementioned lubricant is sodium stearate fumarate.

[0018] [Project 9] The oral solid dosage form according to any one of items 1 to 8 further comprises an excipient.

[0019] [Project 10] According to the oral solid dosage form described in Project 9, the aforementioned excipient is a hydrophilic excipient.

[0020] [Project 11] According to the oral solid dosage form of Project 10, the aforementioned hydrophilic excipient is one or a mixture of two or more selected from sugar alcohols, α-starches, lactose hydrates and crystalline cellulose.

[0021] [Project 12] According to the oral solid dosage form of Project 10, the aforementioned hydrophilic excipient is one or a mixture of two or more selected from sugar alcohols, α-starches and crystalline cellulose.

[0022] [Project 13] According to the oral solid dosage form of Project 10, the aforementioned hydrophilic excipient is a mixture of one or more selected from sugar alcohols and α-starches.

[0023] [Project 14] According to the oral solid dosage form described in Project 10, the aforementioned hydrophilic excipient is a mixture of sugar alcohol and α-starch.

[0024] [Project 15] Oral solid dosage forms according to any one of items 11 to 14, wherein the aforementioned α-starch is partially α-starch.

[0025] [Project 16] Oral solid dosage form according to any one of items 11 to 15, wherein the aforementioned sugar alcohol is D-mannitol.

[0026] [Project 17] The oral solid dosage form according to any one of items 1 to 16 further comprises a disintegrant.

[0027] [Project 18] According to the oral solid dosage form of Project 17, the content of the aforementioned disintegrant is 0.5 to 50.0% by weight relative to 100% by weight of the aforementioned dosage form.

[0028] [Project 19] According to the oral solid dosage form of Project 17, the content of the aforementioned disintegrant is 0.5 to 30.0% by weight relative to 100% by weight of the aforementioned dosage form.

[0029] [Project 20] According to the oral solid dosage form of Project 17, the content of the aforementioned disintegrant is 0.5 to 20.0% by weight relative to 100% by weight of the aforementioned dosage form.

[0030] [Project 21] Oral solid dosage forms according to any one of items 17 to 20, wherein the aforementioned disintegrant is one or a mixture of two or more selected from croscarmellose sodium, glycolic acid starch sodium and crospovidone.

[0031] [Project 22] Oral solid dosage forms according to any one of items 17 to 20, wherein the aforementioned disintegrant is one or a mixture of two or more selected from croscarmellose sodium and glycolic acid starch sodium.

[0032] [Project 23] Oral solid dosage form according to any one of items 17 to 20, wherein the aforementioned disintegrant is croscarmellose sodium.

[0033] [Project 24] The oral solid dosage form according to any one of items 1 to 23, wherein, relative to 100% by weight, the content of the aforementioned 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvation thereof, is 0.5 to 70% by weight.

[0034] [Project 25] The oral solid dosage form according to any one of items 1 to 23, wherein, relative to 100% by weight, the content of the aforementioned 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is 10 to 50% by weight.

[0035] [Project 26] The oral solid dosage form according to any one of items 1 to 23, wherein, relative to 100% by weight, the content of the aforementioned 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvation thereof, is 15 to 40% by weight.

[0036] [Project 27] The oral solid dosage form according to any one of items 1 to 23, wherein, relative to 100% by weight, the content of the aforementioned 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is 15 to 38% by weight.

[0037] [Project 28] The oral solid dosage form according to any one of items 1 to 23, wherein, relative to 100% by weight of the aforementioned dosage form, the content of the aforementioned 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is 20 to 38% by weight.

[0038] [Project 29] The oral solid dosage form according to any one of items 1 to 28 is manufactured using fluidized bed granulation.

[0039] [Project 30] The oral solid dosage form according to any one of items 1 to 29 is film-coated with a coating agent.

[0040] [Project 31] An oral solid dosage form according to any one of items 1 to 30, used for the treatment and / or prevention of tumors.

[0041] Invention Effects The oral solid dosage form disclosed herein, by incorporating binders and lubricants in higher amounts than conventionally used, enables the provision of oral solid dosage forms with excellent dissolution and storage stability. Furthermore, by using high amounts of binders and lubricants, tableting obstacles can be suppressed while maintaining good dissolution and excellent storage stability. Detailed Implementation

[0042] The present disclosure will now be described in further detail. The embodiments provided below are provided to better understand the present disclosure, and the scope of the disclosure is not limited to what is described below. Furthermore, the following embodiments can be used alone or in combination.

[0043] In this disclosure, "average particle size" refers to the cumulative 50% particle size D50 in a volumetric reference determination of powder particles. This average particle size is determined according to a volumetric reference using a laser diffraction particle size distribution measuring device (e.g., Particle Viewer manufactured by Powrex, SALD-3000J manufactured by Shimadzu Corporation, or HELOS & RODOS manufactured by Sympatec Corporation).

[0044] In this disclosure, "compression obstacle" refers to the phenomenon in the tablet manufacturing process (i.e., the compression process) where the compound adheres to the surface of the punch (punch sticking) and the phenomenon of surface peeling (top cracking), and the phenomenon of damage to the side of the tablet caused by friction between the powder being compressed and the metal adhesion surface (die friction), etc.

[0045] In this disclosure, unless otherwise specified, "content" refers to the amount or content (wt / wt) of the formulation when the total amount of the preparation is set to 100% by weight. It should be noted that weight% is also expressed as wt%.

[0046] In this disclosure, "excellent storage stability" means a formulation characteristic that shows little increase in the amount of relevant substances in the purity test of the storage stability test and maintains good dissolution in the dissolution test after storage.

[0047] "Preservation" refers to placing, storing, or storing the manufactured preparation in a suitable container. During preservation, the container may be sealed or left open, and may be protected from light or not. Examples of preservation include storage at room temperature, room temperature, in a cool place, refrigerated storage, or frozen storage. Examples of storage temperatures include standard temperature: 20°C, room temperature: 15–25°C, room temperature: 1–30°C, slightly warm: 30–40°C, in a cool place: 1–15°C, refrigerated: 2–6°C, and frozen: approximately -20°C to -18°C, but are not limited to these. The relative humidity (%RH) during preservation can be any value from 0 to 100%RH, preferably 40–60%RH, but is not limited to this. Examples of storage periods include several hours, several days, several weeks, several months, or several years, but are not limited to these. The above-mentioned preservation-related parameters can be appropriately selected according to the properties of the preparation and the storage conditions. "Storage stability testing" is a stability test used to confirm whether the quality of a manufactured formulation is maintained. It is conducted using storage conditions that promote chemical or physical changes in the formulation. The test results can be used to evaluate the chemical effects of long-term storage using specified storage methods. They can also be used to evaluate the effects of short-term deviations from storage methods that may occur during transportation. Depending on the temperature / relative humidity, there are long-term tests (e.g., 25°C / 60%RH), accelerated tests (e.g., 40°C / 75%RH), and severity tests (e.g., 50°C / 85%RH), etc. The accelerated or severe tests described in this instruction manual are conducted by setting the conditions of a thermo-humidifier to higher temperature / relative humidity (e.g., 40°C / 75%RH or 50°C / 85%RH), placing the prepared solid dosage form in a suitable container (e.g., an HDPE bottle or a brown screw-top test tube made of glass) and storing it in the thermo-humidifier for a certain storage period (e.g., 1, 3, or 6 months, or 2 or 4 weeks) with the container open or tightly closed. In the storage stability test, controlling the amount of relevant substances below a specified level is necessary for providing the dosage form with excellent quality to patients. The specified level of relevant substances is a standard of 3.0% or less of total relevant substances.

[0048] In this disclosure, "good dissolution" means, for example, that when a dissolution test of a formulation is performed under the following dissolution test conditions according to the dissolution test paddle method of the 18th edition of the Japanese Pharmacopoeia, a dissolution rate of 80% or more, preferably 85% or more, is shown at a time point of 15 minutes.

[0049] Another way to describe "good dissolution" is to indicate a dissolution rate of 70% or more, preferably 80% or more, and more preferably 85% or more at a 10-minute time point. Yet another way to describe "good dissolution" is to indicate a dissolution rate of 80% or more, preferably 85% or more, at a 5-minute time point.

[0050] Test solution: 0.1 mol / L hydrochloric acid test solution Propeller speed: 50 rpm Test solution: 900mL Test solution temperature: 37±0.5℃ [1] Oral solid dosage forms "Oral solid dosage forms" refer to solid dosage forms of a certain shape that are administered orally. Solid dosage forms include those that are formulated in dosage forms such as tablets, capsules, granules, fine granules, pills, and powders.

[0051] The oral solid dosage forms disclosed herein specifically refer to those formulated as tablets, capsules, granules, or fine granules. Tablets or capsules are preferred examples of oral solid dosage forms. Tablets are even more preferred examples of oral solid dosage forms.

[0052] To facilitate administration or prevent the decomposition of the active ingredient, the oral solid dosage form (e.g., tablet) of this disclosure can be coated with a coating agent. In this case, the oral solid dosage form of this disclosure can be called a film-coated tablet. Film-coated tablets are typically tablets formulated by coating plain tablets with a suitable coating agent such as a polymer compound.

[0053] The oral solid dosage form disclosed herein comprises (1) a drug, (2) a binder, (3) a lubricant, and may further comprise (4) an excipient, (5) a disintegrant, and may further comprise (6) an additive, to the extent that it does not affect the formulation characteristics of the present disclosure.

[0054] In the case of tablets, the form includes uncoated tablets, film-coated tablets formed by coating the surface of uncoated tablets (sometimes referred to as FC tablets in this specification), and sugar-coated tablets formed by applying sugar coating to the surface of uncoated tablets, preferably uncoated tablets or film-coated tablets.

[0055] (1) Drugs In this disclosure, "pharmaceutical" refers to the active ingredient of this disclosure, namely, 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide (this compound) or a pharmaceutically acceptable salt thereof, or a hydrate or solvation thereof, having the following structure.

[0056] It should be noted that "the hydrate or solvation of the compound or its pharmaceutically acceptable salt, or its hydrate or solvation" means the hydrate or solvation of the compound and the hydrate or solvation of the pharmaceutically acceptable salt of the compound.

[0057] In this disclosure, examples of "pharmaceutically acceptable salts" include hydrochloride, citrate, fumarate, maleate, phosphate, succinate, sulfate, tartrate, benzenesulfonate, hydrobromide, etc., but are not limited to these.

[0058] "Tartrate of this compound" refers to 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide 1L(+)-tartrate.

[0059] 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 the case where the water molecules are organic solvent molecules. The organic solvents capable of forming the solvates in this disclosure can be appropriately selected based on the type and properties of the substance; 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 based on the stability of the solvate.

[0060] The content of the drug disclosed herein is typically 0.1 to 96% by weight relative to 100% of the formulation, with preferred examples being 0.5 to 70% by weight. More preferred examples include 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 20 to 36% by weight. Further preferred examples include 20 to 30% by weight.

[0061] During formulation, drugs can be pulverized to a desired particle size as needed. The average particle size of the drug is typically 0.1–100 μm, with preferred examples being 0.1–80 μm, more preferred examples being 0.1–50 μm, and even more preferred examples being 1–20 μm. The average particle size of the drug is acceptable as long as it is within the above range as a raw material, but it can vary during the manufacturing process.

[0062] (2) Adhesive "Adhesive" refers to a component used to impart adhesive force to powders, form and maintain the shape of the formulation, and water-soluble polymeric adhesives are preferred in this disclosure. There is no particular limitation on the term "water-soluble polymeric adhesive," and examples include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, copovidone, polyethylene glycol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, ethyl acetate-vinylpyrrolidone copolymer, polyvinyl alcohol-polyethylene glycol-graft copolymer, α-starch, dextrin, dextran, pullulan, alginate, gelatin, and pectin. More preferred examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinyl alcohol. A further preferred example is hydroxypropylcellulose. One or more of the above-mentioned water-soluble polymeric adhesives may be used. In the case of the representative adhesive hydroxypropylcellulose, it is typically used at a formulation of 2-3%.

[0063] When hydroxypropyl cellulose is used as a water-soluble polymer binder, the preparation of drug-containing granules (i.e., granulation) in formulation can be carried out well, and formulations with excellent operability and good disintegration properties can also be obtained.

[0064] The viscosity of the 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.

[0065] The content of the binder, relative to 100% by weight of the formulation, is typically 4.0 to 20% by weight, with preferred examples being 4.0 to 10% by weight. More preferred examples include 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 4.5 to 5.0% by weight. Further preferred examples include 5.0 to 5.5% by weight and 5.0 to 6.0% by weight.

[0066] The adhesive disclosed herein can be dissolved in solvents such as water and granulated while being dispersed. Alternatively, the adhesive can be added together with other components and granulated while spraying water or other solvents.

[0067] (3) Lubricant "Lubricant" refers to the component added during the manufacturing process of capsules and tablets to improve the flowability and filling properties of powder, and to prevent adhesion, when filling capsules or compressing them into tablets. In the case of tablets, the lubricant can be mixed with other components before tableting, or it can be sprayed onto the mortar and pestle during tableting.

[0068] There are no particular limitations on the lubricant used; examples include magnesium stearate, sodium stearate fumarate, talc, polyethylene glycol, silica, or hydrogenated vegetable oil. Magnesium stearate and sodium stearate are preferred examples, and sodium stearate is an even more preferred example. One or more of the above-mentioned lubricants may be used simultaneously. When sodium stearate fumarate is used as a lubricant, it can suppress tableting obstacles during tablet preparation and also yield formulations with excellent handling and good disintegration properties. The lubricant is usually formulated at 1% or less, and even in cases where it is more, it is only about 2%. Commonly used lubricants include magnesium stearate.

[0069] The content of the lubricant, relative to 100% by weight of the formulation, is typically 0.1 to 20% by weight, with preferred examples 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 even more preferred examples being 4.0 to 6.0% by weight.

[0070] (4) Excipients "Excipients" refer to components added to improve the form, volume, dilution, and ease of handling of a formulation when the active pharmaceutical ingredient alone cannot achieve sufficient "volume" during dosage form preparation. This implies that they not only increase volume but also improve the mixability of powders, enhance granulation properties during particle production in granules, improve the filling, adhesion, and flowability of tablets during compression, and improve the filling properties of capsules in capsules.

[0071] Examples of "excipients" include hydrophilic and non-hydrophilic excipients, with hydrophilic excipients being preferred.

[0072] As a hydrophilic excipient, hydrophilic excipients commonly used in formulation can be used, with sugars, crystalline cellulose, or sugar alcohols being preferred examples.

[0073] The types of sugars or sugar alcohols used here are not particularly limited, and examples include, for instance, α-starch, D-mannitol, erythritol, xylitol, maltitol, sorbitol, lactose, sucrose, or trehalose. Preferred examples include D-mannitol, erythritol, lactose, or trehalose. More preferred examples include α-starch, D-mannitol, or lactose. Most preferred examples include α-starch and D-mannitol. The hydrophilic excipient can be selected from one or more of the above.

[0074] The content of the excipient is typically 0.1 to 90% by weight relative to 100% of the formulation, with preferred examples being 10 to 90% by weight, more preferably 30 to 80% by weight, and even more preferably 40 to 70% by weight.

[0075] The content of D-mannitol is typically 0.1 to 90% by weight relative to 100% of the formulation, with preferred examples being 1 to 80% by weight, and more preferably 30 to 60% by weight.

[0076] Specific examples of "α-starch" include "α-starch" or "partially α-starch" in pharmaceutical additive standards, as well as "Pregelatinized starch" in USP / NF and "Starch, pregelatinized" in Ph.Eur. "Partially α-starch" is a preferred example of "α-starch". Specific examples of commercially available α-starch or partially α-starch include PC-10 (trade name, distributor: Asahi Kasei Corporation), SWELSTAR (trade name, distributor: Asahi Kasei Corporation), Starch1500 and Starch 1500G (trade name, distributor: Colorcon), or LYCATAB C (trade name, distributor: Roquette), etc., but are not limited to these. Any product whose composition is α-starch or partially α-starch and whose purity and other standards meet the criteria of those skilled in the art can be used. Examples of raw materials for α-starch include corn starch, potato starch, wheat starch, rice starch, cassava starch, and various other starches.

[0077] The content of α-starch is typically 0.1 to 50% by weight relative to 100% of the formulation, with preferred examples being 1 to 40% by weight, and more preferably 10 to 30% by weight.

[0078] (5) Disintegrants "Disintegrant" refers to an ingredient added to disintegrate and disperse solid dosage forms such as tablets or granules into particles.

[0079] The term "disintegrant" is not particularly limited, and examples include corn starch, croscarmellose sodium, glycolic acid starch sodium (or carboxymethyl starch sodium), low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl ethyl cellulose, and croscarmellose. Preferred examples include croscarmellose sodium, glycolic acid starch sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose. More preferred examples include croscarmellose sodium, glycolic acid starch sodium, and croscarmellose. Further preferred examples include croscarmellose sodium. The disintegrant can be selected from one or more of the above.

[0080] The content of the disintegrant, relative to 100% by weight of the formulation, is typically 0.1 to 50.0% by weight, with preferred examples being 0.5 to 50.0% by weight or 0.5 to 30.0% by weight. More preferred examples include 0.5 to 20% by weight, 0.5 to 30.0% by weight, 1.0 to 30.0% by weight or 1.0 to 20.0% by weight. Even more preferred examples include 0.5 to 20.0% by weight, 2.0 to 10.0% by weight, 1.0 to 10.0% by weight or 2.0 to 5.0% by weight.

[0081] (6) Additives The term "additive" refers to substances other than the active ingredients in a formulation. It refers to ingredients used to improve the effectiveness of the active ingredients and the formulation, facilitate formulation, stabilize quality, or improve usability.

[0082] In the formulations disclosed herein, non-toxic and inert additives commonly used in the pharmaceutical industry may be added as needed, provided that they do not affect the therapeutic effect of the drug disclosed herein. Examples of such additives include those used in common oral formulations that do not affect the therapeutic effect of the drug disclosed herein. Examples of such additives include, for instance, stabilizers, flavoring agents, sweeteners, odorants, fragrances, antioxidants, antistatic agents, fluidizing agents, colorants, plasticizers, anti-agglomerates, and brightening agents.

[0083] The content of the additive can be set arbitrarily, and can be 0.001 to 10% by weight relative to 100% of the formulation, with preferred examples being 0.005 to 10% by weight, and more preferably 0.01 to 5% by weight. As another preferred method, a formulation without additives can be provided.

[0084] "Coating agent" refers to the component used to coat the surface of a preparation. It is used to prevent contact with water, air, and light, mask odors and bitterness, impart sustained-release and enteric properties to the preparation, or enhance the appearance and increase the value of the product.

[0085] The coating agent is not particularly limited, and examples include coating agents composed of substrates such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, 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, and ethyl acrylate-methyl methacrylate copolymer, and plasticizers such as polyethylene glycol, propylene glycol, glyceryl triacetate, triethyl citrate, glycerol, and glyceryl fatty acid esters, but are not limited to these. Furthermore, additives such as titanium dioxide, iron oxide, talc, and colorants can be added. Mixtures of these additives can also be used; for example, OPADRY can be cited.

[0086] "Coloring agents" refer to ingredients used to identify capsules, tablets, etc., to shield the contents of the medicine from light, or to add value to the product. There are no particular limitations on coloring agents; examples include tar pigments, lake pigments, yellow ferric oxide, ferric oxide, or titanium dioxide. Furthermore, after film coating, carnauba wax, talc, etc., can also be added as brightening agents.

[0087] The preparation of the oral formulation disclosed herein varies depending on the desired dosage form, and can be prepared according to conventional methods to the desired dosage form.

[0088] (1) Preparation of aqueous solution of adhesive: The adhesive is dissolved in pure water. The amount of adhesive relative to the amount of pure water is, for example, in the range of 1 to 20% by weight, and preferably in the range of 2 to 8% by weight.

[0089] (2) Preparation of drug-containing granules according to this disclosure: Granulation is performed in a granulator containing the drug, water-soluble excipient, and disintegrant of this disclosure, while dispersing the binder prepared in step (1) above. Alternatively, granulation can be performed in a granulator containing the drug, water-soluble excipient, disintegrant, and binder of this disclosure, while spraying a solvent such as water.

[0090] Examples of granulation devices include, for instance, fluidized bed granulation, high-share granulation, rotary fluidized bed granulation, and twin-screw granulation. However, they are not limited to these types.

[0091] (3) Drying of granules: The granules are dried under reduced pressure or normal pressure. This drying is carried out such that the weight loss, as measured by an infrared moisture meter, is, for example, 4% by weight or less, preferably 2% by weight or less.

[0092] (4) Lubricant formulation: Add lubricant to the dried granules from step (3) above and mix. Mix using a mixer classified as a diffusion mixer (Tumble). Examples include tumble blenders, V-type mixers, double cone mixers, and bin tumble mixers. However, this is not a limitation.

[0093] (5) Tableting: The above mixture is compressed into tablets. Examples of tableting devices include tablet presses. The compression pressure is selected and set based on the tablet hardness, for example, within the range of 20 to 250 N.

[0094] (6) Apply film coating as needed: The tablets can be coated with a film as needed. Examples of coating devices include, for instance, coating pans. Preferred examples include devices classified as perforated coating systems.

[0095] (7) Drying: The tablets obtained as described above are dried. Drying is carried out under reduced pressure or normal pressure, such that the weight loss after drying, as measured by an infrared moisture meter, is, for example, less than 4% by weight, preferably less than 2% by weight.

[0096] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation, and (3) A lubricant comprising 2.0 to 10.0% by weight of 100% of the formulation, It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0097] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, comprising 5.0 to 6.0% by weight relative to 100% of the formulation, and (3) The lubricant comprises 4.0 to 6.0% by weight relative to 100% of the formulation. It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0098] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, at a concentration of 4.5 to 6.0% by weight relative to 100% of the formulation, and (3) A lubricant comprising 2.0 to 10.0% by weight of 100% of the formulation, It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0099] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation, and (3) The lubricant comprises 4.0 to 10.0% by weight relative to 100% of the formulation. It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0100] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, at a concentration of 4.5 to 6.0% by weight relative to 100% of the formulation, and (3) The lubricant comprises 4.0 to 10.0% by weight relative to 100% of the formulation. It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0101] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, at a concentration of 5.0 to 5.5% by weight relative to 100% of the formulation, and (3) The lubricant comprises 4.0 to 10.0% by weight relative to 100% of the formulation. It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0102] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, comprising 5.0 to 6.0% by weight relative to 100% of the formulation, and (3) The lubricant comprises 4.0 to 10.0% by weight relative to 100% of the formulation. It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0103] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, at a concentration of 5.0 to 5.5% by weight relative to 100% of the formulation, and (3) A lubricant comprising 2.0 to 10.0% by weight of 100% of the formulation, It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0104] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, at a concentration of 4.5 to 6.0% by weight relative to 100% of the formulation, and (3) A lubricant comprising 2.0 to 6.0% by weight of 100% of the formulation, It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0105] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, at a concentration of 4.5 to 6.0% by weight relative to 100% of the formulation, and (3) The lubricant comprises 4.0 to 6.0% by weight relative to 100% of the formulation. It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0106] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The adhesive, at a concentration of 5.0 to 5.5% by weight relative to 100% of the formulation, and (3) A lubricant comprising 2.0 to 6.0% by weight of 100% of the formulation, It may further include (4) excipients, (5) disintegrants, and / or (6) additives as needed.

[0107] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, (2) The hydroxypropyl cellulose content is 5.0–6.0% by weight relative to 100% of the formulation. (3) Sodium stearate at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) Cross-linked sodium carboxymethyl cellulose, Furthermore, it may include (6) additives as needed.

[0108] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 15–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0109] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0110] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 15–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0111] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 2.0 to 10.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0112] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 10.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0113] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 2.0 to 10.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0114] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 10.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0115] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 2.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0116] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0117] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 2.0 to 10.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0118] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 10.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0119] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 2.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0120] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20–38% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0121] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20-30% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 2.0 to 10.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0122] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20-30% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 10.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0123] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20-30% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0124] In one embodiment of this disclosure, an oral solid dosage form is provided, comprising: (1) 20-30% by weight of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, relative to 100% by weight of the formulation. (2) Hydroxypropyl cellulose, and (3) Sodium stearate at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation. (4) A mixture of partially α-starch and D-mannitol, and (5) 0.5–20.0% by weight of croscarmellose sodium relative to 100% of the formulation, Furthermore, it may include (6) additives as needed.

[0125] [2] Drug uses of oral solid dosage forms The disclosed drug exhibits anticancer activity by inhibiting the binding of MLL (mixed lineage leukemia) fusion proteins fused with representative fusion partner genes such as AF4 and AF9 that cause MLL leukemia to menin, and is effective as an antitumor agent. Therefore, this disclosure relates to pharmaceutical compositions, therapeutic agents, and / or preventative measures for treating cancer, preferably oral solid dosage forms, comprising the drug of this disclosure.

[0126] In this disclosure, "prevention" refers to the act of administering the drug of this disclosure, which is an active ingredient, to a healthy person who has not yet developed a disease or whose health condition has not deteriorated at the time of administration. "Preventive agent" refers to those administered to such healthy persons, for example, those intended to prevent the onset of a disease, and is expected to be particularly suitable for persons who have previously had disease symptoms or are considered to have an increased risk of developing a disease. "Treatment" refers to the act of administering the drug of this disclosure, which is an active ingredient, to a person (patient) diagnosed by a physician as having developed a disease. "Therapeutic agent" refers to those administered to such patients, for example, those intended to alleviate the disease or symptoms, prevent the disease or symptoms from worsening, or restore the patient to a state before the onset of the disease. Furthermore, even if the purpose of administration is to prevent the worsening of the disease or symptoms, as long as the administration is to a patient, it is considered a therapeutic act.

[0127] In this disclosure, "cancer" and "tumor" have the same meaning, both referring to malignant tumors, and including cancer, sarcoma, and hematologic malignancies. Specific examples of "cancer" or "tumor" include, for example, acute leukemia (including MLL acute leukemia, MLL partial tandem repeat acute leukemia, NPM mutation acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumors, head and neck cancer, etc. Esophageal cancer, thyroid cancer, 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, skin cancer, etc. In addition, the above-mentioned tumors are sometimes accompanied by increased expression or mutation of specific genes. Examples of tumors with increased gene expression include tumors with high expression of the HOXa gene cluster and tumors with high expression of the MEIS gene cluster. Examples of tumors with gene mutations include tumors with p53 gain-of-function mutations.

[0128] To enhance their efficacy, the disclosed drugs can be used in combination with "concomitant agents." Examples of "concomitant agents" include antitumor alkylating agents, antitumor metabolic antagonists, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum coordination 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, epigenetic-related molecule inhibitors, protein post-translational modification inhibitors, and other antitumor agents. Specific examples of "combined medications" include, for instance, azacitidine, vorinostat, decitabine, romidesin, idarubicin, daunorubicin, doxorubicin, enoxabin, cytarabine, mitoxantrone, thioguanine, etoposide, ifosfamide, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, ramustine, all-trans retinoic acid, tamibarbitine, cisplatin, carboplatin, oxaliplatin, irinotecan, bleomycin, mitomycin C, methotrexate, paclitaxel, docetaxel, gemcitabine, tamoxifen, thiotepa, tegafur, fluorouracil, everolimus, tesimolimus, gefitinib, erlotinib, imatinib, crizotinib. The following are listed: Nifedipine, Osimertinib, Afatinib, Dasatinib, Bosutinib, Vandetanib, Sunitinib, Axitinib, Pazopanib, Lenvatinib, Lapatinib, Nilotinib, Ibrutinib, Ceritinib, Alectinib, Tofacitinib, Baricitinib, Ruxolitinib, Olaparib, Sorafenib, Vemurafenib, Dabrafenib, Trametinib, Palbocicib, Bortezomib, Carfilzomib, Rituximab, Cetuximab, Trastuzumab, Bevacizumab, Panitumumab, Nivolumab, Atezolizumab, Mogamulizumab, Alemumab, Ofatumab, Ipilimumab, Ramoximumab, Bentuximab, Gelatinumab, Ozolmicin, Izolmicin, Ozolmicin, etc.

[0129] The timing of administration of the disclosed drug and its concomitant medication is not limited; they can be administered to the recipient simultaneously or at appropriate intervals. Furthermore, the drug and its concomitant medication can be formulated as a combination, or administered in a separate formulation from the disclosed drug, or via a separate route of administration. The dosage of the concomitant medication can be appropriately selected based on clinically used dosages. Moreover, the ratio of the disclosed drug to the concomitant medication can be appropriately selected based on the recipient, route of administration, recipient's disease, symptoms, and combination.

[0130] The administration of this compound or its pharmaceutically acceptable salts, hydrates, or solvates may be by oral or non-oral administration, with oral administration being preferred. The dosage varies depending on the method of administration, the patient's symptoms, age, etc., and is typically in the range of 0.01–30 mg / kg / day, preferably 0.05–20 mg / kg / day, and more preferably 0.1–10 mg / kg / day. Other preferred dosage ranges include typically 0.01 mg–1600 mg / day, preferably 0.1 mg–1200 mg / day, more preferably 0.5 mg–1000 mg / day, further preferably 1 mg–800 mg / day, and most preferably 5 mg–600 mg / day. The dosage may be administered once or several times a day, for example, one, two, or three doses per administration. Example

[0131] The following are examples of embodiments of this disclosure, but these embodiments are for illustrative purposes only and do not limit the scope of this disclosure. Furthermore, changes may be made to this disclosure without departing from its scope. It should be noted that the compound names shown in the following examples, experimental examples, and comparative examples do not necessarily follow IUPAC nomenclature.

[0132] In this embodiment, test example, and comparative example, unless otherwise specified, % in the solution represents (wt%), and % in the particles represents weight.

[0133] Unless otherwise specified, the additives used in these embodiments, test examples, and comparative examples are the following substances.

[0134] Hydroxypropyl cellulose (HPC-L (6-10 mPa·s)) 注1） )): Japan Soda Co., Ltd. Polyvinyl alcohol (GOHSENOL) TM EG-05P (4.5~6.1mm) 2 / s 注2） )) Hydroxypropyl methylcellulose (TC-5) TM R (6mPa·s) 注1） Shin-Etsu Chemical Industry Co., Ltd. Partially α-oxidized starch (PCS) TM PC-10: Asahi Kasei Chemicals Co., Ltd.'s sodium carboxymethyl cellulose (Ac-Di-Sol) TM ): DuPont Kollidone TM CL): BASF Sodium hydroxyacetic acid starch (Primojel) TM DFE Pharma Mannitol (PEARLITOL 50C): Roquette Sodium stearate fumarate (PRUV) TM JRS PHARMA GmbH & Co.KG Polishing wax 105: WAX Co., Ltd., Japan Yellow ferric oxide (S): Kiseki Chemical Co., Ltd. Ferric oxide (S): Keisei Chemical Co., Ltd. It should be noted that the OPADRY used in this embodiment is a film coating agent that does not affect dissolution.

[0135] Note 1) Manufacturer's catalog value for 20℃, 2% solution.

[0136] Note 2) Manufacturer's catalog value for 20℃, 4% solution.

[0137] Example 1: Tablets containing the tartrate salt of this compound (1) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 1-1.

[0138] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (1) 2850g of pure water was transferred to a SUS-made beaker, and 150g of HPC-L was slowly added while stirring until dissolved. After standing for 24 hours, the solution was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (1).

[0139] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 1-2 and the manufacturing conditions described in Table 1-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 1-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (1) in the amounts described in Table 1-2 was sprayed while fluidizing. Then, 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 710 μm openings to produce granulated tartrate containing this compound.

[0140] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing tartrate of this compound using the amounts specified in Table 1-4. Add granulated tartrate of this compound in the amounts specified in Table 1-4 to a plastic bag, followed by adding sodium stearate fumarate in the amounts specified in Table 1-4, and perform bag mixing (rotate 50 times longitudinally, 50 times laterally, for a total of 100 rotations).

[0141] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound contained in 50 mg per tablet, under the conditions shown in Table 1-5.

[0142] (5) Preparation of membrane coating solution (1) 540.0g of pure water was taken into a SUS tank, and 60.0g of a coating mixture containing hydroxypropyl methylcellulose, titanium dioxide, propylene glycol, yellow ferric oxide, and ferric oxide was slowly added while stirring, and the mixture was dispersed and dissolved. The solution was then passed through a 108μm sieve to prepare a membrane coating solution (1).

[0143] (6) Manufacturing of film-coated tablets containing tartrate salts of this compound Film-coated tablets containing the tartrate salt of this compound were manufactured under the conditions described in Tables 1-6. First, 231.16 g of uncoated tablets were added to a coating machine (FREUND Sangyo Co., Ltd., HC-LABO type). The coating pan was jogged while heating under the conditions described in Tables 1-6 until the exhaust temperature reached 45°C. Next, the coating pan was rotated at 20 rpm while spraying the film coating solution (1) under the conditions described in Tables 1-6, and film coating was performed until the coating weight reached approximately 3.8 mg. Then, the coating pan was rotated at 12 rpm while drying until the exhaust temperature reached 50°C. After removing the tablets, Polishing wax 105 was added, followed by bag mixing and polishing.

[0144] Example 2: Tablets containing tartrate of this compound (2) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 2-1.

[0145] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (2) Take 1900g of pure water into a SUS beaker, and slowly add 100g of HPC-L while stirring until dissolved. After standing for 24 hours, stir again to prepare a 5wt% hydroxypropyl cellulose solution (2).

[0146] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 2-2 and the manufacturing conditions described in Table 2-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex, Multiplex MP-01 type) in the amounts described in Table 2-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5.5 wt% hydroxypropyl cellulose solution (2) in the amounts described in Table 2-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0147] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing tartrate of this compound using the amounts specified in Table 2-4. Add granulated tartrate of this compound to a plastic bag using the amounts specified in Table 2-4, followed by the addition of sodium stearate fumarate as specified in Table 2-4, and perform bag mixing (rotate 50 times longitudinally, 50 times laterally, for a total of 100 rotations).

[0148] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (manufactured by Kikusui Seisakusho, VELC) under the conditions shown in Table 2-5, with each tablet containing 50 mg of the tartrate salt of this compound.

[0149] Example 3: Tablets containing tartrate of this compound (3) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 3-1.

[0150] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (3) Take 2850g of pure water into a SUS beaker, and slowly add 150g of HPC-L while stirring until dissolved. After standing for 24 hours, stir again to prepare a 5wt% hydroxypropyl cellulose solution (3).

[0151] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 3-2 and the manufacturing conditions described in Table 3-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 3-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5wt% hydroxypropyl cellulose solution (3) in the amounts described in Table 3-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0152] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing the tartrate salt of this compound using the amounts specified in Table 3-4. In a 10L V-type container, add the granulated tartrate salt containing the compound in the amounts specified in Table 3-4, followed by the addition of sodium stearate fumarate in the amounts specified in Table 3-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0153] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (manufactured by Kikusui Seisakusho, VELC) under the conditions shown in Table 3-5, with each tablet containing 25 mg of the tartrate salt of this compound.

[0154] (5) Preparation of membrane coating solution (2) Weigh 1800.00 g of pure water. Add 0.32 g of yellow ferric oxide and 0.16 g of ferric oxide to a portion of the pure water and disperse using Robomics (TKHOMO MIXER MARK2.5 type). While stirring, slowly add 199.52 g of a coating component mixture containing hydroxypropyl methylcellulose, titanium dioxide, and propylene glycol to the remaining pure water and disperse and dissolve it. Add a solution containing dispersed pigments to this solution. Finally, pass the solution through a 108 μm sieve to prepare a membrane coating solution (2).

[0155] (6) Manufacturing of film-coated tablets containing tartrate salts of this compound Film-coated tablets containing the tartrate salt of this compound were manufactured under the conditions described in Table 3-6. First, 400.00 g of uncoated tablets were added to a coating machine (manufactured by Freund Sangyo Co., Ltd., HC-LABO type). The coating pan was jogged while heating under the conditions described in Table 3-6 until the exhaust temperature reached 45°C. Next, the coating pan was rotated at 20 rpm while spraying the film coating solution (2) under the conditions described in Table 3-6, and film coating was performed until the coating weight reached approximately 2.4 mg. Then, the coating pan was rotated at 12 rpm while drying until the exhaust temperature reached 50°C. After removing the tablets, Polishing wax 105 was added, followed by bag mixing and polishing.

[0156] Example 4: Tablets containing tartrate of this compound (4) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 4-1.

[0157] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (4) Take 2850g of pure water into a SUS beaker, and slowly add 150g of HPC-L while stirring until dissolved. After standing for 24 hours, stir again to prepare a 5wt% hydroxypropyl cellulose solution (4).

[0158] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 4-2 and the manufacturing conditions described in Table 4-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 4-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5wt% hydroxypropyl cellulose solution (4) in the amounts described in Table 4-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0159] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing the tartrate salt of this compound using the amounts specified in Table 4-4. In a 10L V-type container, add the granulated tartrate salt containing the compound in the amounts specified in Table 4-4, followed by the addition of sodium stearate fumarate in the amounts specified in Table 4-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0160] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound contained in 50 mg per tablet, under the conditions shown in Table 4-5.

[0161] (5) Preparation of membrane coating solution (3) Weigh 900.00 g of pure water. Add 0.24 g of yellow ferric oxide to a portion of the pure water and disperse it using Robomics (TKHOMO MIXER MARK2.5 type). While stirring, slowly add 99.76 g of a coating mixture containing hydroxypropyl methylcellulose, titanium dioxide, and propylene glycol to the remaining pure water and disperse and dissolve it. Add a solution containing dispersed pigments to this solution. Finally, pass the solution through a 108 μm sieve to prepare a membrane coating solution (3).

[0162] (6) Manufacturing of film-coated tablets containing tartrate salts 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 added to a coating machine (manufactured by Freund Sangyo Co., Ltd., HC-LABO type). While the coating pan was jogging, heating was performed under the conditions described in Table 4-6 until the exhaust temperature reached 45°C. Next, while the coating pan was rotating at 20 rpm, film coating solution (3) was sprayed under the conditions described in Table 4-6 to perform film coating until the coating weight reached approximately 3.8 mg. Then, while the coating pan was rotating at 12 rpm, drying was performed until the exhaust temperature reached 50°C. After removing the tablets, Polishing wax 105 was added, followed by bag mixing and polishing.

[0163] Example 5: Tablets containing tartrate of this compound (5) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 5-1.

[0164] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (5) Take 2850g of pure water into a SUS beaker, and slowly add 150g of HPC-L while stirring until dissolved. After standing for 24 hours, stir again to prepare a 5wt% hydroxypropyl cellulose solution (5).

[0165] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 5-2 and the manufacturing conditions described in Table 5-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 5-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (5) in the amounts described in Table 5-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0166] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing the tartrate salt of this compound using the amounts specified in Table 5-4. In a 10L V-type container, add the granulated tartrate salt containing the compound in the amounts specified in Table 5-4, followed by the addition of sodium stearate fumarate in the amounts specified in Table 5-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0167] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) under the conditions shown in Table 5-5, with the tartrate of this compound containing 125 mg per tablet.

[0168] (5) Preparation of membrane coating solution (4) Weigh 900.00 g of pure water. Add 0.24 g of ferric oxide to a portion of the pure water and disperse it using Robomics (TKHOMO MIXER MARK2.5 type). While stirring, slowly add 99.76 g of a coating component mixture containing hydroxypropyl methylcellulose, titanium dioxide, and propylene glycol to the remaining pure water and disperse and dissolve it. Add a solution containing dispersed pigments to this solution. Finally, pass the solution through a 108 μm sieve to prepare a membrane coating solution (4).

[0169] (6) Manufacturing of film-coated tablets containing tartrate salts 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 added to a coating machine (FREUND Sangyo Co., Ltd., HC-LABO type). The coating pan was jogged while heating under the conditions described in Table 5-6 until the exhaust temperature reached 45°C. Next, the coating pan was rotated at 20 rpm while spraying the film coating solution (4) under the conditions described in Table 1-6, and film coating was performed until the coating weight reached approximately 6.0 mg. Then, the coating pan was rotated at 12 rpm while drying until the exhaust temperature reached 50°C. After removing the tablets, Polishing wax 105 was added, followed by bag mixing and polishing.

[0170] Example 6: Tablets containing tartrate of this compound (6) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 6-1.

[0171] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (6) Take 2850g of pure water into a SUS beaker, and slowly add 150g of HPC-L while stirring until dissolved. After standing for 24 hours, stir again to prepare a 5wt% hydroxypropyl cellulose solution (6).

[0172] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 6-2 and the manufacturing conditions described in Table 6-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 6-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (6) in the amounts described in Table 6-2 was sprayed while fluidizing. Then, 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 710 μm openings to produce granulated tartrate containing this compound.

[0173] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing the tartrate salt of this compound using the amounts specified in Table 6-4. In a 10L V-type container, add the granulated tartrate salt containing the compound in the amounts specified in Table 6-4, followed by the addition of sodium stearate fumarate in the amounts specified in Table 6-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0174] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound contained in 50 mg per tablet, under the conditions shown in Table 6-5.

[0175] Example 7: Tablets containing tartrate of this compound (7) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 7-1.

[0176] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (7) Take 2850g of pure water into a SUS beaker, and slowly add 150g of HPC-L while stirring until dissolved. After standing for 24 hours, stir again to prepare a 5wt% hydroxypropyl cellulose solution (7).

[0177] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 7-2 and the manufacturing conditions described in Table 7-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex, Multiplex MP-01 type) in the amounts described in Table 7-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (7) in the amounts described in Table 7-2 was sprayed while fluidizing. Then, 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 710 μm openings to produce granulated tartrate containing this compound.

[0178] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing the tartrate salt of this compound using the amounts specified in Table 7-4. In a 10L V-type container, add the granulated tartrate salt containing the compound in the amounts specified in Table 7-4, followed by the addition of sodium stearate fumarate in the amounts specified in Table 7-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0179] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound contained in 50 mg per tablet, under the conditions shown in Table 7-5.

[0180] Example 8: Tablets containing tartrate of this compound (8) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 8-1.

[0181] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (8) Take 2850g of pure water into a SUS beaker, and slowly add 150g of HPC-L while stirring until dissolved. After standing for 24 hours, stir again to prepare a 5wt% hydroxypropyl cellulose solution (8).

[0182] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 8-2 and the manufacturing conditions described in Table 8-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 8-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (8) in the amounts described in Table 8-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0183] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing tartrate of this compound using the amounts specified in Table 8-4. In a 10L V-type container, add granulated tartrate particles containing this compound in the amounts specified in Table 8-4, followed by sodium stearate in the amounts specified in Table 8-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0184] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (manufactured by Kikusui Seisakusho, VELC) under the conditions shown in Table 8-5, with each tablet containing 25 mg of the tartrate salt of this compound.

[0185] (5) Preparation of membrane coating solution (5) Weigh 1800.00 g of pure water. Add 0.32 g of yellow ferric oxide and 0.16 g of ferric oxide to a portion of the pure water and disperse using Robomics (TKHOMO MIXER MARK2.5 type). While stirring, slowly add 199.52 g of a coating component mixture containing hydroxypropyl methylcellulose, titanium dioxide, and propylene glycol to the remaining pure water and disperse and dissolve it. Add a solution containing dispersed pigments to this solution. Finally, pass the solution through a 108 μm sieve to prepare a membrane coating solution (5).

[0186] (6) Manufacturing of film-coated tablets containing tartrate salts of this compound Film-coated tablets containing the tartrate salt of this compound were manufactured under the conditions described in Table 8-6. First, 400.06 g of uncoated tablets were added to a coating machine (manufactured by Freund Industries, Ltd., HC-LABO type). The coating pan was jogged while heating under the conditions described in Table 8-6 until the exhaust temperature reached 45°C. Next, the coating pan was rotated at 20 rpm while spraying the film coating solution (5) under the conditions described in Table 8-6, and film coating was performed until the coating weight reached approximately 2.4 mg. Then, the coating pan was rotated at 12 rpm while drying until the exhaust temperature reached 50°C. After removing the tablets, Polishing wax 105 was added, followed by bag mixing and polishing.

[0187] Example 9: Tablets containing tartrate of this compound (9) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 9-1.

[0188] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (9) Take 3325g of pure water into a SUS beaker, and slowly add 175g of HPC-L while stirring until dissolved. After standing for 24 hours, stir again to prepare a 5wt% hydroxypropyl cellulose solution (9).

[0189] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 9-2 and the manufacturing conditions described in Table 9-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 9-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (9) in the amounts described in Table 9-2 was sprayed while fluidizing. Then, 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 710 μm openings to produce granulated tartrate containing this compound.

[0190] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing tartrate of this compound using the amounts specified in Table 9-4. In a plastic bag, add granulated tartrate containing this compound in the amounts specified in Table 9-4, followed by adding sodium stearate fumarate in the amounts specified in Table 9-4, and perform bag mixing (rotate 50 times longitudinally, 50 times laterally, for a total of 100 rotations).

[0191] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound containing 125 mg per tablet, under the conditions shown in Table 9-5.

[0192] Example 10: Tablets containing the tartrate salt of this compound (10) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 10-1.

[0193] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (10) 24624g of pure water was transferred to a SUS-made beaker, and 1296g of HPC-L was slowly added while stirring until dissolved. After standing for 24 hours, the solution was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (10).

[0194] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated granules containing the tartrate of this compound were manufactured under the addition amounts described in Table 10-2 and the manufacturing conditions described in Table 10-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator dryer (FREUND Sangyo Co., Ltd., NFLF-30SJC type) in the amounts described in Table 10-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (10) in the amounts described in Table 10-2 was sprayed while fluidizing. Then, the mixture was dried while fluidizing until the exhaust temperature reached 45°C, and then removed from the container. The removed granules were then dry-granulated using a conical mill to produce granulated granules containing the tartrate of this compound.

[0195] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing tartrate of this compound using the amounts specified in Table 10-4. In a 110L hopper bottle, add granulated tartrate particles containing this compound in the amounts specified in Table 10-4, followed by sodium stearate fumarate in the amounts specified in Table 10-4. Mix at 20 rpm for 15 minutes using a mixer (Yamazaki Metal Industries, Ltd., MB02-001 model).

[0196] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, AQUARIUS 3-A type) under the conditions shown in Table 10-5, with the tartrate of this compound containing 125 mg per tablet.

[0197] (5) Preparation of membrane coating solution (6) Weigh 10800g of pure water. Add 9.6g of yellow ferric oxide and 4.8g of ferric oxide to a portion of the pure water and disperse using Robomics (TKHOMOJETTER O type, HOMO MIXER MARKII40 type). While stirring, slowly add 1185.6g of a coating mixture containing hydroxypropyl methylcellulose, titanium dioxide, and propylene glycol to the remaining pure water and disperse and dissolve it. Add a solution containing dispersed pigments to this solution. Finally, pass the solution through a 108μm sieve to prepare a membrane coating solution (6).

[0198] (6) Manufacturing of film-coated tablets containing tartrate salts of this compound Film-coated tablets containing the tartrate salt of this compound were manufactured under the conditions described in Table 10-6. Uncoated tablets for film coating were added to a coating machine (FREUND Sangyo Co., Ltd., AQC-80 type), and the coating pan was jogged while heating under the conditions in Table 10-6 until the exhaust temperature reached 50°C. Next, the film coating solution (6) was sprayed while the coating pan was rotated at 10 rpm under the conditions in Table 10-6 until the coating weight reached approximately 7.5 mg. Then, the coating pan was rotated intermittently at 4.0 rpm while drying until the exhaust temperature reached 60°C. After drying, Polishing wax 105 was added to the tablets to manufacture film-coated tablets.

[0199] Example 11: Tablets containing tartrate of this compound (11) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 11-1.

[0200] B. Manufacturing Method (1) Preparation of 5wt% polyvinyl alcohol solution (1) Take about 500g of pure water into a SUS beaker, slowly add 100g of EG-05P and disperse it. Heat about 1500g of pure water to 80°C and add it to the dispersed solution to dissolve it. After standing for 24 hours, stir again and correct the weight of the evaporated pure water portion to prepare a 5wt% polyvinyl alcohol solution (1) with a total weight of 2000g.

[0201] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 11-2 and the manufacturing conditions described in Table 11-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 11-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% polyvinyl alcohol solution (1) in the amounts described in Table 11-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0202] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing the tartrate salt of this compound using the amounts specified in Table 11-4. In a 10L V-type container, add the granulated tartrate salt containing the compound in the amounts specified in Table 11-4, followed by the addition of sodium stearate fumarate in the amounts specified in Table 11-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0203] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) under the conditions shown in Table 11-5, with each tablet containing 25 mg of the tartrate salt of this compound.

[0204] Example 12: Tablets containing tartrate of this compound (12) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 12-1.

[0205] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (11) 2375g of pure water was transferred to a SUS-made beaker, and 125g of HPC-L was slowly added while stirring until dissolved. After standing for 24 hours, the solution was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (11).

[0206] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 12-2 and the manufacturing conditions described in Table 12-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and crospovidone in the amounts described in Table 12-2 were added to a fluidized bed granulator / dryer (Powrex Corporation, Multiplex MP-01 type), and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (11) in the amounts described in Table 12-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0207] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing the tartrate salt of this compound using the amounts specified in Table 12-4. In a 10L V-type container, add the granulated tartrate salt containing the compound in the amounts specified in Table 12-4, followed by the addition of sodium stearate fumarate in the amounts specified in Table 12-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0208] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound containing 25 mg per tablet, under the conditions shown in Table 12-5.

[0209] Example 13: Tablets containing tartrate of this compound (13) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 13-1.

[0210] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (12) 2375g of pure water was transferred to a SUS-made beaker, and 125g of HPC-L was slowly added while stirring until dissolved. After standing for 24 hours, the solution was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (12).

[0211] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 13-2 and the manufacturing conditions described in Table 13-3. First, the addition amounts of the compound's tartrate, D-mannitol, partially α-starch, and sodium glycolate starch as described in Table 13-2 were added to a fluidized bed granulator / dryer (Powrex Corporation, Multiplex MP-01 type), and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (12) as described in Table 13-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0212] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder of tartrate containing this compound using the amounts specified in Table 13-4. In a 10L V-type container, add granulated tartrate containing this compound in the amounts specified in Table 13-4, followed by sodium stearate in the amounts specified in Table 13-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0213] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound containing 25 mg per tablet, under the conditions shown in Table 13-5.

[0214] Example 14: Tablets containing tartrate of this compound (14) In this embodiment, the α-starch is partially processed using the product described below.

[0215] STARCH 1500 TM Colorcon A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 14-1.

[0216] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (13) 2375g of pure water was transferred to a SUS-made beaker, and 125g of HPC-L was slowly added while stirring until dissolved. After standing for 24 hours, the solution was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (13).

[0217] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 14-2 and the manufacturing conditions described in Table 14-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 14-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (13) in the amounts described in Table 14-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0218] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing the tartrate salt of this compound using the amounts specified in Table 14-4. In a 10L V-type container, add the granulated tartrate salt containing the compound in the amounts specified in Table 14-4, followed by the addition of sodium stearate fumarate in the amounts specified in Table 14-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0219] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound containing 25 mg per tablet, under the conditions shown in Table 14-5.

[0220] Comparative Example 1: Tablets containing tartrate of this compound (15) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 15-1.

[0221] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (14) 684g of pure water was transferred to a SUS-made beaker, and 36g of HPC-L was slowly added while stirring until dissolved. After standing for 24 hours, the solution was stirred again to prepare a 5wt% hydroxypropyl cellulose solution (14).

[0222] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 15-2 and the manufacturing conditions described in Table 15-3. First, the addition amounts of the compound's tartrate, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (14) was sprayed while fluidizing (the addition amounts described in Table 15-2). Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0223] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing tartrate of this compound using the amounts specified in Table 15-4. Add granulated tartrate of this compound to a plastic bag using the amounts specified in Table 15-4, followed by the addition of sodium stearate fumarate as specified in Table 15-4, and perform bag mixing (rotate 50 times longitudinally, 50 times laterally, for a total of 100 rotations).

[0224] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (manufactured by Kikusui Seisakusho, VELC) under the conditions shown in Table 15-5, with each tablet containing 50 mg of the tartrate salt of this compound.

[0225] Comparative Example 2: Tablets containing tartrate of this compound (16) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 16-1.

[0226] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl cellulose solution (15) Take 684g of pure water into a SUS-made beaker, and slowly add 36g of HPC-L while stirring until dissolved. After standing for 24 hours, stir again to prepare a 5wt% hydroxypropyl cellulose solution (15).

[0227] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 16-2 and the manufacturing conditions described in Table 16-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex, Multiplex MP-01 type) in the amounts described in Table 16-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl cellulose solution (15) in the amounts described in Table 16-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0228] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder containing tartrate of this compound using the amounts specified in Table 16-4. In a plastic bag, add granulated tartrate of this compound in the amounts specified in Table 16-4, followed by the addition of magnesium stearate in the amounts specified in Table 16-4, and perform bag mixing (rotate longitudinally 50 times, laterally 50 times, for a total of 100 rotations).

[0229] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound contained in 50 mg per tablet, under the conditions shown in Table 16-5.

[0230] Comparative Example 3: Tablets containing tartrate of this compound (17) A. Formulation of tablets containing tartrates of this compound To manufacture granulated particles, mixed powders and flakes containing the compositions of Table 17-1.

[0231] B. Manufacturing Method (1) Preparation of 5wt% hydroxypropyl methylcellulose solution (1) 1900g of pure water was transferred to a SUS-made beaker, and 100g of HPC-L was slowly added while stirring until dissolved. After standing for 24 hours, the solution was stirred again to prepare a 5wt% hydroxypropyl methylcellulose solution (1).

[0232] (2) Manufacturing of granulated particles of tartrate containing this compound Granulated tartrate containing this compound was manufactured under the addition amounts described in Table 17-2 and the manufacturing conditions described in Table 17-3. First, the tartrate of this compound, D-mannitol, partially α-starch, and croscarmellose sodium were added to a fluidized bed granulator (Powrex Corporation, Multiplex MP-01 type) in the amounts described in Table 17-2, and mixed while fluidizing until the exhaust temperature reached 40°C. Next, a 5 wt% hydroxypropyl methylcellulose solution (1) in the amounts described in Table 17-2 was sprayed while fluidizing. Then, 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 710 μm sieve to produce granulated tartrate containing this compound.

[0233] (3) Preparation of mixed powders of tartrate salts containing this compound Prepare a mixed powder of tartrate containing this compound using the amounts specified in Table 17-4. In a 10L V-type container, add granulated tartrate containing this compound in the amounts specified in Table 17-4, followed by sodium stearate in the amounts specified in Table 17-4. Mix at 40 rpm for 10 minutes using a mixer (Tsutsui Rikikaku Equipment Co., Ltd., S-5 type).

[0234] (4) Manufacturing of tartrate tablets containing this compound Unprocessed tablets were manufactured using a rotary tablet press (Kikusui Seisakusho, VELC) with the tartrate salt of this compound containing 25 mg per tablet, under the conditions shown in Table 17-5.

[0235] The quality of the formulations obtained by the above methods was evaluated using the following methods.

[0236] Experimental Example 1: Evaluation of tableting performance and determination of tablet shape, hardness, and abrasion. For Examples 1-14 and Comparative Examples 1-2, tableting performance was evaluated, and the thickness, hardness, and abrasion of the unprocessed tablets were measured. The thickness of the unprocessed tablets was measured using a special digital thickness gauge 547-301, and the hardness was measured using a tablet breaking strength tester TH-203MP manufactured by Toyama Sangyo, with the average value recorded for every 5 or 10 tablets. Furthermore, the abrasion test of the tablets was performed according to the test method described in the Japanese Pharmacopoeia using a FRIABILATOR TFT-1200 manufactured by Toyama Sangyo. The test results are shown in Table 18.

[0237] According to Table 18, Examples 1-14 exhibited good tableting properties, hardness, and abrasion resistance. In Comparative Example 1, which contained 2% binder and 2% lubricant, sticking occurred, resulting in poor tableting properties and reduced tablet hardness. Furthermore, in Comparative Example 2, which used 1% magnesium stearate as a lubricant, in addition to sticking, die friction was observed, and the hardness was further reduced compared to Comparative Example 1, making continuous tableting difficult. This demonstrates that by using 4% or more binder and 2% or more lubricant, tablets exhibiting significantly superior tableting properties and high hardness can be manufactured.

[0238] Test Example 2: Dissolution Test For Examples 1-14 and Comparative Example 3, dissolution tests were conducted under the following conditions in accordance with the general test method of the Japanese Pharmacopoeia for dissolution testing.

[0239] <Dissolution Test Conditions> Method: Dissolution test (paddle method) according to the general test method of the Japanese Pharmacopoeia. Speed: 50 rpm Test solution volume: 900mL Test solution temperature: 37℃±0.5℃ Test solution: 0.1N HCl <Preparation of Sample Solution> Place a tablet in a test apparatus containing 900 mL of test solution. At 5, 10, and 15 minutes after the start of the test, collect 10 mL of the test solution using a 10 mL syringe and filter it slowly using a membrane filter with a pore size of less than 0.45 μm. Remove at least 2 mL of the initial filtrate and use this as the sample solution.

[0240] <Preparation of Standard Solutions> Weigh 50.00 mg of the tartrate salt of this compound into a 300 mL volumetric flask and dissolve it using the dissolution test solution. Then weigh 10 mL of this solution into a 30 mL volumetric flask and dissolve it using the dissolution test solution. Use this solution as the stock solution for the standard solution.

[0241] The stock solution was diluted according to the dosage of each sample, and the resulting solution was used as a standard solution sample.

[0242] <High Performance Liquid Chromatography Analysis Conditions 1> Analysis condition 1 was used in the experiments of Example 1 and Example 2.

[0243] High Performance Liquid Chromatography Apparatus: Shimadzu UFLC-XR Detection wavelength: 260 nm Column: Waters manufactured, Xselect CSH C18 150mm × 4.6mm ID, particle size 3.5μm Mobile phase: Water / methanol / perchloric acid mixture (1000 / 1000 / 1) Analysis time: 5 minutes Flow rate: 0.8 mL / min Column temperature: 40℃ Injection volume: 5 μL 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.

[0244] High Performance Liquid Chromatography Apparatus: Shimadzu UFLC-XR Detection wavelength: 260 nm Column: Waters manufactured, Xselect CSH C18 150mm × 4.6mm ID, particle size 3.5μm Mobile phase: Water / methanol / perchloric acid mixture (1000 / 1000 / 3) Analysis time: 5 minutes Flow rate: 0.8 mL / min Column temperature: 40℃ Injection volume: 5 μL Sample cooler temperature: 25℃ Syringe washing solution: methanol / water mixture (1 / 1) The results of the dissolution test are shown in Table 19.

[0245] As shown in Table 19, the uncoated tablets or FC tablets of the present invention dissolve rapidly and are expected to have high absorption in vivo. Furthermore, although a slight difference was observed in the initial dissolution phase with and without film coating, the dissolution rate at 15 minutes showed almost no difference and had no effect on dissolution performance. Even with the use of relatively large amounts of binders and lubricants, tablets exhibiting good dissolution performance and rapid dissolution were manufactured.

[0246] Experimental Example 3: Storage Stability Test (Purity Test) Set the conditions of the constant temperature and humidity chamber to 40℃ / 75%RH or 50℃ / 85%RH. Place the raw flakes prepared in Examples 1 to 14 into HDPE bottles or brown screw-top test tubes (material: glass). After storing them in the constant temperature and humidity chamber for a specified period in an opened state, conduct a purity test to evaluate the quality of the relevant substances.

[0247] Test Condition 1 Test condition 1 was used in the tests of Example 1 and Example 2.

[0248] Detector: Ultraviolet spectrophotometer (measurement wavelength 220 nm) Column: Waters manufactured, Xselect CSH C18 150mm × 4.6mm ID, particle size 3.5μm Column temperature: a constant temperature around 40℃ Mobile phase A: Water / perchloric acid mixture (10000:1) Mobile phase B: Methanol Elution method: Gradient method Flow rate: 0.8 mL / min Area measurement range: 50 minutes after sample injection Sample cooler temperature: 5℃ Dissolving solvent: a mixture of water, methanol, and perchloric acid (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.

[0249] Detector: Ultraviolet spectrophotometer (measurement wavelength 220 nm) Column: Waters manufactured, Xselect CSH C18 150mm × 4.6mm ID, particle size 3.5μm Column temperature: a constant temperature around 40℃ Mobile phase A: Water / perchloric acid mixture (10000:1) Mobile phase B: Methanol Elution method: Gradient method Flow rate: 0.8 mL / min Area measurement range: 60 minutes after sample injection Sample cooler temperature: 25℃ Dissolving solvent: a mixture of water, methanol, and perchloric acid (1000 / 1000 / 3). Syringe washing solution: methanol / water mixture (1 / 1) Based on the peak area values ​​obtained from the liquid chromatography, the amount of related substances relative to this compound was calculated. The results of the total amount of related substances detected are shown in Tables 20-1 and 20-2.

[0250] As shown in Tables 20-1 and 20-2, no increase in related substances was observed in the preservation stability test of the raw film of the present invention, indicating good preservation stability.

[0251] Experimental Example 4: Storage Stability Test (Dissolution Test) The conditions of the constant temperature and humidity chamber were set to 40°C / 75%RH. The unpackaged tablets or FC tablets prepared in Examples 1 to 14 were placed in HDPE bottles and stored in the constant temperature and humidity chamber for a specified period of time in the opened state. Then, the dissolution test was carried out under the conditions described in Test Example 2 in accordance with the general test method of the Japanese Pharmacopoeia.

[0252] The results of the dissolution test are shown in Tables 21-1 and 21-2.

[0253] As shown in Tables 21-1 and 21-2, the uncoated tablets or FC tablets of the present invention dissolve rapidly and are expected to have high absorption in vivo. Furthermore, although a slight difference can be observed in the initial dissolution phase with and without film coating, the dissolution rate at 15 minutes shows almost no difference and has no effect on dissolution performance. Even with the use of relatively large amounts of binders and lubricants, tablets exhibiting good dissolution performance and rapid dissolution have been manufactured.

[0254] The above results indicate that the formulation disclosed herein exhibits good dissolution and storage stability, and thus, when provided in tablet form, can suppress tableting obstacles.

[0255] As described above, this disclosure has been illustrated using preferred embodiments; however, it should be understood that the scope of this disclosure should be interpreted solely by the claims. It should be understood that all patents, patent applications, and other documents referenced in this specification should be incorporated herein by reference in the same manner as their contents specifically described herein.

[0256] Industrial practicality According to this disclosure, an oral solid dosage form with suppressed compression barriers and excellent dissolution properties can be provided, which contains (i) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvation thereof, as the active ingredient, and contains (ii) a binder and (iii) a lubricant in high amounts.

Claims

1. Oral solid dosage forms, which contain: (1) 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvation thereof, (2) The adhesive, at a concentration of 4.0 to 6.0% by weight relative to 100% of the formulation, and (3) A lubricant comprising 2.0 to 10.0% by weight of 100% of the formulation.

2. The oral solid dosage form according to claim 1, wherein, The content of the adhesive is 5.0 to 6.0% by weight relative to 100% by weight of the formulation.

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

4. The oral solid dosage form according to claim 3, wherein, The water-soluble polymeric adhesive is hydroxypropyl cellulose or polyvinyl alcohol.

5. The oral solid dosage form according to claim 3, wherein, The water-soluble polymeric adhesive is hydroxypropyl cellulose.

6. The oral solid dosage form 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 formulation.

7. The oral solid dosage form according to any one of claims 1 to 5, wherein, The content of the lubricant is 4.0 to 6.0% by weight relative to 100% by weight of the formulation.

8. The oral solid dosage form according to any one of claims 1 to 7, wherein, The lubricant is sodium stearate fumarate.

9. The oral solid dosage form according to any one of claims 1 to 8, further comprising an excipient.

10. The oral solid dosage form according to claim 9, wherein, The excipient is a hydrophilic excipient.

11. The oral solid dosage form according to claim 10, wherein, The hydrophilic excipient is one or a mixture of two or more selected from sugar alcohols, α-starches, lactose hydrates and crystalline cellulose.

12. The oral solid dosage form according to claim 10, wherein, The hydrophilic excipient is one or a mixture of two or more selected from sugar alcohols, α-starches, and crystalline cellulose.

13. The oral solid dosage form according to claim 10, wherein, The hydrophilic excipient is one or a mixture of two or more selected from sugar alcohols and α-starches.

14. The oral solid dosage form according to claim 10, wherein, The hydrophilic excipient is a mixture of sugar alcohols and α-starches.

15. The oral solid dosage form according to any one of claims 11 to 14, wherein, The α-type starches mentioned are partially α-type starches.

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

17. The oral solid dosage form according to any one of claims 1 to 16, further comprising a disintegrant.

18. The oral solid dosage form 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 formulation.

19. The oral solid dosage form 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 formulation.

20. The oral solid dosage form 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 formulation.

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, glycolic acid starch sodium, and croscarmellose.

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 glycolic acid starch sodium.

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

24. The oral solid dosage form according to any one of claims 1 to 23, wherein, The content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or its pharmaceutically acceptable salt, or its hydrate or solvation, is 0.5 to 70% by weight relative to 100% of the formulation.

25. The oral solid dosage form according to any one of claims 1 to 23, wherein, The content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or its pharmaceutically acceptable salt, or its hydrate or solvation, is 10 to 50% by weight relative to 100% of the formulation.

26. The oral solid dosage form according to any one of claims 1 to 23, wherein, The content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or its pharmaceutically acceptable salt, or its hydrate or solvation, is 15 to 40% by weight relative to 100% of the formulation.

27. The oral solid dosage form according to any one of claims 1 to 23, wherein, The content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or its pharmaceutically acceptable salt, or its hydrate or solvation, is 15 to 38% by weight relative to 100% of the formulation.

28. The oral solid dosage form according to any one of claims 1 to 23, wherein, The content of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy]-N,N-bis(propane-2-yl)benzamide or its pharmaceutically acceptable salt, or its hydrate or solvation, is 20-38% by weight relative to 100% by weight of the formulation.

29. The oral solid dosage form according to any one of claims 1 to 28, wherein it is manufactured using fluidized bed granulation.

30. The oral solid dosage form according to any one of claims 1 to 29, wherein it is coated with a coating agent.

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

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