Pharmaceutical preparation in the form of granules, preparation, method of production of the pharmaceutical preparation and methods for the production of tablets and for the production of capsules.

Abstract

Pharmaceutical preparation in the form of granules, preparation, method of production of a pharmaceutical preparation and methods for the production of tablets and for the production of capsules.A pharmaceutical preparation is disclosed in the form of granules with nuclear particles and a coating layer coating the nuclear particles, wherein the nuclear particles are composed of a drug, a first nuclear particle component, a second nuclear particle component and a surfactant; the drug is an aniline derivative represented by the following general formula (i): [formula 1] wherein w represents s or o, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; the first nuclear particle component is at least one crystalline cellulose having a shape selected from a needle shape and a substantially columnar shape; and the second nuclear particle component is at least one pharmaceutically acceptable additive having a substantially spherical shape.The pharmaceutical preparation may contain a therapeutically effective amount of a poorly water-soluble drug (CDK9 inhibitor) and has excellent flowability sufficient for practical production.

Description

1 / 37 “PHARMACEUTICAL PREPARATION IN GRANULE FORM, PREPARATION, METHOD OF PRODUCTION OF THE PHARMACEUTICAL PREPARATION AND METHODS FOR THE PRODUCTION OF TABLETS AND FOR THE PRODUCTION OF CAPSULES” Field of Invention

[001] The patent application contains a priority claim based on Japanese Patent Application No. 2019-84695 (filing date: April 25, 2019), which was previously filed in Japan and the contents of which are incorporated herein in their entirety by reference.

[002] The present invention relates to a pharmaceutical preparation and a method for its production. Background of the Invention

[003] It is known that an aniline derivative, such as N-[5-fluoro2-(1-piperidinyl)phenyl]isonicotinothioamide serving as a CDK9 inhibitor, can be used as an antiviral drug to suppress viral production (e.g., (Unpatent Documents 1 to 4).

[004] However, some CDK9 inhibitors have low solubility in water. Because of this, it is difficult for those contained in preparations to dissolve in water in an effective quantity and produce a sufficient medicinal effect.

[005] Generally, as a solid preparation that can contain a poorly water-soluble drug in a therapeutically effective amount, soft capsules are widely used (e.g., Patent Document 1). However, soft capsules are often large compared to other solid preparations, such as tablets. Because of this, soft capsules have the problem of being difficult for children / elderly people with poor swallowing ability and patients with impaired swallowing ability to take. In addition, soft capsules have an inherent risk of Petition 870260057434, dated 12 / 06 / 2026, page 23 / 134 2 / 37 “easy leakage”, although the risk varies depending on the production method. Furthermore, soft capsules are flexible and change shape easily. Therefore, the presence or absence of capsule deformation must be visually inspected by a person or examined by a specialized inspection machine, resulting in increased production costs. The high cost compared to other solid preparations, such as tablets, is a problem.

[006] In contrast, when mixing a poorly water-soluble drug into tablets, the poorly water-soluble drug is dissolved in a solvent before the tablets are formed. However, it is difficult to dissolve an effective amount of the poorly water-soluble drug in a solvent contained in a volume acceptable for tablet preparation.

[007] It is known that granules composed of a drug and a solubilizing substance in combination are contained in pharmaceutical preparations. It is also known that a surfactant can be used as a solubilizing substance and that the granules can be coated (e.g., Patent Document 2). However, a surfactant has adhesiveness / stickiness and reduces flowability. The surfactant for use in the production of a pharmaceutical preparation, such as tablets, has the problem of its content being limited.

[008] As described above, if a solubilizing substance, such as a surfactant, is used to add a large amount of a poorly water-soluble drug, such as a CDK9 inhibitor, to a pharmaceutical preparation, sufficient fluidity cannot be obtained during the production of the dosage form. Since poor fluidity affects the formation of, for example, tablets, it is difficult to mix a therapeutically effective amount of a drug when the dosage form, such as tablets, is formed. Petition 870260057434, dated 12 / 06 / 2026, page 24 / 134 3 / 37 List of citations Patent Documents

[009] Patent Document 1: National Publication of International Patent Application No. 2003-508386.

[010] Patent Document 2: National Publication of International Patent Application No. 2007-517062. Documents unrelated to patents

[011] Non-Patent Document 1: Ajiro et al., Clin Cancer Res. September 15, 2018; 24 (18): 4518-4528. doi: 10.1158 / 1078-0432. CCR-173119. Epub April 30, 2018.

[012] Non-Patent Document 2: Tanaka et al., Antiviral Res. September 2016; 133: 156-64. doi: 10.1016 / j.antiviral.2016.08.008. Epub 2016, August 8.

[013] Non-Patent Document 3: Okamoto et al., Antiviral Res. November 2015; 123: 1-4. doi: 10.1016 / j.antiviral.2015.08.012. Epub August 21, 2015.

[014] Non-Patent Document 4: Yamamoto et al., J Clin Invest. August 2014; 124 (8): 3479-88. doi: 10.1172 / JCI73805. Epub 2014 July 8. Brief Description of the Invention

[015] In view of the circumstances, it has been desired to develop a pharmaceutical preparation containing a therapeutically effective amount of a CDK9 inhibitor and having excellent flowability sufficient for practical production.

[016] The present inventors conducted intensive studies and prepared a pharmaceutical preparation, which has nuclear particles containing a nuclear particle component having a predetermined shape and a drug (CDK9 inhibitor) in combination and a coating layer coating the nuclear particles. As a result, they revealed that the Petition 870260057434, dated 12 / 06 / 2026, page 25 / 134 4 / 37 A pharmaceutical preparation may contain a surfactant and the drug in large quantities and with excellent flowability. The present invention was made based on these findings.

[017] The present invention includes the following inventions: [1] A pharmaceutical preparation in the form of granules containing nuclear particles and a coating layer that coats the nuclear particles, wherein: The nuclear particles are composed of a drug, a first nuclear particle component, a second nuclear particle component, and a surfactant; the drug is an aniline derivative represented by the following general formula (I): [Formula 1] F wherein W represents S or O, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, the first nuclear particle component is at least a crystalline cellulose having a shape selected from a needle shape and a substantially columnar shape, and the second nuclear particle component is at least a pharmaceutically acceptable additive having a substantially spherical shape; [2] The pharmaceutical preparation according to [1], wherein the drug is an aniline derivative represented by the following formula (Ia): Petition 870260057434, dated 12 / 06 / 2026, page 26 / 134 5 / 37 [Formula 2] F or a pharmaceutically acceptable salt, or a hydrate thereof; [3] The pharmaceutical preparation according to [1] or [2], wherein an average aspect ratio of the first nuclear particle component is 1.8 or more; [4] The pharmaceutical preparation according to [3], where the average aspect ratio of the first nuclear particle component is 1.8 to 10.0; [5] The pharmaceutical preparation, according to any one of [1] to [4], where an average aspect ratio of the second nuclear particle component is 1.0 to 1.7; [6] The pharmaceutical preparation according to [5], where the average aspect ratio of the second nuclear particle component is 1.0 to 1.5; [7] A pharmaceutical preparation, according to any one of [1] to [6], in which a particle size ratio of 50% (D50) of the second nuclear particle component based on volume distribution to a particle size ratio of 50% (D50) of the first nuclear particle component based on volume distribution is 1:1.1 or less; [8] A pharmaceutical preparation, according to any one of [1] to [7], in which a difference in the average aspect ratio between the first nuclear particle component and the second nuclear particle component is 0.5 or more; [9] The pharmaceutical preparation, according to any one of [1] to [8], in which the second nuclear particle component is composed of at Petition 870260057434, dated 12 / 06 / 2026, page 27 / 134 6 / 37 minus two different components;

[10] The pharmaceutical preparation, according to any one of [1] to [9], in which the mass ratio of the first nuclear particle component and the second nuclear particle component is from 1:1 to 1:10;

[11] The pharmaceutical preparation, according to any one of [1] to

[10] , in which a mass ratio of a total mass of the first nuclear particle component and of the second nuclear particle component to a mass of surfactant is 1:0.01 to 1:0.6;

[12] The pharmaceutical preparation, according to any one of [1] to

[11] , in which the mass ratio of the surfactant and the drug is from 1:0.1 to 1:10;

[13] The pharmaceutical preparation, according to any one of [1] to

[12] , in which a mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component and the mass of the coating layer is 1:0.05 to 1:0.3;

[14] A pharmaceutical preparation according to any one of [1] to

[13] , wherein the second nuclear particle component is at least one pharmaceutically acceptable additive selected from the group consisting of sugars and inorganic compounds;

[15] The pharmaceutical preparation, according to any one of [1] to

[14] , in which the second nuclear particle component is at least one selected from the group consisting of glucose, fructose, lactose, lactose hydrate, sucrose, white sugar, compressed sugar, refined powdered sugar, ammonium alginate, starch, potato starch, wheat starch, corn starch, rice starch, mannitol, sorbitol, phosphate, magnesium carbonate, magnesium oxide, calcium carbonate, calcium sulfuric acid, dextrates, dextrin, dextrose, polymethacrylate, glyceryl palmitostearate, isomaltose, lactitol, kaolin, lactitol, maltitol, maltodextrin, maltose, trehalose, xylitol, starch Petition 870260057434, dated 12 / 06 / 2026, page 28 / 134 7 / 37 gelatinized starch, modified gelatinized starch, tapioca starch and sodium chloride;

[16] The pharmaceutical preparation, according to any one of [1] to

[15] , in which the surfactant is a non-ionic surfactant;

[17] The pharmaceutical preparation according to

[16] , in which the non-ionic surfactant is polysorbate;

[18] A pharmaceutical preparation according to any one of [1] to

[17] , wherein the coating layer contains a water-soluble coating agent;

[19] The pharmaceutical preparation according to

[18] , wherein the water-soluble coating agent is at least one component selected from the group consisting of a polyalkylene glycol, a polysaccharide and derivatives thereof;

[20] The pharmaceutical preparation according to

[18] or

[19] , wherein the water-soluble coating agent is at least one selected from the group consisting of polyethylene glycol, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, a methacrylic acid copolymer, a vinylpyridine copolymer, an alkyl vinylpyridine copolymer, an aminocellulose derivative, diethylaminoethyl methacrylate, polyvinylacetal diethyl aminoacetate, a dimethylaminoethyl methacrylate copolymer, cellulose acetate-N,N-di-n-butyl hydroxypropyl ether, a vinylpyridine copolymer and a free acid of the acrylic acid series, a copolymer of an alkyl vinylpyridine and a free acid of the acrylic acid series, a vinylpyridine copolymer, a free acid of the acrylic acid series and a vinyl monomer, a copolymer of an alkyl vinylpyridine, a free acid of the acrylic acid series and a monomer vinyl,a copolymer of 2-methyl-5-vinylpyridine-methacrylic acid, poly-2-(vinylphenyl)glycine, a copolymer of morpholine-ne-ethyl acrylate-methacrylic acid, shellac, cellulose acetate phthalate, a copolymer of methyl acrylate-methacrylic acid, a methyl copolymer, Petition 870260057434, dated 12 / 06 / 2026, page 29 / 134 8 / 37 methacrylate - methacrylic acid, zein, hydroxypropylmethylcellulose phthalate and an aminoalkyl methacrylate copolymer;

[21] The pharmaceutical preparation, according to any one of [1] to

[20] , in which a degree of agglomeration of the pharmaceutical preparation is 70% or less;

[22] A pharmaceutical preparation according to any one of [1] to

[21] , in which the degree of agglomeration of the pharmaceutical preparation is less than a degree of agglomeration of the nuclear particles;

[23] The pharmaceutical preparation, according to any one of [1] to

[22] , wherein a particle size of 50% (D50) of the pharmaceutical preparation based on volume distribution is 100 to 400 pm;

[24] A preparation containing the pharmaceutical preparation according to any one of [1] to

[23] and having a dosage form selected from the group consisting of a granule, a tablet, a capsule, a powder and a pill;

[25] A method for producing a pharmaceutical preparation in the form of granules with nuclear particles and a coating layer that coats the nuclear particles, including: (a) mixing a first nuclear particle component and a second nuclear particle component to obtain a nuclear particle mixture, (b) dissolving or suspending a drug in a mixture of a surfactant and a solvent to obtain a mixed solution, (c) bringing the nuclear particle mixture obtained in (a) into contact with the mixture obtained in (b) to obtain nuclear particles containing the first nuclear particle component, the second nuclear particle component, drug and surfactant, and (d) coating the nuclear particles obtained in (c) to obtain Petition 870260057434, dated 12 / 06 / 2026, page 30 / 134 9 / 37 a pharmaceutical preparation, in which: The drug is an aniline derivative represented by the following general formula (I): [Formula 3] F wherein W represents S or O, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, the first nuclear particle component is at least a crystalline cellulose having a shape selected from a needle shape and a substantially columnar shape, and the second nuclear particle component is at least a pharmaceutically acceptable additive having a substantially spherical shape;

[26] The production method, according to

[25] , in which the drug is an aniline derivative represented by the following formula (Ia): [Formula 4] su (I —a) or a pharmaceutically acceptable salt thereof, or a hydrate thereof;

[27] The production method, according to

[25] or

[26] , in which an average aspect ratio of the first nuclear particle component is Petition 870260057434, dated 12 / 06 / 2026, page 31 / 134 10 / 37 1.8 or more;

[28] The production method, according to

[27] , in which the average aspect ratio of the first nuclear particle component is 1.8 to 10.0;

[29] The production method, according to any one of

[25] to

[28] , in which an average aspect ratio of the second nuclear particle component is 1.0 to 1.7;

[30] The production method, according to

[29] , in which the average aspect ratio of the second nuclear particle component is 1.0 to 1.5;

[31] The production method, according to any one of

[25] to

[30] , wherein a particle size ratio of 50% (D50) of the second nuclear particle component based on the volume distribution to the particle size ratio of 50% (D50) of the first nuclear particle component based on the volume distribution is 1:1.1 or less;

[32] The production method, according to any one of

[25] to

[31] , in which the second nuclear particle component is composed of at least two different components;

[33] The production method according to any one of

[25] to

[32] , including further (e) obtaining a granular preparation by adding a pharmaceutically acceptable additive to the pharmaceutical preparation obtained in (d);

[34] The production method according to any one of

[25] to

[32] , including further (e') obtaining a capsule-like preparation enclosing the pharmaceutical preparation obtained in (d) with a film made of gelatin or a plant-derived material;

[35] A method for producing tablets, including forming tablets from the pharmaceutical preparation according to any one of [1] to

[23] ;

[36] A method for the production of capsules, including the Petition 870260057434, dated 12 / 06 / 2026, page 32 / 134 11 / 37 encapsulation of the pharmaceutical preparation according to any one of [1] to

[23] ;

[018] According to the present invention, it is possible to provide a pharmaceutical preparation in the form of granules containing a therapeutically effective amount of a drug and having excellent flowability sufficient for practical production. According to the present invention, it is possible to suppress the agglomeration that reduces the flowability of a pharmaceutical preparation. As a result, the pharmaceutical preparation with excellent flowability is achieved. Because of this, a poorly water-soluble component can be mixed in a large quantity in a pharmaceutical preparation, such as tablets (tablet formation is inhibited by low flowability). Furthermore, even if the pharmaceutical preparation of the present invention is stored for a long time, it is possible to suppress the leakage of the surfactant contained in the core particles to the surface of the pharmaceutical preparation. Brief Description of the Drawings

[019] Figure 1A shows an electron micrograph of a needle-shaped crystalline cellulose (CEOLUS KG-1000).

[020] Figure 1B shows an electron micrograph of a needle-shaped crystalline cellulose (CEOLUS UF-702).

[021] Figure 2 shows an electron micrograph of a second nuclear particle component (substantially spherical particles: lactose hydrate).

[022] Figure 3 shows an electron micrograph of a second nuclear particle component (substantially spherical particles: corn starch). Detailed Description of the Invention

[023] Now, the present invention will be described in more detail. Petition 870260057434, dated 12 / 06 / 2026, page 33 / 134 12 / 37 specifically. Note that, in the descriptive report, the numeric range expressed by “a” means the range including numeric values ​​before and after “a” as the minimum and maximum values, respectively. In the descriptive report, the expression “A or B” means that one or both A and B are included, unless otherwise specified and except where interpreted in a limited way from the context. Pharmaceutical preparation

[024] The pharmaceutical preparation of the present invention is a pharmaceutical preparation in the form of granules with nuclear particles and a coating layer that coats the nuclear particles. The nuclear particles and the coating layer will be described individually below. Nuclear particles

[025] Nuclear particles are composed of a drug, a first nuclear particle component, a second nuclear particle component, and a surfactant. The first nuclear particle component is needle-shaped and / or substantially columnar crystalline cellulose (hereinafter sometimes referred to simply as “needle-shaped crystalline cellulose”). The second nuclear particle component is at least one pharmaceutically acceptable additive with a substantially spherical shape.

[026] Since nuclear particles contain a first nuclear particle component and a second nuclear particle component that is significantly different in shape, many voids can be formed between the first nuclear particle component and the second nuclear particle component. As a result, the surface area in which a liquid component is internally contained increases in nuclear particles. Because of this, a large amount of the liquid component can be contained within nuclear particles. Furthermore, since the Petition 870260057434, dated 12 / 06 / 2026, page 34 / 134 13 / 37 Nuclear particles can contain a large amount of a surfactant that serves as a solubilizer; as the liquid component, a poorly water-soluble drug can be dissolved or suspended. Although not limited by a theory, it is considered that a pharmaceutical preparation containing a large amount of a poorly water-soluble drug in nuclear particles can be produced based on such a mechanism. First component of a nuclear particle

[027] According to one embodiment of the present invention, the first nuclear particle component to be used in nuclear particles is needle-shaped crystalline cellulose. The needle-shaped crystalline cellulose serving as the first nuclear particle of the present invention is derived from crystalline cellulose that can be added for the preparation of a pharmaceutical preparation. The needle-shaped crystalline cellulose is sufficient, provided it contains a needle-shaped and / or substantially columnar crystal at a rate sufficient to produce the effect of the present invention. The lower limit of the rate of needle-shaped and / or substantially columnar crystalline cellulose in the first nuclear particle component, while not particularly limited, is preferably 60%, more preferably 70%, and even more preferably 80%. The upper limit of this may be, for example, 100%, 98%, 95%, and 90%.Although the rate range of needle-shaped and / or substantially columnar crystalline cellulose in the first nuclear particle component is not particularly limited, the range of the number of crystalline particles is preferably 60 to 100%, more preferably 70 to 100%, and even more preferably 80 to 100%. In the descriptive report, “needle-shaped crystalline cellulose” refers to crystalline cellulose with a significant difference between the vertical and horizontal lengths in a longitudinal cross-section of the microscopic image of crystalline cellulose (projected onto a plane). The difference. Petition 870260057434, dated 12 / 06 / 2026, page 35 / 134 The significant difference between vertical and horizontal lengths in this document can be expressed by, for example, an aspect ratio.

[028] More specifically, the average aspect ratio of the first nuclear particle component, while not particularly limited as long as the effect of the present invention is produced, is greater than the average aspect ratio of the second nuclear particle component. Its lower limit is preferably 1.8, more preferably 2.2, and even more preferably 2.5. The upper limit of the average aspect ratio of the first nuclear particle component, while not particularly limited as long as the effect of the present invention is produced, may be, for example, 10 or 8. The range of the average aspect ratio of the first nuclear particle component, while not particularly limited, is preferably 1.8 to 10, more preferably 2.2 to 10, and even more preferably 2.5 to 10.In the descriptive report, the “aspect ratio” of a nuclear particle component refers to the ratio between the major axis and the minor axis (longest diameter / shortest diameter) of a particle of a nuclear particle component in a particle image obtained by electron microscopy analysis. The “average aspect ratio” of the nuclear particle component refers to an average value of aspect ratios of particles of the nuclear particle component, obtained by randomly selecting 10 or more particles, measuring their aspect ratios, excluding the aspect ratio values ​​of the top 10% and bottom 10%, and averaging the remaining values.

[029] The amount of the first nuclear particle component, although not particularly limited as long as the effect of the present invention is produced, is preferably 5 to 50% by mass relative to the total mass of the pharmaceutical preparation. Petition 870260057434, dated 12 / 06 / 2026, page 36 / 134 15 / 37 Second component of nuclear particle

[030] According to one embodiment of the present invention, the second nuclear particle component to be used in nuclear particles is a pharmaceutically acceptable additive with a substantially spherical shape. In the descriptive report, “substantially spherical” refers to a shape close to a sphere and having no significant difference between the vertical and horizontal lengths in an electron microscopic image (projected onto a plane). A needle-like shape and a substantially columnar shape are not included here. In other words, the second nuclear particle component according to one embodiment is a pharmaceutically acceptable additive that is neither needle-shaped nor columnar.Regarding the "substantially spherical" shape, the shape of an image observed by an electron microscope may not always be a perfect sphere and may be a spherical, ellipsoidal, distorted polyhedral shape (including a cube), or a rounded polyhedral shape, for example.

[031] The average aspect ratio of the second nuclear particle component is smaller than the average aspect ratio of the first nuclear particle component, preferably 1.0 to 1.65, more preferably 1.0 to 1.5, even more preferably 1.0 to 1.3, and even more preferably 1.0 to 1.2. The aspect ratio and average aspect ratio of the second nuclear particle component are the same as those of the first nuclear particle component, respectively.

[032] In the pharmaceutical preparation of the present invention, the amount of the second nuclear particle component, although not particularly limited, provided that the effect of the present invention is produced, is preferably 30 to 90% by mass relative to the total mass of the pharmaceutical preparation.

[033] The particle size of the second component of Petition 870260057434, dated 12 / 06 / 2026, page 37 / 134 16 / 37 nuclear particle, although not particularly limited, provided that the effect of the present invention is produced, is controlled so that the particle size of 50% (D50) of the second nuclear particle component based on volume distribution relative to the particle size of 50% (D50) of the first nuclear particle component based on volume distribution (D50 of the first nuclear particle component: D50 of the second nuclear particle component based on volume distribution) preferably becomes 1:1.1 or less, more preferably 1:0.8 or less, even more preferably 1:0.5 or less, and even more preferably 1:0.1 or less.

[034] As the second nuclear particle component, a single component type can be used alone and two or more component types can be used in combination, and preferably two or more different component types in D50 (50% particle size based on volume distribution) can be used in combination. For example, if the second nuclear particle component is composed of two component types, the D50 values ​​(50% particle size based on volume distribution) of the two component types preferably differ.Note that, in the present invention, if the nuclear particle component contains two or more types of components, the 50% particle size (D50) of the nuclear particle component based on volume distribution is calculated by calculating the mass ratios of individual components relative to the total mass of the components constituting the nuclear particle component, obtaining products by multiplying the ratios of the respective components by the D50 (50% particle size based on volume distribution) of the respective components, and summing the products. Assuming that the nuclear particle component contains two types of components, A and B, with a and b as... Petition 870260057434, dated 12 / 06 / 2026, page 38 / 134 17 / 37 a mass, respectively, and D50a and D50b as D50 (the 50% particle sizes based on the volume distribution), respectively, D50 (the 50% particle size based on the volume distribution) of the nuclear particle component can be calculated according to the following equation: D50 (50% particle size based on ab in volume distribution) of the nuclear particle component = a + b x D50A + a + b X^$θB (Equation 1)

[035] The component(s) constituting the second nuclear particle component, which are not particularly limited as long as they are pharmaceutically acceptable components, include, for example, sugars (e.g., sugar, a sugar hydrate, a sugar alcohol) and inorganic compounds.

[036] Examples of sugars include, but are not particularly limited to, monosaccharides such as glucose, disaccharides such as lactose and sucrose, and polysaccharides such as starch. Examples of starch include potato starch, wheat starch, corn starch, and rice starch. Corn starch is preferably used as a sugar.

[037] Examples of sugar hydrates include, but are not particularly limited to, any hydrates of the sugars mentioned above. Preferably, a lactose hydrate is used.

[038] Examples of sugar alcohols include, but are not particularly limited to, sugar alcohols of any sugars. Preferably, mannitol or sorbitol is used.

[039] Examples of inorganic compounds include, but are not particularly limited to, phosphates, such as anhydrous calcium phosphate.

[040] The first nuclear particle component has a larger average aspect ratio than the second nuclear particle component. A Petition 870260057434, dated 12 / 06 / 2026, p. 39 / 134 18 / 37 The difference in the average aspect ratio between the first and second nuclear particle components is preferably large. More specifically, the difference in the average aspect ratio between the first and second nuclear particle components (the average aspect ratio of the first nuclear particle component - the average aspect ratio of the second nuclear particle component) is preferably 0.5 or more, more preferably 0.6 or more, and even more preferably 0.7 or more.

[041] The difference (apparent compacted density - apparent poured density) between the apparent compacted density and apparent poured density of a mixture (nuclear particle mixture) containing the first and second nuclear particle components is not particularly limited, provided that the effect of the present invention is produced. The lower limit thereof is preferably 0.15, more preferably 0.16, and even more preferably 0.17, while the upper limit is preferably 0.25, more preferably 0.24, and even more preferably 0.23. The range of the difference is preferably 0.15 to 0.25, more preferably 0.16 to 0.24, and even more preferably 0.17 to 0.23.Note that, in the present invention, the compacted apparent density and the poured apparent density can be measured, for example, by a commercially available powder characteristic tester (PT-R powder tester (trademark), manufactured by HOSOKAWA MICRONE CORPORATION). The measurement method using the powder tester is specifically described in the 17th revised Japanese Pharmacopoeia. More specifically, a mixture of nuclear particles is uniformly supplied, from above through a sieve, to a cylindrical container with the same dimensions as the measuring container, which are defined in Method 3 (measurement method of apparent density and compacted density) described in the 17th revision of the Japanese Pharmacopoeia. The excess of the nuclear particle mixture is scraped from the top of the container, and then the mixture is... Petition 870260057434, dated 12 / 06 / 2026, page 40 / 134 19 / 37 weighed. In this way, the apparent density (pour-inapparent density) of the approximately packed mixture is measured. Then, an auxiliary cylinder is placed in the container, and then the mixture of nuclear particles is added up to the level of the upper edge of the auxiliary cylinder and beaten 180 times. After the compaction is complete, the auxiliary cylinder is removed. The excess particle mixture was scraped from the top of the container and the mixture was weighed. In this way, the apparent density (derived apparent density) of the densely beaten mixture by compaction is measured.

[042] The particle sizes (diameters) of the particles constituting the first and second nuclear particle components are not particularly limited, provided that the effect of the present invention is produced. The D50 (50% particle size based on volume distribution) of the first nuclear particle component is preferably 50 to 200 pm, more preferably 60 to 150 pm, and even more preferably 70 to 100 pm. The D50 (50% particle size based on volume distribution) of the second nuclear particle component is preferably 1 to 300 pm, more preferably 5 to 200 pm, and even more preferably 10 to 150 pm.In the present invention, the diameter of the particles constituting a nuclear particle component and the 50% particle size based on the volume distribution can be measured using, for example, a commercially available particle size distribution meter (e.g., Mastersizer 3000, manufactured by Spectris) according to laser diffractometry (measurement method: dry system, scattering intensity: 1% or more, light scattering model: Mie scattering theory). Note that D50 (50% particle size based on volume distribution) refers to the particle size corresponding to 50% by volume in the cumulative volume distribution curve (total volume: 100%) showing the volume-based particle size distribution obtained by measurement accordingly. Petition 870260057434, dated 12 / 06 / 2026, page 41 / 134 20 / 37 with laser diffractometry.

[043] The total mass of the first and second nuclear particle components, although not particularly limited, provided the effect of the present invention is produced, is for example 20 to 90% by weight in relation to the total mass of the pharmaceutical preparation.

[044] The mass ratio of the first nuclear particle component and the second nuclear particle component (mass of the first nuclear particle component: mass of the second nuclear particle component), although not particularly limited, provided the effect of the present invention is produced, is, for example, 1:1 to 1:10. Surfactant

[045] The pharmaceutical preparation of the present invention contains a surfactant that can dissolve or suspend a drug in nuclear particles. The surfactant is not particularly limited, provided it is pharmaceutically acceptable. For example, a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant can be used. Examples of cationic surfactants include a primary amine salt, an alkyltrimethylammonium salt, an alkylpyridinium salt, and an alkyl polyoxyethylene amine. Examples of anionic surfactants include a fatty acid salt, a rosin salt, an alkyl polyoxyethylene sulfate, an olefin sulfonate, an alkylnaphthalene sulfonate, a lignin sulfonate, and an alkyl phosphate. Examples of amphoteric surfactants include an N-alkyl β-amino propionate, an N-alkyl sulfobetaine, an N-alkyl hydroxysulfobetaine, and lecithin.Examples of nonionic surfactants include a polyoxyethylene alkyl ether, a polyoxyethylene fatty acid ester, a sorbitan fatty acid ester, a sucrose fatty acid ester, a polyglycerin fatty acid ester, and a polyoxyethylene sorbitan fatty acid ester. Of these, the surfactant is preferably a nonionic surfactant, more preferably a... Petition 870260057434, dated 12 / 06 / 2026, p. 42 / 134 21 / 37 polysorbate, and even more preferably, polysorbate 80. These surfactants can be used alone or in combination of two or more. The surfactant can be dissolved in, for example, water or an alcohol and put into use.

[046] The amount of surfactant is not particularly limited, provided that the effect of the present invention is produced. The lower limit of the mass ratio of surfactant to the total amount of nuclear particle components (total mass of nuclear particle components: mass of surfactant) is preferably 1:0.001, and more preferably 1:0.01. The upper limit thereof, while not particularly limited, is preferably 1:0.6, more preferably 1:0.4, and even more preferably 1:0.3. The range of the mass ratio of surfactant to the total amount of nuclear particle components, while not particularly limited, is preferably 1:0.001 to 1:0.6, more preferably 1:0.01 to 1:0.4, and even more preferably 1:0.01 to 1:0.3. Drug

[047] The pharmaceutical preparation of the present invention contains, in its core, an aniline derivative represented by the following general formula (I): [Formula 5] F where W represents S or O, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. The drug is preferably present in a dissolved or suspended state in a surfactant (hereinafter sometimes referred to as a “mixed solution”) as mentioned above. Note that, in the report Petition 870260057434, dated 12 / 06 / 2026, p. 43 / 134 22 / 37 descriptive, the case in which part of a drug is dissolved and another part of the drug is suspended is also included in the meaning of "solvent or suspension".

[048] As the drug represented by general formula (I), specifically, N-[5-fluoro-2-(1-piperidinyl)phenyl]isonicotinothioamide (FIT-039) represented by the following formula (Ia) may be mentioned. [Formula 6] F (Ia)

[049] The pharmaceutical preparation of the present invention may contain another drug in addition to the drug mentioned above. Examples of other drugs may include an antiviral agent, an anti-inflammatory agent, and an immune enhancer.

[050] In the pharmaceutical preparation of the present invention, the amount of the drug is not particularly limited, provided that the pharmaceutical preparation of the present invention produces the desired effect. The lower limit of the mass ratio of the drug to the total amount of the nuclear particle components (the mass of a drug: the total mass of the nuclear particle components) is preferably 0.01:1, more preferably 0.02:1, and even more preferably 0.03:1. The upper limit of this, although not particularly limited, is preferably 0.5:1, and more preferably 0.2:1. The range of the mass ratio of the drug to the total amount of the nuclear particle components, although not particularly limited, is preferably 0.01:1 to 0.5:1, more Petition 870260057434, dated 12 / 06 / 2026, page 44 / 134 23 / 37 preferably 0.02:1 to 0.5:1, and even more preferably 0.03:1 to 0.2:1.

[051] In the pharmaceutical preparation of the present invention, the amount of a drug is not particularly limited, provided that the pharmaceutical preparation of the present invention produces the desired effect. The lower limit of a mass ratio of drug to surfactant (mass of drug: mass of surfactant) is preferably 0.05:1, more preferably 0.1:1, and even more preferably 0.5:1. The upper limit of this, although not particularly limited, is preferably 5:1, and more preferably 3:1. The range of the mass ratio of a drug to a surfactant, although not particularly limited, is preferably 0.05:1 to 5:1, more preferably 0.1:1 to 5:1, and even more preferably 0.5:1 to 3:1.

[052] In the pharmaceutical preparation of the present invention, the degree of agglomeration of nuclear particles, although not particularly limited, is preferably 90% or less, more preferably 70% or less, and even more preferably 50% or less.

[053] The degree of agglomeration can be measured using a commercially available powder characteristic tester. Examples of powder characteristic testers include the PTR powder tester (trademark) (manufactured by HOSOKAWA MICRONE CORPORATION). Measurement conditions are, for example, as follows: Mesh opening: (upper stage) 710 pm, (intermediate stage) 355 pm, (lower stage) 250 pm; Sampling volume: 2 g or 3 g; and Stirring time: 119 seconds.

[054] Under the above conditions, the values ​​of the individual terms in the following equations are measured: X = [mass of powder remaining in the upper stage] / mass of Petition 870260057434, dated 12 / 06 / 2026, page 45 / 134 24 / 37 loaded powder x 100 (Equation 2); Y = [mass of powder remaining in the intermediate stage] / mass of powder loaded x 100 x 0.6 (Equation 3); and Z = [mass of powder remaining in the lower stage] / mass of powder loaded x 100 x 0.2 (Equation 4).

[055] The total value of “X”, “Y”, and “Z” is used as a degree of agglomeration (%). Coating layer

[056] The coating layer coats the nuclear particles to successfully suppress leakage of a surfactant and drug contained in the nuclear particles to the surface of a pharmaceutical preparation. As a result, leakage of a surfactant is suppressed by a coating layer, agglomeration and a decrease in the fluidity of a pharmaceutical preparation can be suppressed.

[057] The component(s) that make up the coating layer are not particularly limited; for example, a water-soluble coating agent may be mentioned. Water-soluble coating agents may be used alone or in combination of two or more.

[058] According to one embodiment, the water-soluble coating agent preferably contains at least one component selected from a polyalkylene glycol and a polysaccharide or a derivative thereof.

[059] The polysaccharide or a derivative thereof is preferably a cellulose derivative, such as methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose. Cellulose derivatives may be used alone or in combination of two or more.

[060] Examples of polyalkylene glycol include polyethylene glycol. Petition 870260057434, dated 12 / 06 / 2026, page 46 / 134 25 / 37

[061] According to another preferred embodiment, examples of the coating agent to be used in the coating layer include hydroxypropylcellulose, hydroxypropylmethylcellulose, a methacrylic acid copolymer, a vinylpyridine copolymer, an alkyl vinylpyridine copolymer, an aminocellulose derivative, diethylaminoethyl methacrylate, polyvinyl acetal diethylaminoacetate, a diethylaminoethyl methacrylate copolymer, cellulose acetate-N,N-di-n-butyl hydroxypropyl ether, a vinylpyridine copolymer and a free acrylic acid series, a copolymer of an alkyl vinylpyridine and a free acrylic acid series, a copolymer of vinylpyridine, a free acrylic acid series and a vinyl monomer, a copolymer of an alkyl vinylpyridine, a free acrylic acid series and a vinyl monomer, 2-methyl-5-vinylpyridine-methacrylic acid copolymer, poly-2-(vinylphenyl)glycine,A copolymer of morpholine-N-β-ethyl acrylate-methacrylic acid, shellac, cellulose acetate phthalate, a copolymer of methyl acrylate-methacrylic acid, a copolymer of methyl methacrylate-methacrylic acid, zein, hydroxypropylmethylcellulose phthalate, and an aminoalkyl methacrylate copolymer. These can be used alone or in combination of two or more.

[062] According to one embodiment, the coating agent may be used in combination with a plasticizer. Examples of plasticizers include acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, sorbitol, dextrin, diethyl phthalate, glycerin, polyalkylene glycol, polyethylene glycol monoethyl ether, propylene glycol, benzyl benzoate, purified water, sorbitol, a sorbitan solution, triacetin, tributyl citrate, triethyl citrate, and chlorobutanol. Of these plasticizers, preferably a polyalkylene glycol, and more preferably polyethylene glycol (macrogol) is used. These plasticizers may be used alone or in combination of two or more. Petition 870260057434, dated 12 / 06 / 2026, page 47 / 134 26 / 37

[063] The component that constitutes the coating layer can be used directly or, if necessary, dissolved in, for example, water or an alcohol, and put into use.

[064] In the pharmaceutical preparation of the present invention, the amount of the coating layer is not particularly limited, provided that the pharmaceutical preparation of the present invention produces a desired effect. The lower limit of the ratio of the mass of the coating layer to the total mass of nuclear particles (mass of the coating layer: total mass of nuclear particles) is preferably 0.001:1, and more preferably 0.002:1. The upper limit of the same, although not particularly limited, is preferably 0.1:1, more preferably 0.05:1, and even more preferably 0.02:1. The range of the ratio between the mass of the coating layer and the total mass of nuclear particles, although not particularly limited, is preferably from 0.001:1 to 0.1:1, more preferably from 0.002:1 to 0.05:1, and even more preferably from 0.002:1 to 0.02:1. Other components

[065] The pharmaceutical preparation of the present invention may contain pharmaceutically acceptable additives, which are different from the components that constitute the core particles and the coating layer, provided that the effect of the present invention is not impeded. Examples of additives include an excipient, a disintegrant, a lubricant, a binder, a fluidizer, a sweetener, a fragrance, and a coloring agent. These additives may have two functions per agent and may be used alone or in combination of two or more.

[066] Since the pharmaceutical preparation of the present invention has a coating layer covering the nuclear particles, leakage of a surfactant and a drug contained in the nuclear particles Petition 870260057434, dated 12 / 06 / 2026, page 48 / 134 27 / 37 of the pharmaceutical preparation is suppressed. As a result, clumping of the pharmaceutical preparation can be suppressed.

[067] The degree of agglomeration of the pharmaceutical preparation is preferably 70% or less, more preferably 60% or less, and even more preferably 50% or less. The measurement of the degree of agglomeration of the pharmaceutical preparation can be carried out in the same way as in the measurement of the degree of agglomeration of nuclear particles mentioned above.

[068] It is preferable that the degree of agglomeration of the pharmaceutical preparation be better (lower) than that of the nuclear particles.

[069] The particle size of the pharmaceutical preparation is not particularly limited. The D50 (50% particle size based on volume distribution) is 100 to 400 µm, and more preferably 120 to 250 µm. The measurement of the 50% particle size (D50) of a pharmaceutical preparation based on volume distribution is carried out in the same way as in the measurement of a nuclear particle component mentioned above.

[070] The pharmaceutical preparation of the present invention can be used directly or can be processed into various dosage forms. The dosage form of the pharmaceutical preparation is not particularly limited, provided that the effect of the present invention is produced. Examples of dosage forms include granules, tablets, pills, capsules, and powders. Of these, granules, tablets, and capsules are preferred. Hard capsules are mentioned, as are capsules. Pharmaceutical preparation production method

[071] A method for producing the pharmaceutical preparation of the present invention is not particularly limited and a method known in the field of art can be used. The production conditions for the pharmaceutical preparation can be suitably controlled, depending on the types of particle core components, surfactant, drug components and Petition 870260057434, dated 12 / 06 / 2026, page 49 / 134 28 / 37 coating layer. As the drug, a drug represented by the general formula (I) above is used. More specifically, the pharmaceutical preparation of the present invention can be produced, for example, in accordance with the following procedure. Firstly, a first component of nuclear particles, i.e., needle-shaped and / or substantially columnar crystalline cellulose, and a second component of nuclear particles, i.e., at least one pharmaceutically acceptable additive having a substantially spherical shape, are mixed using a fluidized bed granulator (e.g., FD-MP-01D, manufactured by Powrex Corp.) to obtain a mixture of nuclear particles (primary particles). Separately, a drug is added to a surfactant and stirred by a mixer (NZ-1200, manufactured by TOKYO RIKAKIKAI CO, LTD.) to obtain a mixed solution (drug solution) in which the drug is dissolved or suspended.Next, the resulting mixture and the mixed solution are brought into contact with each other using a fluidized bed granulator to fix the mixed solution onto the nuclear particles (in the mixture) to obtain nuclear particles. The contact between the mixture and the mixed solution is achieved by a method, for example, spraying the mixed solution onto the mixture, or immersing the mixture in the mixed solution. Subsequently, a nuclear particle component is dried, as needed, and then the nuclear particles are coated with a component (coating layer component) that constitutes a coating layer. The coating of the nuclear particles is formed by a method, for example, spraying the coating layer component onto the nuclear particles, or immersing the nuclear particles in (a solution of) the coating layer component.Next, the particles, composed of nuclear particles and a coating layer that covers the nuclear particles, are dried until a pharmaceutical preparation is obtained. Petition 870260057434, dated 12 / 06 / 2026, p. 50 / 134 29 / 37

[072] A method for forming tablets from a pharmaceutical preparation is not particularly limited, and a method known in the technical field can be used. The conditions for tablet formation are not particularly limited and can be appropriately controlled, depending, for example, on the types of core particle components, surfactant, drug, and coating layer components. As a method for forming tablets from a pharmaceutical preparation, for example, a method for forming tablets from a pharmaceutical preparation by a tablet press such as a rotary tablet press or a single-shot tablet press can be used. Of these, a method of compressing the pharmaceutical preparation by a rotary tablet press is preferred. As a rotary tablet press, for example, VIRGEM 0512SS2AY manufactured by KIKUSUI can be mentioned.If the tablets contain pharmaceutically acceptable additive(s) other than the pharmaceutical preparation of the present invention, the pharmaceutical preparation of the present invention and the pharmaceutically acceptable additive(s) are first mixed and then pressed. A method for mixing the pharmaceutical preparation and additives is not particularly limited and a method known in the field of the art may be used. As a method for mixing the pharmaceutical preparation and additives, for example, a method using a mixer such as a V-shaped mixer is mentioned. More specifically, the V-shaped mixer (TCV-20) manufactured by Tokuju CORPORATION may be used for mixing.

[073] A method for encapsulating the pharmaceutical preparation is not particularly limited and a method known in the technical field may be used. More specifically, the pharmaceutical preparation is encapsulated by placing the preparation in a capsule formed from a film of, for example, gelatin or plant-derived material. A method for Petition 870260057434, dated 12 / 06 / 2026, page 51 / 134 30 / 37 Placing the preparation into the capsule formed by a film is not particularly limited and a method known in the technical field can be employed, such as drill powder filling (auger), die compression system powder filling and vibration type powder filling can be used. For example, in drill powder filling, powdered or granular pharmaceutical preparation supplied / poured from a funnel into cap-shaped containers, each having an open end and usually formed by a gelatin film, and placed directly into the capsule bodies in a predetermined quantity by the use of an agitation blade and rotational pressure of a drill, and then the cap-shaped containers are coaxially joined to produce capsules. Examples

[074] Now, the present invention will be described more specifically based on the following examples, but the present invention is not limited to these examples. Note that, in the Examples, “average particle size (D50)” means “50% particle size based on volume distribution,” unless otherwise specified. METHOD for preparing nuclear particles

[075] Lactose hydrate (SuperTab (registered trademark), average particle size (D50): 120 µm, manufactured by DFE Pharma) and corn starch (defined by the Japanese Pharmacopoeia, average particle size (D50): 15 µm, manufactured by Nihon Shokuhin Kako Co., Ltd.) were prepared as substantially spherical particles; and crystalline cellulose (CEOLUS UF-702, average particle size (D50): 140 µm, manufactured by Asahi Kasei Corporation), and crystalline cellulose (CEOLUS KG1000, average particle size (D50): 80 µm, manufactured by Asahi Kasei Corporation) were prepared as needle-shaped and / or substantially columnar crystalline cellulose. Image measurement was performed in Petition 870260057434, dated 12 / 06 / 2026, page 52 / 134 31 / 37 electron microscope (VE-7800, manufactured by KEYENCE). Figures 1A and B show electron micrographs of needle-shaped and / or substantially columnar crystalline cellulose, CEOLUS KG-1000 and CEOLUS UF-702, respectively. Figure 2 shows an electron micrograph of lactose hydrate (substantially spherical particles). Figure 3 shows an electron micrograph of corn starch (substantially spherical particles).

[076] According to the prescriptions shown in Table 1, a lactose hydrate (SuperTab (registered trademark), average aspect ratio of 1.39, average particle size (D50): 120 µm, manufactured by DFE Pharma), and corn starch (defined by the Japanese Pharmacopoeia, average aspect ratio: 1.23; average particle size (D50): 15 µm, manufactured by Nihon Shokuhin Kako Co., Ltd.) as substantially spherical particles; Crystalline cellulose (CEOLUS UF-702, average aspect ratio: 2.63, average particle size (D50): 140 µm, manufactured by Asahi Kasei Corporation), and (CEOLUS KG-1000, average aspect ratio: 4.20, average particle size (D50): 80 µm, manufactured by Asahi Kasei Corporation) as needle-like crystalline cellulose, were sieved separately through a 355 µm sieve, placed in a polyethylene bag and premixed.Note that the average aspect ratio of each nuclear particle component was measured by obtaining particle images using an electron microscope (VE-7800, manufactured by KEYENCE) and the images were analyzed; more specifically, selecting 10 particles from the images, measuring the aspect ratios of the 10 particles, removing the top 10% and bottom 10% aspect ratio values, and calculating the average of the remaining aspect ratio values. In Table 1, the unit of numerical values ​​is grams (g), unless otherwise specified. Petition 870260057434, dated 12 / 06 / 2026, page 53 / 134 32 / 37 Table 1 Example of test Comparative Example 1 Example 1 Example 2 Example 3 Nuclear particle First component of nuclear particle Crystalline cellulose (CEOLUS UF-702) - 125 62.5 125 Second component of nuclear particle Corn starch 125 125 62.5 125 Lactose hydrate (Super Tab) 125 - 417.5 187.5 Surfactant Polysorbate 80 75 75 25 150 Solvent Ethanol 300 300 200 300 Drug FIT-039CT 31.25 31.25 62.5 125 Coating layer Coating agent Hypromellose 2910 (TC-5E) 16 16 1.24 32 Macrogol 6000SP 1.6 1.6 0.124 3.2 Solvent Purified water 232.4 232.4 308.6 284.8 Pharmaceutical preparation (coated granules) 373.85 373.85 631.364 747.7 First nuclear particle component D50: second nuclear particle component D50 - 1:0.1 1:0.8 1:0.6

[077] Next, the mixtures of Examples and Example Comparative samples were loaded into a fluidized bed granulator (FD-MP01D, manufactured by Powrex Corp.) and a mixture of nuclear particles (primary particles) was mixed in (preheating step) under the conditions shown in Table 2. Table 2<Etapa de préaquecimento> Air supply temperature (°C) Air flow rate (m3 / minute) Mixing time (minutes) 60 0.3 or more 10 <Etapa de granulação> Agitator rotation speed, Sedimentation prevention rate, Air supply temperature (°C), Air flow rate (m3 / minute), Preheating time Petition 870260057434, dated 12 / 06 / 2026, page 54 / 134 33 / 37 60 0.3 Time to reach 60°C Damper opening degree (°) Spray pressure (MPa) Spray flow rate (L / minute) 10 0.1 40 Pump flow rate (ml / minute) Scraping time (seconds) Interval time (seconds) 7 0.3 40 Spray quantity (g / minute) Product temperature (°C) Reference 7 Approximately 30 Confirmation of damage by pressure of the filter and product Measurement of the apparent density of a mixture of nuclear particles.

[078] The apparent compacted density and the poured density of each of the nuclear particle mixtures (primary particles), which were obtained according to the prescriptions of Comparative Example 1 and Examples 1 and 2, were measured. More specifically, the bulk densities were measured by the PTR powder tester (registered trademark) (produced by HOSOKAWA MICRONE CORPORATION) in accordance with Method 3 (described in the 17th revised Japanese Pharmacopoeia, as the apparent density and compacted density measurement). The nuclear particle mixture was uniformly fed from above through a sieve into a cylindrical container having the same dimensions as the measuring container defined by Method 3. The excess nuclear particle mixture was scraped from the top of the container, and the mixture was weighed. In this way, the apparent density (poured apparent density) of the slightly compressed mixture was measured.Next, an auxiliary cylinder was placed in the container, and then the nuclear particle mixture was added up to the level of the upper edge of the auxiliary cylinder and compacted 180 times. After compaction was complete, the auxiliary cylinder was removed. The excess nuclear particle mixture was scraped from the top of the container, and the mixture was weighed. In this way, the apparent density (packed apparent density) of the densely compacted mixture was measured. Then it was... Petition 870260057434, dated 12 / 06 / 2026, page 55 / 134 34 / 37 calculated the difference between the compacted apparent density and the spilled apparent density of each of the nuclear particle mixtures (compacted apparent density - spilled apparent density). The results are shown in Table 3. In addition, the compacted apparent density and the spilled apparent density of the nuclear particle mixture (primary particles), which was obtained according to the prescription of Example 3, were measured in the same way as mentioned above. The difference (compacted apparent density - spilled apparent density) between the compacted apparent density and the spilled apparent density of the nuclear particle mixture of Example 3 was 0.221. Table 3 Test Case Example Comparative 1 Example 1 Example 2 Degree of agglomeration before coating (%) 24.1 42.3 84.6 Degree of agglomeration after coating (%) - 17.5 16.3 Apparent density compacted with apparent density poured of the nuclear particle mixture (g / cc) 0.295 0.218 0.221 Granular particles were produced or not XOO Tablets were produced or not XOO

[079] In accordance with each of the prescriptions shown in Table 1 shows that a surfactant was added to a 500 ml beaker and mixed / stirred using a mixer (NZ-1200, manufactured by TOKYO RIKAKIKAI CO, LTD.) at a rate of 400 to 900 rpm. After the mixture was stirred to a homogeneous state, the drug was added and further stirred / mixed to obtain a drug solution.

[080] Next, the drug solution was sprayed onto each of the mixtures of nuclear particles (primary particles) obtained above by means of the use of a fluidized bed granulator (FD-MP-01 D, manufactured by Powrex Corp.) to obtain nuclear particles, i.e., primary particles. Petition 870260057434, dated 12 / 06 / 2026, page 56 / 134 35 / 37 linked to the drug solution (granulation step). The fluidized bed granulator conditions were defined as shown in Table 2. Measuring the degree of agglomeration of nuclear particles

[081] The degrees of agglomeration of the nuclear particles of the pharmaceutical preparations obtained in Examples 1 and 2 and in the Comparative Example were evaluated using a powder characteristics assessment device (PT-R Powder Tester (registered trademark), manufactured by HOSOKAWA MICRONE CORPORATION). The conditions of the powder characteristics tester were defined as shown below: Mesh opening: (upper stage) 710 pm, (intermediate stage) 355 pm, (lower stage) 250 pm; Sampling volume: 2 g or 3 g; and Stirring time: 119 seconds.

[082] The terms of the following equations were measured under the conditions above: X = [mass of powder remaining in the upper stage] / mass of powder loaded x 100 (Equation 2); Y = [mass of powder remaining in the intermediate stage] / mass of powder loaded x 100 x 0.6 (Equation 3); and Z = [mass of powder remaining in the lower stage] / mass of powder loaded x 100 x 0.2 (Equation 4).

[083] The total value of “X”, “Y” and “Z” was used as the degree of agglomeration (%). The results are shown in Table 3.

[084] The coating layer components according to each of the prescriptions shown in Table 1 were placed in a stainless steel container and stirred / mixed by a mixer (NZ-1200, manufactured by TOKYO RIKAKIKAI CO, LTD.) at a rate of 400 to 900 rpm to obtain coating layer solutions. Petition 870260057434, dated 12 / 06 / 2026, page 57 / 134 36 / 37

[085] Next, the coating layer solutions were sprayed onto the corresponding nuclear particles obtained above using a fluidized bed granulator (FD-MP-01D, manufactured by Powrex Corp.) and dried at 60 °C for 15 minutes to obtain pharmaceutical preparations with nuclear particles coated with the coating layer solution. The fluidized bed granulator conditions were defined as shown in Table 4. Table 4 <Etapa de revestimento>Agitator rotation rate Sedimentation prevention rate Air supply temperature (°C) Air flow rate (m3 / minute) Preheating time 80 0.3 - Damper opening degree (°) Spray pressure (MPa) Spray flow rate (L / minute) 10 0.1 40 Pump flow rate (ml / minute) Scraping time (seconds) Interval time (seconds) 4 0.3 4 Spray quantity (g / minute) Product temperature (°C) Reference 4 Approximately 30 Filter and product pressure damage confirmation

[086] The degrees of agglomeration of the pharmaceutical preparations obtained in Examples 1 and 2 and in Comparative Example 1 were measured in the same manner as in the aforementioned measurement for nuclear particles. The results are shown in Table 3.

[087] As is evident from the results in Table 3, since the pharmaceutical preparation according to the prescription of Comparative Example 1 (using a second nuclear particle component alone was used as a nuclear particle component) was significantly agglomerated, the degree of agglomeration of the pharmaceutical preparation (degree of agglomeration after the Petition 870260057434, dated 12 / 06 / 2026, page 58 / 134 37 / 37 coating) was not measured. Furthermore, the pharmaceutical preparation according to the prescription of Comparative Example 1 was not produced in either granular or tablet form. In contrast, the pharmaceutical preparations according to the prescriptions of Examples 1 and 2 (using a first nuclear particle component (crystalline cellulose) and a second nuclear particle component used in combination for a nuclear particle component) had satisfactory flowability once agglomeration of the preparation was suppressed. Additionally, the pharmaceutical preparations according to the prescriptions of Examples 1 and 2 were successfully produced in granules and formed into tablets by compression. Similarly, granules and tablets were successfully obtained from the pharmaceutical preparation according to the prescription of Example 3.Furthermore, it was confirmed that pharmaceutical preparations according to Examples 1 to 3 produced according to a prescription in which the mixing ratio of the first and second nuclear particle components were altered (first nuclear particle component D50 : second nuclear particle component D50 at 1:1.1) suppress agglomeration and have satisfactory flowability. Note that in the case where CEOLUS KG-1000 (average aspect ratio 4.20, average particle size (D50): 80 µm, manufactured by Asahi Kasei Corporation) was used as the first nuclear particle component and the ratio of the first nuclear particle component D50 : the second nuclear particle component D50 was controlled to be 1:1.1 or less, it was confirmed that agglomeration of the pharmaceutical preparation is suppressed and satisfactory flowability is obtained. Industrial Applicability

[088] According to the present invention, it is possible to provide a pharmaceutical preparation containing a therapeutically effective amount of a poorly water-soluble drug (CDK9 inhibitor) and having excellent flowability sufficient for practical production. Petition 870260057434, dated 12 / 06 / 2026, page 59 / 134

Claims

1 / 9 Claims 1. PHARMACEUTICAL PREPARATION IN GRANULE FORM, characterized by comprising nuclear particles and a coating layer coating the nuclear particles, wherein: the nuclear particles comprise a drug, a first nuclear particle component, a second nuclear particle component and a non-ionic surfactant, the drug is an aniline derivative represented by the following general formula (I): [Formula 1] F wherein W represents S or O, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, the first nuclear particle component is at least one crystalline cellulose having a shape selected from a needle shape and a substantially columnar shape, and the second nuclear particle component is at least one pharmaceutically acceptable additive having a substantially spherical shape,Nuclear particles are clustered particles formed from the first nuclear particle component and the second nuclear particle component; nuclear particles have voids formed between the first nuclear particle component and the second nuclear particle component, and a large amount of the drug and surfactant are retained in Petition 870260057434, dated 12 / 06 / 2026, page. 60 / 134 2 / 9 empty spaces, in which the surfactant is present as a liquid component, and at least one of the following conditions is satisfied: (i) a mass ratio of the first nuclear particle component to the second nuclear particle component is 1:1 to 1:10, (ii) an average aspect ratio of the first nuclear particle component is 1.8 or more and an average aspect ratio of the second nuclear particle component is 1.0 to 1.7, or (iii) the needle-shaped and / or substantially columnar shape ratio in the first nuclear particle component is 60 to 100%.

2. PREPARATION, according to claim 1, characterized by the coating layer covering the nuclear particles.

3. A preparation according to any one of claims 1 to 2, characterized in that the drug is attached to at least a portion of the surface of at least one of the first nuclear particle component and the second nuclear particle component.

4. PREPARATION, according to any one of claims 1 to 3, characterized in that the drug is an aniline derivative represented by the following formula (Ia): [Formula 2] F or a pharmaceutically acceptable salt, or a hydrate thereof.

5. PREPARATION, according to any one of claims 1 to 4, characterized by the drug and surfactant being retained in the empty spaces of the nuclear particles. Petition 870260057434, dated 12 / 06 / 2026, p. 61 / 134 3 / 9 6. PREPARATION, according to any one of claims 1 to 5, characterized in that the average aspect ratio of the first nuclear particle component is 1.8 or more, and the average aspect ratio of the second nuclear particle component is 1.0 to 1.

7.

7. PREPARATION, according to any one of claims 1 to 6, characterized in that the average aspect ratio of the first nuclear particle component is from 1.8 to 10.

0.

8. A preparation according to any one of claims 1 to 7, characterized in that the average aspect ratio of the second nuclear particle component is 1.0 to 1.

5.

9. A preparation according to any one of claims 1 to 8, characterized in that a particle size ratio of 50% (D50) of the second nuclear particle component, based on volume distribution, to a particle size ratio of 50% (D50) of the first nuclear particle component, based on volume distribution, is 1:1.1 or less.

10. A preparation according to any one of claims 1 to 9, characterized in that the difference in the average aspect ratio between the first nuclear particle component and the second nuclear particle component is 0.5 or more.

11. A preparation according to any one of claims 1 to 10, characterized in that the second nuclear particle component is composed of at least two different components.

12. PREPARATION, according to any one of claims 1 to 11, characterized in that the mass ratio of the first nuclear particle component to the second nuclear particle component is from 1:1 to 1:

10.

13. PREPARATION, according to any of the claims 1 to 12, characterized by a mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component to the mass of the surfactant being from 1:0.01 to 1:0.

6.

14. PREPARATION, according to any one of claims 1 to 13, characterized in that the mass ratio of the surfactant to the drug is from 1:0.1 to 1:

10.

15. PREPARATION, according to any one of claims 1 to 14, characterized in that the mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component and the mass of the coating layer is from 1:0.05 to 1:0.

3.

16. PREPARATION, according to any one of claims 1 to 15, characterized in that the second nuclear particle component is at least one pharmaceutically acceptable additive selected from the group consisting of sugars and inorganic compounds.

17. PREPARATION, according to any one of claims 1 to 16, characterized in that the second nuclear particle component is at least one selected from the group consisting of glucose, fructose, lactose, lactose hydrate, sucrose, white sugar, compressed sugar, refined powdered sugar, ammonium alginate, starch, potato starch, wheat starch, corn starch, rice starch, mannitol, sorbitol, phosphate, magnesium carbonate, magnesium oxide, calcium carbonate, calcium sulfuric acid, dextrates, dextrin, dextrose, polymethacrylate, glyceryl palmitostearate, isomaltose, lactitol, kaolin, lactitol, maltitol, maltodextrin, maltose, trehalose, xylitol, gelatinized starch, modified gelatinized starch, tapioca starch and sodium chloride.

18. PREPARATION, according to any one of claims 1 to 17, characterized in that the non-ionic surfactant is polysorbate.

19. PREPARATION, according to any of the claims 1 to 18, as described in Petition 870260057434, dated 12 / 06 / 2026, page 63 / 134 5 / 9, characterized by the coating layer containing a water-soluble coating agent.

20. PREPARATION, according to any one of claims 1 to 19, characterized in that the water-soluble coating agent is at least one component selected from the group consisting of a polyalkylene glycol, a polysaccharide, and derivatives thereof.

21. A preparation according to any one of claims 1 to 20, characterized in that the water-soluble coating agent is at least one selected from the group consisting of polyethylene glycol, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, a methacrylic acid copolymer, a vinylpyridine copolymer, an alkyl vinylpyridine copolymer, an aminocellulose derivative, diethylaminoethyl methacrylate, polyvinylacetal diethyl aminoacetate, a dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N,N-di-n-butyl hydroxypropyl ether, a vinylpyridine and acrylic acid series free acid copolymer, an alkyl vinylpyridine and acrylic acid series free acid copolymer, a vinylpyridine, acrylic acid series free acid and vinyl monomer copolymer, an alkyl vinylpyridine, acrylic acid series free acid copolymer free acid and a vinyl monomer,a copolymer of 2-methyl-5-vinylpyridine-methacrylic acid, poly-2-(vinylphenyl)glycine, a morpholine-ne-ethyl acrylate-methacrylic acid copolymer, shellac, cellulose acetate phthalate, a methyl acrylate-methacrylic acid copolymer, a methyl methacrylate-methacrylic acid copolymer, zein, hydroxypropylmethylcellulose phthalate and an aminoalkyl methacrylate copolymer.

22. PREPARATION, according to any one of claims 1 to 21, characterized in that the degree of agglomeration of the pharmaceutical preparation is 70% or less. Petition 870260057434, dated 12 / 06 / 2026, p. 64 / 134 6 / 9 23. A preparation according to any one of claims 1 to 22, characterized in that the degree of agglomeration of the pharmaceutical preparation is less than the degree of agglomeration of the nuclear particles.

24. PREPARATION, according to any one of claims 1 to 23, characterized in that the particle size of 50% (D50) of the pharmaceutical preparation based on the volume distribution is 100 to 400 µm.

25. PREPARATION, characterized by comprising the pharmaceutical preparation, as defined in any one of claims 1 to 24, and having a dosage form selected from the group consisting of a granule, a tablet, a capsule, a powder and a pill.

26. METHOD FOR PRODUCING THE PHARMACEUTICAL PREPARATION, in the form of granules with nuclear particles and a coating layer coating the nuclear particles, as defined in claim 1, characterized by comprising: (a) mixing a first nuclear particle component and a second nuclear particle component to obtain a nuclear particle mixture, (b) dissolving or suspending a drug in a mixture of a non-ionic surfactant and a solvent to obtain a mixed solution, (c) contacting the nuclear particle mixture obtained in (a) with the mixture obtained in (b) to obtain nuclear particles containing the first nuclear particle component, the second nuclear particle component, the drug and the non-ionic surfactant, wherein the voids formed between the first nuclear particle component and the second nuclear particle component, and the drug and the non-ionic surfactant are incorporated and retained in the voids,the surfactant is present as a liquid component, and (d) coating the nuclear particles obtained in (c) to obtain a pharmaceutical preparation, wherein Petition 870260057434, dated 12 / 06 / 2026, page 65 / 134 7 / 9 the drug is an aniline derivative represented by the following general formula (I): [Formula 3] F wherein W represents S or O, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, the first nuclear particle component is at least a crystalline cellulose having a shape selected from a needle shape and a substantially columnar shape, and the second nuclear particle component is at least a pharmaceutically acceptable additive with a substantially spherical shape, the nuclear particles have voids between the first nuclear particle component and the second nuclear particle component, and have the capacity to contain a large amount of the drug and the surfactant in the voids,wherein the surfactant is present as a liquid component, and at least one of the following conditions is met: (i) a mass ratio of the first nuclear particle component to the second nuclear particle component is 1:1 to 1:10, (ii) an average aspect ratio of the first nuclear particle component is 1.8 or more and an average aspect ratio of the second nuclear particle component is 1.0 to 1.7, or (iii) the needle-shaped and / or substantially columnar shape ratio in the first nuclear particle component is 60 to 100%.

27. METHOD, according to claim 26, characterized by the coating layer being adjacent to the nuclear particles.

28. METHOD, according to any one of claims 26 to 27, characterized in that the drug is fixed to the surface of at least one of the first nuclear particle component and the second nuclear particle component.

29. METHOD, according to any one of claims 26 to 28, characterized in that the drug is an aniline derivative represented by the following formula (Ia): [Formula 4] F ( I - a) or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

30. METHOD, according to any one of claims 26 to 29, characterized in that the drug and the surfactant are retained in the empty spaces of the nuclear particles.

31. METHOD, according to any one of claims 26 to 30, characterized in that the average aspect ratio of the first nuclear particle component is 1.8 or more, and the average aspect ratio of the second nuclear particle component is 1.0 to 1.

7.

32. METHOD, according to any one of claims 26 to 31, characterized in that the average aspect ratio of the first nuclear particle component is from 1.8 to 10.

0.

33. METHOD, according to any one of claims 26 to 32, characterized in that the average aspect ratio of the second component of the nuclear particle is from 1.0 to 1.

5.

34. METHOD, according to any one of claims 26 to 33, characterized in that a particle size ratio of 50% (D50) of the second nuclear particle component, based on the volume distribution, to the particle size ratio of 50% (D50) of the first nuclear particle component, based on the volume distribution, is 1:1.1 or less.

35. METHOD, according to any one of claims 26 to 34, characterized in that the second nuclear particle component is composed of at least two different components.

36. METHOD, according to any one of claims 26 to 35, characterized by further comprising (e) obtaining a granular preparation by adding a pharmaceutically acceptable additive to the pharmaceutical preparation obtained in (d).

37. METHOD, according to any one of claims 26 to 36, characterized by further comprising (e') obtaining a capsule-type preparation enclosing the pharmaceutical preparation obtained in (d) in a film made of gelatin or a plant-derived material.

38. METHOD FOR PRODUCING TABLETS, characterized by comprising the formation of tablets from the pharmaceutical preparation, as defined in any one of claims 1 to 24.

39. METHOD FOR THE PRODUCTION OF CAPSULES, characterized by comprising the encapsulation of the pharmaceutical preparation, as defined in any one of claims 1 to 24. Petition 870260057434, dated 12 / 06 / 2026, pp. 68 / 134

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