JP7847966B2 - Pharmaceutical preparations and methods for manufacturing the same - Google Patents

Description

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

Traditionally, many active ingredients and additives used in the pharmaceutical field are liquid at room temperature, making it difficult to incorporate them in the required amounts when formulating granules or tablets.

Soft capsules are widely used as solid dosage forms containing components that are liquid at room temperature (e.g., Patent Document 1). However, soft capsules can be difficult to administer to children, the elderly, and patients with impaired swallowing ability, as they sometimes have a larger diameter than other solid dosage forms such as tablets. Furthermore, due to their nature, soft capsules are prone to leakage depending on the manufacturing method. Additionally, because soft capsules are soft and easily deformed, they require visual inspection or specialized inspection equipment to check for deformation, resulting in higher manufacturing costs compared to other solid dosage forms such as tablets.

On the other hand, tablets are used as a solid dosage form that can incorporate liquid components. When incorporating liquid components into tablets, the general method involves mixing the liquid and solid components before tableting to obtain particles with the liquid component adhering to the surface of the solid component, and then compressing these particles into tablets. However, this method causes the liquid component present on the surface of the solid component within the particles to aggregate or adsorb, reducing the fluidity of the particles and making tablet formation difficult. In particular, when attempting to prepare tablets containing a similar amount of liquid component as soft capsules, the particles obtained by mixing the liquid and solid components have low fluidity, making tablet formation extremely difficult. Therefore, only a small amount of liquid component can be incorporated into tablets, enough not to significantly reduce fluidity.

Incidentally, when formulating poorly water-soluble drugs, it is known that poorly water-soluble drugs are often combined with solid dispersions to improve their solubility (for example, Patent Document 2). Common methods for combining poorly water-soluble drugs with solid dispersions include spray drying and melting. However, spray drying requires large machinery, and melting involves high-temperature heat treatment to dissolve the drug, which carries the risk of denaturation and decomposition during the process.

Furthermore, while techniques for preparing tablets containing large amounts of liquid components by adsorbing liquid substances onto porous materials such as silica gel are known (for example, Patent Document 3), such techniques require processing under vacuum, which poses the problem of requiring expensive equipment.

Furthermore, while a method is known to suppress the decrease in the fluidity of a formulation by encapsulating the liquid component in a neutral or alkaline resin, the use of resin may affect the dissolution behavior of the liquid component, making it difficult to obtain the desired dissolution behavior.

Furthermore, a method is known in which a liquid active ingredient is prepared in the form of an oil-in-water emulsion, this emulsion solution is sprayed onto a powder to adhere it, and then dried to remove the water, thereby obtaining a powder to which the active ingredient is attached (for example, Patent Document 4). Additionally, a method is known in which a drug and a water-soluble polymer are coated onto an inert carrier and dried to form particles (for example, Patent Document 5).

Furthermore, granules comprising a powdered or finely granular component and a liquid component, with improved fluidity, are also known (for example, Patent Document 6).

Furthermore, drug formulations containing granules formulated by combining a drug with a solubilizing agent are known, and it is known that surfactants can be used as solubilizing agents, and that the granules can be coated (for example, Patent Document 7). However, surfactants have adhesive and viscous properties, which reduces fluidity, so there is a problem in that the amount that can be used when preparing pharmaceutical formulations such as tablets is limited.

While pharmaceutical formulations containing liquid components are being developed, the fluidity of formulations containing large amounts of liquid components decreases. Therefore, in pharmaceutical formulations such as tablets, where reduced fluidity affects formulation, it has been difficult to easily incorporate a sufficient amount of liquid component to dissolve a therapeutically effective dose of the drug.

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

Under these circumstances, there is a need for pharmaceutical formulations that contain a sufficient amount of non-volatile solvent to dissolve a therapeutically effective dose of drug, or a non-volatile solvent useful as a pharmaceutical, and possess excellent fluidity to withstand actual manufacturing.

As a result of diligent research by the present inventors, we have discovered that in a pharmaceutical formulation comprising core particles and a coating layer covering the core particles, by adjusting the specific surface area of the core particle components to a specific range, it is possible to incorporate a large amount of non-volatile solvent and drug into the core particles and to form a pharmaceutical formulation in granular form with excellent fluidity. This invention is based on this finding.

The present invention encompasses the following inventions.
[1] A pharmaceutical preparation in granular form comprising a core particle and a coating layer covering the core particle,
The nuclear particle comprises a drug, a nuclear particle component, and a non-volatile solvent.
The BET specific surface area of the aforementioned nuclear particle component is 0.45 ^m² /g or more.
The pharmaceutical preparation wherein the content of the non-volatile solvent per unit mass of the pharmaceutical preparation is 10 mg or more.
[2] The pharmaceutical preparation according to [1], wherein the BET specific surface area of the nuclear particle component is 0.5 to 3 ^m² /g.
[3] The pharmaceutical preparation according to [1] or [2], wherein the porosity of the core particles is 40% or more. [4] The pharmaceutical preparation according to any one of [1] to [3], wherein the core particle component is a solid additive.
[5] The pharmaceutical preparation according to any one of [1] to [4], wherein the core particle component comprises crystalline cellulose.
[6] The pharmaceutical preparation according to any one of [1] to [5], wherein at least a portion of the nuclear particle components are in direct or indirectly in contact with each other via the nonvolatile solvent.
[7] A pharmaceutical preparation according to any one of [1] to [6], wherein at least a portion of the drug is dissolved in the non-volatile solvent.
[8] The pharmaceutical preparation according to any one of [1] to [7], wherein at least a portion of the nonvolatile solvent coats at least a portion of the nuclear particle component.
[9] The pharmaceutical preparation according to any one of [1] to [8], wherein the mass ratio of the non-volatile solvent to the drug is 1:0.1 to 1:10.
[10] The pharmaceutical preparation according to any one of [1] to [9], wherein the mass ratio of the total mass of the nuclear particle components to the non-volatile solvent is 1:0.01 to 1:0.6.
[11] The pharmaceutical preparation according to any one of [1] to [10], wherein the non-volatile solvent comprises at least one selected from the group consisting of surfactants, vitamins, and fatty acid glycerides.
[12] The pharmaceutical preparation according to [11], wherein the surfactant is a nonionic surfactant.
[13] The pharmaceutical preparation according to [12], wherein the nonionic surfactant is polysorbate.
[14] The pharmaceutical preparation according to [11], wherein the fatty acid glyceride is a medium-chain fatty acid glyceride.
[15] A pharmaceutical preparation according to any one of [1] to [14], wherein the logP value of the drug is -2 to 7.
[16] A pharmaceutical preparation according to any one of [1] to [15], wherein the logP value of the drug is -1.9 to 6.5.
[17] A pharmaceutical preparation according to any one of [1] to [16], wherein the drug comprises a poorly water-soluble drug.
[18] The pharmaceutical preparation according to [17], wherein the poorly water-soluble drug comprises at least one selected from the group consisting of hormones, anticancer agents, antibacterial agents and antiviral agents.
[19] The pharmaceutical preparation according to any one of [1] to [18], wherein the coating layer comprises a water-soluble coating agent.
[20] The pharmaceutical preparation according to [19], wherein the water-soluble coating agent comprises at least one component selected from the group consisting of polyalkylene glycol, polysaccharides, and derivatives thereof.
[21] The water-soluble coating agent is polyethylene glycol, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methacrylic acid copolymer, vinylpyridine copolymer, alkyl vinylpyridine copolymer, aminocellulose derivative, diethylaminoethyl methacrylate, polyvinyl acetal diethylaminoacetate, dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N,N-di-n-butylhydroxypropyl ether, copolymer of vinylpyridine and acrylic acid free acid, copolymer of alkyl vinylpyridine and acrylic acid free acid, A pharmaceutical preparation according to [19] or [20], wherein at least one selected from the group consisting of nylpyridine, an acrylic acid free acid and a vinyl monomer, an alkyl vinylpyridine, an acrylic acid free acid and a vinyl monomer, 2-methyl-5-vinylpyridine-methacrylate copolymer, poly-2-(vinylphenyl)glycine, morpholino-N-β-ethyl acrylate-methacrylate copolymer, shellac, cellulose acetate phthalate, methyl acrylate-methacrylate copolymer, methyl methacrylate-methacrylate copolymer, zein, hydroxypropyl methylcellulose phthalate and aminoalkyl methacrylate copolymer.
[22] The pharmaceutical preparation according to any one of [1] to [21], wherein the degree of aggregation of the pharmaceutical preparation is 70% or less.
[23] A pharmaceutical preparation according to any one of [1] to [22], wherein the degree of aggregation of the pharmaceutical preparation is lower than the degree of aggregation of the nucleus particles.
[24] The pharmaceutical preparation according to any one of [1] to [23], wherein the 50% particle size (D50) of the volume distribution standard of the pharmaceutical preparation is 100 to 400 μm.
A preparation comprising any of the pharmaceutical preparations described in [25] [1] to [24], and having a dosage form selected from the group consisting of granules, tablets, capsules, powders, and pills.
[26] The preparation according to [25], having a tablet dosage form with a degree of abrasion of 1.0% or less.
[27] A method for producing a pharmaceutical preparation in granular form comprising a core particle and a coating layer covering the core particle,
(a) A step of preparing the nuclear particle components that make up the nuclear particle,
(b) A step of dissolving or suspending a drug in a non-volatile solvent to obtain a mixture,
(c) A step of contacting the core particle component prepared in step (a) with the mixture obtained in step (b) to obtain core particles comprising the core particle component, a drug, and a non-volatile solvent, and
(d) The process includes a step of coating the nucleus particles obtained in step (c) to obtain a pharmaceutical formulation,
The BET specific surface area of the aforementioned nuclear particle component is 0.45 ^m² /g or more.
The manufacturing method wherein the content of the non-volatile solvent per unit mass of the pharmaceutical preparation is 10 mg or more.
[28] The manufacturing method according to [27], wherein the BET specific surface area of the nuclear particle component is 0.5 to 3 ^m² /g.
[29] The manufacturing method according to [27] or [28], wherein the porosity of the nucleus particles is 40% or more.
[30] The manufacturing method according to any one of [27] to [29], wherein the nuclear particle component is a solid additive.
[31] The manufacturing method according to any one of [27] to [30], wherein the core particle component comprises crystalline cellulose.
[32] The method for producing a non-volatile solvent according to any one of [27] to [31], wherein the non-volatile solvent comprises at least one selected from the group consisting of surfactants, vitamins, and fatty acid glycerides.
[33] The manufacturing method according to any one of [27] to [32], further comprising the step of adding a pharmaceutically acceptable additive to the pharmaceutical preparation obtained in step (d) and granulating it to obtain a granular preparation.
[34] The manufacturing method according to any one of [27] to [32], further comprising the step of encapsulating the pharmaceutical preparation obtained in step (d) in a film made of gelatin or a plant-derived raw material to obtain a capsule-shaped preparation.
A method for producing a tablet, comprising the step of compressing a pharmaceutical preparation described in any of [35] [1] to [26] to obtain a tablet.
A method for producing a capsule, comprising the step of encapsulating a pharmaceutical preparation described in any of [36] [1] to [26] in a capsule.
[37] The manufacturing method according to [35], wherein the degree of abrasion of the tablet is 1.0% or less.

According to the present invention, it is possible to provide a pharmaceutical formulation in the form of granules that contains a large amount of non-volatile solvent while possessing excellent fluidity. Furthermore, according to the present invention, aggregation, which causes a decrease in the fluidity of the pharmaceutical formulation, can be suppressed. That is, because excellent fluidity is achieved in the pharmaceutical formulation, a large amount of non-volatile solvent can be incorporated into pharmaceutical formulations such as tablets, where formulation is inhibited by reduced fluidity, using easy methods such as fluidized bed granulation. As a result, according to the present invention, even poorly water-soluble drugs can be incorporated into the pharmaceutical formulation in therapeutically effective amounts. Moreover, even when the pharmaceutical formulation of the present invention is stored for a long period of time, leakage of the non-volatile solvent contained in the core particles to the surface of the pharmaceutical formulation can be suppressed.

Figure 1 shows photographs and diagrams illustrating the results of three-dimensional void analysis of granular pharmaceutical formulations.

Detailed description of the invention

The present invention will be described in detail below. In this specification, numerical ranges indicated using "~" mean the range that includes the numerical values before and after "~" as the minimum and maximum values, respectively. In this specification, when the expression "A or B" is used, unless otherwise specified or interpreted restrictively from the context, it means that either or both are included.

[Pharmaceutical preparations]
The pharmaceutical formulation of the present invention is a granular pharmaceutical formulation comprising a core particle and a coating layer that coats the core particle. The core particle and the coating layer will be described below.

<Nuclear particle>
The pharmaceutical formulation of the present invention comprises a nuclear particle comprising a drug, a nuclear particle component, and a non-volatile solvent. The nuclear particle component constituting the nuclear particle has a specific range of specific surface area, thereby allowing a larger amount of non-volatile solvent to be contained within the nuclear particle than in conventional formulations.

(core particle component)
The core particles comprise a core particle component having a specific range with respect to the specific surface area measured by the BET method (so-called "BET specific surface area," also simply referred to as "specific surface area" in this specification). Specifically, the lower limit of the BET specific surface area of the core particle component is 0.45 ^m² /g, preferably 0.47 ^m² /g, and more preferably 0.5 ^m² /g. The upper limit of the BET specific surface area of the core particle component is not particularly limited as long as the effects of the present invention are achieved, but for example, it may be 10 ^m² /g, 5 ^m² /g, 3 ^m² /g, 2 ^m² /g, or ^{1.5 m²} /g. The range of the BET specific surface area of the core particle component is preferably 0.45 to 10 ^m² /g, more preferably 0.47 to 5 ^m² /g, and even more preferably 0.5 to 3 ^m² /g. The BET specific surface area of the core particle component can be measured by the BET method using a specific surface area and pore distribution analyzer (BELSORP®-miniX, manufactured by Microtrac-Bell Co., Ltd.). Specifically, a molecule with a known adsorption area (e.g., nitrogen molecule) can be adsorbed onto the core particle component at the temperature of liquid nitrogen, and the BET specific surface area of the core particle component can be measured from the amount of adsorption. When a core particle contains a core particle component having such a BET specific surface area, preferably at least a portion of the core particle components come into contact with each other directly or indirectly via a non-volatile solvent, so that many voids can be formed between the core particle components within the core particle. As a result, a large surface area to which liquid components can adhere is created within the core particle, so that the core particle can contain a large amount of liquid components. Furthermore, since the core particle can contain a large amount of non-volatile solvents such as surfactants used as solubilizers as liquid components, it can dissolve or suspend drugs that are poorly water-soluble. While not bound by theory, it is believed that such a mechanism makes it possible to manufacture pharmaceutical formulations containing large amounts of poorly soluble drugs within nuclear particles.

According to a preferred embodiment, the core particles have voids between multiple core particle components, and at least a portion of the non-volatile solvent is retained in the voids between the multiple core particle components. In a particularly preferred embodiment, at least a portion of the drug is dissolved or suspended in the non-volatile solvent, and the non-volatile solvent in which the drug is dissolved or suspended is retained in the voids between the multiple core particle components.

In a preferred embodiment, the type and amount of the core particle component are appropriately selected so that the porosity of the core particles containing the core particle component falls within a specific range. The lower limit of the porosity of the core particles is not particularly limited as long as the effects of the present invention are achieved, but is preferably 40%, more preferably 45%, and even more preferably 50%. The upper limit of the porosity of the core particles is not particularly limited as long as the effects of the present invention are achieved, but is preferably 80%, more preferably 65%, and even more preferably 60%. The range of the porosity of the core particles is not particularly limited as long as the effects of the present invention are achieved, but is preferably 40-80%, more preferably 45-70%, and even more preferably 50-60%. In this invention, the porosity of the nuclear particles can be determined, for example, by performing X-ray CT microstructural analysis of the nuclear particles using a commercially available X-ray CT scanner (Scanco medical AG μCT50, Scanco medical AG IPL image processing language software, manufactured by SCANCO MEDICAL), and measuring the porosity of the nuclear particles.

In a preferred embodiment, the core particle components contained in the core particles are solid additives. The lower limit of the solid additive content in the core particles is not particularly limited as long as the effects of the present invention are achieved, but is preferably 85% by mass, more preferably 90% by mass, and even more preferably 95% by mass, relative to the total mass of the core particle components. Furthermore, the upper limit of the solid additive content in the core particles is not particularly limited as long as the effects of the present invention are achieved, but can be, for example, 100% by mass, 99% by mass, 98% by mass, etc., relative to the total mass of the core particle components, and is preferably 100% by mass.

The particle shape of the solid additive as the core particle component is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately selected. Examples of solid additives include needle-shaped components (needle-shaped particles) and approximately spherical components (approximately spherical particles). According to a preferred embodiment, the core particle component, as a solid additive, contains a sufficient proportion of needle-shaped components (needle-shaped particles) and approximately spherical components (approximately spherical particles) to achieve the effects of the present invention. The lower limit of the total mass (total number) of needle-shaped and approximately spherical components in the solid additive contained in the core particle component is not particularly limited as long as the effects of the present invention are achieved, but can be, for example, 60%, 70%, 80%, 90%, etc., relative to the total mass (total number) of the solid additive. Furthermore, the upper limit of the total mass (total number) of needle-shaped and approximately spherical components in the solid additive contained in the core particle component is not particularly limited as long as the effects of the present invention are achieved, but can be, for example, 100%, 98%, 95%, 90%, etc., relative to the total mass (total number) of the solid additive. Furthermore, the range of the total mass (total number) of needle-shaped and substantially spherical components in the solid additive contained in the core particle component is not particularly limited as long as the effects of the present invention are achieved. However, it can be, for example, 60-100%, 70-100%, 80-100%, 90-100%, etc., relative to the total mass (total number) of the solid additive.

In this specification, "needle-shaped component" and "needle-shaped particle" refer to a component (particle) in which, in a cross-section along the long axis of an image (shape transferred to a plane) measured by an electron microscope, there is a significant difference between its vertical and horizontal lengths. Here, the significant difference between vertical and horizontal lengths can be expressed, for example, by the aspect ratio.

Specifically, the average aspect ratio of the needle-shaped component of the core particle is not particularly limited as long as the effects of the present invention are achieved, but its lower limit is preferably 1.8, more preferably 2.2, and even more preferably 2.5. Furthermore, the upper limit of the average aspect ratio of the needle-shaped component of the core particle is not particularly limited as long as the effects of the present invention are achieved, but it can be, for example, 10 or 8. Also, the range of the average aspect ratio of the needle-shaped component of the core particle is not particularly limited as long as the effects of the present invention are achieved, but it is preferably 1.8 to 10, more preferably 2.2 to 10, and even more preferably 2.5 to 10.

The average aspect ratio of the approximately spherical component of the core particle is not particularly limited as long as the effects of the present invention are achieved, but its lower limit can be, for example, 1.0 or 1.2. The upper limit of the average aspect ratio of the approximately spherical component of the core particle is not particularly limited as long as the effects of the present invention are achieved, but is preferably 1.65, more preferably 1.5, and even more preferably 1.2. Furthermore, the range of the average aspect ratio of the approximately spherical component of the core particle is not particularly limited as long as the effects of the present invention are achieved, but is preferably 1.0 to 1.65, more preferably 1.0 to 1.5, and even more preferably 1.0 to 1.2.

In this specification, "aspect ratio" of a nuclear particle component refers to the ratio of the major axis to the minor axis (major axis/minor axis) of a nuclear particle component in particle image analysis using an electron microscope. Furthermore, "average aspect ratio" of a nuclear particle component refers to the average aspect ratio of nuclear particle components obtained by measuring the aspect ratios of 10 or more arbitrarily selected nuclear particle components and excluding the aspect ratios of the top 10% and bottom 10% of nuclear particle components. Also, in this specification, "aspect ratio of nuclear particle components between X and Y" means that, with respect to the aspect ratio of a group of 10 or more arbitrarily selected nuclear particle components, the aspect ratio of the nuclear particle components obtained by excluding the top 10% and bottom 10% of the aspect ratios falls within the range of X to Y.

The types of core particle components are not particularly limited as long as their BET specific surface area falls within the range described above and they are pharmaceutically acceptable. Examples include sugars (including sugars, sugar hydrates, sugar alcohols, etc.) and inorganic compounds. Furthermore, core particle components can be used individually or in combination of two or more. When two or more core particle components are used in combination, the BET specific surface area of the core particle components refers to the BET specific surface area of the total core particle components (i.e., the mixture of two or more core particle components).

The sugars used are not particularly limited, but examples include monosaccharides such as glucose, disaccharides such as lactose and sucrose, polysaccharides such as cellulose (e.g., crystalline cellulose) and starch. Examples of starches include potato starch, wheat starch, corn starch, and rice starch. Preferably, crystalline cellulose and corn starch are used as the sugars.

The sugar hydrate is not particularly limited, but examples include any hydrate of the sugars mentioned above, and lactose hydrate is preferably used.

The sugar alcohol is not particularly limited, but any sugar alcohol derived from any sugar is used, and preferably, mannitol, sorbitol, etc. are used.

Inorganic compounds are not particularly limited, but examples include silicates such as porous calcium silicate and phosphates such as anhydrous calcium phosphate.

In a preferred embodiment, sugars are used as the core particle component. In a further preferred embodiment, crystallized cellulose (crystalline cellulose) is used as the core particle component. In another preferred embodiment, silicates such as porous calcium silicate or pharmaceutically acceptable components that have been pulverized to have a BET specific surface area of 0.45 ^m² /g or more are used as the core particle component.

According to a preferred embodiment, the mass ratio of needle-shaped components to approximately spherical components in the core particle component (mass of needle-shaped components: mass of approximately spherical components) is not particularly limited as long as the BET specific surface area of the core particle component satisfies the range described above and the effects of the present invention are achieved. Preferably, it is 1:0.2 to 1:2, more preferably 1:0.5 to 1:1.5, even more preferably 1:0.6 to 1:1.2, and particularly preferably 1:0.6 to 1:0.8. In particular, when crystalline cellulose is included as the core particle component, the mass ratio of needle-shaped components to approximately spherical components in the core particle component is preferably 1:0.4 to 1:1, more preferably 1:0.5 to 1:0.8, and even more preferably 1:0.6 to 1:0.7.

In a preferred embodiment, the difference between the hard and loose bulk density of the core particle component (hard bulk density - loose bulk density) is not particularly limited as long as the effects of the present invention are achieved, but is preferably 0.05 to 0.25, more preferably 0.075 to 0.15, and even more preferably 0.08 to 0.1. In particular, when only crystalline cellulose is used as the core particle component, the difference between the hard and loose bulk density of the crystalline cellulose is preferably 0.05 to 0.15, more preferably 0.07 to 0.12, and even more preferably 0.08 to 0.1. In the present invention, the hard bulk density and loose bulk density can be measured, for example, using a commercially available powder property evaluation device (Powder Tester® PT-R, manufactured by Hosokawa Micron Corporation). The specific measurement method involves using a powder tester to uniformly supply the nucleus particle mixture from above through a sieve into a cylindrical container of the same size as the measurement container for bulk density and tap density measurement method 3 described in the 17th edition of the Japanese Pharmacopoeia. The bulk density in a loosely packed state (loose bulk density) is measured by leveling the top surface and weighing. Next, an auxiliary cylinder is placed on top of this container, and the nucleus particle mixture is added up to its upper rim, followed by 180 tappings. After completion, the auxiliary cylinder is removed, and the nucleus particle mixture is leveled on the top surface of the container and weighed to measure the bulk density in a tightly packed state (firm bulk density) after tapping.

According to a preferred embodiment, the particle size of the core particle component is not particularly limited as long as the effects of the present invention are achieved, but the average particle size (D50) is preferably 50 to 200 μm, more preferably 60 to 150 μm, and even more preferably 70 to 100 μm. The particle size of the core particle component and the average particle size can be measured, for example, using a commercially available particle size analyzer (e.g., Mastersizer 3000, manufactured by Spectris) by laser diffraction (measurement method: dry method, scattering intensity: 1% or more, light scattering model: Mie scattering theory).

According to preferred embodiments, the content of the core particle component in the pharmaceutical formulation is not particularly limited as long as the effects of the present invention are achieved, but is preferably 10 to 95% by mass, more preferably 20 to 90% by mass, more preferably 30 to 80% by mass, more preferably 40 to 70% by mass, and more preferably 50 to 60% by mass, relative to the total mass of the pharmaceutical formulation. Furthermore, the content of the core particle component in the tablet-formed pharmaceutical formulation is not particularly limited as long as the effects of the present invention are achieved, but is preferably 1 to 60% by mass, more preferably 5 to 50% by mass, more preferably 10 to 40% by mass, more preferably 15 to 35% by mass, and more preferably 15 to 25% by mass.

(Non-volatile solvent)
The pharmaceutical formulation of the present invention contains a specific amount of non-volatile solvent in its core particles. According to a preferred embodiment, at least a portion of the non-volatile solvent coats at least a portion of the core particle components. The non-volatile solvent content, expressed as the mass of non-volatile solvent in the core particles per unit mass (unit g (grams)) of the pharmaceutical formulation, has a lower limit of greater than 0 g, is preferably 10 mg, more preferably 20 mg, and even more preferably 40 mg. The upper limit of the mass of non-volatile solvent in the core particles per unit mass of the pharmaceutical formulation is not particularly limited as long as the effects of the present invention are achieved, but from the viewpoint of ensuring the solubility of poorly soluble drugs, it is, for example, 600 mg. The range of the mass of non-volatile solvent in the core particles per unit mass of the pharmaceutical formulation is preferably 1 to 600 mg, more preferably 10 to 400 mg, and even more preferably 40 to 300 mg. In this way, by containing a larger amount of non-volatile solvent in the core particles than conventional formulations, a larger amount of drug can be dissolved or suspended in the non-volatile solvent, and as a result, the pharmaceutical formulation can contain a larger amount of drug. Therefore, according to a preferred embodiment, at least a portion of the drug is dissolved or suspended in a non-volatile solvent. Furthermore, the pharmaceutical formulation of the present invention may have the characteristic of being less prone to abrasion such as cracking or chipping when processed to obtain formulations having various dosage forms (for example, by tableting). This is thought to be because the pharmaceutical formulation of the present invention may contain a large amount of non-volatile solvent such as a surfactant, and for example, when processing into tablets, the non-volatile solvent seeps out when the pharmaceutical formulation is tableted, strengthening the bonds between the pharmaceutical formulations, and as a result the resulting tablets become less prone to abrasion.

As a non-volatile solvent, a component capable of dissolving or suspending a drug within the core particles can be used. Examples of such non-volatile solvents include surfactants. Furthermore, as a non-volatile solvent, a component that possesses medicinal properties itself or has antioxidant properties as an additive can also 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 fatty acid glycerides. The components constituting the non-volatile solvent may be used individually or in combination of two or more.

The surfactant is not particularly limited as long as it is pharmaceutically acceptable, but for example, cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants, etc., can be used. Examples of cationic surfactants include primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, etc. Examples of anionic surfactants include fatty acid salts, rosinates, alkylpolyoxyethylene sulfates, α-olefin sulfonates, alkylnaphthalene sulfonates, lignin sulfonates, alkyl phosphates, etc. Examples of amphoteric surfactants include N-alkylβ-aminopropionic acid, N-alkyl sulfobetaine, N-alkylhydroxysulfobetaine, lecithin, etc. Examples of nonionic surfactants include alkyl polyoxyethylene ethers, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, etc. Of these, the surfactant preferably contains a nonionic surfactant, more preferably polysorbate, and even more preferably polysorbate 80. Surfactants may be used individually or in combination of two or more types.

The vitamins used are not particularly limited, but examples include vitamin E (tocopherol and tocotrienol). Preferably, vitamin E is used, more preferably tocopherol, and even more preferably α-tocopherol. The vitamins may be used individually or in combination of two or more.

Any of the following fatty acid glycerides can be used: short-chain fatty acid glycerides, medium-chain fatty acid glycerides, and long-chain fatty acid glycerides. Furthermore, any of these fatty acid glycerides can be monoglycerides, diglycerides, or triglycerides. In preferred embodiments, medium-chain fatty acid glycerides are used. Fatty acid glycerides may be used individually or in combination of two or more types. Additionally, fatty acid glycerides may be used in combination with esters of fatty acids other than fatty acid glycerides and alcohols, or esters of various acids and glycerol, as described later.

The fatty acids constituting fatty acid glycerides are not particularly limited and can be used. Examples of short-chain fatty acids include fatty acids with 2 to 4 carbon atoms, such as acetic acid, propionic acid, isobutyric acid, and butyric acid. Examples of medium-chain fatty acids include fatty acids with 5 to 12 carbon atoms, such as isovaleric acid, caproic acid, lactic acid, succinic acid, heptylic acid, caprylic acid, capric acid, and lauric acid. Examples of long-chain fatty acids include fatty acids with 13 or more carbon atoms, such as myristic acid, pentadecyl acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid, eleostearic acid, arachidic acid, meadic acid, arachidonic acid, behenic acid, lignoceric acid, nervonic acid, cerotic acid, montanic acid, and melissic acid.

In a preferred embodiment, medium-chain fatty acid glycerides are used as the fatty acid glycerides.

Fatty acid glycerides can be used as is, or as part of a composition containing fatty acid glycerides. Examples of compositions containing fatty acid glycerides include vegetable oils and fats, animal oils and fats, hydrogenated oils obtained from vegetable oils and fats or animal oils and fats, and oily substances (waxes).

Examples of vegetable oils include olive oil, soybean oil, rapeseed oil, safflower oil, corn oil, camellia oil, coconut oil, castor oil, peanut oil, sesame oil, cottonseed oil, and wheat germ oil.

Examples of animal fats include beef tallow, pork tallow, chicken fat, and sheep fat.

Examples of oily substances (waxes) include carnauba wax, beeswax, bleached beeswax, paraffin, liquid paraffin, petrolatum (white petrolatum, yellow petrolatum), microcrystalline wax, lanolin, and squalane.

Esters of fatty acids other than fatty acid glycerides and alcohols can also be used. Examples of such esters include higher alcohol fatty acid esters, glycol fatty acid esters, and polyglycerol fatty acid esters.

In addition to fatty acid glycerides, esters of various acids with glycerin can also be used. Examples of such esters include triacylglycerol (triacetin), which is a triester of acetic acid and glycerin.

When using drugs with low water solubility (poorly water-soluble drugs) as formulations for pharmaceutical products, it is preferable that the non-volatile solvent contains a surfactant capable of dissolving or suspending the poorly water-soluble drug. Furthermore, it is preferable that the non-volatile solvent contains a surfactant or vitamins.

The components constituting the non-volatile solvent may be used as is, but may also be used with other solvents, preferably volatile solvents such as water or alcohol, as needed. For example, if the components constituting the non-volatile solvent have high viscosity, they may be used with volatile solvents such as water or alcohol during the production of the pharmaceutical formulation of the present invention to reduce their viscosity. Specifically, if the non-volatile solvent contains highly viscous vitamin E, it is preferable to use the non-volatile solvent in combination with an alcohol such as ethanol.

The content of the non-volatile solvent in the pharmaceutical formulation is not particularly limited as long as the effects of the present invention are achieved. However, the lower limit of the ratio of the mass of the non-volatile solvent to the mass of the core particle component (mass of core particle component: mass of non-volatile solvent) is preferably 1:0.001, more preferably 1:0.01, more preferably 1:0.05, more preferably 1:0.08, more preferably 1:0.1, more preferably 1:0.2, and particularly preferably 1:0.3. The upper limit is not particularly limited as long as the effects of the present invention are achieved, but is preferably 1:1, more preferably 1:0.8, more preferably 1:0.6, and particularly preferably 1:0.5. Furthermore, when the non-volatile solvent is a surfactant, the range of the ratio of the mass of the surfactant to the mass of the core particle component is not particularly limited as long as the effects of the present invention are achieved, but is preferably 1:0.001 to 1:1, more preferably 1:0.01 to 1:0.8, more preferably 1:0.08 to 1:0.6, more preferably 1:0.1 to 1:0.5, and particularly preferably 1:0.3 to 1:0.5.

(Drugs)
The pharmaceutical formulation of the present invention comprises a drug within a core particle. The drug is preferably dissolved or suspended in the non-volatile solvent described above. In a preferred embodiment, the drug is attached to the surface of the core particle component within the core particle. The drug is not particularly limited, and any drug that produces the desired effect in the pharmaceutical formulation of the present invention can be used. Furthermore, the drug may be used alone or in combination of two or more types.

In a preferred embodiment, the drug has a logP value within a specific range. The logP 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 considered to be the value listed in Pubchem (https://pubchem.ncbi.nlm.nih.gov/). For drugs not listed in Pubchem, the logP value can be measured according to the flask shaking method compliant with Japanese Industrial Standard Z7260-107. Specifically, first, 1-octanol and distilled water are shaken at 25°C for 24 hours to equilibrate. Next, 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 are added. The mixture is shaken at 25°C for 4 days. The 1-octanol phase and aqueous phase are separated by centrifugation, and the concentration of the sample in each phase is measured by HPLC. The logP value is taken as the common logarithm of the partition coefficient between the two phases.

Specific examples of drugs include vitamins, hormones, anticancer drugs, antibacterial agents, antiviral agents, hyperlipidemia treatments, central nervous system agents, immunosuppressants, peripheral nervous system agents, hemorrhoid treatments, cardiovascular agents, metabolic drugs, digestive system agents, and leprosy agents.

The pharmaceutical formulation of the present invention can contain a large amount of non-volatile solvent within its core particles, making it possible to dissolve or suspend even poorly water-soluble drugs in the non-volatile solvent and incorporate them into the core particles. Therefore, according to a preferred embodiment, the drug contains a poorly water-soluble drug. While not particularly limited, poorly water-soluble drugs include those with a solubility in water under physiological pH conditions (mass of drug dissolved in 100 g of water (g)) of 10 to 20 μg/ml. Furthermore, poorly water-soluble drugs include those classified as Class II and IV in the Biopharmaceuticals Classification System (BCS) defined by the U.S. Food and Drug Administration (FDA).

Vitamin supplements are not particularly limited, but examples include fat-soluble vitamins and water-soluble vitamins. Examples of fat-soluble vitamins include 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/anoirin), vitamin B2 (such as riboflavin), vitamin B6 (such as pyridoxine, pyridoxal, and pyridoxamine), vitamin B12 (such as cobalamin), niacin (such as folic acid, nicotinic acid, and nicotinamide), pantothenic acid, biotin, and ascorbic acid (vitamin C).

Hormonal preparations are physiologically active substances that utilize the inherent physiological or pharmacological effects of various hormones to exert specific effects on specific cells in the body. While not particularly limited, hormonal preparations include hormones derived from the hypothalamus, anterior pituitary gland, posterior pituitary gland, thyroid gland, pancreatic islets of Langerhans, adrenal cortex, adrenal medulla, gonads, and digestive organs. Specifically, examples include progesterone, levonorgestrel, and norethisterone.

As anticancer agents, while not particularly limited, examples include those that have the effect of shrinking or eliminating cancerous tumors, or preventing their growth, in various cancers such as brain tumors, tongue cancer, laryngeal cancer, thyroid cancer, esophageal cancer, stomach cancer, colorectal 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 cancers. Specifically, cyclophosphamide, ifosfamide, thiotepa, melphalan, busulfan, nimustine, ranimustine, dacarbazine, procarbazine, temozolomide, cisplatin, carboplatin, nedaplatin, methotrexate, pemetrexed, uracil, doxifluridine, and gimeracil/oteracil. (gimeracil/oteracil), cytarabine, enocitabine, gemcitabine, 6-mercaptopurine, fludarabine, pentostatin, cladribine, hydroxyurea, doxorubicin, epirubicin, daunorubicin, idarubicin, pirarubicin, mitoxantrone, amurubicin, actinomycin D, bleomycin, pepleomycin, mytomycin C C), aclarubicin, zinostatin, vincristine, vindesine, vinblastine, vinorelbine, paclitaxel, docetaxel, irinotecan, irinotecan active metabolite (SN-38), nogitecan (topotecan), etoposide, prednisolone Prednisolone, dexamethasone, tamoxifen, toremifene, medroxyprogesterone, anastrozole, exemestane, letrozole, rituximab, imatinib, gefitinib, gemtuzumab/ozogamicin Examples include ozogamicin, bortezomib, erlotinib, cetuximab, bevacizumab, sunitinib, sorafenib, dasatinib, panitumumab, asparaginase, tretinoin, arsenic trioxide, folinate, levofolinate, or their salts, or their active metabolites.

Antimicrobial agents are substances that kill or inhibit the growth of fungi or bacteria. Antimicrobial agents targeting fungi are not particularly limited, but examples include polyene antimicrobial agents, fluoropyrimidine antimicrobial agents, imidazole antimicrobial agents, triazole antimicrobial agents, allylamine antimicrobial agents, and candin antimicrobial agents. Specifically, 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 tolcyclate.

Antimicrobial agents targeting bacteria are not particularly limited, but examples include penicillin-based antimicrobial agents, cephalosporin-based antimicrobial agents, carbapenem-based antimicrobial agents, monobactam-based antimicrobial agents and β-lactam-based antimicrobial agents such as penem-based antimicrobial agents, aminoglycoside-based antimicrobial agents, lincomycin-based antimicrobial agents, fosfomycin-based antimicrobial agents, tetracycline-based antimicrobial agents, chloramphenicol-based antimicrobial agents, macrolide-based antimicrobial agents, ketolide-based antimicrobial agents, polypeptide-based antimicrobial agents, glycopeptide-based antimicrobial agents, streptogramin-based antimicrobial agents, quinolone-based antimicrobial agents, sulfonamide-based antimicrobial agents, and oxazolidinone-based antimicrobial agents. Specifically, penicillin G, ampicillin, bacampicillin, renanpicillin, cyclacillin, amoxicillin, pibmecillin, aspoxicillin, cloxacillin, piperacillin, methicillin, ampicillin/cloxacillin, ampicillin/sulbactam, clavulanate/amoxicillin, piperacillin/tazobactam, cefazolin, cepharontine, cephalexin, cefatolidine, ceffloxazine, cefaclor, cefadroxil, cefotiam, cefmetazole, flomoxef, cefminox, cefbuperazone, cefuroxime/axetil, Cefdinir, cefditoren pivoxil, cefteram pivoxil, cefpodoxime proxetil, cefcapene pivoxil, cefotaxime, ceftriaxone, cefoperazone, cefmenoxime, ceftazidime, ceftibutene, cefixime, cefozidime, latamoxef, ceftizoxime, cefpirome, cefozopran, cefepime, cefoperazone sulbactam, imipenem, panipenem, meropenem, biapenem, doripenem, tebipenem, aztreonam, sulbactam, tazobactam, carmonam, faropenem, kanamycin, streptoma Icin, Neomycin, Gentamycin, Fradiomycin, Tobramycin, Amikacin, Arbekacin, Astromycin, Isepamycin, Bekanamycin, Dibekacin, Micronomycin, Netylmycin, Paromomycin, Ribostamycin, Shisomycin, Spectinomycin, Lincomycin, Clindamycin, Fosfomycin, Tetracycline, Oxytetracycline, Demethylchlortetracycline, Doxycycline, Minocycline, Chloramphenicol, Erythromycin, Clarithromycin, Azithromycin, Josaman Examples include Icin, Spiramycin, Midekamicin, Rokitamycin, Kitasamycin, Telithromycin, Colistin, Polymyxin, Bacitracin, Vancomycin, Teicoplanin, Quinupristin/Dalfopristin, Nalidixic acid, Pyromidic acid, Pipemidic acid, Norfloxacin, Enoxacin, Ofloxacin, Ciprofloxacin, Tosufloxacin, Lomefloxacin, Levofloxacin, Sparfloxacin, Gatifloxacin, Moxifloxacin, Garenoxacin, Sitafloxacin, ST combination drugs, Diaphenylsulfone, Linezolid, etc.

Antiviral agents are drugs 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 viral particles, and escapes the host cell. Antiviral agents are not particularly limited, but examples include those that have a therapeutic effect on diseases caused by viral infections such as herpesvirus, cytomegalovirus, human papillomavirus, respiratory syncytial virus (RSV), influenza virus, human immunodeficiency virus, hepatitis B virus, and hepatitis C virus. Specifically, examples include Zovirax, Acyclovin, Viclox (acyclovir), Valtrex (valacyclovir), Denosine (ganciclovir), Arasena A (vidarabine), Relenza (zanamivir hydrate), Tamiflu (oseltamivir phosphate), Symmetrel (amantadine), Retrovir (zidovudine), Videx (didanosine), Epivir, Zefix (lamivudine), Fortbase (zaquinavir), Norvir (ritonavir), and N-[5-fluoro-2-(1-piperidinyl)phenyl]isonicotinthioamide.

Examples of hyperlipidemia treatment agents, though not particularly limited, include ethyl eicosapentate, ethyl omega-3 fatty acids, clofibrate, and polyene phosphatidylcholine.

Examples of central nervous system agents include, but are not limited to, indomethacin farnesil and nalfurafine hydrochloride.

Immunosuppressants are not particularly limited, but examples include cyclosporine.

Peripheral nerve agents are not particularly limited, but examples include tafamidis meglumine.

While not particularly limited, examples of hemorrhoid treatments include tribenoside.

Examples of circulatory system agents include, but are not limited to, nifedipine and ubicarenone.

Examples of metabolites include, but are not limited to, nintedanib ethanesulfonate.

Examples of drugs used for gastrointestinal disorders include, but are not limited to, gefarnate, sodium picosulfate hydrate, and lubiprostone.

While not particularly limited, examples of leprosy treatments include 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 produces the desired effect. However, the ratio of the mass of the drug to the mass of the core particle component (mass of core particle component: mass of drug) has a lower limit, preferably 1:0.01, more preferably 1:0.02, and even more preferably 1:0.03. The upper limit is not particularly limited, but is preferably 1:0.5, more preferably 1:0.2. Furthermore, the range of the ratio of the mass of the drug to the mass of the core particle component is not particularly limited, but is preferably 1:0.01 to 1:0.5, more preferably 1:0.02 to 1:0.5, and even more preferably 1:0.03 to 1:0.2.

Furthermore, the drug content 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. However, the lower limit of the ratio of the mass of the drug to the mass of the non-volatile solvent (mass of non-volatile solvent:mass of drug) is preferably 1:0.01, more preferably 1:0.03, more preferably 1:0.05, more preferably 1:0.1, more preferably 0.3, and more preferably 1:0.5. The upper limit is not particularly limited, but is preferably 1:5, more preferably 1:3, and more preferably 1:1. The range of the ratio of the mass of the drug to the mass of the non-volatile solvent is not particularly limited, but is preferably 1:0.05 to 1:5, more preferably 1:0.1 to 1:3, and even more preferably 1:0.5 to 1:1.

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, more preferably 50% or less, and more preferably 30% or less.

The degree of cohesiveness can be measured using a commercially available powder property evaluation device. An example of such a device is the Powder Tester® PT-R (manufactured by Hosokawa Micron Corporation). The measurement conditions are, for example, as follows:
Sieve opening: (Top row) 710 μm, (Middle row) 355 μm, (Bottom row) 250 μm
Sample size: 2g or 3g
Vibration time: 119 seconds

Under the above conditions, measure the value of each item in the following formula.
X = [Mass of powder remaining in the upper sieve] / Mass of powder added × 100
Y = [Mass of powder remaining in the middle sieve] / Mass of powder added × 100 × 0.6
Z = [Mass of powder remaining in the lower sieve] / Mass of powder added × 100 × 0.2
The sum of the three values X, Y, and Z above is defined as the degree of cohesion (%).

<Coating layer>
The coating layer can coat the core particles, preventing non-volatile solvents and drugs contained in the core particles from leaking onto the surface of the pharmaceutical formulation. As a result of the coating layer suppressing the leakage of non-volatile solvents, aggregation of the pharmaceutical formulation is suppressed, and a decrease in the fluidity of the pharmaceutical formulation can be prevented. In a preferred embodiment, the coating layer is located adjacent to the core particles described above.

The components constituting the coating layer are not particularly limited as long as the effects of the present invention are achieved, but examples include water-soluble coating agents. The water-soluble coating agent may be used alone or in combination of two or more types.

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

The polysaccharide or its derivative is preferably a cellulose derivative, such as methylcellulose, hydroxymethylcellulose, or hydroxypropylmethylcellulose. A single cellulose derivative may be used, or two or more may be used in combination.

Examples of polyalkylene glycols include polyethylene glycol.

Furthermore, according to another preferred embodiment, the coating agent used in the coating layer may be hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer, vinylpyridine copolymer, alkyl vinylpyridine copolymer, aminocellulose derivative, diethylaminoethyl methacrylate, polyvinyl acetal diethylaminoacetate, dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N,N-di-n-butylhydroxypropyl ether, copolymer of vinylpyridine and acrylic acid free acid, alkyl vinylpyridine and acrylic acid free acid Examples include copolymers with acids, copolymers of vinylpyridine, acrylic acid-based free acids, and vinyl monomers, copolymers of alkylvinylpyridine, acrylic acid-based free acids, and vinyl monomers, 2-methyl-5-vinylpyridine-methacrylate copolymer, poly-2-(vinylphenyl)glycine, morpholino-N-β-ethyl acrylate-methacrylate copolymer, shellac, cellulose acetate phthalate, methyl acrylate-methacrylate copolymer, methyl methacrylate-methacrylate copolymer, zein, hydroxypropyl methylcellulose phthalate, and aminoalkyl methacrylate copolymer. The coating agent may be used individually or in combination of two or more types.

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 monoglycerides, 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 preferred, and polyethylene glycol (macrogol) is more preferred. The plasticizer may be used alone or in combination of two or more types.

The components constituting the coating layer may be used as is, but may also be dissolved in a solvent, preferably a volatile solvent such as water or alcohol, as needed. For example, if the components constituting the coating layer have high viscosity, they may be dissolved in a volatile solvent such as water or alcohol to reduce their viscosity during the manufacture of the pharmaceutical formulation of the present invention. Note that all or part of the volatile solvent such as water or alcohol may remain in the coating layer of the manufactured pharmaceutical formulation, or it may be removed by evaporation or other means during the manufacturing process of the pharmaceutical formulation. It is preferable that most of the volatile solvent such as water or alcohol is removed from the coating layer of the manufactured pharmaceutical formulation, and preferably all of it is removed.

The mass of the coating layer 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. However, the ratio of the mass of the coating layer to the total mass of the nucleus particles (total mass of nucleus particles : mass of the coating layer) has a lower limit of preferably 1:0.001, more preferably 1:0.002. The upper limit is not particularly limited, but is preferably 1:0.1, more preferably 1:0.05, and even more preferably 1:0.02. Furthermore, the range of the ratio of the mass of the coating layer to the total mass of the nucleus particles is not particularly limited, but is preferably 1:0.001 to 1:0.1, more preferably 1:0.002 to 1:0.05, and even more preferably 1:0.002 to 1:0.02.

<Other ingredients>
The pharmaceutical formulation of the present invention may contain pharmaceutically acceptable additives different from the components constituting the core particles and coating layer described above, as long as they do not interfere with the effects of the present invention. Examples of additives include excipients, disintegrants, lubricants, binders, fluidizers, sweeteners, flavorings, and colorants. These additives may have one component that performs two or more functions. Furthermore, an additive may be used alone or in combination of two or more.

The pharmaceutical formulation of the present invention, having a coating layer that covers the core particles, suppresses the leakage of non-volatile solvents and drugs contained in the core particles from the pharmaceutical formulation, and as a result, suppresses aggregation of the pharmaceutical formulation.

According to a preferred embodiment, the pharmaceutical formulation of the present invention has a specific degree of cohesion. The degree of cohesion of the pharmaceutical formulation is preferably 70% or less, more preferably 60% or less, and even more preferably 50% or less. The degree of cohesion of the pharmaceutical formulation can be measured by the same method as the measurement of the degree of cohesion of the nucleus particles described above.

Furthermore, it is preferable that the degree of aggregation of the pharmaceutical formulation is improved (lower) than that of the core particles.

The particle size of the pharmaceutical formulation is not particularly limited as long as the effects of the present invention are achieved, but preferably the average particle size (D50) is 100 to 400 μm, and more preferably 120 to 250 μm. The average particle size of the pharmaceutical formulation can be measured by the same method as the measurement of the average particle size of the core particle components described above.

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

In formulations such as tablets and pills containing the granular pharmaceutical formulation of the present invention, the lower limit of the content of the pharmaceutical formulation of the present invention is not particularly limited, but can be, for example, 20%, 25%, or 30% of the total mass of the formulation. Furthermore, the upper limit of the content of the pharmaceutical formulation of the present invention is not particularly limited, but can be, for example, 90%, 80%, or 75% of the total mass of the formulation.

The pharmaceutical formulation of the present invention has the characteristic of being less susceptible to abrasion such as cracking or chipping when processed to obtain formulations with various dosage forms. Specifically, the formulations obtained from the pharmaceutical formulation of the present invention preferably have an abrasion degree of 1.0% or less, more preferably 0.5% or less, even more preferably 0.3% or less, even more preferably 0.2% or less, and particularly preferably 0%.

Furthermore, the pharmaceutical formulation of the present invention, when formulated, particularly as a tablet, can exhibit the additional effect of low abrasion despite low hardness. Specifically, the hardness of the formulation obtained from the pharmaceutical formulation of the present invention is preferably 150 N or less, more preferably 130 N or less, more preferably 100 N or less, more preferably 80 N or less, more preferably 70 N or less, more preferably 60 N or less, more preferably 50 N or less, more preferably 40 N or less, and particularly preferably 30 N or less.

[Methods for manufacturing pharmaceutical preparations]
The method for producing the pharmaceutical formulation of the present invention is not particularly limited, and known methods can be used. The conditions in the production of the pharmaceutical formulation can be appropriately adjusted depending on the type of core particle component, non-volatile solvent, drug, coating layer component, etc. Specifically, the pharmaceutical formulation of the present invention can be produced, for example, by following the procedure below. First, the drug is added to a non-volatile solvent and stirred using a stirrer (NZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) to obtain a drug solution in which the drug is dissolved or suspended. Next, the core particle component with a BET specific surface area of 0.45 ^m² /g or more and the drug solution are introduced into a fluid bed granulator (for example, FD-MP-01D, manufactured by Powrec Co., Ltd.) and brought into contact to adhere the mixed liquid to the core particle component and obtain core particles. Here, contact between the core particle component and the drug solution can be performed by, in addition to the above method, for example, by spraying the drug solution onto the core particle component or by immersing the core particle component in the drug solution. Next, the obtained core particles are dried as necessary, and then coated with components constituting the coating layer (coating layer components). Here, the coating of the core particles is carried out, for example, by spraying the coating layer component onto the core, or by immersing the core particles in the coating layer component. Next, the particles having the core particles and the coating layer covering the core particles are dried to obtain a pharmaceutical formulation.

The method for tableting the pharmaceutical formulation 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 type of core particle component, non-volatile solvent, drug, coating layer component, etc. Examples of methods for tableting the pharmaceutical formulation include tableting using a tablet press such as a rotary tablet press or a single-stroke tablet press. Of these, tableting the pharmaceutical formulation using a rotary tablet press is preferred. Examples of rotary tablet presses include the VIRGO 0512SS2AY manufactured by Kikusui Seisakusho Co., Ltd. If the tablets contain pharmaceutically acceptable additives in addition to the pharmaceutical formulation of the present invention, the pharmaceutical formulation of the present invention and the pharmaceutically acceptable additives are mixed before tableting. The method for mixing the pharmaceutical formulation and the additives is not particularly limited, and can be done using known methods. Examples of methods for mixing the pharmaceutical formulation and the additives include mixing using a mixer such as a V-type mixer. Specifically, mixing can be done using a V-type mixer (TCV-20) manufactured by Tokuju Kogyo Co., Ltd.

The method for forming a pharmaceutical preparation into a capsule is not particularly limited, and known methods can be used. Specifically, the pharmaceutical preparation is manufactured by filling a capsule shell made of gelatin or plant-derived raw materials. The filling of the capsule shell is not particularly limited and can be carried out by known methods such as auger-type powder filling, daikon press-type powder filling, or vibration-type powder filling. For example, in auger-type powder filling, a predetermined amount of the pharmaceutical preparation in powder or granule form, which is dropped from a hopper into a cap-shaped container with two open ends, usually formed from a gelatin shell, is directly filled into the capsule body by the rotational pressure of stirring blades and an auger. The capsule is then manufactured by coaxially connecting these containers.

The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

[Methods for preparing pharmaceutical preparations]
The granular pharmaceutical formulations of each example and comparative example were prepared by the following method.
As core particle components, we prepared lactose monohydrate (SuperTab®, average aspect ratio 1.39, average particle size 120 μm, manufactured by DFE Pharma), corn starch (Japanese Pharmacopoeia corn starch, average aspect ratio 1.23, average particle size 15 μm, manufactured by Nippon Shokuhin Kako Co., Ltd.), crystalline cellulose (CEOLUS UF-702, average aspect ratio 2.63, average particle size 90 μm, manufactured by Asahi Kasei Corporation), and broad crystalline cellulose (CEOLUS KG-1000, average aspect ratio 4.20, average particle size 50 μm, manufactured by Asahi Kasei Corporation). The average aspect ratio of each nuclear particle component is calculated by acquiring particle images using an electron microscope (VE-7800, manufactured by KEYENCE), measuring the aspect ratio of 10 arbitrarily selected particles, and excluding the aspect ratios of the top 10% and bottom 10% of the particles.

According to the formulations shown in Table 1, each core particle component was sieved through a 355 μm sieve and pre-mixed in a polyethylene bag. Note that during the preparation of the granular pharmaceutical formulations in each example and comparative example, some of the components shown in Table 1, particularly the solvent, are lost through volatilization. Unless otherwise specified, the units of the values in Table 1 are grams (g).

<Calculation of the specific surface area of nuclear particles>
First, the BET specific surface area of each component constituting the core particle was determined as follows. For crystalline cellulose, the BET method was used with a specific surface area and pore distribution analyzer (BELSORP®-miniX, manufactured by Microtrac-Bell Co., Ltd.). Specifically, for crystalline cellulose, nitrogen molecules were adsorbed onto the crystalline cellulose, and the BET specific surface area of the crystalline cellulose was calculated from the amount of adsorption. For lactose monohydrate, the value described in Micromeritics Instrument Corp. Application Note #163 was used. For corn starch, the value described in the Pharmaceutical Additives Handbook, Yakuji Nippo Co., Ltd. was used.

Next, the specific surface area of the nucleus particles was calculated from the BET specific surface area values of crystalline cellulose, lactose monohydrate, and corn starch, as well as the content values of each nucleus particle component. Specifically, it was calculated as the value obtained by dividing the sum of the products of the mass and specific surface area of each nucleus particle component in the nucleus particle by the total mass of the nucleus particle (see formula below).
[Mathematics 1]
{(Mass of lactose monohydrate × Specific surface area of lactose monohydrate) + (Mass of corn starch × Specific surface area of corn starch) + (Mass of crystalline cellulose × Specific surface area of crystalline cellulose)} / Total mass of core particle components

<Measurement of bulk density of nuclear particle mixture>
For each nucleus particle component obtained by pre-mixing, the firm and loose bulk densities were measured. Specifically, using a Powder Tester® PT-R (manufactured by Hosokawa Micron Corporation), the nucleus particle mixture was uniformly supplied from above through a sieve into a cylindrical container of the same size as the measuring container for Method 3 of the bulk density and tap density measurement method described in the 17th edition of the Japanese Pharmacopoeia. The bulk density in a loosely packed state (loose bulk density) was measured by leveling the top surface and weighing. Next, an auxiliary cylinder was placed on top of this container, and the nucleus particle mixture was added up to its upper rim, and tapping was performed 180 times. After completion, the auxiliary cylinder was removed, and the nucleus particle mixture was leveled on the top surface of the container and weighed to measure the bulk density in a tightly packed state after tapping (firm bulk density). Furthermore, the difference between the firm and loose bulk density (firm bulk density - loose bulk density) was calculated for each nucleus particle component. The results are shown in Table 1.

Furthermore, according to the formulations shown in Table 1, each non-volatile solvent (polysorbate 80) and solvent (ethanol) were added to 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 homogeneous, each drug (FIT-039, norethisterone) was added, and the mixture was further stirred and mixed to obtain the drug solution. For Example 3, Comparative Examples 2 and 3, lactose monohydrate (Pharmatose 450M) was added instead of the drugs. The logP values for FIT-039 and norethisterone are shown in Table 1.

Next, a fluidized bed granulator (FD-MP-01D, manufactured by Powrec Co., Ltd.) was used to spray the drug solution onto each core particle component to obtain core particles to which the drug solution had adhered. The settings for the fluidized bed granulator were as shown in Table 2 below.

<Measurement of cohesion>
The degree of cohesion (degree of cohesion before coating) of the obtained core particles was measured using a powder properties evaluation device (Powder Tester® PT-R, manufactured by Hosokawa Micron Corporation). The settings for the powder properties evaluation device were as follows.
Sieve opening: (Top row) 710 μm, (Middle row) 355 μm, (Bottom row) 250 μm
Sample size: 2g or 3g
Vibration time: 119 seconds

Under the above conditions, the values of each item in the following formula were measured.
X = [Mass of powder remaining in the upper sieve] / Mass of powder added × 100
Y = [Mass of powder remaining in the middle sieve] / Mass of powder added × 100 × 0.6
Z = [Mass of powder remaining in the lower sieve] / Mass of powder added × 100 × 0.2
The sum of the three values X, Y, and Z above was used to determine the degree of cohesion (%).

Furthermore, according to the formulations shown in Table 1, each coating layer component was placed in a stainless steel container and stirred and mixed at 400-900 rpm using a stirrer (NZ-1200, manufactured by Tokyo Rikakikai Co., Ltd.) to obtain the coating layer solution.

Next, using a fluidized bed granulator (FD-MP-01D, manufactured by Pawrec Co., Ltd.), 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 granular pharmaceutical formulation in which the core particles were coated with the coating layer. The settings for the fluidized bed granulator were as shown in Table 3 below. In Examples 1 to 8, granulation was performed without any problems, and granular pharmaceutical formulations were prepared. However, in Comparative Examples 1 to 3, because the specific surface area of the core particles was small, a large amount of non-volatile solvent could not be retained within the core particles, and the adhesive (viscous) non-volatile solvent leaked out from the core particles. As a result, the fluidity of the core particles decreased during the granulation process, making it difficult to proceed with the process, and thus granular pharmaceutical formulations could not be prepared.

The degree of aggregation (aggregation after coating) of the granular pharmaceutical formulations obtained in each example was measured using the same method as the measurement of the degree of aggregation (aggregation before coating) of the core particles described above. The results are shown in Table 1 above. In all examples of granular pharmaceutical formulations, the degree of aggregation after coating (pharmaceutical formulation) was lower than that before coating (each particle).

<Measurement of porosity of core particles in pharmaceutical formulations>
The porosity of the core particles of the granular pharmaceutical formulations obtained in Examples 5 to 8 was measured by X-ray CT microstructure analysis using a commercially available X-ray CT scanner (Scanco medical AG μCT50, software Scanco medical AG IPL image processing language, manufactured by SCANCO MEDICAL). The results are shown in Table 1. Note that the porosity values of the core particles of the pharmaceutical formulations in each example are the average values of the porosity of three granular particles of the pharmaceutical formulation. Figure 1 shows the results of the X-ray CT microstructure analysis of one granular particle of the pharmaceutical formulation from Example 5, which underwent porosity analysis.

[Preparation of tablets]
Tablets containing the granular pharmaceutical formulation of the example were prepared by the following method.
2243.10 g of the granular pharmaceutical formulation of Example 5 was mixed with 2871.9 g of lactose monohydrate (SuperTab®, manufactured by DFE Pharma), 390 g of crystalline cellulose (CEOLUS UF-711, manufactured by Asahi Kasei Corporation), 60 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Industrial Co., Ltd.), 375 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.), and 60 g of magnesium stearate (Magnesium Stearate-S, manufactured by NOF Corporation), using a mixer (V-type mixer TCV-20, manufactured by Tokuju Kogyo Co., Ltd.). The resulting mixture was then compressed into tablets using a rotary tablet press (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.) to prepare tablets containing the pharmaceutical formulation of Example 5. The tableting conditions are shown in Table 4 below. Note that the tableting conditions vary due to the elongation of the punch and die during tableting; therefore, the following tableting conditions are the initial conditions.

The granular pharmaceutical formulations of Examples 2-4 and 6-8 were mixed and compressed into tablets in the same manner as the pharmaceutical formulation of Example 5 described above. In all cases, tablet compression was performed without any problems, and tablets were successfully prepared.

<Measuring the hardness of tablets>
The hardness of each tablet in the examples was measured by the following method.
One tablet was placed between two pressure plates of a tablet hardness tester (KHT-20N, manufactured by Fujiwara Seisakusho Co., Ltd.), and one of the pressure plates was moved at a constant speed to measure the force (N (Newtons)) just before the tablet broke. The measurement results are shown in Table 1.

The results in Table 1 show that the hardness of the tablets tends to decrease as the mass of the non-volatile solvent contained in the tablets increases.

<Measurement of tablet wear>
The degree of abrasion of each tablet in the examples was measured by the following method.
Twenty tablets were precisely weighed using a tablet wear tester (e.g., EKDS, manufactured by Kayagaki Medical Science Industry Co., Ltd.) and placed in the drum of the tester. After rotating the drum 100 times, the tablets were removed. After removing any powder adhering to the tablets as before the test, the mass was precisely weighed, and the amount of wear before and after the test was defined as the tablet wear degree. The measurement results are shown in Table 1.

The results in Table 1 demonstrate that the tablets in the examples did not abrade despite their low hardness.

Furthermore, the results in Table 1 demonstrate that the pharmaceutical formulation of the present invention yields tablets with low abrasion despite low hardness. Tablets with low hardness typically exhibit high abrasion, making the tablets of the present invention, with their low abrasion despite low hardness, extremely unique. Such tablets offer high manufacturing yield and, at the same time, facilitate chewing and swallowing during oral administration, making them easy to ingest. While the mechanism by which these characteristics are achieved is not clear, it is presumed that non-volatile solvents such as surfactants used in the production of granular pharmaceutical formulations leach out during tableting, strengthening the bonds between the pharmaceutical formulations, and consequently making the resulting tablets less prone to abrasion.

According to the present invention, it is possible to provide granules containing a non-volatile solvent useful for the manufacture of pharmaceuticals such as surfactants and vitamins, and possessing excellent fluidity that can withstand actual manufacturing processes.

Claims (2)

A pharmaceutical preparation in granular form comprising a core particle and a coating layer that covers the core particle,
The nuclear particle comprises a drug, a nuclear particle component, and a non-volatile solvent.
The BET specific surface area of the aforementioned nuclear particle component is 0.45 to 10 ^m² / g .
The amount of the non-volatile solvent per unit mass of the pharmaceutical preparation is 10 mg or more.
The pharmaceutical formulation wherein the non-volatile solvent is one or more selected from the group consisting of surfactants, vitamin E, and fatty acid glycerides . The pharmaceutical preparation according to claim 1 , wherein the porosity of the nucleus particles is 40% or more.