Pharmaceutical preparations and methods for manufacturing the same

Abstract

To provide granules that include non-volatile solvent such as surfactant and vitamins useful for production of a medicine, and have excellent flowability durable for actual production.SOLUTION: A pharmaceutical preparation of a granule form comprises nuclear particles and a coating layer coating the nuclear particles, in which the nuclear particles include a medicine, a nuclear particle component and non-volatile solvent, a BET specific surface area of the nuclear particle component is 0.45 m2 / g or more, and the content of the non-volatile solvent per unit mass of the pharmaceutical preparation is 10 mg or more.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical formulation and a method for producing the same. [Background technology]

[0002] Traditionally, many active ingredients and additives used in the pharmaceutical field are liquid at room temperature, making it difficult to incorporate the required amount when formulating them into granules or tablets.

[0003] Soft capsules are widely used as solid dosage forms containing components that are liquid at room temperature (liquid components) (for example, Patent Document 1). However, soft capsules can have a larger diameter than other solid dosage forms such as tablets, making them difficult to administer to children, the elderly, and patients with impaired swallowing ability. Furthermore, due to their nature, soft capsules are prone to leakage depending on the manufacturing method. In addition, because soft capsules are soft and easily deformed, they require visual inspection by humans or inspection equipment to check for deformation, resulting in higher manufacturing costs compared to other solid dosage forms such as tablets.

[0004] On the other hand, tablets are used as a solid dosage form that can contain liquid components. When incorporating liquid components into tablets, the general method involves mixing the liquid component and solid component before tableting to obtain particles in which the liquid component adheres to the surface of the solid component, and then compressing these particles into tablets. However, with this method, the liquid component present on the surface of the solid component within the particles causes aggregation and adsorption between particles, reducing the fluidity of the particles and making it difficult to form tablets. In particular, when attempting to prepare tablets containing the same amount of liquid component as soft capsules, the particles obtained by mixing the liquid component and solid component have low fluidity, making tableting extremely difficult. Therefore, only a small amount of liquid component can be incorporated into tablets, in an amount that does not significantly reduce fluidity.

[0005] 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 to improve their low solubility (for example, Patent Document 2). Spray drying and melting methods are commonly used to combine poorly water-soluble drugs with solid dispersions. However, the spray drying method has the problem of requiring large machinery, and the melting method has the problem that the drug may be denatured or decomposed during the high-temperature heat treatment required to dissolve the drug.

[0006] Furthermore, while there are known techniques for preparing tablets containing large amounts of liquid components by adsorbing liquid substances onto porous materials such as silica gel (for example, Patent Document 3), such techniques require processing under vacuum, which poses the problem of requiring expensive equipment.

[0007] Furthermore, a method is known in which the fluidity of the formulation is suppressed by encapsulating the liquid component in a neutral or alkaline resin. However, the use of resin may affect the dissolution behavior of the liquid component, making it difficult to obtain the desired dissolution behavior.

[0008] 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 to it, and the water is removed by drying to obtain a powder to which the active ingredient is attached (for example, Patent Document 4). In addition, 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).

[0009] Furthermore, granules comprising a powdered or finely granular component and a liquid component, with improved fluidity, are also known (for example, Patent Document 6).

[0010] 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 sticky properties and reduce fluidity, so there is a problem that the amount that can be used when preparing pharmaceutical formulations such as tablets is limited.

[0011] As described above, pharmaceutical formulations containing liquid components are being developed. However, pharmaceutical formulations containing large amounts of liquid components experience reduced fluidity. 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 amount of drug. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] Special Publication No. 2003-508386 [Patent Document 2] Special Publication No. 2010-526848 [Patent Document 3] Special Publication No. 2010-512142 [Patent Document 4] International Publication No. 2009 / 001786 [Patent Document 5] Special Publication No. 2001-511156 [Patent Document 6] Japanese Patent Application Laid-Open No. 61-185327 [Patent Document 7] Special Publication No. 2007-517062 [Overview of the Initiative]

[0013] Under these circumstances, there is a need 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 useful as a pharmaceutical, and that have excellent fluidity to withstand actual manufacturing.

[0014] As a result of intensive studies by the present inventors, in a pharmaceutical preparation comprising a nuclear particle and a coating layer that coats the nuclear particle, by adjusting the specific surface area of the nuclear particle component constituting the nuclear particle to a specific range, a large amount of a nonvolatile solvent and a drug can be contained in the nuclear particle, and it has been found that a pharmaceutical preparation in a granular form having excellent fluidity can be formed. The present invention is based on such findings.

[0015] The present invention includes the following inventions. [1] A pharmaceutical preparation in a granular form comprising a nuclear particle and a coating layer that coats the nuclear particle, wherein the nuclear particle contains a drug, a nuclear particle component, and a nonvolatile solvent, the BET specific surface area of the nuclear particle component is 0.45 m 2 / g or more, and the content of the nonvolatile 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 m 2 / g. [3] The pharmaceutical preparation according to [1] or [2], wherein the porosity of the nuclear particle is 40% or more [4] The pharmaceutical preparation according to any one of [1] to [3], wherein the nuclear particle component is a solid additive. [5] The pharmaceutical preparation according to any one of [1] to [4], wherein the nuclear particle component contains crystalline cellulose. [6] The pharmaceutical preparation according to any one of [1] to [5], wherein at least a part of the nuclear particle components are in direct or indirect contact with each other via the nonvolatile solvent. [7] The pharmaceutical preparation according to any one of [1] to [6], wherein at least a part of the drug is dissolved in the nonvolatile solvent. [8] The pharmaceutical preparation according to any one of [1] to [7], wherein at least a part of the nonvolatile solvent coats at least a part of the nuclear particle component. [9] The pharmaceutical preparation according to any one of [1] to [8], wherein the mass ratio of the nonvolatile solvent to the drug is 1:0.1 to 1:10.

[10] A 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] , comprising the drug described above.

[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] , which is 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-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.

[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 nuclear 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) A step of coating the nucleus particles obtained in step (c) to obtain a pharmaceutical product. Includes, The BET specific surface area of ​​the aforementioned nuclear particle component is 0.45 m². 2 / 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 BET specific surface area of ​​the nuclear particle component is 0.5 to 3 m² 2 The manufacturing method described in

[27] , which is / 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] A method for producing the core particle component 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] (e) A 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] (e')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 tablets, 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 tablets is 1.0% or less.

[0016] 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 having excellent fluidity. Furthermore, according to the present invention, aggregation that 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, which are otherwise difficult to formulate due to decreased fluidity, by simple methods such as fluid 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. [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1 shows photographs and diagrams illustrating the results of three-dimensional void analysis of granular pharmaceutical formulations. Detailed description of the invention

[0018] The present invention will be described in detail below. In this specification, numerical ranges indicated using "~" mean a range that includes the numbers before and after "~" as the minimum and maximum values, respectively. In this specification, when the expression "A or B" is used, it means that either or both are included unless otherwise specified or the context restricts its interpretation.

[0019] [Pharmaceutical preparations] The pharmaceutical preparation of the present invention is a granular pharmaceutical preparation comprising nuclear particles and a coating layer that coats the nuclear particles. Hereinafter, each of the nuclear particles and the coating layer will be described.

[0020] <Nuclear particles> The pharmaceutical preparation of the present invention comprises nuclear particles containing a drug, a nuclear particle component, and a non-volatile solvent. The nuclear particle component constituting the nuclear particles has a specific range of specific surface area, whereby a larger amount of non-volatile solvent than before can be contained in the nuclear particles.

[0021] (Nuclear particle component) The nuclear particles comprise a nuclear particle component having a specific range with respect to the specific surface area measured by the BET method (so-called "BET specific surface area", which is also simply referred to as "specific surface area" in this specification). Specifically, the lower limit value of the BET specific surface area of the nuclear particle component is 0.45 m 2 / g, preferably 0.47 m 2 / g, more preferably 0.5 m 2 / g. Also, the upper limit value of the BET specific surface area of the nuclear particle component is not particularly limited as long as the effects of the present invention are achieved. For example, 10 m 2 / g, 5 m 2 / g, 3 m 2 / g, 2 m 2 / g, 1.5 m 2 / g. Also, the range of the BET specific surface area of the nuclear particle component is preferably 0.45 to 10 m 2 / g, more preferably 0.47 to 5 m 2 / g, even more preferably 0.5 to 3 m 2The value is / 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 poorly water-soluble drugs. 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.

[0022] In a preferred embodiment, the core particles have voids between a plurality of core particle components, and at least a portion of the non-volatile solvent is retained in the voids between the plurality of 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 plurality of core particle components.

[0023] In a preferred embodiment, the type and amount of the nuclear particle component are appropriately selected so that the porosity of the nuclear particle containing the nuclear particle component falls within a specific range. The lower limit of the porosity of the nuclear particle 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 nuclear particle 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 nuclear particle 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 the present invention, the porosity of the nuclear particle can be determined, for example, by performing X-ray CT microstructure analysis of the nuclear particle using a commercially available X-ray CT device (Scanco medical AG μCT50, software Scanco medical AG IPL image processing language, manufactured by SCANCO MEDICAL) and measuring the voids in the nuclear particle.

[0024] In a preferred embodiment, the core particle components contained in the core particles are solid additives. The lower limit of the content of solid additives 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. The upper limit of the content of solid additives 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.

[0025] 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 selected as appropriate. As the solid additive, for example, needle-shaped components (needle-shaped particles), substantially spherical components (substantially spherical particles), etc., can be used. 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 substantially spherical components (substantially spherical particles) to achieve the effects of the present invention. The lower limit 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, 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 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, 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, but 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.

[0026] In this specification, "needle-shaped component" and "needle-shaped particle" refer to a component (particle) in which there is a significant difference between its vertical and horizontal lengths in a cross-section along the long axis of an image (shape transferred to a plane) measured by an electron microscope. Here, the significant difference between vertical and horizontal lengths can be expressed, for example, by the aspect ratio.

[0027] 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. Furthermore, 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.

[0028] The average aspect ratio of the substantially spherical component of the core particle component 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, 1.2, etc. The upper limit of the average aspect ratio of the substantially spherical component of the core particle component 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. The range of the average aspect ratio of the substantially spherical component 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 to 1.65, more preferably 1.0 to 1.5, and even more preferably 1.0 to 1.2.

[0029] In this specification, "aspect ratio" of a nuclear particle component means the ratio of the major axis to the minor axis (major axis / minor axis) of the nuclear particle component in particle image analysis using an electron microscope. Furthermore, "average aspect ratio" of a nuclear particle component means 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. Furthermore, in this specification, "aspect ratio of nuclear particle components is X~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 nuclear particle components falls within the range of X~Y.

[0030] 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. 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).

[0031] The sugars 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.

[0032] The sugar hydrate is not particularly limited, but examples include any hydrate of the sugars mentioned above, and lactose hydrate is preferably used.

[0033] The sugar alcohol is not particularly limited, but any sugar alcohol derived from any sugar is used, and preferably mannitol, sorbitol, etc.

[0034] Examples of inorganic compounds include, but are not limited to, silicates such as porous calcium silicate and phosphates such as anhydrous calcium phosphate.

[0035] 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 a BET specific surface area of ​​0.45 m² are used as the core particle component. 2 A pharmaceutically acceptable core particle component containing a finely powdered substance is used, with a concentration of at least / g.

[0036] In preferred embodiments, the mass ratio of needle-shaped components to substantially spherical components in the core particle component (mass of needle-shaped components:mass of substantially spherical components) is not particularly limited as long as the BET specific surface area of ​​the core particle component satisfies the above-described range and the effects of the present invention are achieved, but is preferably 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 substantially 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.

[0037] In a preferred embodiment, the difference between the stiff bulk density and the loose bulk density of the core particle component (stiff 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 stiff bulk density and the 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 stiff 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, and tapping is performed 180 times. 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 (tight bulk density) after tapping.

[0038] In 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, by laser diffraction (measurement method: dry method, scattering intensity: 1% or more, light scattering model: Mie scattering theory) using a commercially available particle size analyzer (e.g., Mastersizer 3000, manufactured by Spectris).

[0039] In 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.

[0040] (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.

[0041] As a non-volatile solvent, a component capable of dissolving or suspending a drug within the core particle can be used. Examples of such non-volatile solvents include surfactants. Furthermore, as a non-volatile solvent, a component that itself has medicinal properties 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.

[0042] 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 includes 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.

[0043] 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. One type of vitamin may be used alone, or two or more types may be used in combination.

[0044] 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. One type of fatty acid glyceride may be used alone, or two or more types may be used in combination. 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.

[0045] The fatty acids that make up 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.

[0046] In a preferred embodiment, medium-chain fatty acid glycerides are used as the fatty acid glycerides.

[0047] Fatty acid glycerides can be used as fatty acid glycerides themselves, or as 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).

[0048] Examples of vegetable oils include olive oil, soybean oil, rapeseed oil, safflower oil, corn oil, camellia oil, coconut oil, castor oil, olive oil, peanut oil, sesame oil, cottonseed oil, and wheat germ oil.

[0049] Examples of animal fats include beef tallow, pork tallow, chicken fat, and sheep fat.

[0050] Examples of oily substances (waxes) include carnauba wax, beeswax, bleached beeswax, paraffin, liquid paraffin, petrolatum (white petrolatum, yellow petrolatum), microcrystalline wax, lanolin, and squalane.

[0051] 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.

[0052] 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 with glycerin.

[0053] 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.

[0054] 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 in the manufacture 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.

[0055] 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, but 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.

[0056] (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.

[0057] 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.

[0058] 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 in accordance 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, and the mixture is shaken 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 taken as the common logarithm of the partition coefficient between the two phases.

[0059] Specific examples of drugs include vitamins, hormones, anticancer drugs, antibacterial agents, antiviral agents, drugs for treating hyperlipidemia, central nervous system drugs, immunosuppressants, peripheral nervous system drugs, drugs for treating hemorrhoids, drugs for the circulatory system, metabolic drugs, drugs for digestive diseases, and drugs for leprosy.

[0060] Since the pharmaceutical formulation of the present invention can contain a large amount of non-volatile solvent in its core particles, even poorly water-soluble drugs can be dissolved or suspended in the non-volatile solvent and incorporated into the core particles. Therefore, according to a preferred embodiment, the drug contains a poorly water-soluble drug. Poorly water-soluble drugs are not particularly limited, but include drugs whose solubility in water under physiological pH conditions (mass of drug dissolved in 100g of water (g)) is 10 to 20 μg / ml. Furthermore, poorly water-soluble drugs include drugs classified as Class II and IV in the Biopharmaceuticals Classification System (BCS) defined by the U.S. Food and Drug Administration (FDA).

[0061] 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 (aneurin), 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).

[0062] 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. Specific examples include progesterone, levonorgestrel, and norethisterone.

[0063] Anticancer agents, though not particularly limited, include those that reduce or eliminate cancerous tumors, or prevent 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, gimeracil / oteracil (gimeracil·oteracil), cytarabine, enocitabine, gemcitabine, 6-mercaptopurine, fuludarabine, pentostatin, cladribine, hydroxyurea, doxorubicin, epirubicin, daunorubicin, idarubicin, pirarubicin, mitoxantrone, amurubicin, actinomycin D, bleomycin, pepleomycin, mytomycin CC) aclarubicin, zinostatin, vincristine, vindesine, vinblastine, vinorelbine, paclitaxel, docetaxel, irinotecan, irinotecan active metabolite (SN-38), nogitecan, tonotecan, 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.

[0064] Antimicrobial agents are agents that have the effect of killing or inhibiting 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.

[0065] Antimicrobial agents targeting bacteria are not particularly limited, but 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, oxazolidinone-based antimicrobial agents, and others. 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, Fachlor, 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, ra Tamoxef, ceftizoxime, cefpirome, cefozopran, cefepime, cefoperazone, sulbactam, imipenem, panipenem, meropenem, biapenem, doripenem, tebipenem, aztreonam, sulbactam, tazobactam, carmonam, faropenem, kanamycin, streptomycin, neomycin, gentamicin, 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,Examples include azithromycin, josamycin, 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, trimethoprim-sulfamethoxazole, diaphenylsulfone, and linezolid.

[0066] 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.

[0067] While not particularly limited, examples of hyperlipidemia treatment agents include ethyl eicosapentate, ethyl omega-3 fatty acids, clofibrate, and polyene phosphatidylcholine.

[0068] Examples of central nervous system agents include, but are not limited to, indomethacin farnesil and nalfurafine hydrochloride.

[0069] Immunosuppressants are not particularly limited, but examples include cyclosporine.

[0070] Peripheral nerve agents are not particularly limited, but examples include tafamidis meglumine.

[0071] While not particularly limited, examples of hemorrhoid treatments include tribenoside.

[0072] Examples of circulatory system agents include, but are not limited to, nifedipine and ubicarenone.

[0073] Examples of metabolites include, but are not limited to, nintedanib ethanesulfonate.

[0074] Examples of agents used for gastrointestinal diseases include, but are not limited to, gefarnate, sodium picosulfate hydrate, and lubiprostone.

[0075] While not particularly limited, leprosy treatments include clofazimine, for example.

[0076] 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, but the lower limit of the ratio of the mass of the drug to the mass of the core particle component (mass of core particle component: mass of drug) is 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. 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.

[0077] 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 produces the desired effect, but the lower limit of the ratio of the mass of the drug to the mass of the nonvolatile solvent (mass of nonvolatile 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. Furthermore, the range of the ratio of the mass of the drug to the mass of the nonvolatile 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.

[0078] 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.

[0079] 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

[0080] 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 (%).

[0081] <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.

[0082] 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.

[0083] According to a preferred embodiment, the water-soluble coating agent preferably comprises at least one component selected from polyalkylene glycol and polysaccharides or derivatives thereof.

[0084] 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.

[0085] Examples of polyalkylene glycols include polyethylene glycol.

[0086] Furthermore, according to another preferred embodiment, the coating agent used for 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 alone or in combination of two or more types.

[0087] 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, chlorobutanol, and the like. Of these plasticizers, polyalkylene glycol is preferred, and polyethylene glycol (macrogol) is more preferred. One plasticizer may be used alone, or two or more may be used in combination.

[0088] 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 necessary. 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. Preferably, 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.

[0089] 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, but the ratio of the mass of the coating layer to the total mass of the nucleus particles (total mass of nucleus particles : mass of 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. 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.

[0090] <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, additives may be used individually or in combination of two or more.

[0091] Since the pharmaceutical formulation of the present invention includes a coating layer that covers the core particles, leakage of non-volatile solvents and drugs contained in the core particles from the pharmaceutical formulation is suppressed, and as a result, aggregation of the pharmaceutical formulation can be suppressed.

[0092] 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.

[0093] Furthermore, it is preferable that the degree of aggregation of the pharmaceutical formulation is improved (lower) than that of the core particles.

[0094] 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 component described above.

[0095] 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, powders, etc. Of these, granules, tablets, and capsules are preferred. Hard capsules are also an example of capsules.

[0096] 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%, 30%, etc., relative to 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%, 75%, etc., relative to the total mass of the formulation.

[0097] The pharmaceutical formulations of the present invention have the characteristic of being less susceptible to abrasion such as cracking or chipping when processed to obtain formulations having various dosage forms. Specifically, formulations obtained from the pharmaceutical formulations of the present invention have an abrasion degree of preferably 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%.

[0098] Furthermore, when the pharmaceutical formulation of the present invention is formulated, particularly as a tablet, it may exhibit the additional effect of having low abrasion despite having low hardness. Specifically, the hardness of the formulation obtained from the pharmaceutical formulation of the present invention is preferably 150N or less, more preferably 130N or less, more preferably 100N or less, more preferably 80N or less, more preferably 70N or less, more preferably 60N or less, more preferably 50N or less, more preferably 40N or less, and particularly preferably 30N or less.

[0099] [Manufacturing method for 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 the 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 BET specific surface area is 0.45 m². 2A core particle component of 1 / g or more and a drug solution are introduced into a fluid bed granulator (e.g., FD-MP-01D, manufactured by Powrec Co., Ltd.) and brought into contact to allow the mixed solution to adhere to the core particle component and obtain core particles. In addition to the above method, contact between the core particle component and the drug solution can also be performed by, for example, spraying the drug solution onto the core particle component or immersing the core particle component in the drug solution. Next, the obtained core particles are dried as needed, and then coated with components constituting the coating layer (coating layer components). In this case, coating of the core particles can be performed by, for example, spraying the coating layer components onto the core or immersing the core particles in the coating layer components. Finally, particles having the core particles and the coating layer covering the core particles are dried to obtain a pharmaceutical preparation.

[0100] 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. As an example of a method for tableting the pharmaceutical formulation, one can use a tablet press such as a rotary tablet press or a single-stroke tablet press to compress the pharmaceutical formulation. Of these, it is preferable to tabletize the pharmaceutical formulation using a rotary tablet press. An example of a rotary tablet press is 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 beforehand before tableting. The method for mixing the pharmaceutical formulation and the additives is not particularly limited, and can be done using known methods. As an example of a method for mixing the pharmaceutical formulation and the additives, one can use a mixer such as a V-type mixer to mix them. Specifically, mixing can be done using a V-type mixer (TCV-20) manufactured by Tokuju Kogyosho Co., Ltd.

[0101] 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 a capsule body by the rotational pressure of stirring blades and an auger, and then the containers are coaxially joined to produce a capsule. [Examples]

[0102] The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

[0103] [Methods for preparing pharmaceutical formulations] The granular pharmaceutical formulations of each example and comparative example were prepared by the following method. As core particle components, 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) were prepared. The average aspect ratio of each core particle component was determined 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 ratio values ​​of the top 10% and bottom 10% of particles.

[0104] 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). [Table 1]

[0105] <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-Bel 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.

[0106] 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 sum of the products of the mass and specific surface area of ​​each nucleus particle component divided by the total mass of the nucleus particles (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

[0107] <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 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) 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.

[0108] 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. In 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, respectively.

[0109] 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. [Table 2]

[0110] <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

[0111] 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 (%).

[0112] 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 a coating layer solution.

[0113] 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. [Table 3]

[0114] 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 of the granular pharmaceutical formulations in each example, the degree of aggregation after coating (pharmaceutical formulation) was lower than that before coating (each particle).

[0115] <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.

[0116] [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 preparation 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 (Type V 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 preparation 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. [Table 4]

[0117] The granular pharmaceutical preparations of Examples 2-4 and 6-8 were also mixed and compressed into tablets in the same manner as the pharmaceutical preparation of Example 5 described above. Tablets were successfully prepared for all pharmaceutical preparations without any problems.

[0118] <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.

[0119] 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.

[0120] <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.

[0121] The results in Table 1 show that the tablets in the examples did not abrade despite having low hardness.

[0122] Furthermore, the results in Table 1 show that the pharmaceutical formulation of the present invention yields tablets with low abrasion despite low hardness. Tablets with low hardness typically have high abrasion, so the tablets of the present invention, which have low abrasion despite low hardness, possess extremely unique characteristics. Such tablets have a high yield during manufacturing and also have the advantage of being easy to chew and swallow in the mouth during oral administration, making them easy to take. Although the mechanism by which these characteristics are achieved is not clear, it is presumed that non-volatile solvents such as surfactants used when manufacturing granular pharmaceutical formulations seep out when the pharmaceutical formulations are compressed into tablets, strengthening the bonds between the pharmaceutical formulations, and as a result the resulting tablets become less prone to abrasion. [Industrial applicability]

[0123] 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 having excellent fluidity that can withstand actual manufacturing.

Claims

1. 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. ２ / 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.

2. The pharmaceutical preparation according to claim 1, wherein the porosity of the nucleus particles is 40% or more.

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