JP7640453B2 - Pharmaceutical preparations and methods for their manufacture - Google Patents

Description

This patent application claims priority to a previously filed Japanese patent application, Patent Application No. 2019-84688 (filing date: April 25, 2019). The entire disclosure of this prior patent application is hereby incorporated by reference into this specification.

The present invention relates to a pharmaceutical formulation and a method for producing the same.

Traditionally, many of the active ingredients and additives used in the pharmaceutical industry are in a liquid state at room temperature, making it difficult to incorporate them in the required amounts into granules or tablets.

As a solid preparation containing such a component in a liquid state (liquid component) at room temperature, soft capsules are widely used (for example, Patent Document 1). However, soft capsules may have a larger diameter than other solid preparations such as tablets, making them difficult to take for children and elderly people with poor swallowing ability, and patients with reduced swallowing ability. In addition, due to their nature, soft capsules have a risk of leakage depending on the manufacturing method. Furthermore, soft capsules are soft and easily deformed, so they must be inspected for deformation visually or using a dedicated inspection machine, and there is also the problem that the manufacturing costs are higher than other solid preparations such as tablets.

On the other hand, tablets are used as solid preparations that can be mixed with liquid ingredients. When mixing liquid ingredients with tablets, a method is generally used in which the liquid ingredient and solid ingredient are mixed before tableting to obtain particles with the liquid ingredient attached to the surface of the solid ingredient, and the obtained particles are tableted. However, in such a method, the liquid ingredient present on the surface of the solid ingredient in the particle causes aggregation or adsorption between the particles, which reduces the fluidity of the particle, making it difficult to tablet the particle. In particular, when trying to prepare a tablet containing the same amount of liquid ingredient as a soft capsule, the particles obtained by mixing the liquid ingredient and the solid ingredient have low fluidity and are extremely difficult to tablet. Therefore, only a small amount of liquid ingredient can be mixed with the tablet, which does not significantly reduce the fluidity.

Incidentally, when formulating poorly water-soluble drugs, it is known that poorly water-soluble drugs are used in combination with solid dispersions or the like in order to improve the poor solubility of the poorly water-soluble drugs (for example, Patent Document 2). Spray drying and melting methods are commonly used as methods for combining poorly water-soluble drugs with solid dispersions. However, the spray drying method has the problem that it requires large machinery, and the melting method has the problem that the drug may be denatured or decomposed during the process of high-temperature heat treatment to dissolve the drug.

Furthermore, in order to prepare tablets containing a large amount of liquid ingredients, a technique is known in which liquid substances are adsorbed onto porous substances such as silica gel (for example, Patent Document 3), but to realize such a technique, processing in a vacuum state is necessary, which poses the problem of requiring expensive equipment.

In addition, a method is known in which the decrease in fluidity of the formulation is suppressed by encapsulating the liquid components in a neutral or alkaline resin, but there is a problem in that the use of resin may affect the dissolution behavior of the liquid components, making it difficult to obtain the desired dissolution behavior.

A method is also known in which a liquid active ingredient is prepared in the form of an oil-in-water emulsion, the emulsion solution is sprayed onto a powder to adhere it, and the powder is dried to remove the water, thereby obtaining a powder to which the active ingredient is adhered (e.g., Patent Document 4). Furthermore, a method is also known in which a drug and a water-soluble polymer are applied to an inert carrier, and then dried to form particles (e.g., Patent Document 5).

Granules that are made of a powder or fine particle component and a liquid component and have improved fluidity are also known (for example, Patent Document 6).

Drug formulations containing granules in which a drug and a solubilizing agent are combined are also known, and it is known that a surfactant can be used as the solubilizing agent and that the granules can be coated (e.g., Patent Document 7). However, since surfactants have adhesive and tacky properties and reduce fluidity, there is a problem that the amount of surfactant that can be used in the preparation of pharmaceutical formulations such as tablets is limited.

Thus, pharmaceutical preparations containing liquid components are being developed. However, because pharmaceutical preparations containing large amounts of liquid components have reduced fluidity, it has been difficult to say that it is easy to incorporate a sufficient amount of liquid component to dissolve a therapeutically effective amount of drug in pharmaceutical preparations such as tablets, where reduced fluidity affects the formulation.

Special Publication No. 2003-508386 Special Publication No. 2010-526848 Special Publication No. 2010-512142 International Publication No. 2009/001786 Special Publication No. 2001-511156 Japanese Patent Publication No. 185327/1983 Special Publication No. 2007-517062

In light of this situation, there is a demand for pharmaceutical formulations that contain a sufficient amount of non-volatile solvent to dissolve a therapeutically effective amount of drug, or a non-volatile solvent that is useful as a pharmaceutical, and have excellent fluidity that can withstand actual manufacturing.

As a result of intensive research, the inventors prepared a pharmaceutical formulation comprising a core particle containing a drug together with a core particle component having a specific shape, and a coating layer that covers the core particle, and found that the pharmaceutical formulation can contain large amounts of non-volatile solvent and drug, and has excellent fluidity. The present invention is based on this finding.

The present invention includes the following inventions.
[1] A pharmaceutical preparation in the form of granules comprising a core particle and a coating layer that coats the core particle,
the core particle comprises a drug, a first core particle component, a second core particle component, and a non-volatile solvent;
The first core particle component is at least one type of crystalline cellulose having a shape selected from a needle shape and a roughly columnar shape,
The pharmaceutical formulation, wherein the second core particle component is at least one pharma- ceutically acceptable excipient having a substantially spherical shape.
[2] The pharmaceutical formulation according to [1], wherein the average aspect ratio of the first core particle component is 1.8 or more.
[3] The pharmaceutical formulation according to [2], wherein the average aspect ratio of the first core particle component is 1.8 to 10.0.
[4] The pharmaceutical preparation according to any one of [1] to [3], wherein the average aspect ratio of the second core particle component is 1.0 to 1.7.
[5] The pharmaceutical formulation according to [4], wherein the average aspect ratio of the second core particle component is 1.0 to 1.5.
[6] The pharmaceutical preparation according to any one of [1] to [5], wherein the difference in average aspect ratio between the first core particle component and the second core particle component is 0.5 or more.
[7] The pharmaceutical preparation according to any one of [1] to [6], wherein the ratio of the 50% particle size (D50) based on volume distribution of the second core particle component to the 50% particle size (D50) based on volume distribution of the first core particle component is 1:1.1 or less.
[8] The pharmaceutical formulation according to any one of [1] to [7], wherein the second core particle component consists of at least two different components.
[9] The pharmaceutical preparation according to any one of [1] to [8], wherein the mass ratio of the first core particle component to the second core particle component is 1:1 to 1:10.
[10] The pharmaceutical formulation according to any one of [1] to [9], wherein a mass ratio of the total mass of the first core particle component and the second core particle component to the non-volatile solvent is 1:0.01 to 1:0.6.
[11] The pharmaceutical formulation according to any one of [1] to [10], wherein the mass ratio of the non-volatile solvent to the drug is 1:0.1 to 1:10.
[12] The pharmaceutical formulation according to any one of [1] to [11], wherein a mass ratio of the total mass of the first core particle component and the second core particle component to the mass of the coating layer is 1:0.05 to 1:0.3.
[13] The pharmaceutical formulation according to any one of [1] to [12], wherein the second core particle component is at least one pharma- ceutically acceptable additive selected from the group consisting of saccharides and inorganic compounds.
[14] The pharmaceutical preparation according to any one of [1] to [13], wherein the second core 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 sulfate, dextrates, dextrin, dextrose, polymethacrylate, glyceryl palmitostearate, isomalt, lactitol, kaolin, lactitol, maltitol, maltodextrin, maltose, trehalose, xylitol, pregelatinized starch, modified pregelatinized starch, tapioca starch, and sodium chloride.
[15] The pharmaceutical formulation according to any one of [1] to [14], wherein the non-volatile solvent comprises at least one selected from the group consisting of surfactants, vitamins, and oils and fats.
[16] The pharmaceutical formulation according to [15], wherein the surfactant is a nonionic surfactant.
[17] The pharmaceutical formulation according to [16], wherein the nonionic surfactant is a polysorbate.
[18] The pharmaceutical formulation according to [15], wherein the oil or fat is a glycerin fatty acid ester.
[19] The pharmaceutical formulation according to [18], wherein the glycerol fatty acid ester is a medium-chain fatty acid triglyceride.
[20] The pharmaceutical formulation according to any one of [1] to [19], wherein the log P value of the drug is from −2 to 7.
[21] The pharmaceutical formulation according to any one of [1] to [20], wherein the log P value of the drug is from −1.9 to 6.5.
[22] The pharmaceutical formulation according to any one of [1] to [21], wherein the drug comprises a poorly water-soluble drug.
[23] The pharmaceutical formulation according to [22], wherein the poorly water-soluble drug comprises at least one selected from the group consisting of hormonal agents, anticancer agents, antibacterial agents, and antiviral agents (excluding N-[5-fluoro-2-(1-piperidinyl)phenyl]isonicotinthioamide).
[24] The pharmaceutical formulation according to any one of [1] to [23], wherein the coating layer comprises a water-soluble coating agent.
[25] The pharmaceutical formulation according to [24], wherein the water-soluble coating agent comprises at least one component selected from the group consisting of polyalkylene glycols, polysaccharides, and derivatives thereof.
[26] The water-soluble coating agent is selected from the group consisting of polyethylene glycol, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methacrylic acid copolymer, vinylpyridine copolymer, alkylvinylpyridine copolymer, aminocellulose derivative, diethylaminoethyl methacrylate, polyvinyl acetal diethylaminoacetate, dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N,N-di-n-butyl hydroxylpropyl ether, copolymer of vinylpyridine and acrylic acid-based free acid, copolymer of alkylvinylpyridine and acrylic acid-based free acid, biphenyl, acrylate ... The pharmaceutical formulation according to [24] or [25], wherein the copolymer is at least one selected from the group consisting of a copolymer of an alkylpyridine, an acrylic free acid, and a vinyl monomer, a copolymer of an alkylvinylpyridine, an acrylic free acid, and a vinyl monomer, a 2-methyl-5-vinylpyridine-methacrylic acid copolymer, poly-2-(vinylphenyl)glycine, morpholino-N-β-ethylacrylate-methacrylic acid copolymer, shellac, cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, zein, hydroxypropyl methylcellulose phthalate, and aminoalkyl methacrylate copolymer.
[27] The pharmaceutical preparation according to any one of [1] to [26], wherein the degree of aggregation of the pharmaceutical preparation is 70% or less.
[28] The pharmaceutical preparation according to any one of [1] to [27], wherein the degree of aggregation of the pharmaceutical preparation is lower than the degree of aggregation of the core particles.
[29] The pharmaceutical preparation according to any one of [1] to [28], wherein the pharmaceutical preparation has a volume distribution-based 50% particle size (D50) of 100 to 400 μm.
[30] A formulation comprising the pharmaceutical formulation according to any one of [1] to [29], and having a dosage form selected from the group consisting of granules, tablets, capsules, powders and pills.
[31] A method for producing a pharmaceutical preparation in the form of granules having a core particle and a coating layer that coats the core particle, comprising the steps of:
(a) mixing a first core particle component and a second core particle component to obtain a core particle mixture;
(b) dissolving or suspending a drug in a non-volatile solvent to obtain a mixture;
(c) contacting the core particle mixture obtained in step (a) with the mixed solution obtained in step (b) to obtain core particles containing the first core particle component, the second core particle component, a drug, and a non-volatile solvent; and
(d) coating the core particles obtained in step (c) to obtain a pharmaceutical formulation,
The first core particle component is at least one type of crystalline cellulose having a shape selected from a needle shape and a roughly columnar shape,
The above-mentioned manufacturing method, wherein the second core particle component is at least one pharma- ceutically acceptable excipient having a substantially spherical shape.
[32] The manufacturing method according to [31], wherein the average aspect ratio of the first core particle component is 1.8 or more.
[33] The method according to [32], wherein the average aspect ratio of the first core particle component is 1.8 to 10.0.
[34] The method according to any one of [31] to [33], wherein the average aspect ratio of the second core particle component is 1.0 to 1.7.
[35] The method according to [34], wherein the average aspect ratio of the second core particle component is 1.0 to 1.5.
[36]
The manufacturing method according to any one of [31] to [35], wherein the ratio of the 50% particle diameter (D50) based on volume distribution of the second core particle component to the 50% particle diameter (D50) based on volume distribution of the first core particle component is 1:1.1 or less.
[37] The method according to any one of [31] to [36], wherein the second core particle component is made of at least two different components.
[38] The method according to any one of [31] to [37], wherein the non-volatile solvent comprises at least one selected from the group consisting of surfactants, vitamins, and oils and fats.
[39] The method according to any one of [31] to [38], further comprising the step of: (e) adding a pharma- ceutically acceptable additive to the pharmaceutical preparation obtained in step (d) and granulating the mixture to obtain a granular preparation.
[40] The method according to any one of [31] to [38], further comprising the step of (e') encapsulating the pharmaceutical preparation obtained in step (d) in a shell made of gelatin or a plant-derived material to obtain a capsule-shaped preparation.
[41] A method for producing a tablet, comprising a step of compressing the pharmaceutical formulation according to any one of [1] to [29] to obtain a tablet.
[42] A method for producing a capsule, comprising a step of encapsulating the pharmaceutical preparation according to any one of [1] to [29] into a capsule.

According to the present invention, it is possible to provide a pharmaceutical preparation in the form of granules that has excellent fluidity while containing a large amount of non-volatile solvent. In addition, according to the present invention, it is possible to suppress aggregation that reduces the fluidity of the pharmaceutical preparation. That is, since excellent fluidity is realized in the pharmaceutical preparation, a large amount of non-volatile solvent can be incorporated into pharmaceutical preparations such as tablets, whose formulation is hindered by reduced fluidity, by a simple method such as fluidized bed granulation. As a result, according to the present invention, even if a poorly water-soluble drug is used, it is possible to incorporate a therapeutically effective amount of the drug into the pharmaceutical preparation. Furthermore, the pharmaceutical preparation of the present invention can suppress leakage of the non-volatile solvent contained in the core particles to the surface of the pharmaceutical preparation even when stored for a long period of time.

1A and 1B are electron micrographs of the first core particle component (needle crystalline cellulose). Fig. 1A is an electron micrograph of needle crystalline cellulose (CEOLUS KG-1000), and Fig. 1B is an electron micrograph of needle crystalline cellulose (CEOLUS UF-702). FIG. 2 is an electron microscope photograph of the second core particle component (approximately spherical particles: lactose hydrate). FIG. 3 is an electron microscope photograph of the second core particle component (approximately spherical particles: corn starch).

Description of the Invention

The present invention will be described in detail below. In this specification, a numerical range indicated using "~" means a range including the numerical values before and after "~" as the minimum and maximum values, respectively. In this specification, when an expression such as "A or B" is used, it means that either one or both are included, unless otherwise specified or interpreted in a restrictive manner based on the context.

Pharmaceutical Preparations
The pharmaceutical preparation of the present invention is in the form of granules having a core particle and a coating layer that coats the core particle. The core particle and the coating layer will be described below.

<Nuclear Particles>
The core particle comprises a drug, a first core particle component, a second core particle component and a non-volatile solvent, the first core particle component being acicular and/or roughly cylindrical crystalline cellulose (hereinafter sometimes simply referred to as "acicular crystalline cellulose"), and the second core particle component being at least one type of pharma- ceutically acceptable excipient having a roughly spherical shape.

Since the core particle comprises a first core particle component and a second core particle component that are significantly different in shape, many voids can be formed between the first core particle component and the second core particle component. As a result, the core particle has a large surface area in which the liquid component can be contained, and therefore the core particle can contain a large amount of liquid component. Furthermore, since the core particle can contain a large amount of non-volatile solvent such as a surfactant used as a solubilizing agent as the liquid component, poorly water-soluble drugs can be dissolved or suspended. Without being bound by theory, it is believed that such a mechanism makes it possible to produce a pharmaceutical formulation that contains a large amount of poorly soluble drugs in the core particle.

(First Core Particle Component)
According to one embodiment of the present invention, the first core particle component used in the core particle is needle-shaped crystalline cellulose. The needle-shaped crystalline cellulose, which is the first core particle component used in the present invention, is derived from crystalline cellulose that can be added in the preparation of a pharmaceutical preparation. The needle-shaped crystalline cellulose may contain a sufficient proportion of needle-shaped and/or roughly columnar crystals to achieve the effects of the present invention. The lower limit of the proportion of needle-shaped and/or roughly columnar crystalline cellulose in the first core particle component is not particularly limited, but is preferably 60%, more preferably 70%, and even more preferably 80% in terms of the number of crystals (particles). The upper limit can be, for example, 100%, 98%, 95%, 90%, etc. The range of the proportion of needle-shaped and/or roughly columnar crystalline cellulose in the first core particle component is not particularly limited, but is preferably 60 to 100%, more preferably 70 to 100%, and even more preferably 80 to 100% in terms of the number of crystals (particles). As used herein, the term "acicular crystalline cellulose" refers to crystalline cellulose that has a significant difference between its length and width in a cross section along the long axis of the crystalline cellulose on an image (shape transferred onto a flat surface) measured by an electron microscope. Here, the significant difference between its length and width can be expressed, for example, by the aspect ratio.

Specifically, the average aspect ratio of the first core particle component is not particularly limited as long as the effect of the present invention is achieved, but is larger than the average aspect ratio of the second core particle component, and the 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 core particle component is not particularly limited as long as the effect of the present invention is achieved, and can be, for example, 10 or less, 8 or less, etc. The range of the average aspect ratio of the first core particle component is not particularly limited, but is preferably 1.8 to 10, more preferably 2.2 to 10, and even more preferably 2.5 to 10. In this specification, the "aspect ratio" of the core particle component means the ratio of the major axis to the minor axis of the core particle component (major axis/minor axis) in particle image analysis using an electron microscope. In addition, the "average aspect ratio" of a core particle component means the average aspect ratio of the core particle components obtained by measuring the aspect ratios of 10 or more arbitrarily selected core particle components and excluding the aspect ratio values of the core particle components in the top 10% and bottom 10% of the aspect ratio values.

The amount of the first core particle component is not particularly limited as long as the effects of the present invention are achieved, but is preferably 5 to 50% by mass relative to the total mass of the pharmaceutical formulation.

(Second Core Particle Component)
According to one embodiment of the present invention, the second core particle component used in the core particle is a pharma- ceutically acceptable additive having a substantially spherical shape. In this specification, the term "substantially spherical" refers to a shape that is similar to a sphere with no significant difference in length and width on an image measured by an electron microscope (shape transferred to a flat surface), and does not include needle-like and substantially cylindrical shapes. Thus, according to one embodiment, the second core particle component is a non-needle-like and non-cylindrical pharma- ceutically acceptable additive. The term "substantially spherical" does not necessarily mean that the image measured by an electron microscope is a perfect sphere itself, and may be, for example, a distorted sphere, an ellipsoid, a polyhedron (including a cube), or a polyhedron with rounded corners.

The average aspect ratio of the second core particle component is smaller than the average aspect ratio of the first core particle component, and is 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. With respect to the second core particle component, the aspect ratio of the core particle component and the average aspect ratio of the core particle component are each the same as those defined for the first core particle component.

The amount of the second core particle component in the pharmaceutical formulation of the present invention is not particularly limited as long as the effects of the present invention are achieved, but is preferably 30 to 90% by mass relative to the total mass of the pharmaceutical formulation.

The particle diameter of the second core particle component is not particularly limited as long as the effects of the present invention are achieved, but the ratio of the 50% particle diameter (D50) based on volume distribution of the second core particle component to the 50% particle diameter (D50) based on volume distribution of the first core particle component (50% particle diameter (D50) based on volume distribution of the first core particle component: 50% particle diameter (D50) based on volume distribution of the second core particle component) is preferably adjusted to 1:1.1 or less, more preferably 1:0.5 or less, and even more preferably 1:0.1 or less.

The second core particle component may be a single component or a combination of two or more components, but preferably a combination of two or more components having different 50% particle diameters (D50) based on volume distribution. For example, when the second core particle component is composed of two components, it is preferable that the 50% particle diameters (D50) based on volume distribution of each component are different. In the present invention, when the core particle component contains two or more components, the 50% particle diameter (D50) based on volume distribution of the core particle component is calculated by calculating the ratio of the mass of each component to the total mass of the components constituting the core particle component, calculating the product of the ratio and the 50% particle diameter (D50) based on volume distribution for each component, and calculating the sum of these products. For example, when the core particle component contains two kinds of components A and B, the masses of components A and B are a and b, respectively, and the 50% particle diameters (D50) of A and B on a volume distribution basis are D50 _A and D50 _B , respectively, the 50% particle diameter (D50) on a volume distribution basis of the core particle component is calculated by the following formula:

The components constituting the second core particle component are not particularly limited as long as they are pharma- ceutically acceptable components, but examples include sugars (including sugars, sugar hydrates, sugar alcohols, etc.), inorganic compounds, etc.

The sugar is not particularly limited, but examples thereof include 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. As the sugar, corn starch is preferably used.

The sugar hydrate is not particularly limited, but may be, for example, any hydrate of the sugars listed above, and preferably lactose hydrate is used.

The sugar alcohol is not particularly limited, but may be any sugar alcohol derived from any sugar, preferably mannitol or sorbitol.

Inorganic compounds include, but are not limited to, phosphates such as anhydrous calcium phosphate.

It is preferable that the first core particle component has a larger average aspect ratio than the second core particle component, and the difference between the average aspect ratios of the first and second core particle components is large. Specifically, the difference between the average aspect ratios of the first and second core particle components (average aspect ratio of the first core particle component - average aspect ratio of the second core particle component) is preferably 0.5 or more, more preferably 0.6 or more, and even more preferably 0.7 or more.

The difference between the compacted bulk density and the loose bulk density (compacted bulk density - loose bulk density) of the mixture of the first and second core particle components (core particle mixture) is not particularly limited as long as the effects of the present invention are achieved, but the lower limit is preferably 0.15, more preferably 0.16, and even more preferably 0.17, the upper limit is preferably 0.25, more preferably 0.24, and even more preferably 0.23, and the range is preferably 0.15 to 0.25, more preferably 0.16 to 0.24, and even more preferably 0.17 to 0.23. In the present invention, the compacted bulk density and the loose bulk density can be measured, for example, using a commercially available powder property evaluation device (Powder Tester (registered trademark) PT-R, manufactured by Hosokawa Micron Corporation). As a specific measurement method, a powder tester is used to uniformly supply the core particle mixture from above through a sieve into a cylindrical container of the same size as the measurement container in the third method of bulk density and tapped density measurement described in the 17th revised Japanese Pharmacopoeia, and the bulk density in a loosely packed state (loose bulk density) is measured by leveling off the top surface and weighing. Next, an auxiliary cylinder is placed on top of the container, and the core particle mixture is added up to the top edge of the cylinder, and tapping is performed 180 times. After completion, the auxiliary cylinder is removed, and the core particle mixture is leveled off at the top surface of the container and weighed, and the bulk density in a densely packed state after tapping (tight bulk density) is measured.

The diameters (particle diameters) of the particles constituting the first and second core particle components are not particularly limited as long as the effects of the present invention are achieved, but for the first core particle component, the 50% particle diameter (D50) based on volume distribution is preferably 50 to 200 μm, more preferably 60 to 150 μm, and even more preferably 70 to 100 μm. For the second core particle component, the 50% particle diameter (D50) based on volume distribution is preferably 1 to 300 μm, more preferably 5 to 200 μm, and even more preferably 10 to 150 μm. The diameters of the particles constituting the core particle components in the present invention and the 50% particle diameter based on volume distribution can both be measured by a laser diffraction method (measurement method: dry, scattering intensity: 1% or more, light scattering model: Mie scattering theory) using, for example, a commercially available particle size distribution meter (e.g., Mastersizer3000, manufactured by Spectris). The 50% particle size (D50) based on volume distribution means a particle size at 50% volume in a cumulative volume distribution curve in a volume-based particle size distribution obtained by measurement using a laser diffraction method, with the total volume being 100%.

The total mass of the first and second core particle components is not particularly limited as long as the effects of the present invention are achieved, but is, for example, 20 to 90% by weight relative to the total mass of the pharmaceutical formulation.

The mass ratio of the first core particle component to the second core particle component (mass of the first core particle component:mass of the second core particle component) is not particularly limited as long as the effects of the present invention are achieved, but is, for example, 1:1 to 1:10.

(Non-volatile Solvent)
The pharmaceutical preparation of the present invention comprises a non-volatile solvent. In the present specification, the non-volatile solvent may be a component capable of dissolving or suspending a drug in the core particle. Examples of such components include surfactants, oils and fats. In particular, oils and fats have the advantage that by dissolving or suspending a drug in them, the drug can be blocked from contact with air (oxygen) and its oxidation can be prevented. In addition, when a drug is poorly water-soluble, oils and fats have the advantage that the poorly water-soluble drug can be dissolved in the oils and fats, thereby improving its absorbability in a subject to which the pharmaceutical preparation is administered (promoting and assisting absorption of the drug). In addition, oils and fats have the advantage that they can be a source of nutrition for the living body and help maintain and improve the health of a subject to which the pharmaceutical preparation is administered. In addition, as the non-volatile solvent, a component that has a medicinal effect by itself or has an antioxidant effect as an additive can be used. Examples of such components include vitamins. The non-volatile solvent of the present invention preferably contains at least one selected from the group consisting of surfactants, vitamins, and oils and fats. The components contained in the non-volatile solvent may be used alone or in combination of two or more.

The surfactant is not particularly limited as long as it is pharma- ceutically acceptable, and examples of the surfactant that can be used include cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants. Examples of cationic surfactants include primary amine salts, alkyl trimethylammonium salts, alkyl pyridinium salts, and alkyl polyoxyethylene amines. Examples of anionic surfactants include fatty acid salts, rosin acid salts, alkyl polyoxyethylene sulfate salts, α-olefin sulfonates, alkyl naphthalene sulfonates, lignin sulfonates, and alkyl phosphate salts. Examples of amphoteric surfactants include N-alkyl β-aminopropionic acid, N-alkyl sulfobetaines, N-alkyl hydroxysulfobetaines, and lecithin. Examples of nonionic surfactants include alkyl polyoxyethylene ethers, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. Of these, the surfactant preferably includes a nonionic surfactant, more preferably a polysorbate, and even more preferably polysorbate 80. These surfactants may be used alone or in combination of two or more.

Vitamins include, but are not limited to, vitamin E (tocopherol and tocotrienol). As vitamins, vitamin E is preferably used, more preferably tocopherol, and even more preferably α-tocopherol. These vitamins may be used alone or in combination of two or more.

The oils and fats include esters of glycerol and fatty acids (fatty acid esters) and derivatives thereof, and compositions containing fatty acid esters and/or derivatives thereof as the main component. The fatty acids constituting the fatty acid esters are not particularly limited, and any of short-chain fatty acids with 2 to 4 carbon atoms, medium-chain fatty acids with 5 to 10 carbon atoms, and long-chain fatty acids with 11 or more carbon atoms can be used, but medium-chain fatty acids are preferred. The fatty acids may be linear or branched, but linear fatty acids are preferred. The number of fatty acids ester-bonded to glycerol is not particularly limited, and may be one (monoglyceride), two (diglyceride), or three (triglyceride), but three (triglyceride) is preferred. When the number of fatty acids ester-bonded to glycerol is two or more, the fatty acids may be the same or different from each other. Preferred fatty acid esters include, for example, medium-chain fatty acid triglycerides consisting of glycerol and three medium-chain fatty acids, and long-chain fatty acid triglycerides consisting of glycerol and three long-chain fatty acids. Examples of fatty acid esters include triacetin, isopropyl myristate, and the like. Examples of derivatives of fatty acid esters include acetyl triethyl citrate, and the like. These fatty acid esters and their derivatives may be used alone or in combination of two or more. Furthermore, fatty acid esters and their derivatives may be used in combination with a composition containing fatty acid esters and/or their derivatives as the main component, as described below.

The composition containing fatty acid esters and/or their derivatives as the main component is not particularly limited, but examples thereof include vegetable oils, mineral oils, etc. Examples of such compositions include olive oil, sesame oil, soybean oil, camellia oil, corn oil, castor oil, rapeseed oil, coconut oil, peanut oil, wheat germ oil, light liquid paraffin, liquid paraffin, squalane, etc. In addition, hardened oils obtained by hydrogenating these compositions can also be used. The compositions containing these fatty acid esters and/or their derivatives as the main component may be used alone or in combination of two or more types. In addition, the compositions containing fatty acid esters and/or their derivatives as the main component may be used in combination with the above-mentioned fatty acid esters and their derivatives.

When a drug with low water solubility (poorly water-soluble drug) is used as the drug to be incorporated in the pharmaceutical preparation, it is preferable that the non-volatile solvent contains a surfactant capable of dissolving or suspending the poorly water-soluble drug. It is also preferable that the non-volatile solvent contains vitamins and oils and fats in addition to the surfactant.

The components contained in the non-volatile solvent may be used alone or in combination of two or more. In particular, when a non-liquid component is used as a component contained in the non-volatile solvent, it is used in combination with another liquid component. For example, when the non-volatile solvent contains vitamin E, it is preferable that vitamin E is used in combination with an alcohol such as ethanol.

The amount of non-volatile solvent is not particularly limited as long as the effects of the present invention are achieved, but the mass ratio to the total amount of core particle components (total mass of core particle components: mass of non-volatile solvent) is preferably 1:0.001 at the lower limit, and more preferably 1:0.01 at the upper limit. The mass ratio of surfactant to the total amount of core particle components is not particularly limited, but is preferably 1:0.6, more preferably 1:0.4, and even more preferably 1:0.3 at the upper limit. The mass ratio of surfactant to the total amount of core particle components is not particularly limited, but 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 at the upper limit.

The viscosity of the non-volatile solvent is not particularly limited as long as the effects of the present invention are achieved, and is, for example, in the range of 10 to 600 mPa·s as the viscosity at 40° C. Specific examples of such non-volatile solvents include surfactants, vitamins, oils and fats, etc., as shown in Table 1 below. The viscosity of the non-volatile solvent can be measured using a commercially available viscometer. An example of the viscometer is the rotational vibration viscometer VISCOMATE VM-10A-L (manufactured by Sekonic Corporation).

(Drugs)
The pharmaceutical preparation of the present invention comprises a drug in the core particle. The drug is preferably present in a state of being dissolved or suspended in the above-mentioned non-volatile solvent. There is no particular limitation on the drug, and any drug that exerts the desired effect in the pharmaceutical preparation of the present invention can be used. In addition, the drug may be used alone or in combination of two or more kinds.

The log P value of the drug is not particularly limited as long as the effects of the present invention are achieved, but is preferably -2 to 7, more preferably -1.9 to 6.5, and even more preferably 1.85 to 6.1.

The logP value of a drug is the value listed in Pubchem (https://pubchem.ncbi.nlm.nih.gov/). The logP value of a drug not listed in Pubchem can be measured according to the flask shaking method in accordance with Japanese Industrial Standards Z7260-107. Specifically, 1-octanol and distilled water are first equilibrated by shaking at 25°C for 24 hours. Then, 10 mg of the drug sample is weighed into a glass bottle with a lid, and 4 mL each of the equilibrated 1-octanol and distilled water is added, followed by shaking at 25°C for 4 days. The 1-octanol phase and the aqueous phase are separated by centrifugation, and the concentration of the sample in each phase is measured by HPLC. The logP value is the common logarithm of the partition coefficient between the two phases.

Specific examples of drugs include vitamins, hormones, anticancer drugs, antibacterial agents, antiviral agents, hyperlipidemic drugs, central nervous system drugs, immunosuppressants, peripheral nervous system drugs, hemorrhoidal disease drugs, circulatory organ drugs, metabolic medicines, gastrointestinal disease drugs, and leprosy drugs.

Since the pharmaceutical preparation of the present invention can contain a large amount of non-volatile solvent in the core particles, even poorly water-soluble drugs can be dissolved or suspended in the non-volatile solvent and contained in the core particles. Therefore, in one embodiment of the present invention, it is preferable that the drug contains a poorly water-soluble drug. Poorly water-soluble drugs include, but are not limited to, drugs whose solubility in water (mass (g) of drug dissolved in 100 g of water) under physiological pH conditions is 10 to 20 μg/ml. Furthermore, poorly water-soluble drugs include drugs classified as Class II and IV in the Biopharmaceutics Classification System (BCS) defined by the U.S. Food and Drug Administration (FDA).

Vitamin preparations include, but are not limited to, fat-soluble vitamins, water-soluble vitamins, etc. Fat-soluble vitamins include, for example, vitamin A such as retinol (A1 alcohol), retinal (A1 aldehyde), retinoic acid (A1 acid), 3-dehydroretinol (A2 alcohol), 3-dehydroretinal (A2 aldehyde), and 3-dehydroretinoic acid (A2 acid), vitamin D such as carotene, flavonoids, ergocalciferol (D2), cholecalciferol (D3), ergosterol, and 7-hydrocholesterol, vitamin E such as α-tocopherol, and vitamin K such as phylloquinone (K1), menaquinone (K2), and menadione (K3). Examples of water-soluble vitamins include vitamin B1 such as thiamine (thiamine), vitamin B2 such as riboflavin, vitamin B6 such as pyridoxine, pyridoxal, pyridoxamine, vitamin B12 such as cobalamin, niacin such as folic acid, nicotinic acid, nicotinamide, pantothenic acid, biotin, and ascorbic acid (vitamin C).

Hormones are physiologically active substances that are formulated from various hormones and exert specific effects on specific cells in the body by utilizing the inherent physiological or pharmacological actions of the hormones. Hormones include, but are not limited to, hormones derived from the hypothalamus, anterior pituitary gland, posterior pituitary gland, thyroid gland, pancreatic islets of Langerhans, adrenal cortex, adrenal medulla, gonads, digestive system, etc. Specific examples include progesterone, levonorgestrel, and norethisterone.

Anticancer agents include, but are not limited to, those that have the effect of shrinking or eliminating cancer tumors or preventing the growth of cancer tumors in various cancers such as brain tumors, tongue cancer, laryngeal cancer, thyroid cancer, esophageal cancer, stomach cancer, colon cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, kidney cancer, prostate cancer, bladder cancer, skin cancer, bone tumors, leukemia, malignant lymphoma, and childhood cancer. Specifically, cyclophosphamide, ifosfamide, thiotepa, melphalan, busulfan, nimustine, ranimustine, dacarbazine, procarbazine, temozolomide, cisplatin, carboplatin, nedaplatin, methotrexate, pemetrexed, uracil, doxifluridine, gimeracil/oteracil (gimeracil/oteracil), cytarabine, enocitabine, gemcitabine, 6-mercaptopurine, fludarabine, pentostatin, cladribine, hydroxyurea, doxorubicin, epirubicin, daunorubicin, idarubicin, pirarubicin, mitoxantrone, amurubicin, actinomycin D, bleomycin, pepleomycin, mitomycin C C), aclarubicin, zinostatin, vincristine, vindesine, vinblastine, vinorelbine, paclitaxel, docetaxel, irinotecan, active metabolite of irinotecan (SN-38), nogitecan, topotecan, etoposide, prednisolone prednisolone, dexamethasone, tamoxifen, toremifene, medroxyprogesterone, anastrozole, exemestane, letrozole, rituximab, imatinib, gefitinib, gemtuzumab ozogamicin ozogamicin), bortezomib, erlotinib, cetuximab, bevacizumab, sunitinib, sorafenib, dasatinib, panitumumab, asparaginase, tretinoin, arsenic trioxide, folinate, levofolinate, or a salt thereof, or an active metabolite thereof.

Antibacterial agents are agents that have the effect of killing or inhibiting the growth of fungi or bacteria. Antibacterial agents for fungi include, but are not limited to, polyene antibacterial agents, fluoropyrimidine antibacterial agents, imidazole antibacterial agents, triazole antibacterial agents, allylamine antibacterial agents, and echinin antibacterial agents. Specific examples include amphotericin B, nystatin, flucytosine, isoconazole, bifonazole, lanoconazole, ketoconazole, luliconazole, clotrimazole, neticonazole, miconazole, fluconazole, itraconazole, fosfluconazole, voriconazole, terbinafine, micafungin, caspofungin, griseofulvin, undecylenic acid, liranaftate, tolnaftate, and tolciclate.

Antibacterial agents targeted against bacteria include, but are not limited to, β-lactam antibacterial agents such as penicillin antibacterial agents, cephalosporin antibacterial agents, carbapenem antibacterial agents, monobactam antibacterial agents, and penem antibacterial agents, aminoglycoside antibacterial agents, lincomycin antibacterial agents, fosfomycin antibacterial agents, tetracycline antibacterial agents, chloramphenicol antibacterial agents, macrolide antibacterial agents, ketolide antibacterial agents, polypeptide antibacterial agents, glycopeptide antibacterial agents, streptogramin antibacterial agents, quinolone antibacterial agents, sulfa antibacterial agents, and oxazolidinone antibacterial agents. Specifically, penicillin G, ampicillin, bacampicillin, lenampicillin, cyclacillin, amoxicillin, pivmecillin, aspoxicillin, cloxacillin, piperacillin, methicillin, ampicillin-cloxacillin, ampicillin-sulbactam, clavulanic acid-amoxicillin, piperacillin-tazobactam, cefazolin, cephalontin, cephalexin, cefatrizine, cefroxadine, cefaclor, cefadroxil, cefotiam, cefmetazole, flomoxef, cefminox, cefbuperazone, cefuroxime axetil, Cefdinir, cefditoren pivoxil, cefteram pivoxil, cefpodoxime proxetil, cefcapene pivoxil, cefotaxime, ceftriaxone, cefoperazone, cefmenoxime, ceftazidime, ceftibuten, cefixime, cefodizime, latamoxef, ceftizoxime, cefpirome, cefozopran, cefepime, cefoperazone sulbactam, imipenem, panipenem, meropenem, biapenem, doripenem, tebipenem, aztreonam, sulbactam, tazobactam, carumonam, faropenem, kanamycin, streptomycin Isin, neomycin, gentamicin, fradiomycin, tobramycin, amikacin, arbekacin, astromycin, isepamicin, bekanamycin, dibekacin, micronomycin, netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin, lincomycin, clindamycin, fosfomycin, tetracycline, oxytetracycline, demethylchlortetracycline, doxycycline, minocycline, chloramphenicol, erythromycin, clarithromycin, azithromycin, josama Examples of such drugs include isin, spiramycin, midecamycin, rokitamycin, kitasamycin, telithromycin, colistin, polymyxin, bacitracin, vancomycin, teicoplanin, quinupristin-dalfopristin, nalidixic acid, piromidic acid, pipemidic acid, norfloxacin, enoxacin, ofloxacin, ciprofloxacin, tosufloxacin, lomefloxacin, levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, garenoxacin, sitafloxacin, ST combination drug, daphenylsulfone, and linezolid.

Antiviral agents are agents that have a therapeutic effect on diseases caused by viral infections by inhibiting some or all of the processes in the cycle in which a virus parasitizes a host cell, forms new virus particles, and escapes the host cell. Antiviral agents include, but are not limited to, agents that have a therapeutic effect on diseases caused by viral infections such as herpes virus, cytomegalovirus, human papilloma virus, respiratory syncytial virus, influenza virus, human immunodeficiency virus, hepatitis B virus, and hepatitis C virus. Specific examples include Zovirax, acyclovine, Vicrox (acyclovir), Valtrex (valaciclovir), Denosine (ganciclovir), Arasena A (vidarabin), Relenza (zanamivir hydrate), Tamiflu (oseltamivir phosphate), Symmetrel (amantadine), Retrovir (zidovudine), Videx (didanosine), Epivir, Zefix (lamivudine), Fortvase (zaquinavir), and Norvir (ritonavir).

Examples of hyperlipidemia treatments include, but are not limited to, ethyl icosapentate, ethyl omega-3 fatty acid, clofibrate, polyene phosphatidylcholine, etc.

Central nervous system agents include, but are not limited to, indomethacin farnesyl, nalfurafine hydrochloride, etc.

Immunosuppressants include, but are not limited to, cyclosporine, etc.

Examples of peripheral nerve agents include, but are not limited to, tafamidis meglumine.

Examples of drugs for treating hemorrhoidal disease include, but are not limited to, tribenoside.

Examples of circulatory system agents include, but are not limited to, nifedipine, ubidecarenone, etc.

Examples of metabolic drugs include, but are not limited to, nintedanib ethanesulfonate, etc.

Drugs for gastrointestinal disorders include, but are not limited to, gefarnate, sodium picosulfate hydrate, lubiprostone, etc.

Examples of leprosy treatments include, but are not limited to, clofazimine.

The amount of drug in the pharmaceutical formulation of the present invention is not particularly limited as long as the pharmaceutical formulation of the present invention exerts the desired effect, but the mass ratio (mass of drug:total mass of core particle components) to the total amount of core particle components has a lower limit of preferably 0.01:1, more preferably 0.02:1, and even more preferably 0.03:1. The upper limit is also not particularly limited, but is preferably 0.5:1, and more preferably 0.2:1. The range of the mass ratio of drug to the total amount of core particle components is also not particularly limited, but is preferably 0.01:1 to 0.5:1, more preferably 0.02:1 to 0.5:1, and even more preferably 0.03:1 to 0.2:1.

The amount of drug in the pharmaceutical formulation of the present invention is not particularly limited as long as the pharmaceutical formulation of the present invention exhibits the desired effect, but the mass ratio to the non-volatile solvent (mass of drug: mass of non-volatile solvent) is preferably 0.05:1 at the lower limit, more preferably 0.1:1, and even more preferably 0.5:1. The upper limit is not particularly limited, but is preferably 5:1, and more preferably 3:1. The range of the mass ratio of drug to surfactant is not particularly limited, but 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.

The degree of aggregation of the core particles in the pharmaceutical formulation of the present invention is not particularly limited, but is preferably 90% or less, more preferably 70% or less, and even more preferably 50% or less.

The degree of aggregation can be measured using a commercially available powder property evaluation device. An example of the powder property evaluation device is Powder Tester (registered trademark) PT-R (manufactured by Hosokawa Micron Corporation). The measurement conditions are, for example, as follows.
Sieve openings: (upper) 710 μm, (middle) 355 μm, (lower) 250 μm
Sample size: 2g or 3g
Vibration time: 119 seconds

Under the above conditions, the values of each item in the following formula are measured.
X = [mass of powder remaining on the upper sieve] / mass of powder charged x 100
Y = [mass of powder remaining on the middle sieve] / mass of powder charged x 100 x 0.6
Z = [mass of powder remaining on the lower sieve] / mass of powder charged x 100 x 0.2
The sum of the three values of X, Y, and Z is the degree of cohesion (%).

<Coating Layer>
The coating layer can cover the core particles and suppress leakage of the non-volatile solvent and drug contained in the core particles to the surface of the pharmaceutical preparation. As a result of the coating layer suppressing leakage of the non-volatile solvent, aggregation of the pharmaceutical preparation can be suppressed and the decrease in the fluidity of the pharmaceutical preparation can be suppressed.

The components constituting the coating layer are not particularly limited, but examples thereof include water-soluble coating agents. The water-soluble coating agents may be used alone or in combination of two or more.

According to one embodiment, the water-soluble coating agent preferably comprises at least one component selected from polyalkylene glycols and polysaccharides or derivatives thereof.

The polysaccharide or its derivative is preferably a cellulose derivative, such as methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, etc. One type of cellulose derivative may be used alone, or two or more types may be used in combination.

Examples of polyalkylene glycols include polyethylene glycol.

According to another preferred embodiment, the coating agent used in the coating layer is, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer, vinylpyridine copolymer, alkyl vinylpyridine copolymer, aminocellulose derivative, diethylaminoethyl methacrylate, polyvinyl acetal diethylamino acetate, dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N,N-di-n-butyl hydroxyl propyl ether, copolymer of vinylpyridine and acrylic acid-based free acid, alkyl vinylpyridine and acrylic acid-based free acid, Examples of the copolymer include a copolymer of vinylpyridine, an acrylic acid-based free acid, and a vinyl monomer, a copolymer of alkylvinylpyridine, an acrylic acid-based free acid, and a vinyl monomer, a 2-methyl-5-vinylpyridine-methacrylic acid copolymer, poly-2-(vinylphenyl)glycine, morpholino-N-β-ethyl acrylate-methacrylic acid copolymer, shellac, cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, zein, hydroxypropyl methylcellulose phthalate, and aminoalkyl methacrylate copolymer. These components may be used alone or in combination of two or more.

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 sorbitan solution, triacetin, tributyl citrate, triethyl citrate, and chlorobutanol. Of these plasticizers, polyalkylene glycol is preferably used, and polyethylene glycol (macrogol) is more preferably used. These plasticizers may be used alone or in combination of two or more.

The components constituting the coating layer may be used as is, or may be dissolved in water, alcohol, etc., if necessary.

The amount of the coating layer in the pharmaceutical preparation of the present invention is not particularly limited as long as the pharmaceutical preparation of the present invention has the desired effect, but the lower limit of the mass ratio to the total mass of the core particles (mass of the coating layer:total mass of the core particles) is preferably 0.001:1, more preferably 0.002:1. The upper limit is also not particularly limited, but is preferably 0.1:1, more preferably 0.05:1, and even more preferably 0.02:1. The range of the mass ratio of the coating layer to the total mass of the core particles is also not particularly limited, but is preferably 0.001:1 to 0.1:1, more preferably 0.002:1 to 0.05:1, and even more preferably 0.002:1 to 0.02:1.

<Other ingredients>
The pharmaceutical preparation of the present invention may contain pharma- ceutical acceptable additives other than the components constituting the core particles and coating layer described above, as long as they do not impede the effects of the present invention. Examples of additives include excipients, disintegrants, lubricants, binders, flow agents, sweeteners, flavorings, colorants, etc. These additives may be ones that perform two or more functions. These additives may be used alone or in combination of two or more.

The pharmaceutical formulation of the present invention has a coating layer that covers the core particles, which prevents leakage of the non-volatile solvent and drug contained in the core particles from the pharmaceutical formulation, thereby suppressing aggregation of the pharmaceutical formulation.

The degree of aggregation of the pharmaceutical formulation is preferably 70% or less, more preferably 60% or less, and even more preferably 50% or less. The degree of aggregation of the pharmaceutical formulation can be measured by the same method as that for measuring the degree of aggregation of the core particles described above.

It is also preferable that the degree of aggregation of the pharmaceutical formulation is improved (lower) than the degree of aggregation of the core particles.

The particle size of the pharmaceutical formulation is not particularly limited, but preferably the 50% particle size (D50) based on volume distribution is 100 to 400 μm, more preferably 120 to 250 μm. The 50% particle size (D50) based on volume distribution of the pharmaceutical formulation can be measured by the same method as the measurement of the 50% particle size (D50) based on volume distribution of the core particle component described above.

The pharmaceutical preparation of the present invention may be used as it is, or may be used as a preparation having various dosage forms. The dosage form of the preparation is not particularly limited as long as the effects of the present invention are achieved, but examples include granules, tablets, pills, capsules, powders, etc. Of these, granules, tablets, and capsules are preferred. Furthermore, examples of capsules include hard capsules.

[Method of manufacturing pharmaceutical preparations]
The method for producing the pharmaceutical preparation of the present invention is not particularly limited, and known methods can be used. The conditions for producing the pharmaceutical preparation can be appropriately adjusted depending on the types of core particle components, non-volatile solvent, drug, coating layer components, etc. Specifically, the pharmaceutical preparation of the present invention can be produced, for example, according to the following procedure. First, a first core particle component, which is acicular and/or roughly columnar crystalline cellulose, and a second core particle component, which is at least one roughly spherical pharma- ceutically acceptable additive, are mixed using a fluidized bed granulator (e.g., FD-MP-01D, manufactured by Powrex Corporation) to obtain a core particle mixture. Meanwhile, a drug is added to a non-volatile solvent and stirred using a stirrer (NZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) to obtain a mixed liquid (drug liquid) in which the drug is dissolved or suspended. Next, the obtained mixture and the mixed liquid are brought into contact with each other using a fluidized bed granulator, and the mixed liquid is attached to the core particle components in the mixture to obtain core particles. Here, the contact between the mixture and the mixed liquid is performed, for example, by a method of spraying the mixed liquid onto the mixture, a method of immersing the mixture in the mixed liquid, or the like. Next, the core particles are dried as necessary, and then coated with a component constituting the coating layer (coating layer component). Here, the core particles are coated, for example, by a method of spraying the coating layer component onto the core, or a method of immersing the core particles in the coating layer component. Next, the particles having the core particles and the coating layer that coats the core particles are dried to obtain a pharmaceutical preparation.

The method of tableting the pharmaceutical preparation is not particularly limited, and known methods can be used. The conditions for tableting are not particularly limited, and can be appropriately adjusted depending on the types of core particle components, non-volatile solvents, drugs, and coating layer components. Examples of methods of tableting the pharmaceutical preparation include a method of tableting the pharmaceutical preparation using a tablet press such as a rotary tablet press or a single shot tablet press. Of these, it is preferable to tablet the pharmaceutical preparation using a rotary tablet press. Examples of rotary tablet presses include VIRGO 0512SS2AY manufactured by Kikusui Seisakusho Co., Ltd. When the tablet contains a pharmaceutical acceptable additive in addition to the pharmaceutical preparation of the present invention, the pharmaceutical preparation of the present invention and the pharmaceutical acceptable additive are mixed in advance and then tableted. The method of mixing the pharmaceutical preparation and the additive is not particularly limited, and can be performed using known methods. Examples of methods of mixing the pharmaceutical preparation and the additive include a method of mixing using a mixer such as a V-type mixer. Specifically, the mixing can be carried out using a V-type mixer (TCV-20) manufactured by Tokuju Machinery Co., Ltd.

There is no particular limitation on the method of making a pharmaceutical preparation into a capsule, and known methods can be used. Specifically, the pharmaceutical preparation is produced by filling a capsule membrane made of gelatin or a plant-derived raw material. The filling into the capsule membrane is not particularly limited, and can be carried out by known methods such as auger-type powder filling, die-compression-type powder filling, and vibration-type powder filling. For example, in auger-type powder filling, a predetermined amount of powdered or granular pharmaceutical preparation is dropped from a hopper into the inside of a cap-shaped container, each of which is open at one end and is usually formed of a gelatin membrane, and then the containers are coaxially joined to produce a capsule.

The present invention will be specifically described below based on examples, but the present invention is not limited to these examples. In the examples, unless otherwise specified, "average particle size (D50)" means "50% particle size based on volume distribution."

[Method of Preparing Core Particles]
As roughly spherical particles, lactose hydrate (SuperTab (registered trademark), average particle size (D50) 120 μm, manufactured by DFE Pharma) and corn starch (official corn starch, average particle size (D50) 15 μm, manufactured by Nihon Shokuhin Kako Co., Ltd.) were prepared, and as needle-shaped and/or roughly columnar crystalline cellulose, crystalline cellulose (CEOLUS UF-702, average particle size (D50) 140 μm, manufactured by Asahi Kasei Corporation) and crystalline cellulose (CEOLUS KG-1000, average particle size (D50) 80 μm, manufactured by Asahi Kasei Corporation) were prepared, and images were measured using an electron microscope (VE-7800, manufactured by KEYENCE). 1A and 1B are electron micrographs of needle-shaped and/or roughly columnar crystalline cellulose CEOLUS KG-1000 and CEOLUS UF-702, respectively, FIG. 2 is an electron micrograph of lactose hydrate (roughly spherical particles), and FIG. 3 is an electron micrograph of corn starch (roughly spherical particles).

According to the formulation shown in Table 2, approximately spherical particles such as lactose hydrate (SuperTab (registered trademark), average aspect ratio 1.39, average particle size (D50) 120 μm, manufactured by DFE Pharma) and corn starch (official corn starch, average aspect ratio 1.23, average particle size (D50) 15 μm, manufactured by Nihon Shokuhin Kako Co., Ltd.), and needle-shaped crystalline cellulose such as crystalline cellulose (CEOLUS UF-702, average aspect ratio 2.63, average particle size (D50) 140 μm, manufactured by Asahi Kasei Co., Ltd.) and (CEOLUS KG-1000, average aspect ratio 4.20, average particle size (D50) 80 μm, manufactured by Asahi Kasei Co., Ltd.) were each sieved through a 355 μm sieve and placed in a polyethylene bag to be premixed. The average aspect ratio of each core particle component refers to the average aspect ratio of particles obtained by acquiring particle images using an electron microscope (VE-7800, manufactured by KEYENCE) and measuring the aspect ratios of 10 arbitrarily selected particles by image analysis, excluding the aspect ratio values of the particles in the top 10% and bottom 10% of aspect ratio values. In Table 2, unless otherwise specified, the unit of numerical values is g (grams).

Next, the mixtures of the respective Examples and Comparative Examples were charged into a fluidized bed granulator (FD-MP-01D, manufactured by Powrex Corporation), and the core particle mixture was mixed under the conditions shown in Table 3 (preheating step).

<Measurement of bulk density of core particle mixture>
The hardened bulk density and loose bulk density of each of the obtained core particle mixtures were measured. Specifically, using a Powder Tester (registered trademark) PT-R (manufactured by Hosokawa Micron Corporation), the core particle mixture was uniformly supplied from above through a sieve into a cylindrical container of the same size as the measurement container of the third method of bulk density and tapped density measurement described in the 17th revised Japanese Pharmacopoeia, and the bulk density in a loosely packed state (loose bulk density) was measured by leveling off the top surface and weighing. Next, an auxiliary cylinder was placed on top of the container, the core particle mixture was added up to the top edge of the container, and tapping was performed 180 times. After completion, the auxiliary cylinder was removed, the core particle mixture was leveled off at the top surface of the container and weighed, and the bulk density (hardened bulk density) in the case of dense filling after tapping was measured. Furthermore, the difference between the hardened bulk density and the loose bulk density (hardened bulk density - loose bulk density) was calculated for each core particle mixture. The results are shown in Table 4.

Furthermore, according to the formulations shown in Table 2, each non-volatile solvent was placed in a 500 mL beaker and stirred and mixed at 400-900 rpm using a stirrer (NZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.). After stirring and mixing until homogenous, each drug was added and further stirred and mixed to obtain a drug solution. The log P value of each drug is as shown in Table 2.

Next, using a fluidized bed granulator (FD-MP-01D, manufactured by Powrex Corporation), the drug liquid was sprayed onto each of the core particle mixtures obtained above to obtain core particles with the drug liquid adhering to the core particle mixture (granulation process). The settings for the fluidized bed granulator were as shown in Table 3 above.

<Measurement of the degree of aggregation of core particles>
The degree of aggregation of the core particles of the obtained pharmaceutical preparations of each of the Examples and Comparative Examples was measured using a powder property evaluation device (Powder Tester (registered trademark) PT-R, manufactured by Hosokawa Micron Corporation). The setting conditions of the powder property evaluation device were as follows.
Sieve openings: (upper) 710 μm, (middle) 355 μm, (lower) 250 μm
Sample size: 2g or 3g
Vibration time: 119 seconds

Under the above conditions, the values of each item in the following formula are measured.
X = [mass of powder remaining on the upper sieve] / mass of powder charged x 100
Y = [mass of powder remaining on the middle sieve] / mass of powder charged x 100 x 0.6
Z = [mass of powder remaining on the lower sieve] / mass of powder charged x 100 x 0.2
The degree of cohesion (%) is the sum of the three values of X, Y, and Z. The results are shown in Table 4.

In addition, according to the formulation shown in Table 2, each coating layer component was placed in a stainless steel container and stirred and mixed at 400 to 900 rpm using a stirrer (NZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) to obtain a coating layer solution.

Next, using a fluidized bed granulator (FD-MP-01D, manufactured by Powrex Corporation), the coating layer solution was sprayed onto each of the core particles obtained above, and dried at 60° C. for 15 minutes to obtain a pharmaceutical preparation in which the core particles were coated with the coating layer solution. The setting conditions for the fluidized bed granulator were as shown in Table 5.

The degree of aggregation of the pharmaceutical preparations of each of the Examples and Comparative Examples was measured using the same method as that used to measure the degree of aggregation of the core particles described above. The results are shown in Table 4 above.

From the results in Table 4, in Comparative Examples 1 to 3 in which only the second core particle component was used as the core particle component, and in Comparative Example 4 in which only the first core particle component was used, it was not possible to produce a pharmaceutical preparation in the form of granules. On the other hand, in the formulations of Examples 1 to 6 in which the first core particle component (crystalline cellulose) and the second core particle component were combined as the core particle component, the aggregation of the pharmaceutical preparation was suppressed and it had good fluidity. Furthermore, in the formulations of Examples 1 to 6, the pharmaceutical preparation could be produced in the form of granules, and in the formulations of Examples 2 to 6, it was also possible to produce tablets by tableting. It should be noted that, although it has not been confirmed whether the formulation of Example 1 can produce tablets by tableting, it is presumed that it is possible to produce tablets by tableting, since the degree of aggregation (degree of aggregation after coating) of the pharmaceutical preparation is suppressed. In addition, even when a pharmaceutical preparation is produced by a formulation in which the non-volatile solvent (polysorbate 80) of Examples 1 to 6 is replaced with fats and oils (medium-chain fatty acid triglyceride), it has been confirmed that the aggregation of the pharmaceutical preparation is suppressed and the fluidity is good. Furthermore, it has been confirmed that these pharmaceutical preparations can be prepared in the form of granules and can also be compressed to produce tablets.

According to the present invention, it is possible to provide granules that contain non-volatile solvents such as surfactants and vitamins that are useful in the production of pharmaceuticals and have excellent fluidity that can withstand actual production.

Claims (14)

A pharmaceutical preparation in the form of granules comprising a core particle and a coating layer coating the core particle,
the core particle comprises a drug, a first core particle component, a second core particle component, and a non-volatile solvent;
the first core particle component is at least one kind of crystalline cellulose having a volume distribution-based 50% average particle size (D50) of 80 μm to 140 μm and a shape selected from needle-like and approximately columnar shapes,
The second core particle component is at least one pharma- ceutically acceptable excipient having a volume distribution-based 50% mean particle diameter (D50) of 15 μm to 120 μm and a substantially spherical shape;
The pharmaceutical preparation, wherein the core particle has a void between the first core particle component and the second core particle component. The pharmaceutical formulation according to claim 1 , wherein the drug and non-volatile solvent are retained in the voids of the core particle. The pharmaceutical formulation according to claim 1 or 2 , wherein the average aspect ratio of the first core particle component is 1.8 to 10.0. The pharmaceutical formulation according to any one of claims 1 to 3 , wherein the second core particle component has an average aspect ratio of 1.0 to 1.7. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the second core particle component is at least one selected from the group consisting of glucose, fructose, lactose, lactose hydrate, sucrose, white 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 sulfate, dextrates, dextrin, dextrose, polymethacrylate, glyceryl palmitostearate, isomalt, lactitol, kaolin, lactitol, maltitol, maltodextrin, maltose, trehalose, xylitol, pregelatinized starch, modified pregelatinized starch, tapioca starch, and sodium chloride. The pharmaceutical formulation according to any one of claims 1 to 5 , wherein the non-volatile solvent comprises at least one member selected from the group consisting of polysorbates , vitamins, and medium-chain triglycerides . The pharmaceutical formulation according to any one of claims 1 to 6 , wherein the drug has a log P value of -2 to 7. The pharmaceutical formulation according to any one of claims 1 to 7, wherein the drug comprises at least one selected from the group consisting of hormonal agents, anticancer agents, antibacterial agents and antiviral agents (excluding N-[5-fluoro- 2- (1-piperidinyl)phenyl]isonicotinthioamide). The coating layer may be any one of polyethylene glycol, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer, vinylpyridine copolymer, alkyl vinylpyridine copolymer, aminocellulose derivative, diethylaminoethyl methacrylate, polyvinyl acetal diethylamino acetate, dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N,N-di-n-butyl hydroxyl propyl ether, copolymer of vinylpyridine and acrylic acid-based free acid, copolymer of alkyl vinylpyridine and acrylic acid-based free acid, vinylpyridine and The pharmaceutical formulation according to any one of claims 1 to 8, comprising at least one selected from the group consisting of copolymers of acrylic free acids and vinyl monomers, copolymers of alkylvinylpyridines, acrylic free acids and vinyl monomers, 2-methyl-5-vinylpyridine-methacrylic acid copolymer, poly-2-(vinylphenyl)glycine, morpholino-N-β-ethylacrylate-methacrylic acid copolymer, shellac, cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, zein, hydroxypropyl methylcellulose phthalate and aminoalkyl methacrylate copolymer. The pharmaceutical preparation according to any one of claims 1 to 9 , wherein the pharmaceutical preparation has a volume distribution-based 50% particle size (D50) of 100 to 400 µm. A pharmaceutical formulation comprising the pharmaceutical formulation according to any one of claims 1 to 10 , and having a dosage form selected from the group consisting of granules, tablets, capsules, powders and pills. A method for producing a pharmaceutical preparation in the form of granules having a core particle and a coating layer that coats the core particle, comprising the steps of:
(a) mixing a first core particle component and a second core particle component to obtain a core particle mixture;
(b) dissolving or suspending a drug in a non-volatile solvent to obtain a mixture;
(c) contacting the core particle mixture obtained in step (a) with the mixed solution obtained in step (b) to obtain core particles containing the first core particle component, the second core particle component, a drug, and a non-volatile solvent; and
(d) coating the core particles obtained in step (c) to obtain a pharmaceutical formulation,
the first core particle component is at least one kind of crystalline cellulose having a volume distribution-based 50% average particle size (D50) of 80 μm to 140 μm and a shape selected from needle-like and approximately columnar shapes,
The second core particle component is at least one pharma- ceutically acceptable excipient having a volume distribution-based 50% mean particle diameter (D50) of 15 μm to 120 μm and a substantially spherical shape;
The above manufacturing method, wherein the core particle has a gap between the first core particle component and the second core particle component. The method of claim 12 , further comprising the step of: (e) adding a pharma- ceutically acceptable additive to the pharmaceutical preparation obtained in step (d) and granulating the mixture to obtain a granular preparation. The method according to claim 12 , further comprising the step of (e') encapsulating the pharmaceutical preparation obtained in step (d) in a shell made of gelatin or a plant-derived material to obtain a capsule-shaped preparation.