WO2020218517A1 - Medicinal preparation and method for manufacturing same - Google Patents

Medicinal preparation and method for manufacturing same Download PDF

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Publication number
WO2020218517A1
WO2020218517A1 PCT/JP2020/017710 JP2020017710W WO2020218517A1 WO 2020218517 A1 WO2020218517 A1 WO 2020218517A1 JP 2020017710 W JP2020017710 W JP 2020017710W WO 2020218517 A1 WO2020218517 A1 WO 2020218517A1
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Prior art keywords
pharmaceutical preparation
nuclear particle
particle component
nuclear
preparation according
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PCT/JP2020/017710
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French (fr)
Japanese (ja)
Inventor
俊行 稲田
隆樹 下平
良成 金山
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富士製薬工業株式会社
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Priority to JP2021516265A priority Critical patent/JPWO2020218517A1/ja
Publication of WO2020218517A1 publication Critical patent/WO2020218517A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • the present invention relates to a pharmaceutical preparation and a method for producing the same.
  • Soft capsules are widely used as solid preparations containing such components (liquid components) in a liquid state at room temperature (for example, Patent Document 1).
  • soft capsules may have a larger diameter than other solid preparations such as tablets, there is a problem that they are difficult to take for children and the elderly with low swallowing ability, patients with poor swallowing ability, and the like. ..
  • soft capsules have a risk of leaking easily depending on the manufacturing method due to their nature.
  • soft capsules are soft and easily deformed, the presence or absence of deformation must be inspected visually by humans or using a dedicated inspection machine. From the viewpoint of manufacturing cost, other tablets and the like can be used. There is a problem that it is expensive compared to solid preparations.
  • tablets are used as a solid preparation that can contain liquid components.
  • a liquid component is blended in a tablet, generally, the liquid component and the solid component are mixed before tableting to obtain particles having the liquid component adhered to the surface of the solid component, and the obtained particles are tableted.
  • the method is taken.
  • it is difficult to tablet the particles because the liquid component existing on the surface of the solid component in the particles causes agglutination and adsorption between the particles and the fluidity of the particles is lowered.
  • the particles obtained by mixing the liquid component and the solid component have low fluidity and are extremely difficult to tablet. is there. Therefore, the liquid component that can be blended in the tablet is only a small amount that does not significantly reduce the fluidity.
  • Patent Document 2 As a method for combining the poorly water-soluble drug and the solid dispersion, a spray-drying method or a melting method is generally used.
  • the spray-drying method has a problem that a large machine is required, and the melting method performs high-temperature heat treatment to dissolve the drug, so that the drug may be denatured and decomposed in the process. There's a problem.
  • Patent Document 3 a technique of adsorbing a liquid substance on a porous substance such as silica gel is also known (for example, Patent Document 3), but such a technique is realized.
  • processing in a vacuum state is required, and there is a problem that an expensive device is required for that purpose.
  • a method of suppressing a decrease in the fluidity of a preparation by encapsulating a liquid component in a neutral or alkaline resin is also known, but the use of the resin may affect the elution behavior of the liquid component. There is a problem that it is property and it is difficult to obtain the desired elution behavior.
  • a method of preparing a liquid active ingredient in the form of an oil-in-water emulsion spraying the emulsion solution onto the powder to attach it, and drying it to remove water to obtain a powder to which the active ingredient is attached.
  • a method in which a drug and a water-soluble polymer are applied to an inert carrier and dried to form particles for example, Patent Document 5).
  • Patent Document 6 granules composed of a powdery or fine granular component and a liquid component and having improved fluidity are also known (for example, Patent Document 6).
  • a drug preparation containing granules containing a combination of a drug and a solubilizer is known, and it is known that a surfactant can be used as the solubilizer and the granules can be coated.
  • a surfactant has adhesiveness and adhesiveness and lowers the fluidity, there is a problem that the blending amount is limited when it is used for the preparation of pharmaceutical preparations such as tablets.
  • a pharmaceutical preparation comprising a nuclear particle containing a drug together with a nuclear particle component having a specific shape and a coating layer covering the nuclear particle was prepared. And it was found that it can contain a large amount of a drug and has excellent fluidity.
  • the present invention is based on such findings.
  • the present invention includes the following inventions.
  • a pharmaceutical preparation in the form of granules comprising nuclear particles and a coating layer covering the nuclear particles.
  • the nuclear particle comprises a drug, a first nuclear particle component, a second nuclear particle component and a non-volatile solvent.
  • the first nuclear particle component is at least one crystalline cellulose having a shape selected from needle-like and substantially columnar.
  • the pharmaceutical formulation, wherein the second nuclear particle component is at least one pharmaceutically acceptable additive that is substantially spherical.
  • the pharmaceutical preparation according to [2], wherein the average aspect ratio of the first nuclear particle component is 1.8 to 10.0.
  • the mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component to the mass of the coating layer is 1: 0.05 to 1: 0.3, [1] to The pharmaceutical preparation according to any one of [11].
  • the second nuclear particle component is any of [1] to [12], wherein the second nuclear particle component is at least one pharmaceutically acceptable additive selected from the group consisting of saccharides and inorganic compounds. Pharmaceutical preparations.
  • the second nuclear particle component is glucose, fructose, lactose, lactose hydrate, sucrose, sucrose, compressed sugar, refined powdered sugar, ammonium alginate, starch, potato starch, wheat starch, corn starch, rice.
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is polysorbate.
  • the pharmaceutical preparation according to [15], wherein the fat and oil is a glycerin fatty acid ester.
  • the pharmaceutical preparation according to [18], wherein the glycerin fatty acid ester is a medium chain fatty acid triglyceride.
  • the poorly water-soluble drug is selected from the group consisting of hormonal agents, anticancer agents, antibacterial agents and antiviral agents (excluding N- [5-fluoro-2- (1-piperidinyl) phenyl] isonicotinthioamide).
  • the pharmaceutical preparation according to [22] which comprises at least one of these.
  • the water-soluble coating agent contains at least one component selected from the group consisting of polyalkylene glycols, polysaccharides, and derivatives thereof.
  • the water-soluble coating agent is polyethylene glycol, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer, vinyl pyridine copolymer, alkyl vinyl pyridine copolymer, amino cellulose derivative, diethyl aminoethyl methacrylate, polyvinyl acetal.
  • [27] The pharmaceutical preparation according to any one of [1] to [26], wherein the degree of cohesion of the pharmaceutical preparation is 70% or less.
  • a preparation comprising the pharmaceutical preparation according to any one of [1] to [29] and having a dosage form selected from the group consisting of granules, tablets, capsules, powders and pills.
  • a method for producing a pharmaceutical preparation in the form of granules which comprises nuclear particles and a coating layer covering the nuclear particles.
  • the process of obtaining nuclear particles containing D) Including the step of coating the nuclear particles obtained in step (c) to obtain a pharmaceutical preparation.
  • the first nuclear particle component is at least one crystalline cellulose having a shape selected from needle-like and substantially columnar.
  • the production method, wherein the second nuclear particle component is at least one pharmaceutically acceptable additive that is substantially spherical.
  • the production method according to [31], wherein the average aspect ratio of the first nuclear particle component is 1.8 or more.
  • the production method according to [32], wherein the average aspect ratio of the first nuclear particle component is 1.8 to 10.0.
  • the production method according to [34], wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.5.
  • the ratio of the 50% particle diameter (D50) of the volume distribution standard of the first nuclear particle component to the 50% particle diameter (D50) of the volume distribution standard of the second nuclear particle component is 1: 1.1 or less. , [31] to [35].
  • the non-volatile solvent contains at least one selected from the group consisting of surfactants, vitamins and fats and oils.
  • a step of encapsulating the pharmaceutical preparation obtained in the (e') step (d) in a film made of gelatin or a plant-derived raw material to obtain a capsule-shaped preparation is further included [31] to [ 38]
  • the production method according to any one of. [41] A method for producing a tablet, which comprises a step of tableting and molding the pharmaceutical preparation according to any one of [1] to [29] to obtain a tablet.
  • a method for producing a capsule which comprises a step of encapsulating the pharmaceutical preparation according to any one of [1] to [29].
  • the present invention it is possible to provide a pharmaceutical preparation in the form of granules having excellent fluidity while containing a large amount of non-volatile solvent. Further, according to the present invention, it is possible to suppress aggregation that causes a decrease in the fluidity of the pharmaceutical preparation. That is, since excellent fluidity is realized in pharmaceutical preparations, a non-volatile solvent can be used even for pharmaceutical preparations such as tablets whose formulation is inhibited by a decrease in fluidity by an easy method such as fluidized bed granulation. Can be blended in large amounts. As a result, according to the present invention, even a poorly water-soluble drug can be blended in a therapeutically effective amount in a pharmaceutical preparation. Furthermore, the pharmaceutical preparation of the present invention can prevent the non-volatile solvent contained in the nuclear particles from leaking to the surface of the pharmaceutical preparation even when stored for a long period of time.
  • FIG. 1A and 1B are electron micrographs of the first nuclear particle component (needle-shaped crystalline cellulose).
  • FIG. 1A is an electron micrograph of acicular crystalline cellulose (CEOLUS KG-1000)
  • FIG. 1B is an electron micrograph of acicular crystalline cellulose (CEOLUS UF-702).
  • FIG. 2 is an electron micrograph of the second nuclear particle component (substantially spherical particles: lactose hydrate).
  • FIG. 3 is an electron micrograph of the second nuclear particle component (substantially spherical particles: corn starch).
  • the pharmaceutical preparation of the present invention is a pharmaceutical preparation in the form of granules comprising nuclear particles and a coating layer covering the nuclear particles.
  • a pharmaceutical preparation in the form of granules comprising nuclear particles and a coating layer covering the nuclear particles.
  • each of the nuclear particles and the coating layer will be described.
  • the nuclear particle comprises a drug, a first nuclear particle component, a second nuclear particle component and a non-volatile solvent, and the first nuclear particle component is a needle-like and / or substantially columnar crystalline cellulose (hereinafter, simply “. It may be referred to as “needle-shaped crystalline cellulose”), and the second nuclear particle component is at least one pharmaceutically acceptable additive having a substantially spherical shape.
  • the nuclear particle contains a first nuclear particle component and a second nuclear particle component having significantly different shapes, many voids are formed between the first nuclear particle component and the second nuclear particle component. Can be done. As a result, a large surface area can be contained in the nuclear particles, so that the nuclear particles can contain a large amount of the liquid component. Since the nuclear particles can contain a large amount of a non-volatile solvent such as a surfactant used as a solubilizer as a liquid component, a poorly water-soluble drug can be dissolved or suspended. Without being bound by theory, it is believed that such a mechanism makes it possible to produce pharmaceutical preparations containing a large amount of sparingly soluble drug in the nuclear particles.
  • a non-volatile solvent such as a surfactant used as a solubilizer as a liquid component
  • the first nuclear particle component used for the nuclear particles is acicular crystalline cellulose.
  • the acicular crystalline cellulose which is the first nuclear particle component used in the present invention is derived from the crystalline cellulose which can be added in the preparation of a pharmaceutical preparation.
  • the needle-shaped crystalline cellulose may contain a sufficient proportion of needle-shaped and / or substantially columnar crystals so that the effects of the present invention can be exhibited.
  • the lower limit of the proportion of acicular and / or substantially columnar crystalline cellulose in the first nuclear particle component is not particularly limited, but the number of crystals (particles) is preferably 60%, more preferably 70%, and even more. It is preferably 80%.
  • the upper limit can be, for example, 100%, 98%, 95%, 90% or the like.
  • the range of the proportion of acicular and / or substantially columnar crystalline cellulose in the first nuclear particle component is not particularly limited, but the number of crystals (particles) is preferably 60 to 100%, more preferably 70 to 100%. , Even more preferably 80 to 100%.
  • "needle-shaped crystalline cellulose” has a remarkable difference in vertical and horizontal lengths in a cross section in the long axis direction of crystalline cellulose on an image (a shape transferred to a plane) measured by an electron microscope. Crystalline cellulose.
  • the remarkable difference in the vertical and horizontal lengths can be expressed by, for example, the aspect ratio.
  • the average aspect ratio of the first nuclear particle component is not particularly limited as long as the effect of the present invention is exhibited, but it is larger than the average aspect ratio of the second nuclear particle component, and the lower limit value is It is preferably 1.8, more preferably 2.2, and even more preferably 2.5.
  • the upper limit of the average aspect ratio of the first nuclear particle component is not particularly limited as long as the effect of the present invention is exhibited, and can be, for example, 10 or less, 8 or less, and the like.
  • the range of the average aspect ratio of the first nuclear particle component is not particularly limited, but is preferably 1.8 to 10, more preferably 2.2 to 10, and even more preferably 2.5 to 10. ..
  • the “aspect ratio” of the nuclear particle component means the value (major axis / minor axis) of the ratio of the major axis to the minor axis of the nuclear particle component in the particle image analysis using an electron microscope.
  • the “average aspect ratio” of the nuclear particle component is the aspect ratio of 10 or more nuclear particle components selected arbitrarily, and the aspect ratio of the upper 10% and lower 10% of the aspect ratio values. It means the average value of the aspect ratios of the nuclear particle components excluding the ratio value.
  • the amount of the first nuclear particle component is not particularly limited as long as the effect of the present invention is exhibited, but is preferably 5 to 50% by mass with respect to the total mass of the pharmaceutical preparation.
  • the second nuclear particle component used for the nuclear particle is a substantially spherical pharmaceutically acceptable additive.
  • substantially spherical refers to a shape that approximates a spherical shape with no significant difference in length and width on an image measured by an electron microscope (shape transferred to a plane), and is needle-shaped and. Does not include a substantially columnar shape. Therefore, according to one embodiment, the second nuclear particle component is a non-needle and non-columnar pharmaceutically acceptable additive.
  • Approximately spherical does not necessarily mean that the image measured by an electron microscope is a perfect spherical shape, for example, a distorted spherical shape, an ellipsoidal shape, a polyhedral shape (including a cube shape), or a polyhedral shape with rounded corners. It may be.
  • the average aspect ratio of the second nuclear particle component is smaller than the average aspect ratio of the first nuclear particle component, preferably 1.0 to 1.65, more preferably 1.0 to 1.5, and more. It is even more preferably 1.0 to 1.3, and even more preferably 1.0 to 1.2.
  • the aspect ratio of the nuclear particle component and the average aspect ratio of the nuclear particle component are the same as those defined for the first nuclear particle component, respectively.
  • the amount of the second nuclear particle component in the pharmaceutical preparation of the present invention is not particularly limited as long as the effect of the present invention is exhibited, but is preferably 30 to 90% by mass with respect to the total mass of the pharmaceutical preparation.
  • the particle size of the second nuclear particle component is not particularly limited as long as the effect of the present invention is exhibited, but the 50% particle size (D50) of the volume distribution standard of the second nuclear particle component is the first nuclear particle.
  • Ratio of component volume distribution standard to 50% particle size (D50) (1st nuclear particle component volume distribution standard 50% particle size (D50): 2nd nuclear particle component volume distribution standard 50% particle size (D50)) is preferably adjusted to be 1: 1.1 or less, more preferably 1: 0.5 or less, and even more preferably 1: 0.1 or less.
  • the second nuclear particle component one kind of component may be used alone, or two or more kinds of components may be used in combination, but preferably, the 50% particle diameter (D50) based on the volume distribution is different. Used in combination with seeds or higher components.
  • the 50% particle diameter (D50) of each component based on the volume distribution is different.
  • the 50% particle diameter (D50) of the volume distribution standard of the nuclear particle component is the total mass of each component constituting the nuclear particle component.
  • the mass ratio is calculated, the product of the ratio and the 50% particle diameter (D50) based on the volume distribution is calculated for each component, and the product is calculated as the sum of the products.
  • the nuclear particle component contains two components A and B, the masses of the components A and B are a and b, respectively, and the 50% particle diameter (D50) of the volume distribution reference of A and B is D50 A and, respectively.
  • the 50% particle diameter (D50) based on the volume distribution of the nuclear particle component is calculated by the following formula:
  • the component constituting the second nuclear particle component is not particularly limited as long as it is a pharmaceutically acceptable component, and examples thereof include sugars (including sugars, sugar hydrates, sugar alcohols, etc.), inorganic compounds, and the like. ..
  • the sugar is not particularly limited, and examples thereof include monosaccharides such as glucose, disaccharides such as lactose and sucrose, and polysaccharides such as starch.
  • monosaccharides such as glucose
  • disaccharides such as lactose and sucrose
  • polysaccharides such as starch.
  • starch include potato starch, wheat starch, corn starch, rice starch and the like.
  • corn starch is preferably used as the sugar.
  • the sugar hydrate is not particularly limited, and examples thereof include any of the above-mentioned sugar hydrates, and lactose hydrate is preferably used.
  • the sugar alcohol is not particularly limited, and examples thereof include sugar alcohols derived from any sugar, and mannitol or sorbitol is preferably used.
  • the inorganic compound is not particularly limited, and examples thereof include phosphates such as anhydrous calcium phosphate.
  • the first nuclear particle component has a larger average aspect ratio than the second nuclear particle component, and the difference between the average aspect ratios of the first and second nuclear particle components is large.
  • the difference in the average aspect ratios of the first and second nuclear particle components is preferably 0.5. As mentioned above, it is more preferably 0.6 or more, and even more preferably 0.7 or more.
  • the difference between the firmness density and the loose bulk density (hardness density-loose bulk density) of the mixture of the first and second nuclear particle components (nuclear particle mixture) is particularly limited as long as the effect of the present invention is exhibited.
  • the lower limit is preferably 0.15, more preferably 0.16, even more preferably 0.17
  • the upper limit is preferably 0.25, more preferably 0.24, even more preferably. Is 0.23
  • the range is preferably 0.15 to 0.25, more preferably 0.16 to 0.24, and even more preferably 0.17 to 0.23.
  • the firmness density and the loose bulk density can be measured using, for example, a commercially available powder property evaluation device (Powder Tester (registered trademark) PT-R, manufactured by Hosokawa Micron Co., Ltd.).
  • a powder tester is used to put the nuclear particle mixture into a cylindrical container of the same size as the measurement container of the bulk density and tap density measurement method 3 described in the 17th revised Japanese Pharmacy.
  • the bulk density (loose bulk density) in a loosely filled state is measured by uniformly supplying the particles from above through a sieve and weighing the top surface.
  • an auxiliary cylinder is fitted on the container, a mixture of nuclear particles is added up to the upper edge, and tapping is performed 180 times.
  • the auxiliary cylinder is removed, the nuclear particle mixture is ground and weighed on the upper surface of the container, and the bulk density (hard bulk density) in the case of tight packing after tapping is measured.
  • the diameters (particle diameters) of the particles constituting the first and second nuclear particle components are not particularly limited as long as the effects of the present invention are exhibited, but the first nuclear particle components are 50% of the volume distribution standard.
  • the particle size (D50) is preferably 50 to 200 ⁇ m, more preferably 60 to 150 ⁇ m, and even more preferably 70 to 100 ⁇ m.
  • the volume distribution-based 50% particle diameter (D50) of the second nuclear particle component is preferably 1 to 300 ⁇ m, more preferably 5 to 200 ⁇ m, and even more preferably 10 to 150 ⁇ m.
  • the diameter of the particles constituting the nuclear particle component in the present invention and the 50% particle diameter based on the volume distribution are both measured by a laser diffraction method (measurement) using, for example, a commercially available particle size distribution meter (for example, Mastersizer3000, manufactured by Spectris). Method: Dry method, scattering intensity: 1% or more, light scattering model: Mie scattering theory).
  • the volume-based 50% particle size (D50) is the volume that is 50% of the cumulative volume distribution curve with the total volume as 100% in the volume-based particle size distribution measured by the laser diffraction method. It means the particle size.
  • the total mass of the first and second nuclear particle components is not particularly limited as long as the effects of the present invention are exhibited, but is, for example, 20 to 90% by weight with respect to the total mass of the pharmaceutical preparation.
  • the mass ratio of the first nuclear particle component to the second nuclear particle component is not particularly limited as long as the effect of the present invention is exhibited. However, for example, it is 1: 1 to 1:10.
  • the pharmaceutical preparation of the present invention comprises a non-volatile solvent.
  • a component capable of dissolving or suspending a drug in the nuclear particles can be used.
  • examples of such components include surfactants, fats and oils, and the like.
  • fats and oils have an advantage that by dissolving or suspending a drug in it, the contact between the drug and air (oxygen) can be blocked and its oxidation can be prevented.
  • the oil-and-fat can improve its absorbability in the subject to which the pharmaceutical preparation is administered because the poorly water-soluble drug is dissolved in the fat (drug). It also has the advantage of promoting and assisting absorption.
  • fats and oils have an advantage that they can serve as a nutritional source for the living body and help maintain or improve the health of the subject to whom the pharmaceutical preparation is administered.
  • a component which itself has a medicinal effect or has an antioxidant effect as an additive can be used as the non-volatile solvent. Examples of such components include vitamins and the like.
  • the non-volatile solvent of the present invention preferably contains at least one selected from the group consisting of surfactants, vitamins and fats and oils.
  • the component contained in the non-volatile solvent one type may be used alone, or two or more types may be used in combination.
  • the surfactant is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants.
  • cationic surfactant include a primary amine salt, an alkyltrimethylammonium salt, an alkylpyridinium salt, an alkylpolyoxyethylene amine and the like.
  • anionic surfactant include fatty acid salts, rosinates, alkylpolyoxyethylene sulfates, ⁇ -olefin sulfonates, alkylnaphthalene sulfonates, lignin sulfonates, alkyl phosphates and the like.
  • amphoteric surfactant examples include N-alkyl ⁇ -aminopropionic acid, N-alkyl sulfobetaine, N-alkyl hydroxy sulfobetaine, lecithin and the like.
  • nonionic surfactant examples include alkyl polyoxyethylene ether, polyoxyethylene fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester and the like.
  • the surfactant preferably contains a nonionic surfactant, more preferably polysorbate, and even more preferably polysorbate 80.
  • One of these surfactants may be used alone, or two or more of these surfactants may be used in combination.
  • the vitamins are not particularly limited, and examples thereof include vitamin E (tocopherol and tocotrienol).
  • vitamin E tocopherol and tocotrienol
  • vitamin E is preferably used, more preferably tocopherol, and even more preferably ⁇ -tocopherol is used.
  • One of these vitamins may be used alone, or two or more of these vitamins may be used in combination.
  • fats and oils include esters of glycerol and fatty acids (fatty acid esters) and derivatives thereof, and compositions containing fatty acid esters and / or derivatives thereof as main components.
  • the fatty acids constituting the fatty acid ester are not particularly limited, and any of short-chain fatty acids having 2 to 4 carbon atoms, medium-chain fatty acids having 5 to 10 carbon atoms, and long-chain fatty acids having 11 or more carbon atoms can be used. However, it is preferably a medium-chain fatty acid.
  • the fatty acid may be a linear fatty acid or a branched fatty acid, but is preferably a linear fatty acid.
  • the number of fatty acids ester-bonded to glycerol is not particularly limited and may be 1 (monoglyceride), 2 (diglyceride) or 3 (triglyceride), but 3 (triglyceride) is preferable. is there.
  • the number of fatty acids ester-bonded to glycerol is two or more, the fatty acids may be the same or different from each other.
  • Preferred fatty acid esters include, for example, medium-chain fatty acid triglycerides consisting of glycerol and three medium-chain fatty acids, and long-chain fatty acid triglycerides consisting of glycerol and three long-chain fatty acids.
  • fatty acid esters examples include triacetin, isopropyl myristate and the like. Further, examples of the fatty acid ester derivative include acetyltriethyl citrate and the like. One of these fatty acid esters and their derivatives may be used alone, or two or more thereof may be used in combination. Further, the fatty acid ester and its derivative may be used in combination with a composition containing the fatty acid ester and / or its derivative described later as a main component.
  • the composition containing a fatty acid ester and / or a derivative thereof as a main component is not particularly limited, and examples thereof include vegetable oils and mineral oils. Examples of such compositions include olive oil, sesame oil, soybean oil, camellia oil, corn oil, castor oil, rapeseed oil, coconut oil, lacquer oil, wheat germ oil, light liquid paraffin, liquid paraffin, squalane and the like. Be done. Further, a hydrogenated oil obtained by hydrogenating these compositions can also be used. As the composition containing these fatty acid esters and / or derivatives thereof as a main component, one type may be used alone, or two or more types may be used in combination. Further, a composition containing a fatty acid ester and / or a derivative thereof as a main component may be used in combination with the fatty acid ester and its derivative described above.
  • the non-volatile solvent contains a surfactant capable of dissolving or suspending the poorly water-soluble drug.
  • the non-volatile solvent preferably contains vitamins and fats and oils in addition to the surfactant.
  • the component contained in the non-volatile solvent one type may be used alone, or two or more types may be used in combination.
  • a non-liquid component when used as the component contained in the non-volatile solvent, it is used in combination with another liquid component.
  • the non-volatile solvent contains vitamin E
  • vitamin E when it is preferable that vitamin E is used in combination with an alcohol such as ethanol.
  • the amount of the non-volatile solvent is not particularly limited as long as the effect of the present invention is exhibited, but the lower limit is preferable as the mass ratio to the total amount of the nuclear particle components (total mass of the nuclear particle components: mass of the non-volatile solvent). Is 1: 0.001, more preferably 1: 0.01.
  • the upper limit is not particularly limited, but is preferably 1: 0.6, more preferably 1: 0.4, and even more preferably 1: 0.3.
  • the range of the mass ratio of the surfactant to the total amount of the nuclear particle components is not particularly limited, but is preferably 1: 0.001 to 1: 0.6, more preferably 1: 0.01 to 1: 0. 4, even more preferably 1: 0.01 to 1: 0.3.
  • the viscosity of the non-volatile solvent is not particularly limited as long as the effects of the present invention are exhibited, and for example, the viscosity range at 40 ° C. is 10 to 600 mPa ⁇ s.
  • Specific examples of such a non-volatile solvent include surfactants, vitamins, fats and oils shown in Table 1 below.
  • the viscosity of the non-volatile solvent can be measured using a commercially available viscometer. Examples of the viscometer include a rotary vibration viscometer VISCOMATE VM-10A-L (manufactured by SEKONIC CORPORATION).
  • the pharmaceutical preparation of the present invention comprises a drug in nuclear particles.
  • the drug preferably exists in a state of being dissolved or suspended in the above-mentioned non-volatile solvent.
  • the drug is not particularly limited, and a drug that exerts a desired effect in the pharmaceutical preparation of the present invention can be used.
  • one type of drug may be used alone, or two or more types may be used in combination.
  • the logP value of the drug is not particularly limited as long as the effects of the present invention are exhibited, but is preferably -2 to 7, more preferably 1.9 to 6.5, and even more preferably 1.85 to 6.1. Is.
  • the logP value of the drug is the value listed in Pubchem (https://pubchem.ncbi.nlm.nih.gov/).
  • the logP value of a drug not listed in Pubchem can be measured according to the flask shaking method according to 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 sample drug is weighed in a glass bottle with a lid, 4 mL each of 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 the value obtained by taking the common logarithm of the partition coefficient between the two phases.
  • Specific drugs include, for example, vitamins, hormones, anticancer agents, antibacterial agents, antiviral agents, hyperlipidemia therapeutic agents, central nervous system agents, immunosuppressive agents, peripheral nerve agents, hemorrhagic disease therapeutic agents, etc. Examples thereof include circulatory organ agents, metabolic drugs, digestive diseases agents, Hansen's disease agents and the like.
  • the drug comprises a poorly water-soluble drug.
  • the poorly water-soluble drug is not particularly limited, and examples thereof include a drug having a solubility in water (mass (g) of the drug soluble in 100 g of water) of 10 to 20 ⁇ g / ml under physiological pH conditions.
  • examples of poorly water-soluble drugs include drugs classified into Class II and IV in the BCS (Biopharmaceutics Classification System) defined by the US Food and Drug Administration (FDA).
  • the vitamin preparation is not particularly limited, and examples thereof include fat-soluble vitamins and water-soluble vitamins.
  • fat-soluble vitamins include retinol (A1 alcohol), retinal (A1 aldehyde), retinoic acid (A1 acid), 3-dehydroretinol (A2 alcohol), 3-dehydroretinal (A2 aldehyde), and 3-dehydroretinoic acid.
  • Vitamin A such as (A2 acid), carotene, flavonoid, ergocalciferol (D2), cholecalciferol (D3), ergosterol, vitamin D such as 7-hydrocholesterol, vitamin E such as ⁇ -tocopherol, phylloquinone (K1) ), Vitamin K such as menaquinone (K2) and menadion (K3).
  • Water-soluble vitamins include vitamin B1 such as thiamine (anoylin), vitamin B2 such as riboflavin, vitamin B6 such as pyridoxine, pyridoxal and pyridoxamine, vitamin B12 such as cobalamine, niacin such as folic acid, nicotinic acid and nicotinamide, and pantothenic acid. , Biotin, ascorbic acid (vitamin C) and the like.
  • Hormonal agents are physiologically active substances that formulate various hormones and exert specific effects on specific cells in the body by utilizing the original physiological or pharmacological effects of the hormones.
  • the hormonal agent is not particularly limited, and examples thereof include hormones derived from the hypothalamus, anterior pituitary gland, posterior pituitary gland, thyroid gland, pancreatic islets of Langerhans, adrenal cortex, adrenal medulla, gonads, digestive organs and the like. Specific examples thereof include progesterone, levonorgestrel and norethisterone.
  • the anticancer agent is not particularly limited, but is limited to brain tumor, tongue cancer, laryngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, colon cancer, liver cancer, cholangiocarcinoma, bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer. , Uterine cancer, kidney cancer, prostate cancer, bladder cancer, skin cancer, bone tumor, leukemia, malignant lymphoma, pediatric cancer, etc., which have the effect of reducing or eliminating the cancer or not increasing the cancer. Can be mentioned.
  • Procarbazine temozolomide
  • cisplatin carboplatin, nedaplatin, metotrexate, pemetrexed, uracil, doxifluridine, doxifluridine oteracil), cytarabine, enocitabine, gemcitabine, 6-mercaptopurine, fuludarabin, pentostatin, cladribine, hydroxyurea, hydroxyurea
  • Doxorubicin epirubicin, daunorubicin, idarubicine, pirarubicin, mitoxantrone, amurubicin, actinomycin D, actinomycin D Pepleomycin, mytomycin C, aclarubicin, zino
  • An antibacterial agent is an agent that has the effect of killing or suppressing the growth of fungi or bacteria.
  • the antibacterial agent for fungi is not particularly limited, and examples thereof include polyene antibacterial agents, fluoropyrimidine antibacterial agents, imidazole antibacterial agents, triazole antibacterial agents, allylamine antibacterial agents, and canin antibacterial agents. ..
  • the antibacterial agent for bacteria is not particularly limited, but is ⁇ -lactam antibacterial agent such as penicillin antibacterial agent, cephem antibacterial agent, carbapenem antibacterial agent, monobactam antibacterial agent and penem antibacterial agent, aminoglycoside type.
  • penicillin G ampicillin, vacampicillin, renanpicillin, cyclacillin, amoxicillin, pibmesillin, aspoxycillin, cloxacillin, piperacillin, methicillin, ampicillin / cloxacillin, ampicillin / sulbactam, clavacilin acid / amoxicillin, clavacylin / amoxicillin, , Cephalexin, cefatridin, cefluxazine, cefaclor, cefadoroxyl, cefotiam, cefmethazole, fromoxef, cefminox, cefbuperazone, cefloxim axetil, cefdinil, cefditoren pivoxil, cefditoren pivoxil, cefteram pivoxil, cefterocelpypoxyl pivoxil Cefoperazone, cefmenoxim, ceftajigym, ceftibuten
  • Antiviral agents have a therapeutic effect on diseases caused by viral infections by infesting host cells with the virus, forming new viral particles, and inhibiting some or all processes in the cycle of escaping the host cells. It is an agent having.
  • the antiviral agent is not particularly limited, but is caused by viral infection such as herpes virus, cytomegalovirus, human papillomavirus, RS virus, influenza virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, etc. Examples thereof include agents having a therapeutic effect on the disease.
  • Zovirax Specifically, Zovirax, Acyclobin, Viclocks (Acyclovir), Baltrex (Balacyclovir), Denosin (Ganciclovir), Aracena A (Vidarabin), Relenza (Zanamivir hydrate), Tamiflu (Oseltamivir phosphate), Symmetrel (Amantazine) , Retroville (Zidovudine), Videx (Zidovudine), Epivir, Zefix (Lamivudine), Fort Base (Zanamivir), Novia (Litnavir), etc.
  • the therapeutic agent for hyperlipidemia is not particularly limited, and examples thereof include ethyl icosapentaenoate, ethyl omega-3 fatty acid, clofibrate, polyenphosphatidylcholine and the like.
  • the central nervous system agent is not particularly limited, and examples thereof include indometacin farnesyl and nalfurafine hydrochloride.
  • the immunosuppressive agent is not particularly limited, and examples thereof include cyclosporine and the like.
  • the peripheral nerve agent is not particularly limited, and examples thereof include tafamidis meglumine.
  • the therapeutic agent for hemorrhoidal disease is not particularly limited, and examples thereof include tribenoside and the like.
  • the circulatory organ preparation is not particularly limited, and examples thereof include nifedipine and ubidecalenone.
  • the metabolic drug is not particularly limited, and examples thereof include nintedanibuethanesulfonate.
  • the agent for digestive disorders is not particularly limited, and examples thereof include gefarnate, picosulfate sodium hydrate, rubiprostone, and the like.
  • the therapeutic agent for leprosy is not particularly limited, and examples thereof include clofazimine and the like.
  • the amount of the drug in the pharmaceutical preparation of the present invention is not particularly limited as long as the pharmaceutical preparation of the present invention exerts a desired effect, but as a mass ratio to the total amount of the nuclear particle components (mass of the drug: total mass of the nuclear particle components).
  • the lower limit is preferably 0.01: 1, more preferably 0.02: 1, and even more preferably 0.03: 1.
  • the upper limit is not particularly limited, but is preferably 0.5: 1, more preferably 0.2: 1.
  • the range of the mass ratio of the drug to the total amount of the nuclear particle components is not particularly limited, but is preferably 0.01: 1 to 0.5: 1, more preferably 0.02: 1 to 0.5: 1. Even more preferably, it is 0.03: 1 to 0.2: 1.
  • the amount of the drug in the pharmaceutical preparation of the present invention is not particularly limited as long as the pharmaceutical preparation of the present invention exerts a desired effect, but is the lower limit as the mass ratio to the non-volatile solvent (mass of drug: mass of non-volatile solvent).
  • the value is preferably 0.05: 1, more preferably 0.1: 1, and even more preferably 0.5: 1.
  • the upper limit is not particularly limited, but is preferably 5: 1, more preferably 3: 1.
  • the range of the mass ratio of the drug to the surfactant is not particularly limited, but is preferably 0.05: 1 to 5: 1, more preferably 0.1: 1 to 5: 1, and even more preferably 0. It is 5: 1 to 3: 1.
  • the degree of cohesion of nuclear particles in the pharmaceutical preparation of the present invention is not particularly limited, but is preferably 90% or less, more preferably 70% or less, and even more preferably 50% or less.
  • the degree of cohesion can be measured using a commercially available powder property evaluation device.
  • the powder property evaluation device include Powder Tester (registered trademark) PT-R (manufactured by Hosokawa Micron Co., Ltd.).
  • the measurement conditions are as follows, for example. Opening of mesh: (upper) 710 ⁇ m, (middle) 355 ⁇ m, (lower) 250 ⁇ m Sampling volume: 2g or 3g Vibration time: 119 seconds
  • the coating layer can coat the nuclear particles and prevent the non-volatile solvent and the drug contained in the nuclear particles from leaking to the surface of the pharmaceutical preparation. As a result of suppressing the leakage of the non-volatile solvent by the coating layer, the aggregation of the pharmaceutical preparation can be suppressed, and the decrease in the fluidity of the pharmaceutical preparation can be suppressed.
  • the components constituting the coating layer are not particularly limited, and examples thereof include water-soluble coating agents.
  • the water-soluble coating agent one type may be used alone, or two or more types may be used in combination.
  • the water-soluble coating agent preferably comprises at least one component selected from polyalkylene glycols and polysaccharides or derivatives thereof.
  • the polysaccharide or its derivative is preferably a cellulose derivative, and examples thereof include methyl cellulose, hydroxymethyl cellulose, and hydroxypropyl methyl cellulose.
  • a cellulose derivative examples thereof include methyl cellulose, hydroxymethyl cellulose, and hydroxypropyl methyl cellulose.
  • One type of cellulose derivative may be used alone, or two or more types may be used in combination.
  • examples of the polyalkylene glycol include polyethylene glycol and the like.
  • the coating agent used for the coating layer includes hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer, vinyl pyridine copolymer, alkyl vinyl pyridine copolymer, amino cellulose derivative, diethyl aminoethyl.
  • Methacrylate polyvinyl acetal diethylaminoacetate, dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N, N-di-n-butylhydroxylpropyl ether, copolymer of vinylpyridine and acrylic acid-based free acid, alkylvinylpyridine and acrylic acid-based Copolymer with free acid, copolymer of vinylpyridine and acrylic acid-based free acid and vinyl monomer, copolymer of alkylvinylpyridine and acrylic acid-based free acid and vinyl monomer, 2-methyl-5-vinylpyridine-methacrylic acid copolymer, Poly-2- (vinylphenyl) glycine, morpholino-N- ⁇ -ethylacrylate-methacrylic acid copolymer, shelac, cellulose acetate phthalate, methylacrylate-methacrylic acid copolymer, methylmethacrylate-methacrylic acid copo
  • the coating agent may be used in combination with a plasticizer.
  • Plasticizers include acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, sorbitol, dextrin, diethyl phthalate, glycerin, polyalkylene glycol, polyethylene glycol monoethyl ether, propylene glycol, benzo Examples thereof include benzyl acid acid, purified water, sorbitol sorbitan solution, triacetin, tributyl citrate, triethyl citrate, chlorobutanol and the like. Of these plasticizers, polyalkylene glycol is preferably used, and polyethylene glycol (macrogol) is more preferable. One of these plasticizers may be used alone, or two or more of these plasticizers may be used in combination.
  • the components constituting the coating layer may be used as they are, but may be dissolved in water, alcohol, etc., if necessary.
  • the amount of the coating layer in the pharmaceutical preparation of the present invention is not particularly limited as long as the pharmaceutical preparation of the present invention exerts a desired effect, but as a mass ratio to the total mass of the nuclear particles (mass of the coating layer: total mass of the nuclear particles).
  • the lower limit is preferably 0.001: 1, more preferably 0.002: 1.
  • the upper limit is not particularly limited, but is preferably 0.1: 1, more preferably 0.05: 1, and even more preferably 0.02: 1.
  • the range of the mass ratio of the coating layer to the total mass of the nuclear particles is not particularly limited, but is preferably 0.001: 1 to 0.1: 1, more preferably 0.002: 1 to 0.05: 1. , Even more preferably 0.002: 1 to 0.02: 1.
  • the pharmaceutical preparation of the present invention may contain a pharmaceutically acceptable additive different from the components constituting the nuclear particles and the coating layer described above, as long as the effects of the present invention are not impaired.
  • the additive include excipients, disintegrants, lubricants, binders, fluidizers, sweeteners, flavors, colorants and the like. These additives may have one component having two or more functions. In addition, these additives may be used alone or in combination of two or more.
  • the pharmaceutical preparation of the present invention includes a coating layer that coats the nuclear particles, leakage of the non-volatile solvent and the drug contained in the nuclear particles from the pharmaceutical preparation is suppressed, and as a result, aggregation of the pharmaceutical preparation is suppressed. Can be done.
  • the degree of cohesion of the pharmaceutical preparation is preferably 70% or less, more preferably 60% or less, and even more preferably 50% or less.
  • the degree of cohesion of the pharmaceutical preparation can be measured by the same method as the above-mentioned measurement of the degree of cohesion of nuclear particles.
  • the degree of cohesion of the pharmaceutical preparation is improved (lower) than the degree of cohesion of the nuclear particles.
  • the particle size of the pharmaceutical preparation is not particularly limited, but preferably the 50% particle size (D50) based on the volume distribution is 100 to 400 ⁇ m, and more preferably 120 to 250 ⁇ m.
  • the measurement of the 50% particle size (D50) based on the volume distribution of the pharmaceutical preparation can be performed by the same method as the measurement of the 50% particle size (D50) based on the volume distribution of the nuclear particle component described above.
  • the pharmaceutical preparation of the present invention may be used as it is, or may be used as a preparation having various dosage forms.
  • the dosage form of the preparation is not particularly limited as long as the effects of the present invention are exhibited, and examples thereof include granules, tablets, pills, capsules, and powders. Of these, granules, tablets and capsules are preferred. Further, examples of the capsule include a hard capsule.
  • the method for producing the pharmaceutical preparation of the present invention is not particularly limited, and a known method can be used.
  • the conditions for producing a pharmaceutical preparation can be appropriately adjusted depending on the types of nuclear particle components, non-volatile solvents, drugs, coating layer components, and the like.
  • the pharmaceutical preparation of the present invention can be produced, for example, according to the following procedure. First, a fluidized bed of a first nuclear particle component, which is acicular and / or substantially columnar crystalline cellulose, and a second nuclear particle component, which is a substantially spherical at least one pharmaceutically acceptable additive.
  • a granulator for example, FD-MP-01D, manufactured by Paulec Co., Ltd.
  • a drug is added to a non-volatile solvent and stirred using a stirrer (NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.) to obtain a mixed solution (drug solution) in which the drug is dissolved or suspended.
  • a stirrer NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.
  • the obtained mixture and the mixed solution are brought into contact with each other using a fluidized bed granulator to attach the mixed solution to the nuclear particle components in the mixture to obtain nuclear particles.
  • the contact between the mixture and the mixed solution is performed, for example, by a method of spraying the mixed solution onto the mixture, a method of immersing the mixed solution in the mixed solution, or the like.
  • the nuclear particles are dried as needed, and then the nuclear particles are coated with a component (coating layer component) constituting the coating layer.
  • the coating of the nuclear particles is performed, for example, by a method of spraying the coating layer component on the nucleus, a method of immersing the nuclear particles in the coating layer component, or the like.
  • the particles having the nuclear particles and the coating layer covering the nuclear particles are dried to obtain a pharmaceutical preparation.
  • the method for tableting a pharmaceutical preparation is not particularly limited, and a known method can be used.
  • the conditions for tableting are not particularly limited, and can be appropriately adjusted depending on the types of nuclear particle components, non-volatile solvents, drugs, coating layer components, and the like.
  • Examples of the method for tableting and molding a pharmaceutical preparation include a method of locking a pharmaceutical preparation using a locking machine such as a rotary locking machine or a single-shot locking machine. Of these, it is preferable to tablet-mold the pharmaceutical preparation using a rotary locking machine.
  • the rotary locking machine include VIRGO 0512SS2AY manufactured by Kikusui Seisakusho Co., Ltd.
  • the pharmaceutical preparation of the present invention and the pharmaceutically acceptable additive are mixed in advance and then tableted.
  • the method for mixing the pharmaceutical preparation and the additive is not particularly limited, and a known method can be used.
  • Examples of the method of mixing the pharmaceutical preparation and the additive include a method of mixing using a mixer such as a V-type mixer. Specifically, mixing can be performed using a V-type mixer (TCV-20) manufactured by Tokuju Kosakusho Co., Ltd.
  • the method of using a pharmaceutical preparation as a capsule is not particularly limited, and a known method can be used. Specifically, it is produced by filling a capsule film made of gelatin, a plant-derived raw material, or the like with a pharmaceutical preparation.
  • the filling of the capsule film is not particularly limited, and can be performed by a known method such as auger type powder filling, radish press type powder filling, and vibration type powder filling.
  • auger-type powder filling a pharmaceutical preparation of powder or granules that is dropped and supplied from a hopper into a cap-shaped body that is usually formed of a gelatin film and has open ends is directly encapsulated by a stirring blade and the rotational pressure of the auger.
  • Capsules can be produced by partially filling the capsules in a predetermined amount and then coaxially bonding the bodies.
  • average particle size (D50) means “50% particle size based on volume distribution”.
  • FIG. 1A and 1B are electron micrographs of needle-shaped and / or substantially columnar crystalline cellulose CEOLUS KG-1000 and CEOLUS UF-702, respectively, and FIG. 2 is an electron micrograph of lactose hydrate (substantially spherical particles). Yes, FIG. 3 is an electron micrograph of corn starch (approximately spherical particles).
  • Lactose hydrate (SuperTab®, average aspect ratio 1.39, average particle size (D50) 120 ⁇ m, manufactured by DFE Pharma), and corn starch (Japanese corn starch) as substantially spherical particles according to the formulation shown in Table 2.
  • the average aspect ratio of each nuclear particle component is the aspect ratio of 10 arbitrarily selected particles measured by acquiring a particle image using an electron microscope (VE-7800, manufactured by KEYENCE) and analyzing the image. It means the average value of the aspect ratios of the particles measured and excluding the values of the aspect ratios of the particles having the upper 10% and the lower 10% of the aspect ratio values. Further, in Table 2, unless otherwise specified, the unit of the numerical value is g (gram).
  • ⁇ Measurement of bulk density of nuclear particle mixture The firmness density and looseness density were measured for each of the obtained nuclear particle mixtures (primary particles). Specifically, using Powder Tester (registered trademark) PT-R (manufactured by Hosokawa Micron Co., Ltd.), a container for measuring bulk density and tap density measurement method 3 described in the 17th revised Japanese Pharmacy Law. The bulk density (loose bulk density) in a loosely filled state is measured by uniformly supplying the nuclear particle mixture through a sieve to a cylindrical container of the same size from above, and weighing by scraping the upper surface. Next, an auxiliary cylinder was fitted on the container, the nuclear particle mixture was added up to the upper edge, and tapping was performed 180 times.
  • Powder Tester registered trademark
  • PT-R manufactured by Hosokawa Micron Co., Ltd.
  • each non-volatile solvent was put into a 500 mL beaker according to the formulation shown in Table 2, and stirred and mixed at 400 to 900 rpm using a stirrer (NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.). After stirring and mixing until uniform, each drug was added, and the mixture was further stirred and mixed to obtain a drug solution.
  • the logP values of each drug are as shown in Table 2.
  • each coating layer component is put into a stainless steel container, and the coating layer solution is prepared by stirring and mixing at 400 to 900 rpm using a stirrer (NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.). Obtained.
  • the coating layer solution was sprayed on each of the core particles obtained above, dried at 60 ° C. for 15 minutes, and the core particles were dried. Obtained a pharmaceutical formulation coated with a coating layer solution.
  • the setting conditions of the fluidized bed granulator are as shown in Table 5.
  • the degree of cohesion of the obtained pharmaceutical preparations of Examples and Comparative Examples was measured by the same method as the above-mentioned measurement of the degree of cohesion of nuclear particles. The results are shown in Table 4 above.
  • Example 1 it has not been confirmed whether or not tablets can be produced by tableting, but since the degree of cohesion (cohesion after coating) of the pharmaceutical preparation is suppressed, the production of tablets by tableting has not been confirmed. Is presumed to be possible. Further, even when a pharmaceutical preparation is produced with a formulation in which the non-volatile solvent (polysorbate 80) of Examples 1 to 6 is replaced with fat (medium chain fatty acid triglyceride), the aggregation of the pharmaceutical preparation is suppressed and the fluidity is good. It has been confirmed that. Furthermore, it has been confirmed that these pharmaceutical preparations can be produced in the form of granules and can be tableted to produce tablets.
  • the non-volatile solvent polysorbate 80

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Abstract

Disclosed is a medicinal preparation that is in the form of granules each comprising a core particle and a coating layer coating the core particle, wherein: the core particle comprises a drug, a first core particle component, a second core particle component and a non-volatile solvent; the first core particle component is at least one kind of crystalline cellulose in a shape selected from a needle-type shape and a nearly columnar shape; and the second core particle component is at least one kind of pharmaceutically acceptable additive in a nearly spherical shape. This medicinal preparation can contain a surfactant, vitamins and a non-volatile solvent such as a fat or oil useful for the production of medicines, while being highly flowable and thus enduring a practical manufacturing process.

Description

医薬製剤およびその製造方法Pharmaceutical preparations and their manufacturing methods
　本特許出願は、先に出願された日本国における特許出願である特願２０１９－８４６８８号（出願日：２０１９年４月２５日）に基づく優先権の主張を伴うものである。この先の特許出願における全開示内容は、引用することにより本明細書の一部とされる。 This patent application is accompanied by a priority claim based on Japanese Patent Application No. 2019-84688 (application date: April 25, 2019), which is a patent application filed earlier in Japan. All disclosures in subsequent patent applications are incorporated herein by reference.
　本発明は、医薬製剤およびその製造方法に関する。 The present invention relates to a pharmaceutical preparation and a method for producing the same.
　従来、医薬品分野で用いられる有効成分および添加剤の中には、常温で液体状態であるため、顆粒剤、錠剤に配合する場合に必要量を配合することが困難な成分が多数存在している。 Conventionally, among the active ingredients and additives used in the pharmaceutical field, there are many ingredients that are difficult to formulate in the required amount when blended in granules and tablets because they are in a liquid state at room temperature. ..
　このような常温で液体状態の成分（液体成分）を含む固形製剤としては、ソフトカプセル剤が広く用いられている（例えば、特許文献１）。しかしながら、ソフトカプセル剤は、錠剤等の他の固形製剤と比較して直径が大きい場合もあるため、嚥下能力の低い小児や高齢者、嚥下能力が低下した患者等には服用しにくいという問題がある。また、ソフトカプセル剤では、その性質上、製造方法によっては液漏れしやすいというリスクがある。さらには、ソフトカプセルは柔らかく、容易に変形することから、人による目視により、または専用の検査機械を用いて変形の有無を検査しなければならない等、製造コストの面からも、錠剤等の他の固形製剤と比較して高いという問題点がある。 Soft capsules are widely used as solid preparations containing such components (liquid components) in a liquid state at room temperature (for example, Patent Document 1). However, since soft capsules may have a larger diameter than other solid preparations such as tablets, there is a problem that they are difficult to take for children and the elderly with low swallowing ability, patients with poor swallowing ability, and the like. .. In addition, soft capsules have a risk of leaking easily depending on the manufacturing method due to their nature. Furthermore, since soft capsules are soft and easily deformed, the presence or absence of deformation must be inspected visually by humans or using a dedicated inspection machine. From the viewpoint of manufacturing cost, other tablets and the like can be used. There is a problem that it is expensive compared to solid preparations.
　一方で、液体成分を配合し得る固形製剤として、錠剤が用いられている。錠剤に液体成分を配合する場合には、一般的に、打錠前に液体成分と固体成分とを混合して、固体成分の表面に液体成分が付着した粒子を得、得られた粒子を打錠する方法がとられている。しかしながら、このような方法では、粒子中の固体成分表面に存在する液体成分が粒子同士の凝集や吸着を引き起こし、粒子の流動性が低下するため、粒子を錠剤化することが困難である。特に、ソフトカプセル剤と同程度の量の液体成分を含有する錠剤を調製しようとすると、液体成分と固体成分とを混合して得られた粒子では流動性が低く、錠剤化することが極めて困難である。従って、錠剤に配合し得る液体成分は、流動性を大きく低下させない程度の少量のみである。 On the other hand, tablets are used as a solid preparation that can contain liquid components. When a liquid component is blended in a tablet, generally, the liquid component and the solid component are mixed before tableting to obtain particles having the liquid component adhered to the surface of the solid component, and the obtained particles are tableted. The method is taken. However, in such a method, it is difficult to tablet the particles because the liquid component existing on the surface of the solid component in the particles causes agglutination and adsorption between the particles and the fluidity of the particles is lowered. In particular, when trying to prepare a tablet containing a liquid component in the same amount as a soft capsule, the particles obtained by mixing the liquid component and the solid component have low fluidity and are extremely difficult to tablet. is there. Therefore, the liquid component that can be blended in the tablet is only a small amount that does not significantly reduce the fluidity.
　ところで、難水溶性薬物を製剤化する場合、難水溶性薬物の溶解性の低さを改善するために、難水溶性薬物と固体分散体等とを組み合わせて用いることが知られている（例えば、特許文献２）。難水溶性薬物と固体分散体とを組み合わせる方法としては、スプレードライ法や溶融法を用いることが一般的である。しかしながら、スプレードライ法は、大型の機械が必要となるという問題があり、溶融法は、薬物を溶解させるために高温の熱処理を行うため、その過程で薬物が変性・分解する可能性があるという問題がある。 By the way, when a poorly water-soluble drug is formulated, it is known to use a poorly water-soluble drug in combination with a solid dispersion or the like in order to improve the low solubility of the poorly water-soluble drug (for example). , Patent Document 2). As a method for combining the poorly water-soluble drug and the solid dispersion, a spray-drying method or a melting method is generally used. However, the spray-drying method has a problem that a large machine is required, and the melting method performs high-temperature heat treatment to dissolve the drug, so that the drug may be denatured and decomposed in the process. There's a problem.
　また、多量の液体成分を配合した錠剤を調製するために、シリカゲル等の多孔性物質に液体物質を吸着させる技術も知られているが（例えば、特許文献３）、そのような技術を実現するためには真空状態での処理が必要であり、そのために高額な装置が必要となるという問題がある。 Further, in order to prepare a tablet containing a large amount of liquid components, a technique of adsorbing a liquid substance on a porous substance such as silica gel is also known (for example, Patent Document 3), but such a technique is realized. For this purpose, processing in a vacuum state is required, and there is a problem that an expensive device is required for that purpose.
　また、中性またはアルカリ性の樹脂中に液体成分を封入することにより、製剤の流動性の低下を抑制する方法も知られているが、樹脂を用いることにより液体成分の溶出挙動が影響を受ける可能性があり、所望の溶出挙動を得ることが困難であるという問題がある。 Further, a method of suppressing a decrease in the fluidity of a preparation by encapsulating a liquid component in a neutral or alkaline resin is also known, but the use of the resin may affect the elution behavior of the liquid component. There is a problem that it is property and it is difficult to obtain the desired elution behavior.
　また、液体の有効成分を水中油型エマルションの形態に調製し、このエマルション溶液を粉体に噴霧して付着させ、乾燥して水を除去することにより、有効成分が付着した粉体を得る方法が知られている（例えば、特許文献４）。さらに、薬物と水溶性高分子とを不活性担体に塗布し、乾燥させて粒子にする方法も知られている（例えば、特許文献５）。 Further, a method of preparing a liquid active ingredient in the form of an oil-in-water emulsion, spraying the emulsion solution onto the powder to attach it, and drying it to remove water to obtain a powder to which the active ingredient is attached. Is known (for example, Patent Document 4). Further, there is also known a method in which a drug and a water-soluble polymer are applied to an inert carrier and dried to form particles (for example, Patent Document 5).
　また、粉末状または微粒状成分と液体成分とからなる顆粒であって、流動性を向上させた顆粒も知られている（例えば、特許文献６）。 Further, granules composed of a powdery or fine granular component and a liquid component and having improved fluidity are also known (for example, Patent Document 6).
　また、薬物と可溶化物質とが組み合わされて配合された顆粒を含む薬物製剤が知られており、可溶化物質として界面活性剤が用いられ得ること、顆粒がコーティングされ得ることが知られている（例えば、特許文献７）。しかしながら、界面活性剤は、付着性・粘着性を有し、流動性を低下させることから、錠剤等の医薬製剤の調製に用いる場合には配合量が制限されるという問題がある。 Further, a drug preparation containing granules containing a combination of a drug and a solubilizer is known, and it is known that a surfactant can be used as the solubilizer and the granules can be coated. (For example, Patent Document 7). However, since the surfactant has adhesiveness and adhesiveness and lowers the fluidity, there is a problem that the blending amount is limited when it is used for the preparation of pharmaceutical preparations such as tablets.
　このように、液体成分を含有する医薬製剤の開発が行われているが、液体成分を多量に含有する医薬製剤では流動性が低下することから、流動性の低下が製剤化に影響を及ぼす錠剤等の医薬製剤においては、治療上有効量の薬物を溶解させるのに十分な量の液体成分を配合することが容易にできるとは言い難かった。 In this way, pharmaceutical preparations containing liquid components have been developed, but since the fluidity of pharmaceutical preparations containing a large amount of liquid components decreases, the reduction in fluidity affects the formulation of tablets. It has been difficult to say that it is possible to easily add a liquid component in an amount sufficient to dissolve a therapeutically effective amount of a drug in a pharmaceutical preparation such as.
特表２００３－５０８３８６号公報Special Table 2003-508386 Gazette 特表２０１０－５２６８４８号公報Special Table 2010-526848 特表２０１０－５１２１４２号公報Special Table 2010-512142 国際公開第２００９／００１７８６号公報International Publication No. 2009/001786 特表２００１－５１１１５６号公報Special Table 2001-511156 特開昭６１－１８５３２７号公報Japanese Unexamined Patent Publication No. 61-185327 特表２００７－５１７０６２号公報Special Table 2007-517062
　このような状況に鑑み、治療上有効量の薬物を溶解させるのに十分な量の不揮発性溶媒、または医薬品として有用な不揮発性溶媒を含み、実際の製造に耐え得る優れた流動性を有する医薬製剤が求められている。 In view of this situation, a drug containing a sufficient amount of a non-volatile solvent to dissolve a therapeutically effective amount of the drug, or a non-volatile solvent useful as a drug, and having excellent fluidity capable of withstanding actual production. Formulations are required.
　本発明者らが鋭意検討した結果、特定の形状を有する核粒子成分と共に薬物を含む核粒子と、該核粒子を被覆する被覆層とを備える医薬製剤を調製したところ、医薬製剤に不揮発性溶媒および薬物を多量に含有させることができ、かつ、優れた流動性を有することを見出した。本発明は、かかる知見に基づくものである。 As a result of diligent studies by the present inventors, a pharmaceutical preparation comprising a nuclear particle containing a drug together with a nuclear particle component having a specific shape and a coating layer covering the nuclear particle was prepared. And it was found that it can contain a large amount of a drug and has excellent fluidity. The present invention is based on such findings.
　本発明には、以下の発明が包含される。
［１］核粒子と該核粒子を被覆する被覆層とを備える顆粒の形態の医薬製剤であって、
　前記核粒子が、薬物、第１の核粒子成分、第２の核粒子成分および不揮発性溶媒を含んでなり、
　前記第１の核粒子成分は、針状および略柱状から選択される形状を有する少なくとも１種の結晶セルロースであり、
　前記第２の核粒子成分は、略球状の少なくとも１種の薬学的に許容可能な添加剤である、前記医薬製剤。
［２］前記第１の核粒子成分の平均アスペクト比が１．８以上である、［１］に記載の医薬製剤。
［３］前記第１の核粒子成分の平均アスペクト比が１．８～１０．０である、［２］に記載の医薬製剤。
［４］前記第２の核粒子成分の平均アスペクト比が１．０～１．７である、［１］～［３］のいずれかに記載の医薬製剤。
［５］前記第２の核粒子成分の平均アスペクト比が１．０～１．５である、［４］に記載の医薬製剤。
［６］前記第１の核粒子成分と第２の核粒子成分との平均アスペクト比の差が０．５以上である、［１］～［５］のいずれかに記載の医薬製剤。
［７］前記第１の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）に対する前記第２の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）の比が１：１．１以下である、［１］～［６］のいずれかに記載の医薬製剤。
［８］前記第２の核粒子成分が、少なくとも２つの異なる成分からなる、［１］～［７］のいずれかに記載の医薬製剤。
［９］前記第１の核粒子成分と第２の核粒子成分との質量比が１：１～１：１０である、［１］～［８］のいずれかに記載の医薬製剤。
［１０］前記第１の核粒子成分および第２の核粒子成分の総質量と、前記不揮発性溶媒との質量比が１：０．０１～１：０．６である、［１］～［９］のいずれかに記載の医薬製剤。
［１１］前記不揮発性溶媒と前記薬物との質量比が１：０．１～１：１０である、［１］～［１０］のいずれかに記載の医薬製剤。
［１２］前記第１の核粒子成分および第２の核粒子成分の総質量と、前記被覆層の質量との質量比が１：０．０５～１：０．３である、［１］～［１１］のいずれかに記載の医薬製剤。
［１３］前記第２の核粒子成分が、糖類および無機化合物からなる群から選択される少なくとも１種の薬学的に許容可能な添加剤である、［１］～［１２］のいずれかに記載の医薬製剤。
［１４］前記第２の核粒子成分が、ブドウ糖、果糖、乳糖、乳糖水和物、ショ糖、白糖、圧縮等、精製粉末砂糖、アルギン酸アンモニウム、デンプン、ジャガイモデンプン、コムギデンプン、トウモロコシデンプン、コメデンプン、マンニトール、ソルビトール、リン酸塩、炭酸マグネシウム、酸化マグネシウム、炭酸カルシウム、硫酸カルシウム、デキストレート類、デキストリン、デキストロース、ポリメタクリレート、パルミトステアリン酸グリセリン、イソマルト、ラクチトール、カオリン、ラクチトール、マルチトール、マルトデキストリン、マルトース、トレハロース、キシリトール、アルファー化デンプン、変性アルファー化デンプン、タピオカデンプン、塩化ナトリウムからなる群から選択される少なくとも１つのものである、［１］～［１３］のいずれかに記載の医薬製剤。
［１５］前記不揮発性溶媒が、界面活性剤、ビタミン類および油脂からなる群から選択される少なくとも１種を含んでなる、［１］～［１４］のいずれかに記載の医薬製剤。
［１６］前記界面活性剤が非イオン性界面活性剤である、［１５］に記載の医薬製剤。
［１７］前記非イオン性界面活性剤がポリソルベートである、［１６］に記載の医薬製剤。
［１８］前記油脂がグリセリン脂肪酸エステルである、［１５］に記載の医薬製剤。
［１９］前記グリセリン脂肪酸エステルが中鎖脂肪酸トリグリセリドである、［１８］に記載の医薬製剤。
［２０］前記薬物のｌｏｇＰ値が－２～７である、［１］～［１９］のいずれかに記載の医薬製剤。
［２１］前記薬物のｌｏｇＰ値が－１．９～６．５である、［１］～［２０］のいずれかに記載の医薬製剤。
［２２］前記薬物が難水溶性薬物を含んでなる、［１］～［２１］のいずれかに記載の医薬製剤。
［２３］前記難水溶性薬物が、ホルモン剤、抗癌剤、抗菌剤および抗ウイルス剤（Ｎ－［５－フルオロ－２－（１－ピペリジニル）フェニル］イソニコチンチオアミドを除く）からなる群から選択される少なくとも１種を含んでなる、［２２］に記載の医薬製剤。
［２４］前記被覆層が、水溶性コーティング剤を含んでなる、［１］～［２３］のいずれかに記載の医薬製剤。
［２５］前記水溶性コーティング剤が、ポリアルキレングリコール、多糖類、およびそれらの誘導体からなる群より選択される少なくとも一つの成分を含んでなる、［２４］に記載の医薬製剤。
［２６］前記水溶性コーティング剤が、ポリエチレングリコール、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メタアクリル酸コポリマー、ビニルピリジンコポリマー、アルキルビニルピリジンコポリマー、アミノセルロース誘導体、ジエチルアミノエチルメタクリレート、ポリビニルアセタールジエチルアミノアセテート、ジメチルアミノエチルメタクリレート－メタクリレートコポリマー、セルロースアセテート－Ｎ，Ｎ－ジ－ｎ－ブチルヒドロキシルプロピルエーテル、ビニルピリジンとアクリル酸系遊離酸とのコポリマー、アルキルビニルピリジンとアクリル酸系遊離酸とのコポリマー、ビニルピリジンとアクリル酸系遊離酸とビニルモノマーとのコポリマー、アルキルビニルピリジンとアクリル酸系遊離酸とビニルモノマーとのコポリマー、２－メチル－５－ビニルピリジン－メタクリル酸コポリマー、ポリ－２－（ビニルフェニル）グリシン、モルホリノ－Ｎ－β－エチルアクリレート－メタクリル酸コポリマー、シェラック、セルロースアセテートフタレート、メチルアクリレート－メタクリル酸コポリマー、メチルメタクリレート－メタクリル酸コポリマー、ゼイン、ヒドロキシプロピルメチルセルロースフタレートおよびアミノアルキルメタクリレートコポリマーからなる群から選択される少なくとも１種である、［２４］または［２５］に記載の医薬製剤。
［２７］前記医薬製剤の凝集度が７０％以下である、［１］～［２６］のいずれかに記載の医薬製剤。
［２８］前記医薬製剤の凝集度が前記核粒子の凝集度よりも低い、［１］～［２７］のいずれかに記載の医薬製剤。
［２９］前記医薬製剤の体積分布基準の５０％粒子径（Ｄ５０）が１００～４００μｍである、［１］～［２８］のいずれかに記載の医薬製剤。
［３０］［１］～［２９］のいずれかに記載の医薬製剤を含んでなり、顆粒剤、錠剤、カプセル剤、散剤および丸剤からなる群から選択される剤形を有する製剤。
［３１］核粒子と該核粒子を被覆する被覆層とを備える顆粒の形態の医薬製剤の製造方法であって、
　（ａ）第１の核粒子成分と、第２の核粒子成分とを混合して核粒子混合物を得る工程、
　（ｂ）不揮発性溶媒に薬物を溶解または懸濁して混合液を得る工程、
　（ｃ）工程（ａ）で得られた核粒子混合物と、工程（ｂ）で得られた混合液とを接触させて第１の核粒子成分、第２の核粒子成分、薬物および不揮発性溶媒を含む核粒子を得る工程、および、
　（ｄ）工程（ｃ）で得られた核粒子を被覆して医薬製剤を得る工程
を含み、
　前記第１の核粒子成分は、針状および略柱状から選択される形状を有する少なくとも１種の結晶セルロースであり、
　前記第２の核粒子成分は、略球状の少なくとも１種の薬学的に許容可能な添加剤である、前記製造方法。
［３２］前記第１の核粒子成分の平均アスペクト比が１．８以上である、［３１］に記載の製造方法。
［３３］前記第１の核粒子成分の平均アスペクト比が１．８～１０．０である、［３２］に記載の製造方法。
［３４］前記第２の核粒子成分の平均アスペクト比が１．０～１．７である、［３１］～［３３］のいずれかに記載の製造方法。
［３５］前記第２の核粒子成分の平均アスペクト比が１．０～１．５である、［３４］に記載の製造方法。
［３６］
　前記第１の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）に対する前記第２の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）の比が１：１．１以下である、［３１］～［３５］のいずれかに記載の製造方法。
［３７］前記第２の核粒子成分が、少なくとも２つの異なる成分からなる、［３１］～［３６］のいずれかに記載の製造方法。
［３８］前記不揮発性溶媒が、界面活性剤、ビタミン類および油脂からなる群から選択される少なくとも１種を含んでなる、［３１］～［３７］のいずれかに記載の製造方法。
［３９］（ｅ）工程（ｄ）で得られた医薬製剤に薬学的に許容可能な添加剤を加えて造粒して、顆粒状の製剤を得る工程をさらに含む、［３１］～［３８］のいずれかに記載の製造方法。
［４０］（ｅ’）工程（ｄ）で得られた医薬製剤を、ゼラチン、または植物由来の原料からなる皮膜に封入して、カプセル状の製剤を得る工程をさらに含む、［３１］～［３８］のいずれかに記載の製造方法。
［４１］［１］～［２９］のいずれかに記載の医薬製剤を打錠成形して錠剤を得る工程を含んでなる、錠剤の製造方法。
［４２］［１］～［２９］のいずれかに記載の医薬製剤をカプセルに封入する工程を含んでなる、カプセル剤の製造方法。 The present invention includes the following inventions.
[1] A pharmaceutical preparation in the form of granules comprising nuclear particles and a coating layer covering the nuclear particles.
The nuclear particle comprises a drug, a first nuclear particle component, a second nuclear particle component and a non-volatile solvent.
The first nuclear particle component is at least one crystalline cellulose having a shape selected from needle-like and substantially columnar.
The pharmaceutical formulation, wherein the second nuclear particle component is at least one pharmaceutically acceptable additive that is substantially spherical.
[2] The pharmaceutical preparation according to [1], wherein the average aspect ratio of the first nuclear particle component is 1.8 or more.
[3] The pharmaceutical preparation according to [2], wherein the average aspect ratio of the first nuclear particle component is 1.8 to 10.0.
[4] The pharmaceutical preparation according to any one of [1] to [3], wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.7.
[5] The pharmaceutical preparation according to [4], wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.5.
[6] The pharmaceutical preparation according to any one of [1] to [5], wherein the difference in the average aspect ratio between the first nuclear particle component and the second nuclear particle component is 0.5 or more.
[7] The ratio of the 50% particle diameter (D50) of the volume distribution standard of the first nuclear particle component to the 50% particle diameter (D50) of the volume distribution standard of the second nuclear particle component is 1: 1.1. The pharmaceutical preparation according to any one of [1] to [6] below.
[8] The pharmaceutical preparation according to any one of [1] to [7], wherein the second nuclear particle component comprises at least two different components.
[9] The pharmaceutical preparation according to any one of [1] to [8], wherein the mass ratio of the first nuclear particle component to the second nuclear particle component is 1: 1 to 1:10.
[10] The mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component to the non-volatile solvent is 1: 0.01 to 1: 0.6, [1] to [1] to [ 9] The pharmaceutical preparation according to any one of.
[11] The pharmaceutical preparation according to any one of [1] to [10], wherein the mass ratio of the non-volatile solvent to the drug is 1: 0.1 to 1:10.
[12] The mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component to the mass of the coating layer is 1: 0.05 to 1: 0.3, [1] to The pharmaceutical preparation according to any one of [11].
[13] The second nuclear particle component is any of [1] to [12], wherein the second nuclear particle component is at least one pharmaceutically acceptable additive selected from the group consisting of saccharides and inorganic compounds. Pharmaceutical preparations.
[14] The second nuclear particle component is glucose, fructose, lactose, lactose hydrate, sucrose, sucrose, compressed sugar, refined powdered sugar, ammonium alginate, starch, potato starch, wheat starch, corn starch, rice. Starch, mannitol, sorbitol, phosphate, magnesium carbonate, magnesium oxide, calcium carbonate, calcium sulfate, dextrose, dextrin, dextrose, polymethacrylate, glycerin palmitostearate, isomalt, lactitol, kaolin, lactitol, martitol, 6. The one according to any one of [1] to [13], which is at least one selected from the group consisting of maltodextrin, maltose, trehalose, xylitol, pregelatinized starch, modified pregelatinized starch, tapioca starch and sodium chloride. Pharmaceutical preparation.
[15] The pharmaceutical preparation according to any one of [1] to [14], wherein the non-volatile solvent contains at least one selected from the group consisting of surfactants, vitamins and fats and oils.
[16] The pharmaceutical preparation according to [15], wherein the surfactant is a nonionic surfactant.
[17] The pharmaceutical preparation according to [16], wherein the nonionic surfactant is polysorbate.
[18] The pharmaceutical preparation according to [15], wherein the fat and oil is a glycerin fatty acid ester.
[19] The pharmaceutical preparation according to [18], wherein the glycerin fatty acid ester is a medium chain fatty acid triglyceride.
[20] The pharmaceutical preparation according to any one of [1] to [19], wherein the logP value of the drug is -2 to 7.
[21] The pharmaceutical preparation according to any one of [1] to [20], wherein the logP value of the drug is -1.9 to 6.5.
[22] The pharmaceutical preparation according to any one of [1] to [21], wherein the drug comprises a poorly water-soluble drug.
[23] The poorly water-soluble drug is selected from the group consisting of hormonal agents, anticancer agents, antibacterial agents and antiviral agents (excluding N- [5-fluoro-2- (1-piperidinyl) phenyl] isonicotinthioamide). The pharmaceutical preparation according to [22], which comprises at least one of these.
[24] The pharmaceutical preparation according to any one of [1] to [23], wherein the coating layer contains a water-soluble coating agent.
[25] The pharmaceutical preparation according to [24], wherein the water-soluble coating agent contains at least one component selected from the group consisting of polyalkylene glycols, polysaccharides, and derivatives thereof.
[26] The water-soluble coating agent is polyethylene glycol, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer, vinyl pyridine copolymer, alkyl vinyl pyridine copolymer, amino cellulose derivative, diethyl aminoethyl methacrylate, polyvinyl acetal. Diethylaminoacetate, dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N, N-di-n-butylhydroxylpropyl ether, copolymer of vinylpyridine and acrylic acid-based free acid, alkylvinylpyridine and acrylic acid-based free acid Copolymers, copolymers of vinylpyridine and acrylic acid-based free acid and vinyl monomer, copolymers of alkylvinylpyridine and acrylic acid-based free acid and vinyl monomer, 2-methyl-5-vinylpyridine-methacrylic acid copolymer, poly-2- (Vinylphenyl) glycine, morpholino-N-β-ethylacrylate-methacrylic acid copolymer, shelac, cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, zein, hydroxypropyl methyl cellulose phthalate and aminoalkyl methacrylate copolymer The pharmaceutical preparation according to [24] or [25], which is at least one selected from the group consisting of.
[27] The pharmaceutical preparation according to any one of [1] to [26], wherein the degree of cohesion of the pharmaceutical preparation is 70% or less.
[28] The pharmaceutical preparation according to any one of [1] to [27], wherein the degree of cohesion of the pharmaceutical preparation is lower than the degree of cohesion of the nuclear particles.
[29] The pharmaceutical preparation according to any one of [1] to [28], wherein the 50% particle size (D50) based on the volume distribution of the pharmaceutical preparation is 100 to 400 μm.
[30] A preparation comprising the pharmaceutical preparation according to any one of [1] to [29] and having a dosage form selected from the group consisting of granules, tablets, capsules, powders and pills.
[31] A method for producing a pharmaceutical preparation in the form of granules, which comprises nuclear particles and a coating layer covering the nuclear particles.
(A) A step of mixing a first nuclear particle component and a second nuclear particle component to obtain a nuclear particle mixture.
(B) A step of dissolving or suspending a drug in a non-volatile solvent to obtain a mixed solution.
(C) The nuclear particle mixture obtained in step (a) and the mixed solution obtained in step (b) are brought into contact with each other to bring the first nuclear particle component, the second nuclear particle component, the drug and the non-volatile solvent. The process of obtaining nuclear particles containing
(D) Including the step of coating the nuclear particles obtained in step (c) to obtain a pharmaceutical preparation.
The first nuclear particle component is at least one crystalline cellulose having a shape selected from needle-like and substantially columnar.
The production method, wherein the second nuclear particle component is at least one pharmaceutically acceptable additive that is substantially spherical.
[32] The production method according to [31], wherein the average aspect ratio of the first nuclear particle component is 1.8 or more.
[33] The production method according to [32], wherein the average aspect ratio of the first nuclear particle component is 1.8 to 10.0.
[34] The production method according to any one of [31] to [33], wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.7.
[35] The production method according to [34], wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.5.
[36]
The ratio of the 50% particle diameter (D50) of the volume distribution standard of the first nuclear particle component to the 50% particle diameter (D50) of the volume distribution standard of the second nuclear particle component is 1: 1.1 or less. , [31] to [35].
[37] The production method according to any one of [31] to [36], wherein the second nuclear particle component comprises at least two different components.
[38] The production method according to any one of [31] to [37], wherein the non-volatile solvent contains at least one selected from the group consisting of surfactants, vitamins and fats and oils.
[39] to [38] to [38], further comprising a step of adding a pharmaceutically acceptable additive to the pharmaceutical preparation obtained in the (e) step (d) and granulating to obtain a granular preparation. ] The manufacturing method described in any one of.
[40] A step of encapsulating the pharmaceutical preparation obtained in the (e') step (d) in a film made of gelatin or a plant-derived raw material to obtain a capsule-shaped preparation is further included [31] to [ 38] The production method according to any one of.
[41] A method for producing a tablet, which comprises a step of tableting and molding the pharmaceutical preparation according to any one of [1] to [29] to obtain a tablet.
[42] A method for producing a capsule, which comprises a step of encapsulating the pharmaceutical preparation according to any one of [1] to [29].
　本発明によれば、不揮発性溶媒を多量に含みつつも、優れた流動性を有する顆粒の形態の医薬製剤を提供することができる。また、本発明によれば、医薬製剤の流動性の低下をもたらす凝集を抑制することができる。すなわち、医薬製剤において優れた流動性が実現されるため、流動層造粒等の容易な方法により、流動性の低下により製剤化が阻害される錠剤等の医薬製剤に対しても、不揮発性溶媒を多量に配合することができる。その結果、本発明によれば、例え難水溶性薬物であっても、医薬製剤中に治療上有効量配合することができる。さらに、本発明の医薬製剤は、長期間保存した場合でも、核粒子に含まれる不揮発性溶媒が医薬製剤の表面に漏出することを抑制することができる。 According to the present invention, it is possible to provide a pharmaceutical preparation in the form of granules having excellent fluidity while containing a large amount of non-volatile solvent. Further, according to the present invention, it is possible to suppress aggregation that causes a decrease in the fluidity of the pharmaceutical preparation. That is, since excellent fluidity is realized in pharmaceutical preparations, a non-volatile solvent can be used even for pharmaceutical preparations such as tablets whose formulation is inhibited by a decrease in fluidity by an easy method such as fluidized bed granulation. Can be blended in large amounts. As a result, according to the present invention, even a poorly water-soluble drug can be blended in a therapeutically effective amount in a pharmaceutical preparation. Furthermore, the pharmaceutical preparation of the present invention can prevent the non-volatile solvent contained in the nuclear particles from leaking to the surface of the pharmaceutical preparation even when stored for a long period of time.
図１ＡおよびＢは、第１の核粒子成分（針状結晶セルロース）の電子顕微鏡写真である。図１Ａは針状結晶セルロース（ＣＥＯＬＵＳ　ＫＧ－１０００）の電子顕微鏡写真であり、図１Ｂは針状結晶セルロース（ＣＥＯＬＵＳ　ＵＦ－７０２）の電子顕微鏡写真である。1A and 1B are electron micrographs of the first nuclear particle component (needle-shaped crystalline cellulose). FIG. 1A is an electron micrograph of acicular crystalline cellulose (CEOLUS KG-1000), and FIG. 1B is an electron micrograph of acicular crystalline cellulose (CEOLUS UF-702). 図２は、第２の核粒子成分（略球状粒子：乳糖水和物）の電子顕微鏡写真である。FIG. 2 is an electron micrograph of the second nuclear particle component (substantially spherical particles: lactose hydrate). 図３は、第２の核粒子成分（略球状粒子：トウモロコシデンプン）の電子顕微鏡写真である。FIG. 3 is an electron micrograph of the second nuclear particle component (substantially spherical particles: corn starch).
発明の具体的説明Specific description of the invention
　以下、本発明について詳細に説明する。なお、本明細書において、「～」を用いて示された数値範囲は、「～」の前後に記載される数値をそれぞれ最小値および最大値として含む範囲を意味する。本明細書中において、「ＡまたはＢ」なる表現を用いて記載した場合は、特に記載がなくまた文脈から限定的に解釈される場合を除き、一方あるいは両者のいずれも含む意味である。 Hereinafter, the present invention will be described in detail. In addition, in this specification, the numerical range indicated by using "-" means the range including the numerical values before and after "-" as the minimum value and the maximum value, respectively. In the present specification, when the expression "A or B" is used, it means that one or both of them are included unless otherwise specified and the interpretation is limited from the context.
［医薬製剤］
　本発明の医薬製剤は、核粒子と該核粒子を被覆する被覆層とを備える顆粒の形態の医薬製剤である。以下、核粒子および被覆層のそれぞれについて説明する。 [Pharmaceutical preparation]
The pharmaceutical preparation of the present invention is a pharmaceutical preparation in the form of granules comprising nuclear particles and a coating layer covering the nuclear particles. Hereinafter, each of the nuclear particles and the coating layer will be described.
＜核粒子＞
　核粒子は、薬物、第１の核粒子成分、第２の核粒子成分および不揮発性溶媒を含んでなり、第１の核粒子成分は針状および／または略柱状の結晶セルロース（以下、単に「針状結晶セルロース」という場合がある。）であり、第２の核粒子成分は略球状を有する少なくとも１種の薬学的に許容可能な添加剤である。 <Nuclear particles>
The nuclear particle comprises a drug, a first nuclear particle component, a second nuclear particle component and a non-volatile solvent, and the first nuclear particle component is a needle-like and / or substantially columnar crystalline cellulose (hereinafter, simply ". It may be referred to as "needle-shaped crystalline cellulose"), and the second nuclear particle component is at least one pharmaceutically acceptable additive having a substantially spherical shape.
　核粒子は、形状が大きく異なる第１の核粒子成分と第２の核粒子成分とを含んでなるため、第１の核粒子成分と第２の核粒子成分との間に多くの空隙を形成し得る。その結果、核粒子中に、液体成分が内包し得る表面積が大きく生じるため、核粒子中に多量の液体成分を含有し得る。そして、核粒子が、液体成分として、可溶化剤として用いられる界面活性剤等の不揮発性溶媒を多量に含有し得ることから、難水溶性の薬物を溶解または懸濁させることができる。理論に拘束されるものではないが、このようなメカニズムにより、核粒子中に多量の難溶性の薬物を含有する医薬製剤を製造することが可能となると考えられる。 Since the nuclear particle contains a first nuclear particle component and a second nuclear particle component having significantly different shapes, many voids are formed between the first nuclear particle component and the second nuclear particle component. Can be done. As a result, a large surface area can be contained in the nuclear particles, so that the nuclear particles can contain a large amount of the liquid component. Since the nuclear particles can contain a large amount of a non-volatile solvent such as a surfactant used as a solubilizer as a liquid component, a poorly water-soluble drug can be dissolved or suspended. Without being bound by theory, it is believed that such a mechanism makes it possible to produce pharmaceutical preparations containing a large amount of sparingly soluble drug in the nuclear particles.
（第１の核粒子成分）
　本発明の一実施態様によれば、核粒子に使用される第１の核粒子成分は、針状結晶セルロースである。本発明で用いられる第１の核粒子成分である針状結晶セルロースは、医薬製剤の調製において添加され得る結晶セルロースに由来する。針状結晶セルロースとしては、本発明の効果が奏されるのに十分な割合の針状および／または略柱状の結晶を含んでいればよい。第１の核粒子成分における針状および／または略柱状の結晶セルロースの割合の下限値は、特に限定されないが、結晶（粒子）の個数として、好ましくは６０％、より好ましくは７０％、より一層好ましくは８０％である。また、上限値は、例えば、１００％、９８％、９５％、９０％等とすることができる。第１の核粒子成分における針状および／または略柱状の結晶セルロースの割合の範囲は、特に限定されないが、結晶（粒子）の個数として、好ましくは６０～１００％、より好ましくは７０～１００％、より一層好ましくは８０～１００％である。本明細書において「針状結晶セルロース」とは、電子顕微鏡により測定される画像上（平面に転写された形状）の結晶セルロースの長軸方向の断面において、縦横の長さに顕著な差がある結晶セルロースをいう。ここで、縦横の長さに顕著な差は、例えば、アスペクト比で表すことができる。 (First nuclear particle component)
According to one embodiment of the present invention, the first nuclear particle component used for the nuclear particles is acicular crystalline cellulose. The acicular crystalline cellulose which is the first nuclear particle component used in the present invention is derived from the crystalline cellulose which can be added in the preparation of a pharmaceutical preparation. The needle-shaped crystalline cellulose may contain a sufficient proportion of needle-shaped and / or substantially columnar crystals so that the effects of the present invention can be exhibited. The lower limit of the proportion of acicular and / or substantially columnar crystalline cellulose in the first nuclear particle component is not particularly limited, but the number of crystals (particles) is preferably 60%, more preferably 70%, and even more. It is preferably 80%. The upper limit can be, for example, 100%, 98%, 95%, 90% or the like. The range of the proportion of acicular and / or substantially columnar crystalline cellulose in the first nuclear particle component is not particularly limited, but the number of crystals (particles) is preferably 60 to 100%, more preferably 70 to 100%. , Even more preferably 80 to 100%. In the present specification, "needle-shaped crystalline cellulose" has a remarkable difference in vertical and horizontal lengths in a cross section in the long axis direction of crystalline cellulose on an image (a shape transferred to a plane) measured by an electron microscope. Crystalline cellulose. Here, the remarkable difference in the vertical and horizontal lengths can be expressed by, for example, the aspect ratio.
　具体的には、第１の核粒子成分の平均アスペクト比は、本発明の効果が奏される限り特に限定されないが、第２の核粒子成分の平均アスペクト比よりも大きく、下限値としては、好ましくは１．８、より好ましくは２．２、より一層好ましくは２．５である。また、第１の核粒子成分の平均アスペクト比の上限値は、本発明の効果が奏される限り特に限定されず、例えば、１０以下、８以下等とすることができる。また、第１の核粒子成分の平均アスペクト比の範囲としては、特に限定されないが、好ましくは１．８～１０、より好ましくは２．２～１０、より一層好ましくは２．５～１０である。本明細書において、核粒子成分の「アスペクト比」とは、電子顕微鏡を用いた粒子画像解析における、核粒子成分の短径に対する長径の比の値（長径／短径）を意味する。また、核粒子成分の「平均アスペクト比」とは、任意に選択した１０個以上の核粒子成分のアスペクト比を測定し、アスペクト比の値の上位１０％および下位１０％の核粒子成分のアスペクト比の値を除外した核粒子成分のアスペクト比の平均値を意味する。 Specifically, the average aspect ratio of the first nuclear particle component is not particularly limited as long as the effect of the present invention is exhibited, but it is larger than the average aspect ratio of the second nuclear particle component, and the lower limit value is It is preferably 1.8, more preferably 2.2, and even more preferably 2.5. The upper limit of the average aspect ratio of the first nuclear particle component is not particularly limited as long as the effect of the present invention is exhibited, and can be, for example, 10 or less, 8 or less, and the like. The range of the average aspect ratio of the first nuclear particle component is not particularly limited, but is preferably 1.8 to 10, more preferably 2.2 to 10, and even more preferably 2.5 to 10. .. In the present specification, the "aspect ratio" of the nuclear particle component means the value (major axis / minor axis) of the ratio of the major axis to the minor axis of the nuclear particle component in the particle image analysis using an electron microscope. The "average aspect ratio" of the nuclear particle component is the aspect ratio of 10 or more nuclear particle components selected arbitrarily, and the aspect ratio of the upper 10% and lower 10% of the aspect ratio values. It means the average value of the aspect ratios of the nuclear particle components excluding the ratio value.
　第１の核粒子成分の量は、本発明の効果が奏される限り特に限定されないが、医薬製剤の総質量に対して、好ましくは５～５０質量％である。 The amount of the first nuclear particle component is not particularly limited as long as the effect of the present invention is exhibited, but is preferably 5 to 50% by mass with respect to the total mass of the pharmaceutical preparation.
（第２の核粒子成分）
　本発明の一実施態様によれば、核粒子に使用される第２の核粒子成分は、略球状の薬学的に許容可能な添加剤である。本明細書において「略球状」とは、電子顕微鏡により測定される画像上（平面に転写された形状）において、縦横の長さに顕著な差が無い球状に近似する形状をいい、針状および略柱状を含まない。したがって、一つの実施態様によれば、第２の核粒子成分は非針状かつ非柱状の薬学的に許容可能な添加剤である。「略球状」は、電子顕微鏡により測定される画像が必ずしも完全な球状そのものである必要はなく、例えば、歪んだ球状、楕円体状、多面体状（立方体状を含む）、角が取れた多面体状であってもよい。 (Second nuclear particle component)
According to one embodiment of the invention, the second nuclear particle component used for the nuclear particle is a substantially spherical pharmaceutically acceptable additive. As used herein, the term "substantially spherical" refers to a shape that approximates a spherical shape with no significant difference in length and width on an image measured by an electron microscope (shape transferred to a plane), and is needle-shaped and. Does not include a substantially columnar shape. Therefore, according to one embodiment, the second nuclear particle component is a non-needle and non-columnar pharmaceutically acceptable additive. "Approximately spherical" does not necessarily mean that the image measured by an electron microscope is a perfect spherical shape, for example, a distorted spherical shape, an ellipsoidal shape, a polyhedral shape (including a cube shape), or a polyhedral shape with rounded corners. It may be.
　第２の核粒子成分の平均アスペクト比は、第１の核粒子成分の平均アスペクト比よりも小さく、好ましくは１．０～１．６５、より好ましくは１．０～１．５であり、より一層好ましくは１．０～１．３、さらにより一層好ましくは１．０～１．２である。第２の核粒子成分に関し、核粒子成分のアスペクト比および核粒子成分の平均アスペクト比は、それぞれ第１の核粒子成分について定義したものと同様である。 The average aspect ratio of the second nuclear particle component is smaller than the average aspect ratio of the first nuclear particle component, preferably 1.0 to 1.65, more preferably 1.0 to 1.5, and more. It is even more preferably 1.0 to 1.3, and even more preferably 1.0 to 1.2. Regarding the second nuclear particle component, the aspect ratio of the nuclear particle component and the average aspect ratio of the nuclear particle component are the same as those defined for the first nuclear particle component, respectively.
　本発明の医薬製剤における第２の核粒子成分の量は、本発明の効果が奏される限り特に限定されないが、医薬製剤の総質量に対して、好ましくは３０～９０質量％である。 The amount of the second nuclear particle component in the pharmaceutical preparation of the present invention is not particularly limited as long as the effect of the present invention is exhibited, but is preferably 30 to 90% by mass with respect to the total mass of the pharmaceutical preparation.
　第２の核粒子成分の粒子径は、本発明の効果が奏される限り特に限定されないが、第２の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）が、第１の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）に対する比（第１の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）：第２の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０））として、好ましくは１：１．１以下であり、より好ましくは１：０．５以下、より一層好ましくは１：０．１以下となるように調整される。 The particle size of the second nuclear particle component is not particularly limited as long as the effect of the present invention is exhibited, but the 50% particle size (D50) of the volume distribution standard of the second nuclear particle component is the first nuclear particle. Ratio of component volume distribution standard to 50% particle size (D50) (1st nuclear particle component volume distribution standard 50% particle size (D50): 2nd nuclear particle component volume distribution standard 50% particle size (D50)) is preferably adjusted to be 1: 1.1 or less, more preferably 1: 0.5 or less, and even more preferably 1: 0.1 or less.
　第２の核粒子成分は、１種の成分を単独で用いてもよく、２種以上の成分を組み合わせて用いてもよいが、好ましくは体積分布基準の５０％粒子径（Ｄ５０）が異なる２種またはそれ以上の成分を組み合わせて用いられる。例えば、第２の核粒子成分が２種の成分から構成される場合、それぞれの成分の体積分布基準の５０％粒子径（Ｄ５０）は異なることが好ましい。なお、本発明において、核粒子成分が２種以上の成分を含む場合、核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）は、核粒子成分を構成する成分の全質量に対する各成分の質量の割合を算出し、各成分についてその割合と体積分布基準の５０％粒子径（Ｄ５０）との積を算出し、それらの積の合計として算出される。例えば、核粒子成分が２種の成分ＡおよびＢを含み、成分ＡおよびＢの質量がそれぞれａおよびｂであり、ＡおよびＢの体積分布基準の５０％粒子径（Ｄ５０）がそれぞれＤ５０ＡおよびＤ５０Ｂである場合、核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）は以下の式により算出される：
Figure JPOXMLDOC01-appb-M000001
 As the second nuclear particle component, one kind of component may be used alone, or two or more kinds of components may be used in combination, but preferably, the 50% particle diameter (D50) based on the volume distribution is different. Used in combination with seeds or higher components. For example, when the second nuclear particle component is composed of two kinds of components, it is preferable that the 50% particle diameter (D50) of each component based on the volume distribution is different. In the present invention, when the nuclear particle component contains two or more kinds of components, the 50% particle diameter (D50) of the volume distribution standard of the nuclear particle component is the total mass of each component constituting the nuclear particle component. The mass ratio is calculated, the product of the ratio and the 50% particle diameter (D50) based on the volume distribution is calculated for each component, and the product is calculated as the sum of the products. For example, the nuclear particle component contains two components A and B, the masses of the components A and B are a and b, respectively, and the 50% particle diameter (D50) of the volume distribution reference of A and B is D50 A and, respectively. In the case of D50 B , the 50% particle diameter (D50) based on the volume distribution of the nuclear particle component is calculated by the following formula:
Figure JPOXMLDOC01-appb-M000001
　第２の核粒子成分を構成する成分は、薬学的に許容可能な成分であれば特に限定されないが、例えば、糖類（糖、糖水和物、糖アルコール等を含む）、無機化合物等が挙げられる。 The component constituting the second nuclear particle component is not particularly limited as long as it is a pharmaceutically acceptable component, and examples thereof include sugars (including sugars, sugar hydrates, sugar alcohols, etc.), inorganic compounds, and the like. ..
　糖としては、特に限定されないが、例えば、ブドウ糖等の単糖類、乳糖およびショ糖等の二糖類、デンプン等の多糖類等が挙げられる。デンプンとしては、例えば、ジャガイモデンプン、コムギデンプン、トウモロコシデンプン、コメデンプン等が挙げられる。糖としては、好ましくはトウモロコシデンプンが用いられる。 The sugar is not particularly limited, and examples thereof include monosaccharides such as glucose, disaccharides such as lactose and sucrose, and polysaccharides such as starch. Examples of starch include potato starch, wheat starch, corn starch, rice starch and the like. As the sugar, corn starch is preferably used.
　糖水和物としては、特に限定されないが、例えば、上述した糖の任意の水和物が挙げられ、好ましくは乳糖水和物が用いられる。 The sugar hydrate is not particularly limited, and examples thereof include any of the above-mentioned sugar hydrates, and lactose hydrate is preferably used.
　糖アルコールとしては、特に限定されないが、任意の糖に由来する糖アルコールが挙げられ、好ましくはマンニトールまたはソルビトールが用いられる。 The sugar alcohol is not particularly limited, and examples thereof include sugar alcohols derived from any sugar, and mannitol or sorbitol is preferably used.
　無機化合物としては、特に限定されないが、無水リン酸カルシウム等のリン酸塩等が挙げられる。 The inorganic compound is not particularly limited, and examples thereof include phosphates such as anhydrous calcium phosphate.
　第１の核粒子成分は、第２の核粒子成分よりも大きい平均アスペクト比を有し、第１および第２の核粒子成分の平均アスペクト比の差は大きいことが好ましい。具体的には、第１および第２の核粒子成分の平均アスペクト比の差（第１の核粒子成分の平均アスペクト比－第２の核粒子成分の平均アスペクト比）は、好ましくは０．５以上、より好ましくは０．６以上、より一層好ましくは０．７以上である。 It is preferable that the first nuclear particle component has a larger average aspect ratio than the second nuclear particle component, and the difference between the average aspect ratios of the first and second nuclear particle components is large. Specifically, the difference in the average aspect ratios of the first and second nuclear particle components (average aspect ratio of the first nuclear particle component-average aspect ratio of the second nuclear particle component) is preferably 0.5. As mentioned above, it is more preferably 0.6 or more, and even more preferably 0.7 or more.
　第１および第２の核粒子成分の混合物（核粒子混合物）のかためかさ密度とゆるみかさ密度との差（かためかさ密度－ゆるみかさ密度）は、本発明の効果が奏される限り特に限定されないが、下限値としては、好ましくは０．１５、より好ましくは０．１６、より一層好ましくは０．１７、上限値としては、好ましくは０．２５、より好ましくは０．２４、より一層好ましくは０．２３であり、範囲としては、好ましくは０．１５～０．２５、より好ましくは０．１６～０．２４、より一層好ましくは０．１７～０．２３である。なお、本発明において、かためかさ密度およびゆるみかさ密度は、例えば、市販の粉体特性評価装置（パウダテスタ（登録商標）ＰＴ－Ｒ、ホソカワミクロン株式会社製）を用いて測定することができる。具体的な測定方法としては、パウダテスタを用いて、第１７改正日本薬局方に記載されている、かさ密度およびタップ密度測定法第３法の測定用容器と同サイズの円筒容器へ核粒子混合物を篩いを通して上方から均一に供給し、上面をすり切って秤量することによって疎充填の状態のかさ密度（ゆるみかさ密度）を測定する。次いで、この容器の上に補助円筒をはめ、この上縁まで核粒子混合物を加えてタッピングを１８０回行なう。終了後、補助円筒を外して容器の上面で核粒子混合物をすり切って秤量し、タッピング後の密充填した場合のかさ密度（かためかさ密度）を測定する。 The difference between the firmness density and the loose bulk density (hardness density-loose bulk density) of the mixture of the first and second nuclear particle components (nuclear particle mixture) is particularly limited as long as the effect of the present invention is exhibited. However, the lower limit is preferably 0.15, more preferably 0.16, even more preferably 0.17, and the upper limit is preferably 0.25, more preferably 0.24, even more preferably. Is 0.23, and the range is preferably 0.15 to 0.25, more preferably 0.16 to 0.24, and even more preferably 0.17 to 0.23. In the present invention, the firmness density and the loose bulk density can be measured using, for example, a commercially available powder property evaluation device (Powder Tester (registered trademark) PT-R, manufactured by Hosokawa Micron Co., Ltd.). As a specific measurement method, a powder tester is used to put the nuclear particle mixture into a cylindrical container of the same size as the measurement container of the bulk density and tap density measurement method 3 described in the 17th revised Japanese Pharmacy. The bulk density (loose bulk density) in a loosely filled state is measured by uniformly supplying the particles from above through a sieve and weighing the top surface. Next, an auxiliary cylinder is fitted on the container, a mixture of nuclear particles is added up to the upper edge, and tapping is performed 180 times. After completion, the auxiliary cylinder is removed, the nuclear particle mixture is ground and weighed on the upper surface of the container, and the bulk density (hard bulk density) in the case of tight packing after tapping is measured.
　第１および第２の核粒子成分を構成する粒子の径（粒子径）は、本発明の効果が奏される限り特に限定されないが、第１の核粒子成分については、体積分布基準の５０％粒子径（Ｄ５０）として、好ましくは５０～２００μｍ、より好ましくは６０～１５０μｍ、より一層好ましくは７０～１００μｍである。また、第２の核粒子成分については、体積分布基準の５０％粒子径（Ｄ５０）として、好ましくは１～３００μｍ、より好ましくは５～２００μｍ、より一層好ましくは１０～１５０μｍである。本発明における核粒子成分を構成する粒子の径および体積分布基準の５０％粒子径は、いずれも、例えば、市販の粒度分布計（例えば、Mastersizer3000、Spectris製）を用いて、レーザー回折法（測定方法：乾式、散乱強度：１％以上、光散乱モデル：Ｍｉｅ散乱理論）により測定することができる。なお、体積分布基準の５０％粒子径（Ｄ５０）とは、レーザー回折法により測定して得られた体積基準粒度分布において、全体積を１００％とした累積体積分布曲線における５０％となる体積の粒子径を意味する。 The diameters (particle diameters) of the particles constituting the first and second nuclear particle components are not particularly limited as long as the effects of the present invention are exhibited, but the first nuclear particle components are 50% of the volume distribution standard. The particle size (D50) is preferably 50 to 200 μm, more preferably 60 to 150 μm, and even more preferably 70 to 100 μm. The volume distribution-based 50% particle diameter (D50) of the second nuclear particle component is preferably 1 to 300 μm, more preferably 5 to 200 μm, and even more preferably 10 to 150 μm. The diameter of the particles constituting the nuclear particle component in the present invention and the 50% particle diameter based on the volume distribution are both measured by a laser diffraction method (measurement) using, for example, a commercially available particle size distribution meter (for example, Mastersizer3000, manufactured by Spectris). Method: Dry method, scattering intensity: 1% or more, light scattering model: Mie scattering theory). The volume-based 50% particle size (D50) is the volume that is 50% of the cumulative volume distribution curve with the total volume as 100% in the volume-based particle size distribution measured by the laser diffraction method. It means the particle size.
　第１および第２の核粒子成分の総質量は、本発明の効果が奏される限り特に限定されないが、医薬製剤の総質量に対して、例えば、２０～９０重量％である。 The total mass of the first and second nuclear particle components is not particularly limited as long as the effects of the present invention are exhibited, but is, for example, 20 to 90% by weight with respect to the total mass of the pharmaceutical preparation.
　第１の核粒子成分と第２の核粒子成分との質量比（第１の核粒子成分の質量：第２の核粒子成分の質量）は、本発明の効果が奏される限り特に限定されないが、例えば１：１～１：１０である。 The mass ratio of the first nuclear particle component to the second nuclear particle component (mass of the first nuclear particle component: mass of the second nuclear particle component) is not particularly limited as long as the effect of the present invention is exhibited. However, for example, it is 1: 1 to 1:10.
（不揮発性溶媒）
　本発明の医薬製剤は、不揮発性溶媒を含んでなる。本明細書において不揮発性溶媒としては、核粒子中において、薬物をその中に溶解または懸濁し得る成分を用いることができる。そのような成分としては、例えば界面活性剤、油脂等が挙げられる。特に油脂は、その中に薬物を溶解または懸濁することにより、薬物と空気（酸素）との接触を遮断し、その酸化を防ぐことができるという利点を有する。また、油脂は、薬物が難水溶性である場合、該難水溶性薬物が油脂中に溶解していることにより、医薬製剤が投与された対象においてその吸収性を向上させることができる（薬物の吸収促進・補助）という利点も有する。また、油脂は、生体の栄養源となり、医薬製剤が投与された対象の健康の維持や増進を助けることができるという利点も有する。また、不揮発性溶媒としては、それ自体が薬効を有したり、添加剤として抗酸化作用等を有する成分を用いることもできる。そのような成分としては、例えばビタミン類等が挙げられる。本発明の不揮発性溶媒は、界面活性剤、ビタミン類および油脂からなる群から選択される少なくとも１種を含むことが好ましい。不揮発性溶媒に含まれる成分は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。 (Non-volatile solvent)
The pharmaceutical preparation of the present invention comprises a non-volatile solvent. As the non-volatile solvent in the present specification, a component capable of dissolving or suspending a drug in the nuclear particles can be used. Examples of such components include surfactants, fats and oils, and the like. In particular, fats and oils have an advantage that by dissolving or suspending a drug in it, the contact between the drug and air (oxygen) can be blocked and its oxidation can be prevented. In addition, when the drug is poorly water-soluble, the oil-and-fat can improve its absorbability in the subject to which the pharmaceutical preparation is administered because the poorly water-soluble drug is dissolved in the fat (drug). It also has the advantage of promoting and assisting absorption. In addition, fats and oils have an advantage that they can serve as a nutritional source for the living body and help maintain or improve the health of the subject to whom the pharmaceutical preparation is administered. Further, as the non-volatile solvent, a component which itself has a medicinal effect or has an antioxidant effect as an additive can be used. Examples of such components include vitamins and the like. The non-volatile solvent of the present invention preferably contains at least one selected from the group consisting of surfactants, vitamins and fats and oils. As the component contained in the non-volatile solvent, one type may be used alone, or two or more types may be used in combination.
　界面活性剤としては、薬学的に許容可能なものである限り特に限定されないが、例えば、陽イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤等を用いることができる。陽イオン性界面活性剤としては、例えば、第１級アミン塩、アルキルトリメチルアンモニウム塩、アルキルピリジニウム塩、アルキルポリオキシエチレンアミン等が挙げられる。陰イオン性界面活性剤としては、例えば、脂肪酸塩、ロジン酸塩、硫酸アルキルポリオキシエチレン塩、α－オレフィンスルホン酸塩、アルキルナフタレンスルホン酸塩、リグニンスルホン酸塩、リン酸アルキル塩等が挙げられる。両性界面活性剤としては、例えば、Ｎ－アルキルβ－アミノプロピオン酸、Ｎ－アルキルスルホベタイン、Ｎ－アルキルヒドロキシスルホベタイン、レシチン等が挙げられる。非イオン性界面活性剤としては、アルキルポリオキシエチレンエーテル、ポリオキシエチレン脂肪酸エステル、ソルビタン脂肪酸エステル、ショ糖脂肪酸エステル、ポリグリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル等が挙げられる。これらのうち、界面活性剤は、好ましくは非イオン性界面活性剤、より好ましくはポリソルベート、より一層好ましくはポリソルベート８０を含む。これらの界面活性剤は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。 The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants. Can be used. Examples of the cationic surfactant include a primary amine salt, an alkyltrimethylammonium salt, an alkylpyridinium salt, an alkylpolyoxyethylene amine and the like. Examples of the anionic surfactant include fatty acid salts, rosinates, alkylpolyoxyethylene sulfates, α-olefin sulfonates, alkylnaphthalene sulfonates, lignin sulfonates, alkyl phosphates and the like. Be done. Examples of the amphoteric surfactant include N-alkyl β-aminopropionic acid, N-alkyl sulfobetaine, N-alkyl hydroxy sulfobetaine, lecithin and the like. Examples of the nonionic surfactant include alkyl polyoxyethylene ether, polyoxyethylene fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester and the like. Of these, the surfactant preferably contains a nonionic surfactant, more preferably polysorbate, and even more preferably polysorbate 80. One of these surfactants may be used alone, or two or more of these surfactants may be used in combination.
　ビタミン類としては、特に限定されないが、ビタミンＥ（トコフェロールおよびトコトリエノール）等が挙げられる。ビタミン類としては、好ましくはビタミンＥ、より好ましくはトコフェロール、より一層好ましくはα－トコフェロールが用いられる。これらのビタミン類は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。 The vitamins are not particularly limited, and examples thereof include vitamin E (tocopherol and tocotrienol). As the vitamins, vitamin E is preferably used, more preferably tocopherol, and even more preferably α-tocopherol is used. One of these vitamins may be used alone, or two or more of these vitamins may be used in combination.
　油脂としては、グリセロールと脂肪酸とのエステル（脂肪酸エステル）およびその誘導体、ならびに脂肪酸エステルおよび／またはその誘導体を主成分として含む組成物が挙げられる。脂肪酸エステルを構成する脂肪酸は特に限定されず、炭素数２～４個の短鎖脂肪酸、炭素数５～１０個の中鎖脂肪酸、および炭素数１１個以上長鎖脂肪酸のいずれも用いることができるが、好ましくは中鎖脂肪酸である。脂肪酸は直鎖状の脂肪酸であってもよく、分岐状の脂肪酸であってもよいが、好ましくは直鎖状の脂肪酸である。また、グリセロールとエステル結合する脂肪酸の数は特に限定されず、１個（モノグリセリド）、２個（ジグリセリド）および３個（トリグリセリド）のいずれであってもよいが、好ましくは３個（トリグリセリド）である。グリセロールとエステル結合する脂肪酸の数が２個以上の場合、脂肪酸は同じであってもよく、互いに異なっていてもよい。好ましい脂肪酸エステルとしては、例えば、グリセロールと３つの中鎖脂肪酸とからなる中鎖脂肪酸トリグリセリド、グリセロールと３つの長鎖脂肪酸とからなる長鎖脂肪酸トリグリセリドが挙げられる。脂肪酸エステルの例としては、トリアセチン、ミリスチン酸イソプロピル等が挙げられる。また、脂肪酸エステルの誘導体の例としては、クエン酸アセチルトリエチル等が挙げられる。これらの脂肪酸エステルおよびその誘導体は１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。また、脂肪酸エステルおよびその誘導体は、後述する脂肪酸エステルおよび／またはその誘導体を主成分として含む組成物と組み合わせて用いてもよい。 Examples of fats and oils include esters of glycerol and fatty acids (fatty acid esters) and derivatives thereof, and compositions containing fatty acid esters and / or derivatives thereof as main components. The fatty acids constituting the fatty acid ester are not particularly limited, and any of short-chain fatty acids having 2 to 4 carbon atoms, medium-chain fatty acids having 5 to 10 carbon atoms, and long-chain fatty acids having 11 or more carbon atoms can be used. However, it is preferably a medium-chain fatty acid. The fatty acid may be a linear fatty acid or a branched fatty acid, but is preferably a linear fatty acid. The number of fatty acids ester-bonded to glycerol is not particularly limited and may be 1 (monoglyceride), 2 (diglyceride) or 3 (triglyceride), but 3 (triglyceride) is preferable. is there. When the number of fatty acids ester-bonded to glycerol is two or more, the fatty acids may be the same or different from each other. Preferred fatty acid esters include, for example, medium-chain fatty acid triglycerides consisting of glycerol and three medium-chain fatty acids, and long-chain fatty acid triglycerides consisting of glycerol and three long-chain fatty acids. Examples of fatty acid esters include triacetin, isopropyl myristate and the like. Further, examples of the fatty acid ester derivative include acetyltriethyl citrate and the like. One of these fatty acid esters and their derivatives may be used alone, or two or more thereof may be used in combination. Further, the fatty acid ester and its derivative may be used in combination with a composition containing the fatty acid ester and / or its derivative described later as a main component.
　脂肪酸エステルおよび／またはその誘導体を主成分として含む組成物としては、特に限定されないが、例えば、植物性油、ミネラルオイル等が挙げられる。そのような組成物の例としては、オリーブ油、ゴマ油、ダイズ油、ツバキ油、トウモロコシ油、ヒマシ油、ナタネ油、ヤシ油、ラッカセイ油、小麦胚芽油、軽質流動パラフィン、流動パラフィン、スクワラン等が挙げられる。また、これらの組成物に水素付加を行うことにより得られる硬化油を用いることもできる。これらの脂肪酸エステルおよび／またはその誘導体を主成分として含む組成物は１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。また、脂肪酸エステルおよび／またはその誘導体を主成分として含む組成物は、上述した脂肪酸エステルおよびその誘導体と組み合わせて用いてもよい。 The composition containing a fatty acid ester and / or a derivative thereof as a main component is not particularly limited, and examples thereof include vegetable oils and mineral oils. Examples of such compositions include olive oil, sesame oil, soybean oil, camellia oil, corn oil, castor oil, rapeseed oil, coconut oil, lacquer oil, wheat germ oil, light liquid paraffin, liquid paraffin, squalane and the like. Be done. Further, a hydrogenated oil obtained by hydrogenating these compositions can also be used. As the composition containing these fatty acid esters and / or derivatives thereof as a main component, one type may be used alone, or two or more types may be used in combination. Further, a composition containing a fatty acid ester and / or a derivative thereof as a main component may be used in combination with the fatty acid ester and its derivative described above.
　医薬製剤に配合する薬物として水溶性が低い薬物（難水溶性薬物）を用いる場合には、不揮発性溶媒が、難水溶性薬物を溶解または懸濁し得る界面活性剤を含むことが好ましい。また、不揮発性溶媒は、界面活性剤に加えてビタミン類、油脂を含むことが好ましい。 When a drug having low water solubility (difficult-water-soluble drug) is used as a drug to be blended in a pharmaceutical preparation, it is preferable that the non-volatile solvent contains a surfactant capable of dissolving or suspending the poorly water-soluble drug. The non-volatile solvent preferably contains vitamins and fats and oils in addition to the surfactant.
　不揮発性溶媒に含まれる成分は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。特に、不揮発性溶媒に含まれる成分として液体でない成分が用いられる場合には、液体である他の成分と組み合わせて用いられる。例えば、不揮発性溶媒がビタミンＥを含む場合には、ビタミンＥはエタノール等のアルコールと組み合わせて用いられることが好ましい。 As the component contained in the non-volatile solvent, one type may be used alone, or two or more types may be used in combination. In particular, when a non-liquid component is used as the component contained in the non-volatile solvent, it is used in combination with another liquid component. For example, when the non-volatile solvent contains vitamin E, it is preferable that vitamin E is used in combination with an alcohol such as ethanol.
　不揮発性溶媒の量は、本発明の効果が奏される限り特に限定されないが、核粒子成分の総量に対する質量比（核粒子成分の総質量：不揮発性溶媒の質量）として、下限値が、好ましくは１：０．００１、より好ましくは１：０．０１である。また、上限値は、特に限定されないが、好ましくは１：０．６、より好ましくは１：０．４、より一層好ましくは１：０．３である。また、核粒子成分の総量に対する界面活性剤の質量比の範囲は、特に限定されないが、好ましくは１：０．００１～１：０．６、より好ましくは１：０．０１～１：０．４、より一層好ましくは１：０．０１～１：０．３である。 The amount of the non-volatile solvent is not particularly limited as long as the effect of the present invention is exhibited, but the lower limit is preferable as the mass ratio to the total amount of the nuclear particle components (total mass of the nuclear particle components: mass of the non-volatile solvent). Is 1: 0.001, more preferably 1: 0.01. The upper limit is not particularly limited, but is preferably 1: 0.6, more preferably 1: 0.4, and even more preferably 1: 0.3. The range of the mass ratio of the surfactant to the total amount of the nuclear particle components is not particularly limited, but is preferably 1: 0.001 to 1: 0.6, more preferably 1: 0.01 to 1: 0. 4, even more preferably 1: 0.01 to 1: 0.3.
　不揮発性溶媒の粘度は、本発明の効果が奏される限り特に限定されず、例えば、４０℃における粘度の範囲として１０～６００ｍＰａ・ｓである。そのような不揮発性溶媒の具体例としては、例えば、下記表１に示す界面活性剤、ビタミン類および油脂等が挙げられる。なお、不揮発性溶媒の粘度の測定は、市販の粘度計を用いて行うことができる。粘度計としては、例えば、回転振動式粘度計VISCOMATE VM-10A-L（株式会社セコニック製）が挙げられる。
Figure JPOXMLDOC01-appb-T000002
 The viscosity of the non-volatile solvent is not particularly limited as long as the effects of the present invention are exhibited, and for example, the viscosity range at 40 ° C. is 10 to 600 mPa · s. Specific examples of such a non-volatile solvent include surfactants, vitamins, fats and oils shown in Table 1 below. The viscosity of the non-volatile solvent can be measured using a commercially available viscometer. Examples of the viscometer include a rotary vibration viscometer VISCOMATE VM-10A-L (manufactured by SEKONIC CORPORATION).
Figure JPOXMLDOC01-appb-T000002
（薬物）
　本発明の医薬製剤は、核粒子中に薬物を含んでなる。薬物は、上述した不揮発性溶媒に溶解または懸濁した状態で存在することが好ましい。薬物としては、特に限定されず、本発明の医薬製剤において所望の効果を奏する薬物を用いることができる。また、薬物は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。 (Drug)
The pharmaceutical preparation of the present invention comprises a drug in nuclear particles. The drug preferably exists in a state of being dissolved or suspended in the above-mentioned non-volatile solvent. The drug is not particularly limited, and a drug that exerts a desired effect in the pharmaceutical preparation of the present invention can be used. In addition, one type of drug may be used alone, or two or more types may be used in combination.
　薬物のｌｏｇＰ値は、本発明の効果が奏される限り特に限定されないが、好ましくは－２～７、より好ましくは－１．９～６．５、より一層好ましくは１．８５～６．１である。 The logP value of the drug is not particularly limited as long as the effects of the present invention are exhibited, but is preferably -2 to 7, more preferably 1.9 to 6.5, and even more preferably 1.85 to 6.1. Is.
　薬物のｌｏｇＰ値は、Pubchem（https://pubchem.ncbi.nlm.nih.gov/）に収載されている値とされる。Pubchemに収載されていない薬物のｌｏｇＰ値の測定は、日本工業規格Ｚ７２６０－１０７に準拠したフラスコ振盪法に従って行うことができる。具体的には、まず、１－オクタノールと蒸留水とを２５℃で２４時間振盪して平衡化させる。次いで、蓋付きガラス瓶に試料となる薬物１０ｍｇを量りとり、平衡化させた１－オクタノールと蒸留水をそれぞれ４ｍＬずつ加え、２５℃で４日間振盪する。遠心分離により１－オクタノール相と水相とを分離し、ＨＰＬＣにより各相の試料の濃度を測定する。２相間の分配係数の常用対数を取った値をｌｏｇＰ値とする。 The logP value of the drug is the value listed in Pubchem (https://pubchem.ncbi.nlm.nih.gov/). The logP value of a drug not listed in Pubchem can be measured according to the flask shaking method according to 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 sample drug is weighed in a glass bottle with a lid, 4 mL each of 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 the value obtained by taking the common logarithm of the partition coefficient between the two phases.
　具体的な薬物としては、例えば、ビタミン剤、ホルモン剤、抗癌剤、抗菌剤、抗ウイルス剤、高脂血症治療剤、中枢神経用剤、免疫抑制剤、末梢神経用剤、痔核疾患治療剤、循環器官用剤、代謝性医薬品、消化器疾患用剤、ハンセン病剤等が挙げられる。 Specific drugs include, for example, vitamins, hormones, anticancer agents, antibacterial agents, antiviral agents, hyperlipidemia therapeutic agents, central nervous system agents, immunosuppressive agents, peripheral nerve agents, hemorrhagic disease therapeutic agents, etc. Examples thereof include circulatory organ agents, metabolic drugs, digestive diseases agents, Hansen's disease agents and the like.
　本発明の医薬製剤は、多量の不揮発性溶媒を核粒子中に含有し得ることから、難水溶性薬物であっても不揮発性溶媒に溶解また懸濁させ、核粒子中に含有させることが可能である。従って、本発明の一つの態様としては、薬物が難水溶性薬物を含んでなることが好ましい。難水溶性薬物としては、特に限定されないが、生理的ｐＨ条件下での水に対する溶解度（水１００ｇに溶ける薬物の質量（ｇ））が１０～２０μｇ／ｍｌである薬物が挙げられる。さらに、難水溶性薬物としては、アメリカ食品医薬品局（ＦＤＡ）が規定する生物薬剤学分類システムＢＣＳ（Biopharmaceutics Classification System）において、クラスＩＩおよびＩＶに分類される薬物が挙げられる。 Since the pharmaceutical preparation of the present invention can contain a large amount of non-volatile solvent in the nuclear particles, even a poorly water-soluble drug can be dissolved or suspended in the non-volatile solvent and contained in the nuclear particles. Is. Therefore, in one aspect of the present invention, it is preferable that the drug comprises a poorly water-soluble drug. The poorly water-soluble drug is not particularly limited, and examples thereof include a drug having a solubility in water (mass (g) of the drug soluble in 100 g of water) of 10 to 20 μg / ml under physiological pH conditions. Furthermore, examples of poorly water-soluble drugs include drugs classified into Class II and IV in the BCS (Biopharmaceutics Classification System) defined by the US Food and Drug Administration (FDA).
　ビタミン剤としては、特に限定されないが、例えば、脂溶性ビタミン、水溶性ビタミン等が挙げられる。脂溶性ビタミンとしては、例えば、レチノール（Ａ１アルコール）、レチナール（Ａ１アルデヒド）、レチノイン酸（Ａ１酸）、３－デヒドロレチノール（Ａ２アルコール）、３－デヒドロレチナール（Ａ２アルデヒド）、３－デヒドロレチノイン酸（Ａ２酸）等のビタミンＡ、カロテン、フラボノイド、エルゴカルシフェロール（Ｄ２）、コレカルシフェロール（Ｄ３）、エルゴステロール、７－ヒドロコレステロール等のビタミンＤ、α－トコフェロール等のビタミンＥ、フィロキノン（Ｋ１）、メナキノン（Ｋ２）、メナジオン（Ｋ３）等のビタミンＫ等が挙げられる。水溶性ビタミンとしては、チアミン（アノイリン）等のビタミンＢ１、リボフラビン等のビタミンＢ２、ピリドキシン、ピリドキサール、ピリドキサミン等のビタミンＢ６、コバラミン等のビタミンＢ１２、葉酸、ニコチン酸、ニコチンアミド等のナイアシン、パントテン酸、ビオチン、アスコルビン酸（ビタミンＣ）等が挙げられる。 The vitamin preparation is not particularly limited, and examples thereof include fat-soluble vitamins and water-soluble vitamins. Examples of fat-soluble vitamins include retinol (A1 alcohol), retinal (A1 aldehyde), retinoic acid (A1 acid), 3-dehydroretinol (A2 alcohol), 3-dehydroretinal (A2 aldehyde), and 3-dehydroretinoic acid. Vitamin A such as (A2 acid), carotene, flavonoid, ergocalciferol (D2), cholecalciferol (D3), ergosterol, vitamin D such as 7-hydrocholesterol, vitamin E such as α-tocopherol, phylloquinone (K1) ), Vitamin K such as menaquinone (K2) and menadion (K3). Water-soluble vitamins include vitamin B1 such as thiamine (anoylin), vitamin B2 such as riboflavin, vitamin B6 such as pyridoxine, pyridoxal and pyridoxamine, vitamin B12 such as cobalamine, niacin such as folic acid, nicotinic acid and nicotinamide, and pantothenic acid. , Biotin, ascorbic acid (vitamin C) and the like.
　ホルモン剤は、各種のホルモンを製剤化し、ホルモン本来の生理作用または薬理作用を利用して、体内の特定の細胞において特定の効果を発揮する生理活性物質である。ホルモン剤としては、特に限定されないが、視床下部、脳下垂体前葉、脳下垂体後葉、甲状腺、膵臓ランゲルハンス島、副腎皮質、副腎髄質、性腺、消化器等に由来するホルモンが挙げられる。具体的には、プロゲステロン、レボノルゲストレル、ノルエチステロン等が挙げられる。 Hormonal agents are physiologically active substances that formulate various hormones and exert specific effects on specific cells in the body by utilizing the original physiological or pharmacological effects of the hormones. The hormonal agent is not particularly limited, and examples thereof include hormones derived from the hypothalamus, anterior pituitary gland, posterior pituitary gland, thyroid gland, pancreatic islets of Langerhans, adrenal cortex, adrenal medulla, gonads, digestive organs and the like. Specific examples thereof include progesterone, levonorgestrel and norethisterone.
　抗癌剤としては、特に限定されないが、脳腫瘍、舌癌、喉頭癌、甲状腺癌、食道癌、胃癌、大腸癌、肝臓癌、胆のう癌、胆管癌、膵臓癌、肺癌、乳癌、卵巣癌、子宮頸癌、子宮癌、腎臓癌、前立腺癌、膀胱癌、皮膚癌、骨腫瘍、白血病、悪性リンパ腫、小児癌等の各種癌において、癌腫を縮小または消滅させるか、または癌腫を増大させない効果を有するものが挙げられる。具体的には、シクロフォスファミド（cyclophosphamide）、イフォスファミド（ifosfamide）、チオテパ（thiotepa）、メルファラン（melphalan）、ブスルファン（busulfan）、ニムスチン（nimustine）、ラニムスチン（ranimustine）、ダカルバジン（dacarbazine）、プロカルバジン（procarbazine）、テモゾロミド（temozolomide）、シスプラチン（cisplatin）、カルボプラチン（carboplatin）、ネダプラチン（nedaplatin）、メトトレキサート（methotrexate）、ペメトレキセド（pemetrexed）、ウラシル（uracil）、ドキシフルリジン（doxifluridine）、ギメラシル／オテラシル（gimeracil・oteracil）、シタラビン（cytarabine）、エノシタビン（enocitabine）、ゲムシタビン（gemcitabine）、６－メルカプトプリン（6-mercaptopurine）、フルダラビン（fuludarabin）、ペントスタチン（pentostatin）、クラドリビン（cladribine）、ヒドロキシウレア（hydroxyurea）、ドキソルビシン（doxorubicin）、エピルビシン（epirubicin）、ダウノルビシン（daunorubicin）、イダルビシン（idarubicine）、ピラルビシン（pirarubicin）、ミトキサントロン（mitoxantrone）、アムルビシン（amurubicin）、アクチノマイシンＤ（actinomycin D）、ブレオマイシン（bleomycine）、ペプレオマイシン（pepleomycin）、マイトマイシンＣ（mytomycin C）、アクラルビシン（aclarubicin）、ジノスタチン（zinostatin）、ビンクリスチン（vincristine）、ビンデシン（vindesine）、ビンブラスチン（vinblastine）、ビノレルビン（vinorelbine）、パクリタキセル（paclitaxel）、ドセタキセル（docetaxel）、イリノテカン（irinotecan）、イリノテカン活性代謝物（SN-38）、ノギテカン（nogitecan、topotecan）、エトポシド（etoposide）、プレドニゾロン（prednisolone）、デキサメタゾン（dexamethasone）、タモキシフェン（tamoxifen）、トレミフェン（toremifene）、メドロキシプロゲステロン（medroxyprogesterone）、アナストロゾール（anastrozole）、エキセメスタン（exemestane）、レトロゾール（letrozole）、リツキシマブ（rituximab）、イマチニブ（imatinib）、ゲフィチニブ（gefitinib）、ゲムツズマブ・オゾガマイシン（gemtuzumab ozogamicin）、ボルテゾミブ（bortezomib）、エルロチニブ（erlotinib）、セツキシマブ（cetuximab）、ベバシズマブ（bevacizumab）、スニチニブ（sunitinib)、ソラフェニブ（sorafenib）、ダサチニブ（dasatinib）、パニツムマブ（panitumumab）、アスパラギナーゼ（asparaginase）、トレチノイン（tretinoin）、三酸化ヒ素（arsenic trioxide）、ホリナート（folinate）、レボホリナート（levofolinate）、またはそれらの塩、またはそれらの活性代謝物等が挙げられる。 The anticancer agent is not particularly limited, but is limited to brain tumor, tongue cancer, laryngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, colon cancer, liver cancer, cholangiocarcinoma, bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer. , Uterine cancer, kidney cancer, prostate cancer, bladder cancer, skin cancer, bone tumor, leukemia, malignant lymphoma, pediatric cancer, etc., which have the effect of reducing or eliminating the cancer or not increasing the cancer. Can be mentioned. Specifically, cyclophosphamide, ifosfamide, thiotepa, melphalan, busulfan, nimustine, ranimustine, dacarbazine, procarbazine. (Procarbazine), temozolomide, cisplatin, carboplatin, nedaplatin, metotrexate, pemetrexed, uracil, doxifluridine, doxifluridine oteracil), cytarabine, enocitabine, gemcitabine, 6-mercaptopurine, fuludarabin, pentostatin, cladribine, hydroxyurea, hydroxyurea Doxorubicin, epirubicin, daunorubicin, idarubicine, pirarubicin, mitoxantrone, amurubicin, actinomycin D, actinomycin D Pepleomycin, mytomycin C, aclarubicin, zinostatin, vincristine, vincristine, vinblastine, vinorelbine, paclitaxel, paclitaxel (Docetaxel), irinotecan, irinotecan active metabolite (SN-38), nogitecan, topotecan, Etoposide, prednisolone, dexamethasone, tamoxifen, toremifene, medroxyprogesterone, anastrozole, exemestane, exemestane Rituximab, imatinib, gefitinib, gemtuzumab ozogamicin, bortezomib, erlotinib, erlotinib, bevacizumab, cetuximab, cetuximab, cetuximab sorafenib), dasatinib, panitumumab, asparaginase, tretinoin, arsenictrioxide, holinate, levofolinate, or their salts, or their salts. Examples include metabolites.
　抗菌剤は、菌類または細菌を死滅または増殖を抑制する効果を有する剤である。菌類を対象とする抗菌剤としては、特に限定されないが、ポリエン系抗菌剤、フロロピリミジン系抗菌剤、イミダゾール系抗菌剤、トリアゾール系抗菌剤、アリルアミン系抗菌剤、キャンディン系抗菌剤等が挙げられる。具体的には、アムホテリシンＢ、ナイスタチン、フルシトシン、イソコナゾール、ビホナゾール、ラノコナゾール、ケトコナゾール、ルリコナゾール、クロトリマゾール、ネチコナゾール、ミコナゾール、フルコナゾール、イトラコナゾール、ホスフルコナゾール、ボリコナゾール、テルビナフィン、ミカファンギン、カスポファンギン、グリセオフルビン、ウンデシレン酸、リラナフタート、トルナフタート、トルシクラート等が挙げられる。 An antibacterial agent is an agent that has the effect of killing or suppressing the growth of fungi or bacteria. The antibacterial agent for fungi is not particularly limited, and examples thereof include polyene antibacterial agents, fluoropyrimidine antibacterial agents, imidazole antibacterial agents, triazole antibacterial agents, allylamine antibacterial agents, and canin antibacterial agents. .. Specifically, amphotericin B, nystatin, flucytosine, isoconazole, bihonazole, lanoconazole, ketoconazole, luriconazole, clotrimazole, neticonazole, miconazole, fluconazole, itraconazole, fosfluconazole, voriconazole, itraconazole, fosfluconazole, voriconazole, terbinazole, micafunginate, terbinazole, micafangin Examples thereof include lylanafutate, tornafutate, and tolcyclate.
　細菌を対象とする抗菌剤としては、特に限定されないが、ペニシリン系抗菌剤、セフェム系抗菌剤、カルバペネム系抗菌剤、モノバクタム系抗菌剤およびペネム系抗菌剤等のβ－ラクタム系抗菌剤、アミノグリコシド系抗菌剤、リンコマイシン系抗菌剤、ホスホマイシン系抗菌剤、テトラサイクリン系抗菌剤、クロラムフェニコール系抗菌剤、マクロライド系抗菌剤、ケトライド系抗菌剤、ポリペプチド系抗菌剤、グリコペプチド系抗菌剤、ストレプトグラミン系抗菌剤、キノロン系抗菌剤、サルファ系抗菌剤、オキサゾリジノン系抗菌剤等が挙げられる。具体的には、ペニシリンＧ、アンピシリン、バカンピシリン、レナンピシリン、シクラシリン、アモキシシリン、ピブメシリン、アスポキシシリン、クロキサシリン、ピペラシリン、メチシリン、アンピシリン・クロキサシリン、アンピシリン・スルバクタム、クラブラン酸・アモキシシリン、ピペラシリン・タゾバクタム、セファゾリン、セファロンチン、セファレキシン、セファトリジン、セフロキサジン、セファクロル、セファドロキシル、セフォチアム、セフメタゾール、フロモキセフ、セフミノックス、セフブペラゾン、セフロキシム・アキセチル、セフジニル、セフジトレン・ピボキシル、セフテラム・ピボキシル、セフポドキシム・プロキセチル、セフカペン・ピボキシル、セフォタキシム、セフトリアキソン、セフォペラゾン、セフメノキシム、セフタジジム、セフチブテン、セフィキシム、セフォジジム、ラタモキセフ、セフチゾキシム、セフピロム、セフォゾプラン、セフェピム、セフォペラゾン・スルバクタム、イミペネム、パニペネム、メロペネム、ビアペネム、ドリペネム、テビペネム、アズトレオナム、スルバクタム、タゾバクタム、カルモナム、ファロペネム、カナマイシン、ストレプトマイシン、ネオマイシン、ゲンタマイシン、フラジオマイシン、トブラマイシン、アミカシン、アルベカシン、アストロマイシン、イセパマイシン、ベカナマイシン、ジベカシン、ミクロノマイシン、ネチルマイシン、パロモマイシン、リボスタマイシン、シソマイシン、スペクチノマイシン、リンコマイシン、クリンダマイシン、ホスホマイシン、テトラサイクリン、オキシテトラサイクリン、デメチルクロルテトラサイクリン、ドキシサイクリン、ミノサイクリン、クロラムフェニコール、エリスロマイシン、クラリスロマイシン、アジスロマイシン、ジョサマイシン、スピラマイシン、ミデカマイシン、ロキタマイシン、キタサマイシン、テリスロマイシン、コリスチン、ポリミキシン、バシトラシン、バンコマイシン、テイコプラニン、キヌプリスチン・ダルホプリスチン、ナリジクス酸、ピロミド酸、ピペミド酸、ノルフロキサシン、エノキサシン、オフロキサシン、シプロフロキサシン、トスフロキサシン、ロメフロキサシン、レボフロキサシン、スパルフロキサシン、ガチフロキサシン、モキシフロキサシン、ガレノキサシン、シタフロキサシン、ＳＴ合剤、ジアフェニルスルホン、リネゾリド等が挙げられる。 The antibacterial agent for bacteria is not particularly limited, but is β-lactam antibacterial agent such as penicillin antibacterial agent, cephem antibacterial agent, carbapenem antibacterial agent, monobactam antibacterial agent and penem antibacterial agent, aminoglycoside type. Antibacterial agents, lincomycin antibacterial agents, phosphomycin antibacterial agents, tetracycline antibacterial agents, chloramphenicol antibacterial agents, macrolide antibacterial agents, ketride antibacterial agents, polypeptide antibacterial agents, glycopeptide antibacterial agents Examples thereof include streptogramin-based antibacterial agents, quinolone-based antibacterial agents, sulfa-based antibacterial agents, and oxazolidinone-based antibacterial agents. Specifically, penicillin G, ampicillin, vacampicillin, renanpicillin, cyclacillin, amoxicillin, pibmesillin, aspoxycillin, cloxacillin, piperacillin, methicillin, ampicillin / cloxacillin, ampicillin / sulbactam, clavacilin acid / amoxicillin, clavacylin / amoxicillin, , Cephalexin, cefatridin, cefluxazine, cefaclor, cefadoroxyl, cefotiam, cefmethazole, fromoxef, cefminox, cefbuperazone, cefloxim axetil, cefdinil, cefditoren pivoxil, cefditoren pivoxil, cefteram pivoxil, cefterocelpypoxyl pivoxil Cefoperazone, cefmenoxim, ceftajigym, ceftibutene, cefixim, cefodizim, ratamoxef, ceftizoxim, cefpyrom, cefosoplan, cepepim, cefoperazone sulbactam, imipenem, panipenem, imipenem, panipenem, melopenem Streptomycin, Neomycin, Gentamycin, Fraradimycin, Tobramycin, Amoxicillin, Albecacin, Astromycin, Isepamicin, Becanamycin, Dibecacin, Micronomycin, Netylmycin, Palomomycin, Ribostamycin, Sysomycin, Spectinomycin, Lincomicillin, Clindamycin Phosphomycin, tetracycline, oxytetracycline, demethylchlortetracycline, doxicyclin, minocycline, chloramphenicol, erythromycin, clarislomycin, aziromycin, josamicillin, spiramycin, midecamicillin, rokitamycin, kitasamicin, terislomycin, choristin, polymyxin Vacomycin, teikoplanin, quinupristin dalhopristin, naridixic acid, pyromidic acid, pipemidic acid, norfloxacin, enoxacin, offloxacin, cyprofloxacin, tosfloxacin, romefloxacin, levofloxacin, spulfloxacin, gachifloxacin, moxicillin, galexacin Citafloxacin, ST mixture, diaphenylsulfone, line Zoride and the like can be mentioned.
　抗ウイルス剤は、ウイルスが宿主となる細胞に寄生し、新しいウイルス粒子を形成し、宿主細胞を脱出するサイクルの一部または全部のプロセスを阻害することで、ウイルス感染に起因する疾患の治療効果を有する剤である。抗ウイルス剤としては、特に限定されないが、例えば、ヘルペスウイルス、サイトメガロウイルス、ヒトパピローマウイルス、ＲＳウイルス、インフルエンザウイルス、ヒト免疫不全ウイルス、Ｂ型肝炎ウイルス、Ｃ型肝炎ウイルス等のウイルス感染に起因する疾患の治療効果を有する剤が挙げられる。具体的には、ゾビラックス、アシクロビン、ビクロックス（アシクロビル）、バルトレックス（バラシクロビル）、デノシン（ガンシクロビル）、アラセナＡ（ビダラビン）、リレンザ（ザナミビル水和物）、タミフル（リン酸オセルタミビル）、シンメトレル（アマンタジン）、レトロビル（ジドブジン）、ヴァイデックス（ジダノシン）、エピビル、ゼフィックス（ラミブジン）、フォートベイス（ザキナビル）、ノービア（リトナビル）等が挙げられる。 Antiviral agents have a therapeutic effect on diseases caused by viral infections by infesting host cells with the virus, forming new viral particles, and inhibiting some or all processes in the cycle of escaping the host cells. It is an agent having. The antiviral agent is not particularly limited, but is caused by viral infection such as herpes virus, cytomegalovirus, human papillomavirus, RS virus, influenza virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, etc. Examples thereof include agents having a therapeutic effect on the disease. Specifically, Zovirax, Acyclobin, Viclocks (Acyclovir), Baltrex (Balacyclovir), Denosin (Ganciclovir), Aracena A (Vidarabin), Relenza (Zanamivir hydrate), Tamiflu (Oseltamivir phosphate), Symmetrel (Amantazine) , Retroville (Zidovudine), Videx (Zidovudine), Epivir, Zefix (Lamivudine), Fort Base (Zanamivir), Novia (Litnavir), etc.
　高脂血症治療剤としては、特に限定されないが、例えば、イコサペント酸エチル、オメガ－３脂肪酸エチル、クロフィブラート、ポリエンホスファチジルコリン等が挙げられる。 The therapeutic agent for hyperlipidemia is not particularly limited, and examples thereof include ethyl icosapentaenoate, ethyl omega-3 fatty acid, clofibrate, polyenphosphatidylcholine and the like.
　中枢神経用剤としては、特に限定されないが、例えば、インドメタシンファルネシル、ナルフラフィン塩酸塩等が挙げられる。 The central nervous system agent is not particularly limited, and examples thereof include indometacin farnesyl and nalfurafine hydrochloride.
　免疫抑制剤としては、特に限定されないが、例えば、シクロスポリン等が挙げられる。 The immunosuppressive agent is not particularly limited, and examples thereof include cyclosporine and the like.
　末梢神経用剤としては、特に限定されないが、例えば、タファミジスメグルミン等が挙げられる。 The peripheral nerve agent is not particularly limited, and examples thereof include tafamidis meglumine.
　痔核疾患治療剤としては、特に限定されないが、例えば、トリベノシド等が挙げられる。 The therapeutic agent for hemorrhoidal disease is not particularly limited, and examples thereof include tribenoside and the like.
　循環器官用剤としては、特に限定されないが、例えば、ニフェジピン、ユビデカレノン等が挙げられる。 The circulatory organ preparation is not particularly limited, and examples thereof include nifedipine and ubidecalenone.
　代謝性医薬品としては、特に限定されないが、例えば、ニンテダニブエタンスルホン酸塩等が挙げられる。 The metabolic drug is not particularly limited, and examples thereof include nintedanibuethanesulfonate.
　消化器疾患用剤としては、特に限定されないが、例えば、ゲファルナート、ピコスルファートナトリウム水和物、ルビプロストン等が挙げられる。 The agent for digestive disorders is not particularly limited, and examples thereof include gefarnate, picosulfate sodium hydrate, rubiprostone, and the like.
　ハンセン病治療剤としては、特に限定されないが、例えば、クロファジミン等が挙げられる。 The therapeutic agent for leprosy is not particularly limited, and examples thereof include clofazimine and the like.
　本発明の医薬製剤における薬物の量は、本発明の医薬製剤が所望の効果を奏する限り特に限定されないが、核粒子成分の総量に対する質量比（薬物の質量：核粒子成分の総質量）として、下限値が、好ましくは０．０１：１、より好ましくは０．０２：１、より一層好ましくは０．０３：１である。また、上限値は、特に限定されないが、好ましくは０．５：１、より好ましくは０．２：１である。また、核粒子成分の総量に対する薬物の質量比の範囲は、特に限定されないが、好ましくは０．０１：１～０．５：１、より好ましくは０．０２：１～０．５：１、より一層好ましくは０．０３：１～０．２：１である。 The amount of the drug in the pharmaceutical preparation of the present invention is not particularly limited as long as the pharmaceutical preparation of the present invention exerts a desired effect, but as a mass ratio to the total amount of the nuclear particle components (mass of the drug: total mass of the nuclear particle components). The lower limit is preferably 0.01: 1, more preferably 0.02: 1, and even more preferably 0.03: 1. The upper limit is not particularly limited, but is preferably 0.5: 1, more preferably 0.2: 1. The range of the mass ratio of the drug to the total amount of the nuclear particle components is not particularly limited, but is preferably 0.01: 1 to 0.5: 1, more preferably 0.02: 1 to 0.5: 1. Even more preferably, it is 0.03: 1 to 0.2: 1.
　また、本発明の医薬製剤における薬物の量は、本発明の医薬製剤が所望の効果を奏する限り特に限定されないが、不揮発性溶媒に対する質量比（薬物の質量：不揮発性溶媒の質量）として、下限値が、好ましくは０．０５：１、より好ましくは０．１：１、より一層好ましくは０．５：１である。また、上限値は、特に限定されないが、好ましくは５：１、より好ましくは３：１である。また、界面活性剤に対する薬物の質量比の範囲は、特に限定されないが、好ましくは０．０５：１～５：１、より好ましくは０．１：１～５：１、より一層好ましくは０．５：１～３：１である。 The amount of the drug in the pharmaceutical preparation of the present invention is not particularly limited as long as the pharmaceutical preparation of the present invention exerts a desired effect, but is the lower limit as the mass ratio to the non-volatile solvent (mass of drug: mass of non-volatile solvent). The value is preferably 0.05: 1, more preferably 0.1: 1, and even more preferably 0.5: 1. The upper limit is not particularly limited, but is preferably 5: 1, more preferably 3: 1. The range of the mass ratio of the drug to the surfactant is not particularly limited, but is preferably 0.05: 1 to 5: 1, more preferably 0.1: 1 to 5: 1, and even more preferably 0. It is 5: 1 to 3: 1.
　本発明の医薬製剤における核粒子の凝集度は、特に限定されないが、好ましくは９０％以下、より好ましくは７０％以下、より一層好ましくは５０％以下である。 The degree of cohesion of nuclear particles in the pharmaceutical preparation of the present invention is not particularly limited, but is preferably 90% or less, more preferably 70% or less, and even more preferably 50% or less.
　凝集度の測定は、市販の粉体特性評価装置を用いて行うことができる。粉体特性評価装置としては、例えば、パウダテスタ（登録商標）ＰＴ－Ｒ（ホソカワミクロン株式会社製）が挙げられる。測定条件は、例えば、以下の通りである。
　篩目開き：（上段）７１０μｍ、（中段）３５５μｍ、（下段）２５０μｍ
　試料採取量：２ｇまたは３ｇ
　振動時間：１１９秒 The degree of cohesion can be measured using a commercially available powder property evaluation device. Examples of the powder property evaluation device include Powder Tester (registered trademark) PT-R (manufactured by Hosokawa Micron Co., Ltd.). The measurement conditions are as follows, for example.
Opening of mesh: (upper) 710 μm, (middle) 355 μm, (lower) 250 μm
Sampling volume: 2g or 3g
Vibration time: 119 seconds
　上記の条件下で、下記式の各項目の値を測定する。
　Ｘ＝［上段の篩に残った粉体質量］／投入した粉体質量×１００
　Ｙ＝［中段の篩に残った粉体質量］／投入した粉体質量×１００×０．６
　Ｚ＝［下段の篩に残った粉体質量］／投入した粉体質量×１００×０．２
　上記Ｘ、Ｙ、Ｚの３つの値の合計をもって、凝集度（％）とする。 Under the above conditions, the value of each item in the following formula is measured.
X = [mass of powder remaining on the upper sieve] / mass of powder charged x 100
Y = [Mass of powder remaining on the middle sieve] / Mass of powder charged x 100 x 0.6
Z = [Mass of powder remaining on the lower sieve] / Mass of powder charged x 100 x 0.2
The sum of the above three values of X, Y, and Z is defined as the degree of cohesion (%).
＜被覆層＞
　被覆層は、核粒子を被覆して、核粒子に含まれる不揮発性溶媒や薬物が医薬製剤の表面に漏出することを抑制することができる。被覆層により不揮発性溶媒の漏出が抑制される結果、医薬製剤の凝集が抑制され、医薬製剤の流動性の低下を抑制することができる。 <Coating layer>
The coating layer can coat the nuclear particles and prevent the non-volatile solvent and the drug contained in the nuclear particles from leaking to the surface of the pharmaceutical preparation. As a result of suppressing the leakage of the non-volatile solvent by the coating layer, the aggregation of the pharmaceutical preparation can be suppressed, and the decrease in the fluidity of the pharmaceutical preparation can be suppressed.
　被覆層を構成する成分としては、特に限定されないが、例えば、水溶性コーティング剤等が挙げられる。水溶性コーティング剤は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。 The components constituting the coating layer are not particularly limited, and examples thereof include water-soluble coating agents. As the water-soluble coating agent, one type may be used alone, or two or more types may be used in combination.
　一つの実施形態によれば、水溶性コーティング剤は、好ましくはポリアルキレングリコールおよび多糖類またはその誘導体から選択される少なくとも一つの成分を含む。 According to one embodiment, the water-soluble coating agent preferably comprises at least one component selected from polyalkylene glycols and polysaccharides or derivatives thereof.
　多糖類またはその誘導体としては、好ましくはセルロース誘導体であり、例えば、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルメチルセルロース等が挙げられる。セルロース誘導体は、１種を単独で用いてもよいが、２種以上を組み合わせて用いてもよい。 The polysaccharide or its derivative is preferably a cellulose derivative, and examples thereof include methyl cellulose, hydroxymethyl cellulose, and hydroxypropyl methyl cellulose. One type of cellulose derivative may be used alone, or two or more types may be used in combination.
　また、ポリアルキレングリコールとしては、例えば、ポリエチレングリコール等が挙げられる。 Further, examples of the polyalkylene glycol include polyethylene glycol and the like.
　また、別の好ましい実施形態によれば、被覆層に使用されるコーティング剤としては、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メタアクリル酸コポリマー、ビニルピリジンコポリマー、アルキルビニルピリジンコポリマー、アミノセルロース誘導体、ジエチルアミノエチルメタクリレート、ポリビニルアセタールジエチルアミノアセテート、ジメチルアミノエチルメタクリレート－メタクリレートコポリマー、セルロースアセテート－Ｎ，Ｎ－ジ－ｎ－ブチルヒドロキシルプロピルエーテル、ビニルピリジンとアクリル酸系遊離酸とのコポリマー、アルキルビニルピリジンとアクリル酸系遊離酸とのコポリマー、ビニルピリジンとアクリル酸系遊離酸とビニルモノマーとのコポリマー、アルキルビニルピリジンとアクリル酸系遊離酸とビニルモノマーとのコポリマー、２－メチル－５－ビニルピリジン－メタクリル酸コポリマー、ポリ－２－（ビニルフェニル）グリシン、モルホリノ－Ｎ－β－エチルアクリレート－メタクリル酸コポリマー、シェラック、セルロースアセテートフタレート、メチルアクリレート－メタクリル酸コポリマー、メチルメタクリレート－メタクリル酸コポリマー、ゼイン、ヒドロキシプロピルメチルセルロースフタレートおよびアミノアルキルメタクリレートコポリマー等が挙げられる。これらの成分は、１種を単独で用いてもよいが、２種以上を組み合わせて用いてもよい。 According to another preferred embodiment, the coating agent used for the coating layer includes hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer, vinyl pyridine copolymer, alkyl vinyl pyridine copolymer, amino cellulose derivative, diethyl aminoethyl. Methacrylate, polyvinyl acetal diethylaminoacetate, dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N, N-di-n-butylhydroxylpropyl ether, copolymer of vinylpyridine and acrylic acid-based free acid, alkylvinylpyridine and acrylic acid-based Copolymer with free acid, copolymer of vinylpyridine and acrylic acid-based free acid and vinyl monomer, copolymer of alkylvinylpyridine and acrylic acid-based free acid and vinyl monomer, 2-methyl-5-vinylpyridine-methacrylic acid copolymer, Poly-2- (vinylphenyl) glycine, morpholino-N-β-ethylacrylate-methacrylic acid copolymer, shelac, cellulose acetate phthalate, methylacrylate-methacrylic acid copolymer, methylmethacrylate-methacrylic acid copolymer, zein, hydroxypropylmethylcellulosephthalate and Examples thereof include aminoalkylmethacrylic acid copolymers. One of these components may be used alone, or two or more thereof may be used in combination.
　一つの実施形態によれば、コーティング剤は可塑剤と組み合わせて用いてもよい。可塑剤としては、クエン酸アセチルトリブチル、クエン酸アセチルトリエチル、ヒマシ油、ジアセチル化モノグリセリド、セバシン酸ジブチル、ソルビトール、デキストリン、フタル酸ジエチル、グリセリン、ポリアルキレングリコール、ポリエチレングリコールモノエチルエーテル、プロピレングリコール、安息香酸ベンジル、精製水、ソルビトールソルビタン液、トリアセチン、クエン酸トリブチル、クエン酸トリエチル、クロロブタノール等が挙げられる。これらの可塑剤のうち、好ましくはポリアルキレングリコール、より好ましくはポリエチレングリコール（マクロゴール）が用いられる。これらの可塑剤は、１種を単独で用いてもよいが、２種以上を組み合わせて用いてもよい。 According to one embodiment, the coating agent may be used in combination with a plasticizer. Plasticizers include acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, sorbitol, dextrin, diethyl phthalate, glycerin, polyalkylene glycol, polyethylene glycol monoethyl ether, propylene glycol, benzo Examples thereof include benzyl acid acid, purified water, sorbitol sorbitan solution, triacetin, tributyl citrate, triethyl citrate, chlorobutanol and the like. Of these plasticizers, polyalkylene glycol is preferably used, and polyethylene glycol (macrogol) is more preferable. One of these plasticizers may be used alone, or two or more of these plasticizers may be used in combination.
　被覆層を構成する成分は、そのまま用いてもよいが、必要に応じて水、アルコール等に溶解して用いてもよい。 The components constituting the coating layer may be used as they are, but may be dissolved in water, alcohol, etc., if necessary.
　本発明の医薬製剤における被覆層の量は、本発明の医薬製剤が所望の効果を奏する限り特に限定されないが、核粒子の総質量に対する質量比（被覆層の質量：核粒子の総質量）として、下限値が、好ましくは０．００１：１、より好ましくは０．００２：１である。また、上限値は、特に限定されないが、好ましくは０．１：１、より好ましくは０．０５：１、より一層好ましくは０．０２：１である。また、核粒子の総質量に対する被覆層の質量比の範囲は、特に限定されないが、好ましくは０．００１：１～０．１：１、より好ましくは０．００２：１～０．０５：１、より一層好ましくは０．００２：１～０．０２：１である。 The amount of the coating layer in the pharmaceutical preparation of the present invention is not particularly limited as long as the pharmaceutical preparation of the present invention exerts a desired effect, but as a mass ratio to the total mass of the nuclear particles (mass of the coating layer: total mass of the nuclear particles). The lower limit is preferably 0.001: 1, more preferably 0.002: 1. The upper limit is not particularly limited, but is preferably 0.1: 1, more preferably 0.05: 1, and even more preferably 0.02: 1. The range of the mass ratio of the coating layer to the total mass of the nuclear particles is not particularly limited, but is preferably 0.001: 1 to 0.1: 1, more preferably 0.002: 1 to 0.05: 1. , Even more preferably 0.002: 1 to 0.02: 1.
＜その他の成分＞
　本発明の医薬製剤は、本発明の効果を妨げない限り、上述した核粒子および被覆層を構成する成分とは異なる薬学的に許容可能な添加剤を含んでいてもよい。添加剤としては、例えば、賦形剤、崩壊剤、滑沢剤、結合剤、流動化剤、甘味料、香料、着色料等が挙げられる。これらの添加物は、１つの成分が２つ以上の機能を担うものであってもよい。また、これらの添加剤は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。 <Other ingredients>
The pharmaceutical preparation of the present invention may contain a pharmaceutically acceptable additive different from the components constituting the nuclear particles and the coating layer described above, as long as the effects of the present invention are not impaired. Examples of the additive include excipients, disintegrants, lubricants, binders, fluidizers, sweeteners, flavors, colorants and the like. These additives may have one component having two or more functions. In addition, these additives may be used alone or in combination of two or more.
　本発明の医薬製剤は、核粒子を被覆する被覆層を備えることから、核粒子に含まれる不揮発性溶媒や薬物の医薬製剤からの漏出が抑制され、その結果、医薬製剤の凝集を抑制することができる。 Since the pharmaceutical preparation of the present invention includes a coating layer that coats the nuclear particles, leakage of the non-volatile solvent and the drug contained in the nuclear particles from the pharmaceutical preparation is suppressed, and as a result, aggregation of the pharmaceutical preparation is suppressed. Can be done.
　医薬製剤の凝集度は、好ましくは７０％以下、より好ましくは６０％以下、より一層好ましくは５０％以下である。医薬製剤の凝集度の測定は、上述した核粒子の凝集度の測定と同様の方法により行うことができる。 The degree of cohesion of the pharmaceutical preparation is preferably 70% or less, more preferably 60% or less, and even more preferably 50% or less. The degree of cohesion of the pharmaceutical preparation can be measured by the same method as the above-mentioned measurement of the degree of cohesion of nuclear particles.
　また、医薬製剤の凝集度は、核粒子の凝集度よりも改善している（低い）ことが好ましい。 Further, it is preferable that the degree of cohesion of the pharmaceutical preparation is improved (lower) than the degree of cohesion of the nuclear particles.
　医薬製剤の粒子径は、特に限定されないが、好ましくは体積分布基準の５０％粒子径（Ｄ５０）が１００～４００μｍであり、より好ましくは１２０～２５０μｍである。医薬製剤の体積分布基準の５０％粒子径（Ｄ５０）の測定は、上述した核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）の測定と同様の方法により行うことができる。 The particle size of the pharmaceutical preparation is not particularly limited, but preferably the 50% particle size (D50) based on the volume distribution is 100 to 400 μm, and more preferably 120 to 250 μm. The measurement of the 50% particle size (D50) based on the volume distribution of the pharmaceutical preparation can be performed by the same method as the measurement of the 50% particle size (D50) based on the volume distribution of the nuclear particle component described above.
　本発明の医薬製剤は、そのまま用いてもよいが、各種の剤形を有する製剤として用いてもよい。製剤の剤形としては、本発明の効果が奏される限り特に限定されないが例えば、顆粒剤、錠剤、丸剤、カプセル剤、散剤等が挙げられる。これらのうち、好ましくは顆粒剤、錠剤およびカプセル剤である。また、カプセル剤としてはハードカプセル剤が挙げられる。 The pharmaceutical preparation of the present invention may be used as it is, or may be used as a preparation having various dosage forms. The dosage form of the preparation is not particularly limited as long as the effects of the present invention are exhibited, and examples thereof include granules, tablets, pills, capsules, and powders. Of these, granules, tablets and capsules are preferred. Further, examples of the capsule include a hard capsule.
［医薬製剤の製造方法］
　本発明の医薬製剤の製造方法は、特に限定されず、公知の方法を用いることができる。医薬製剤の製造における条件は、核粒子成分、不揮発性溶媒、薬物、被覆層成分の種類等により、適宜調整することができる。具体的には、本発明の医薬製剤は、例えば、以下の手順に従って製造することができる。まず、針状および／または略柱状の結晶セルロースである第１の核粒子成分と、略球状の少なくとも１種の薬学的に許容可能な添加剤である第２の核粒子成分とを、流動層造粒機（例えば、ＦＤ－ＭＰ－０１Ｄ、株式会社パウレック製）を用いて混合して、核粒子混合物（一次粒子）を得る。一方で、不揮発性溶媒に薬物を添加して、撹拌機（ＮＺ－１２００、東京理化器械株式会社製）を用いて撹拌して、薬物が溶解または懸濁した混合液（薬物液）を得る。次いで、得られた混合物と混合液とを流動層造粒機を用いて接触させて、混合物中の核粒子成分に混合液を付着させて核粒子を得る。ここで、混合物と混合液との接触は、例えば、混合液を混合物に噴霧する方法、混合液中に混合物を浸漬する方法等により行われる。次いで、核粒子を必要に応じて乾燥させた後、被覆層を構成する成分（被覆層成分）で核粒子を被覆する。ここで、核粒子の被覆は、例えば、被覆層成分を核に噴霧する方法、被覆層成分中に核粒子を浸漬する方法等により行われる。次いで、核粒子と該核粒子を被覆する被覆層とを有する粒子を乾燥させて、医薬製剤を得る。 [Manufacturing method of pharmaceutical preparations]
The method for producing the pharmaceutical preparation of the present invention is not particularly limited, and a known method can be used. The conditions for producing a pharmaceutical preparation can be appropriately adjusted depending on the types of nuclear particle components, non-volatile solvents, drugs, coating layer components, and the like. Specifically, the pharmaceutical preparation of the present invention can be produced, for example, according to the following procedure. First, a fluidized bed of a first nuclear particle component, which is acicular and / or substantially columnar crystalline cellulose, and a second nuclear particle component, which is a substantially spherical at least one pharmaceutically acceptable additive. Mix using a granulator (for example, FD-MP-01D, manufactured by Paulec Co., Ltd.) to obtain a nuclear particle mixture (primary particles). On the other hand, a drug is added to a non-volatile solvent and stirred using a stirrer (NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.) to obtain a mixed solution (drug solution) in which the drug is dissolved or suspended. Next, the obtained mixture and the mixed solution are brought into contact with each other using a fluidized bed granulator to attach the mixed solution to the nuclear particle components in the mixture to obtain nuclear particles. Here, the contact between the mixture and the mixed solution is performed, for example, by a method of spraying the mixed solution onto the mixture, a method of immersing the mixed solution in the mixed solution, or the like. Next, the nuclear particles are dried as needed, and then the nuclear particles are coated with a component (coating layer component) constituting the coating layer. Here, the coating of the nuclear particles is performed, for example, by a method of spraying the coating layer component on the nucleus, a method of immersing the nuclear particles in the coating layer component, or the like. Then, the particles having the nuclear particles and the coating layer covering the nuclear particles are dried to obtain a pharmaceutical preparation.
　医薬製剤を打錠成形する方法は、特に限定されず、公知の方法を用いることができる。打錠成形における条件は、特に限定されず、核粒子成分、不揮発性溶媒、薬物、被覆層成分の種類等により、適宜調整することができる。医薬製剤を打錠成形する方法としては、例えば、医薬製剤をロータリー式打錠機、単発式打錠機等の打錠機を用いて打錠する方法が挙げられる。これらのうち、ロータリー打錠機を用いて医薬製剤を打錠成形することが好ましい。ロータリー打錠機としては、例えば、菊水製作所株式会社製のＶＩＲＧＯ　０５１２ＳＳ２ＡＹ等が挙げられる。錠剤が、本発明の医薬製剤の他に薬学的に許容可能な添加物を含む場合には、予め本発明の医薬製剤と薬学的に許容可能な添加物とを混合した後に打錠する。医薬製剤と添加剤とを混合する方法は、特に限定されず、公知の方法を用いて行うことができる。医薬製剤と添加剤とを混合する方法としては、例えば、Ｖ型混合機等の混合機を用いて混合する方法が挙げられる。具体的には、株式会社徳寿工作所製のＶ型混合機（ＴＣＶ－２０）を用いて混合することができる。 The method for tableting a pharmaceutical preparation is not particularly limited, and a known method can be used. The conditions for tableting are not particularly limited, and can be appropriately adjusted depending on the types of nuclear particle components, non-volatile solvents, drugs, coating layer components, and the like. Examples of the method for tableting and molding a pharmaceutical preparation include a method of locking a pharmaceutical preparation using a locking machine such as a rotary locking machine or a single-shot locking machine. Of these, it is preferable to tablet-mold the pharmaceutical preparation using a rotary locking machine. Examples of the rotary locking machine include VIRGO 0512SS2AY manufactured by Kikusui Seisakusho Co., Ltd. When the tablet contains a pharmaceutically acceptable additive in addition to the pharmaceutical preparation of the present invention, the pharmaceutical preparation of the present invention and the pharmaceutically acceptable additive are mixed in advance and then tableted. The method for mixing the pharmaceutical preparation and the additive is not particularly limited, and a known method can be used. Examples of the method of mixing the pharmaceutical preparation and the additive include a method of mixing using a mixer such as a V-type mixer. Specifically, mixing can be performed using a V-type mixer (TCV-20) manufactured by Tokuju Kosakusho Co., Ltd.
　医薬製剤をカプセル剤とする方法は、特に限定されず、公知の方法を用いることができる。具体的には、医薬製剤を、ゼラチン、または植物由来の原料等からなるカプセル皮膜に充填することによって製造される。カプセル皮膜への充填は、特に限定されず、例えば、オーガー式粉末充填、ダイコンプレス式粉末充填、バイブレーション式粉末充填等の公知の方法により行うことができる。例えば、オーガー式粉末充填では、通常ゼラチン皮膜で形成された互いに一端の開いた帽状容体の内部にホッパーから落下供給された粉末または顆粒の医薬製剤を撹拌羽根とオーガーの回転圧力によって直接カプセルボディに所定量充填した後、それら容体を同軸的に結合することによりカプセル剤を製造することができる。 The method of using a pharmaceutical preparation as a capsule is not particularly limited, and a known method can be used. Specifically, it is produced by filling a capsule film made of gelatin, a plant-derived raw material, or the like with a pharmaceutical preparation. The filling of the capsule film is not particularly limited, and can be performed by a known method such as auger type powder filling, radish press type powder filling, and vibration type powder filling. For example, in auger-type powder filling, a pharmaceutical preparation of powder or granules that is dropped and supplied from a hopper into a cap-shaped body that is usually formed of a gelatin film and has open ends is directly encapsulated by a stirring blade and the rotational pressure of the auger. Capsules can be produced by partially filling the capsules in a predetermined amount and then coaxially bonding the bodies.
　以下、実施例に基づいて本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。なお、本実施例においては、特段の記載がない限り、「平均粒子径（Ｄ５０）」は「体積分布基準の５０％粒子径」を意味する。 Hereinafter, the present invention will be specifically described based on Examples, but the present invention is not limited to these Examples. In this embodiment, unless otherwise specified, "average particle size (D50)" means "50% particle size based on volume distribution".
［核粒子の調製方法］
　略球状粒子として、乳糖水和物（ＳｕｐｅｒＴａｂ（登録商標）、平均粒子径（Ｄ５０）１２０μｍ、ＤＦＥ　Ｐｈａｒｍａ製）、およびトウモロコシデンプン（局方コーンスターチ、平均粒子径（Ｄ５０）１５μｍ、日本食品化工株式会社製）、針状および／または略柱状の結晶セルロースとして、結晶セルロース（ＣＥＯＬＵＳ　ＵＦ－７０２、平均粒子径（Ｄ５０）１４０μｍ、旭化成株式会社製）、および結晶セルロース（ＣＥＯＬＵＳ　ＫＧ－１０００、平均粒子径（Ｄ５０）８０μｍ、旭化成株式会社製）を準備し、電子顕微鏡（ＶＥ－７８００、ＫＥＹＥＮＣＥ製）によって画像測定を行った。図１ＡおよびＢは、それぞれ針状および／または略柱状の結晶セルロースＣＥＯＬＵＳ　ＫＧ－１０００およびＣＥＯＬＵＳ　ＵＦ－７０２の電子顕微鏡写真であり、図２は乳糖水和物（略球状粒子）の電子顕微鏡写真であり、図３はトウモロコシデンプン（略球状粒子）の電子顕微鏡写真である [Method for preparing nuclear particles]
As substantially spherical particles, lactose hydrate (SuperTab (registered trademark), average particle size (D50) 120 μm, manufactured by DFE Pharma), and corn starch (Japanese corn starch, average particle size (D50) 15 μm, Nippon Shokuhin Kako Co., Ltd.) , As needle-shaped and / or substantially columnar crystalline cellulose, crystalline cellulose (CEOLUS UF-702, average particle size (D50) 140 μm, manufactured by Asahi Kasei Co., Ltd.), and crystalline cellulose (CEOLUS KG-1000, average particle size (manufactured by). D50) 80 μm (manufactured by Asahi Kasei Co., Ltd.) was prepared, and image measurement was performed with an electron microscope (VE-7800, manufactured by KEYENCE). 1A and 1B are electron micrographs of needle-shaped and / or substantially columnar crystalline cellulose CEOLUS KG-1000 and CEOLUS UF-702, respectively, and FIG. 2 is an electron micrograph of lactose hydrate (substantially spherical particles). Yes, FIG. 3 is an electron micrograph of corn starch (approximately spherical particles).
　表２に示す処方に従って、略球状粒子として、乳糖水和物（ＳｕｐｅｒＴａｂ（登録商標）、平均アスペクト比１．３９、平均粒子径（Ｄ５０）１２０μｍ、ＤＦＥ　Ｐｈａｒｍａ製）、およびトウモロコシデンプン（局方コーンスターチ、平均アスペクト比１．２３、平均粒子径（Ｄ５０）１５μｍ、日本食品化工株式会社製）、針状結晶セルロースとして、結晶セルロース（ＣＥＯＬＵＳ　ＵＦ－７０２、平均アスペクト比２．６３、平均粒子径（Ｄ５０）１４０μｍ、旭化成株式会社製）、および（ＣＥＯＬＵＳ　ＫＧ－１０００、平均アスペクト比４．２０、平均粒子径（Ｄ５０）８０μｍ、旭化成株式会社製）を、それぞれ３５５μｍ篩で篩過し、ポリエチレン袋に入れて予備混合した。なお、各核粒子成分の平均アスペクト比は、電子顕微鏡（ＶＥ－７８００、ＫＥＹＥＮＣＥ製）を用いて粒子画像を取得し、画像解析により測定した、それぞれ任意に選択した１０個の粒子のアスペクト比を測定し、アスペクト比の値の上位１０％および下位１０％の粒子のアスペクト比の値を除外した粒子のアスペクト比の平均値を意味する。また、表２において、特に示さない場合、数値の単位はｇ（グラム）である。
Figure JPOXMLDOC01-appb-T000003
 Lactose hydrate (SuperTab®, average aspect ratio 1.39, average particle size (D50) 120 μm, manufactured by DFE Pharma), and corn starch (Japanese corn starch) as substantially spherical particles according to the formulation shown in Table 2. , Average aspect ratio 1.23, average particle size (D50) 15 μm, manufactured by Nippon Shokuhin Kako Co., Ltd.), as acicular crystalline cellulose, crystalline cellulose (CEOLUS UF-702, average aspect ratio 2.63, average particle size (D50) ) 140 μm, manufactured by Asahi Kasei Co., Ltd.) and (CEOLUS KG-1000, average aspect ratio 4.20, average particle size (D50) 80 μm, manufactured by Asahi Kasei Co., Ltd.) are sieved through a 355 μm sieve and placed in a polyethylene bag. Premixed. The average aspect ratio of each nuclear particle component is the aspect ratio of 10 arbitrarily selected particles measured by acquiring a particle image using an electron microscope (VE-7800, manufactured by KEYENCE) and analyzing the image. It means the average value of the aspect ratios of the particles measured and excluding the values of the aspect ratios of the particles having the upper 10% and the lower 10% of the aspect ratio values. Further, in Table 2, unless otherwise specified, the unit of the numerical value is g (gram).
Figure JPOXMLDOC01-appb-T000003
　次いで、各実施例および比較例の混合物を流動層造粒機（ＦＤ－ＭＰ－０１Ｄ、株式会社パウレック製）に投入し、表３に示す条件で核粒子混合物（一次粒子）を混合した（予熱工程）。
Figure JPOXMLDOC01-appb-T000004
 Next, the mixture of each example and comparative example was put into a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.), and the nuclear particle mixture (primary particles) was mixed under the conditions shown in Table 3 (preheating). Process).
Figure JPOXMLDOC01-appb-T000004
＜核粒子混合物のかさ密度の測定＞
　得られたそれぞれの核粒子混合物（一次粒子）について、かためかさ密度およびゆるみかさ密度を測定した。具体的には、パウダテスタ（登録商標）ＰＴ－Ｒ（ホソカワミクロン株式会社製）を用いて、第１７改正日本薬局方に記載されている、かさ密度およびタップ密度測定法第３法の測定用容器と同サイズの円筒容器に核粒子混合物を篩いを通して上方から均一に供給し、上面をすり切って秤量することによって疎充填の状態のかさ密度（ゆるみかさ密度）を測定。次いで、この容器の上に補助円筒をはめ、この上縁まで核粒子混合物を加えてタッピングを１８０回行ない、終了後、補助円筒を外して容器の上面で核粒子混合物をすり切って秤量し、タッピング後の密充填した場合のかさ密度（かためかさ密度）を測定した。さらに、各核粒子混合物について、かためかさ密度とゆるみかさ密度の差（かためかさ密度－ゆるみかさ密度）を算出した。結果を表４に示す。 <Measurement of bulk density of nuclear particle mixture>
The firmness density and looseness density were measured for each of the obtained nuclear particle mixtures (primary particles). Specifically, using Powder Tester (registered trademark) PT-R (manufactured by Hosokawa Micron Co., Ltd.), a container for measuring bulk density and tap density measurement method 3 described in the 17th revised Japanese Pharmacy Law. The bulk density (loose bulk density) in a loosely filled state is measured by uniformly supplying the nuclear particle mixture through a sieve to a cylindrical container of the same size from above, and weighing by scraping the upper surface. Next, an auxiliary cylinder was fitted on the container, the nuclear particle mixture was added up to the upper edge, and tapping was performed 180 times. After the completion, the auxiliary cylinder was removed and the nuclear particle mixture was ground and weighed on the upper surface of the container. The bulk density (hard bulk density) in the case of dense packing after tapping was measured. Further, for each mixture of nuclear particles, the difference between the firmness density and the loose bulk density (hardness density-loose bulk density) was calculated. The results are shown in Table 4.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　さらに、表２に示す処方に従って、各不揮発性溶媒を５００ｍＬビーカーに投入し、撹拌機（ＮＺ－１２００、東京理化器械株式会社製）を用いて４００～９００ｒｐｍで撹拌・混合した。均一になるまで撹拌・混合した後、各薬物を添加して、さらに撹拌・混合して薬物液を得た。なお、各薬物のｌｏｇＰ値は表２に示す通りである。 Further, each non-volatile solvent was put into a 500 mL beaker according to the formulation shown in Table 2, and stirred and mixed at 400 to 900 rpm using a stirrer (NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.). After stirring and mixing until uniform, each drug was added, and the mixture was further stirred and mixed to obtain a drug solution. The logP values of each drug are as shown in Table 2.
　次いで、流動層造粒機（ＦＤ－ＭＰ－０１Ｄ、株式会社パウレック製）を用いて、上記で得られた各核粒子混合物（一次粒子）に薬物液を噴霧して、一次粒子に薬物液が付着した核粒子を得た（造粒工程）。流動層造粒機の設定条件は上記表３の通りとした。 Next, using a fluidized bed granulator (FD-MP-01D, manufactured by Paulec Co., Ltd.), the drug solution was sprayed onto each of the nuclear particle mixtures (primary particles) obtained above, and the drug solution was applied to the primary particles. Adhered nuclear particles were obtained (granulation step). The setting conditions of the fluidized bed granulator are as shown in Table 3 above.
＜核粒子の凝集度の測定＞
　得られた各実施例および比較例の医薬製剤の核粒子について、粉体特性評価装置（パウダテスタ（登録商標）ＰＴ－Ｒ、ホソカワミクロン株式会社製）を用いて凝集度を測定した。粉体特性評価装置の設定条件は以下の通りとした。
　篩目開き：（上段）７１０μｍ、（中段）３５５μｍ、（下段）２５０μｍ
　試料採取量：２ｇまたは３ｇ
　振動時間：１１９秒 <Measurement of cohesion of nuclear particles>
The degree of cohesion of the nuclei particles of the obtained pharmaceutical preparations of Examples and Comparative Examples was measured using a powder property evaluation device (Powder Tester (registered trademark) PT-R, manufactured by Hosokawa Micron Co., Ltd.). The setting conditions of the powder property evaluation device were as follows.
Opening of mesh: (upper) 710 μm, (middle) 355 μm, (lower) 250 μm
Sampling volume: 2g or 3g
Vibration time: 119 seconds
　上記の条件下で、下記式の各項目の値を測定する。
　Ｘ＝［上段の篩に残った粉体質量］／投入した粉体質量×１００
　Ｙ＝［中段の篩に残った粉体質量］／投入した粉体質量×１００×０．６
　Ｚ＝［下段の篩に残った粉体質量］／投入した粉体質量×１００×０．２
　上記Ｘ、Ｙ、Ｚの３つの値の合計をもって、凝集度（％）とする。結果を上記表４に示す。 Under the above conditions, the value of each item in the following formula is measured.
X = [mass of powder remaining on the upper sieve] / mass of powder charged x 100
Y = [Mass of powder remaining on the middle sieve] / Mass of powder charged x 100 x 0.6
Z = [Mass of powder remaining on the lower sieve] / Mass of powder charged x 100 x 0.2
The sum of the above three values of X, Y, and Z is defined as the degree of cohesion (%). The results are shown in Table 4 above.
　また、表２に示す処方に従って、各被覆層成分をステンレス容器に投入し、撹拌機（ＮＺ－１２００、東京理化器械株式会社製）を用いて４００～９００ｒｐｍで撹拌・混合して被覆層溶液を得た。 Further, according to the formulation shown in Table 2, each coating layer component is put into a stainless steel container, and the coating layer solution is prepared by stirring and mixing at 400 to 900 rpm using a stirrer (NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.). Obtained.
　次いで、流動層造粒機（ＦＤ－ＭＰ－０１Ｄ、株式会社パウレック製）を用いて、上記で得られた各核粒子に被覆層溶液を噴霧し、６０℃で１５分間乾燥させて、核粒子が被覆層溶液で被覆された医薬製剤を得た。流動層造粒機の設定条件は表５の通りとした。
Figure JPOXMLDOC01-appb-T000006
 Next, using a fluidized bed granulator (FD-MP-01D, manufactured by Paulec Co., Ltd.), the coating layer solution was sprayed on each of the core particles obtained above, dried at 60 ° C. for 15 minutes, and the core particles were dried. Obtained a pharmaceutical formulation coated with a coating layer solution. The setting conditions of the fluidized bed granulator are as shown in Table 5.
Figure JPOXMLDOC01-appb-T000006
　得られた各実施例および比較例の医薬製剤の凝集度を、上述した核粒子の凝集度の測定と同様の方法により測定した。結果を上記表４に示す。 The degree of cohesion of the obtained pharmaceutical preparations of Examples and Comparative Examples was measured by the same method as the above-mentioned measurement of the degree of cohesion of nuclear particles. The results are shown in Table 4 above.
　表４の結果から、核粒子成分として第２の核粒子成分のみを用いた比較例１～３および第１核粒子成分のみを用いた比較例４では、医薬製剤を顆粒の形態として製造することはできなかった。一方、核粒子成分として第１の核粒子成分（結晶セルロース）と第２の核粒子成分とを組み合わせた実施例１～６の処方では、医薬製剤の凝集が抑制され、良好な流動性を有していた。さらに、実施例１～６の処方では、医薬製剤を顆粒の形態として製造することができ、実施例２～６の処方では、打錠して錠剤を製造することもできた。なお、実施例１の処方について、打錠による錠剤の製造の可否は確認されていないが、医薬製剤の凝集度（被覆後の凝集度）が抑制されていることから、打錠による錠剤の製造は可能であると推測される。また、実施例１～６の不揮発性溶媒（ポリソルベート８０）を油脂（中鎖脂肪酸トリグリセリド）に代えた処方で医薬製剤を製造した場合でも、医薬製剤の凝集が抑制され、流動性が良好であることが確認されている。さらに、それらの医薬製剤は顆粒の形態として製造することができ、また、打錠して錠剤を製造することも確認されている。 From the results in Table 4, in Comparative Examples 1 to 3 using only the second nuclear particle component as the nuclear particle component and Comparative Example 4 using only the first nuclear particle component, the pharmaceutical preparation was produced in the form of granules. I couldn't. On the other hand, in the formulations of Examples 1 to 6 in which the first nuclear particle component (crystalline cellulose) and the second nuclear particle component are combined as the nuclear particle component, aggregation of the pharmaceutical preparation is suppressed and good fluidity is obtained. Was. Further, in the formulations of Examples 1 to 6, the pharmaceutical preparation could be produced in the form of granules, and in the formulations of Examples 2 to 6, tablets could be produced to produce tablets. Regarding the formulation of Example 1, it has not been confirmed whether or not tablets can be produced by tableting, but since the degree of cohesion (cohesion after coating) of the pharmaceutical preparation is suppressed, the production of tablets by tableting has not been confirmed. Is presumed to be possible. Further, even when a pharmaceutical preparation is produced with a formulation in which the non-volatile solvent (polysorbate 80) of Examples 1 to 6 is replaced with fat (medium chain fatty acid triglyceride), the aggregation of the pharmaceutical preparation is suppressed and the fluidity is good. It has been confirmed that. Furthermore, it has been confirmed that these pharmaceutical preparations can be produced in the form of granules and can be tableted to produce tablets.
　本発明によれば、界面活性剤やビタミン類等の医薬品製造に有用な不揮発性溶媒を含み、実際の製造に耐え得る優れた流動性を有する顆粒を提供することができる。 According to the present invention, it is possible to provide granules containing a non-volatile solvent useful for manufacturing pharmaceuticals such as surfactants and vitamins and having excellent fluidity that can withstand actual manufacturing.

Claims (42)

  1. 　核粒子と該核粒子を被覆する被覆層とを備える顆粒の形態の医薬製剤であって、
    　前記核粒子が、薬物、第１の核粒子成分、第２の核粒子成分および不揮発性溶媒を含んでなり、
    　前記第１の核粒子成分は、針状および略柱状から選択される形状を有する少なくとも１種の結晶セルロースであり、
    　前記第２の核粒子成分は、略球状の少なくとも１種の薬学的に許容可能な添加剤である、前記医薬製剤。     A pharmaceutical preparation in the form of granules comprising a nucleus particle and a coating layer covering the nucleus particle.
    The nuclear particle comprises a drug, a first nuclear particle component, a second nuclear particle component and a non-volatile solvent.
    The first nuclear particle component is at least one crystalline cellulose having a shape selected from needle-like and substantially columnar.
    The pharmaceutical formulation, wherein the second nuclear particle component is at least one pharmaceutically acceptable additive that is substantially spherical.
  2. 　前記第１の核粒子成分の平均アスペクト比が１．８以上である、請求項１に記載の医薬製剤。 The pharmaceutical preparation according to claim 1, wherein the average aspect ratio of the first nuclear particle component is 1.8 or more.
  3. 　前記第１の核粒子成分の平均アスペクト比が１．８～１０．０である、請求項２に記載の医薬製剤。 The pharmaceutical preparation according to claim 2, wherein the average aspect ratio of the first nuclear particle component is 1.8 to 10.0.
  4. 　前記第２の核粒子成分の平均アスペクト比が１．０～１．７である、請求項１～３のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 3, wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.7.
  5. 　前記第２の核粒子成分の平均アスペクト比が１．０～１．５である、請求項４に記載の医薬製剤。 The pharmaceutical preparation according to claim 4, wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.5.
  6. 　前記第１の核粒子成分と第２の核粒子成分との平均アスペクト比の差が０．５以上である、請求項１～５のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 5, wherein the difference in the average aspect ratio between the first nuclear particle component and the second nuclear particle component is 0.5 or more.
  7. 　前記第１の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）に対する前記第２の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）の比が１：１．１以下である、請求項１～６のいずれか一項に記載の医薬製剤。 The ratio of the 50% particle diameter (D50) based on the volume distribution of the first nuclear particle component to the 50% particle diameter (D50) based on the volume distribution of the second nuclear particle component is 1: 1.1 or less. , The pharmaceutical preparation according to any one of claims 1 to 6.
  8. 　前記第２の核粒子成分が、少なくとも２つの異なる成分からなる、請求項１～７のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 7, wherein the second nuclear particle component comprises at least two different components.
  9. 　前記第１の核粒子成分と第２の核粒子成分との質量比が１：１～１：１０である、請求項１～８のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 8, wherein the mass ratio of the first nuclear particle component to the second nuclear particle component is 1: 1 to 1:10.
  10. 　前記第１の核粒子成分および第２の核粒子成分の総質量と、前記不揮発性溶媒との質量比が１：０．０１～１：０．６である、請求項１～９のいずれか一項に記載の医薬製剤。 Any of claims 1 to 9, wherein the mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component to the non-volatile solvent is 1: 0.01 to 1: 0.6. The pharmaceutical preparation according to paragraph 1.
  11. 　前記不揮発性溶媒と前記薬物との質量比が１：０．１～１：１０である、請求項１～１０のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 10, wherein the mass ratio of the non-volatile solvent to the drug is 1: 0.1 to 1:10.
  12. 　前記第１の核粒子成分および第２の核粒子成分の総質量と、前記被覆層の質量との質量比が１：０．０５～１：０．３である、請求項１～１１のいずれか一項に記載の医薬製剤。 Any of claims 1 to 11, wherein the mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component to the mass of the coating layer is 1: 0.05 to 1: 0.3. The pharmaceutical preparation according to item 1.
  13. 　前記第２の核粒子成分が、糖類および無機化合物からなる群から選択される少なくとも１種の薬学的に許容可能な添加剤である、請求項１～１２のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 12, wherein the second nuclear particle component is at least one pharmaceutically acceptable additive selected from the group consisting of saccharides and inorganic compounds. ..
  14. 　前記第２の核粒子成分が、ブドウ糖、果糖、乳糖、乳糖水和物、ショ糖、白糖、圧縮等、精製粉末砂糖、アルギン酸アンモニウム、デンプン、ジャガイモデンプン、コムギデンプン、トウモロコシデンプン、コメデンプン、マンニトール、ソルビトール、リン酸塩、炭酸マグネシウム、酸化マグネシウム、炭酸カルシウム、硫酸カルシウム、デキストレート類、デキストリン、デキストロース、ポリメタクリレート、パルミトステアリン酸グリセリン、イソマルト、ラクチトール、カオリン、ラクチトール、マルチトール、マルトデキストリン、マルトース、トレハロース、キシリトール、アルファー化デンプン、変性アルファー化デンプン、タピオカデンプン、塩化ナトリウムからなる群から選択される少なくとも１つのものである、請求項１～１３のいずれか一項に記載の医薬製剤。 The second nuclear particle component is glucose, fructose, lactose, lactose hydrate, sucrose, sucrose, compressed, etc., refined powdered sugar, ammonium alginate, starch, potato starch, wheat starch, corn starch, rice starch, mannitol. , Sorbitol, Phosphate, Magnesium Carbonate, Magnesium Oxide, Calcium Carbonate, Calcium Sulfate, Dextrose, Dextrin, Dextrose, Polymethacrylate, Glycerin Palmitostearate, Isomalt, Lactitol, Kaolin, Lactitol, Martinol, Maltodextrin, The pharmaceutical preparation according to any one of claims 1 to 13, which is at least one selected from the group consisting of maltose, trehalose, xylitol, pregelatinized starch, modified pregelatinized starch, tapioca starch and sodium chloride.
  15. 　前記不揮発性溶媒が、界面活性剤、ビタミン類および油脂からなる群から選択される少なくとも１種を含んでなる、請求項１～１４のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 14, wherein the non-volatile solvent contains at least one selected from the group consisting of surfactants, vitamins and fats and oils.
  16. 　前記界面活性剤が非イオン性界面活性剤である、請求項１５に記載の医薬製剤。 The pharmaceutical preparation according to claim 15, wherein the surfactant is a nonionic surfactant.
  17. 　前記非イオン性界面活性剤がポリソルベートである、請求項１６に記載の医薬製剤。 The pharmaceutical preparation according to claim 16, wherein the nonionic surfactant is polysorbate.
  18. 　前記油脂がグリセリン脂肪酸エステルである、請求項１５に記載の医薬製剤。 The pharmaceutical preparation according to claim 15, wherein the fat and oil is a glycerin fatty acid ester.
  19. 　前記グリセリン脂肪酸エステルが中鎖脂肪酸トリグリセリドである、請求項１８に記載の医薬製剤。 The pharmaceutical preparation according to claim 18, wherein the glycerin fatty acid ester is a medium-chain fatty acid triglyceride.
  20. 　前記薬物のｌｏｇＰ値が－２～７である、請求項１～１９のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 19, wherein the logP value of the drug is -2 to 7.
  21. 　前記薬物のｌｏｇＰ値が－１．９～６．５である、請求項１～２０のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 20, wherein the logP value of the drug is 1.9 to 6.5.
  22. 　前記薬物が難水溶性薬物を含んでなる、請求項１～２１のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 21, wherein the drug contains a poorly water-soluble drug.
  23. 　前記難水溶性薬物が、ホルモン剤、抗癌剤、抗菌剤および抗ウイルス剤（Ｎ－［５－フルオロ－２－（１－ピペリジニル）フェニル］イソニコチンチオアミドを除く）からなる群から選択される少なくとも１種を含んでなる、請求項２２に記載の医薬製剤。 The poorly water-soluble drug is at least one selected from the group consisting of hormonal agents, anticancer agents, antibacterial agents and antiviral agents (excluding N- [5-fluoro-2- (1-piperidinyl) phenyl] isoniazid thioamide). The pharmaceutical preparation according to claim 22, which comprises a seed.
  24. 　前記被覆層が、水溶性コーティング剤を含む、請求項１～２３のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 23, wherein the coating layer contains a water-soluble coating agent.
  25. 　前記水溶性コーティング剤が、ポリアルキレングリコール、多糖類、およびそれらの誘導体からなる群より選択される少なくとも一つの成分を含んでなる、請求項２４に記載の医薬製剤。 The pharmaceutical preparation according to claim 24, wherein the water-soluble coating agent contains at least one component selected from the group consisting of polyalkylene glycols, polysaccharides, and derivatives thereof.
  26. 　前記水溶性コーティング剤が、ポリエチレングリコール、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メタアクリル酸コポリマー、ビニルピリジンコポリマー、アルキルビニルピリジンコポリマー、アミノセルロース誘導体、ジエチルアミノエチルメタクリレート、ポリビニルアセタールジエチルアミノアセテート、ジメチルアミノエチルメタクリレート－メタクリレートコポリマー、セルロースアセテート－Ｎ，Ｎ－ジ－ｎ－ブチルヒドロキシルプロピルエーテル、ビニルピリジンとアクリル酸系遊離酸とのコポリマー、アルキルビニルピリジンとアクリル酸系遊離酸とのコポリマー、ビニルピリジンとアクリル酸系遊離酸とビニルモノマーとのコポリマー、アルキルビニルピリジンとアクリル酸系遊離酸とビニルモノマーとのコポリマー、２－メチル－５－ビニルピリジン－メタクリル酸コポリマー、ポリ－２－（ビニルフェニル）グリシン、モルホリノ－Ｎ－β－エチルアクリレート－メタクリル酸コポリマー、シェラック、セルロースアセテートフタレート、メチルアクリレート－メタクリル酸コポリマー、メチルメタクリレート－メタクリル酸コポリマー、ゼイン、ヒドロキシプロピルメチルセルロースフタレートおよびアミノアルキルメタクリレートコポリマーからなる群から選択される少なくとも１種である、請求項２４または２５に記載の医薬製剤。 The water-soluble coating agent is polyethylene glycol, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer, vinyl pyridine copolymer, alkyl vinyl pyridine copolymer, amino cellulose derivative, diethyl aminoethyl methacrylate, polyvinyl acetal diethyl amino acetate, Dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N, N-di-n-butyl hydroxylpropyl ether, copolymer of vinylpyridine and acrylic acid-based free acid, copolymer of alkylvinylpyridine and acrylic acid-based free acid, vinyl Copolymer of pyridine and acrylic acid-based free acid and vinyl monomer, copolymer of alkyl vinyl pyridine and acrylic acid-based free acid and vinyl monomer, 2-methyl-5-vinylpyridine-methacrylic acid copolymer, poly-2- (vinylphenyl) ) A group consisting of glycine, morpholino-N-β-ethylacrylate-methacrylic acid copolymer, shelac, cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, zein, hydroxypropyl methyl cellulose phthalate and aminoalkyl methacrylate copolymer. The pharmaceutical formulation according to claim 24 or 25, which is at least one selected from.
  27. 　前記医薬製剤の凝集度が７０％以下である、請求項１～２６のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 26, wherein the degree of cohesion of the pharmaceutical preparation is 70% or less.
  28. 　前記医薬製剤の凝集度が前記核粒子の凝集度よりも低い、請求項１～２７のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 27, wherein the degree of cohesion of the pharmaceutical preparation is lower than the degree of cohesion of the nuclear particles.
  29. 　前記医薬製剤の体積分布基準の５０％粒子径（Ｄ５０）が１００～４００μｍである、請求項１～２８のいずれか一項に記載の医薬製剤。 The pharmaceutical preparation according to any one of claims 1 to 28, wherein the 50% particle size (D50) based on the volume distribution of the pharmaceutical preparation is 100 to 400 μm.
  30. 　請求項１～２９のいずれか一項に記載の医薬製剤を含んでなり、顆粒剤、錠剤、カプセル剤、散剤および丸剤からなる群から選択される剤形を有する製剤。 A preparation comprising the pharmaceutical preparation according to any one of claims 1 to 29 and having a dosage form selected from the group consisting of granules, tablets, capsules, powders and pills.
  31. 　核粒子と該核粒子を被覆する被覆層とを備える顆粒の形態の医薬製剤の製造方法であって、
    　（ａ）第１の核粒子成分と、第２の核粒子成分とを混合して核粒子混合物を得る工程、
    　（ｂ）不揮発性溶媒に薬物を溶解または懸濁して混合液を得る工程、
    　（ｃ）工程（ａ）で得られた核粒子混合物と、工程（ｂ）で得られた混合液とを接触させて第１の核粒子成分、第２の核粒子成分、薬物および不揮発性溶媒を含む核粒子を得る工程、および、
    　（ｄ）工程（ｃ）で得られた核粒子を被覆して医薬製剤を得る工程
    を含み、
    　前記第１の核粒子成分は、針状および略柱状から選択される形状を有する少なくとも１種の結晶セルロースであり、
    　前記第２の核粒子成分は、略球状の少なくとも１種の薬学的に許容可能な添加剤である、前記製造方法。     A method for producing a pharmaceutical preparation in the form of granules, which comprises nuclear particles and a coating layer covering the nuclear particles.
    (A) A step of mixing a first nuclear particle component and a second nuclear particle component to obtain a nuclear particle mixture.
    (B) A step of dissolving or suspending a drug in a non-volatile solvent to obtain a mixed solution.
    (C) The nuclear particle mixture obtained in step (a) and the mixed solution obtained in step (b) are brought into contact with each other to bring the first nuclear particle component, the second nuclear particle component, the drug and the non-volatile solvent. The process of obtaining nuclear particles containing
    (D) Including the step of coating the nuclear particles obtained in step (c) to obtain a pharmaceutical preparation.
    The first nuclear particle component is at least one crystalline cellulose having a shape selected from needle-like and substantially columnar.
    The production method, wherein the second nuclear particle component is at least one pharmaceutically acceptable additive that is substantially spherical.
  32. 　前記第１の核粒子成分の平均アスペクト比が１．８以上である、請求項３１に記載の製造方法。 The production method according to claim 31, wherein the average aspect ratio of the first nuclear particle component is 1.8 or more.
  33. 　前記第１の核粒子成分の平均アスペクト比が１．８～１０．０である、請求項３２に記載の製造方法。 The production method according to claim 32, wherein the average aspect ratio of the first nuclear particle component is 1.8 to 10.0.
  34. 　前記第２の核粒子成分の平均アスペクト比が１．０～１．７である、請求項３１～３３のいずれか一項に記載の製造方法。 The production method according to any one of claims 31 to 33, wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.7.
  35. 　前記第２の核粒子成分の平均アスペクト比が１．０～１．５である、請求項３４に記載の製造方法。 The production method according to claim 34, wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.5.
  36. 　前記第１の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）に対する前記第２の核粒子成分の体積分布基準の５０％粒子径（Ｄ５０）の比が１：１．１以下である、請求項３１～３５のいずれか一項に記載の製造方法。 The ratio of the 50% particle diameter (D50) based on the volume distribution of the first nuclear particle component to the 50% particle diameter (D50) based on the volume distribution of the second nuclear particle component is 1: 1.1 or less. , The manufacturing method according to any one of claims 31 to 35.
  37. 　前記第２の核粒子成分が、少なくとも２つの異なる成分からなる、請求項３１～３６のいずれか一項に記載の製造方法。 The production method according to any one of claims 31 to 36, wherein the second nuclear particle component comprises at least two different components.
  38. 　前記不揮発性溶媒が、界面活性剤、ビタミン類および油脂からなる群から選択される少なくとも１種を含んでなる、請求項３１～３７のいずれか一項に記載の製造方法。 The production method according to any one of claims 31 to 37, wherein the non-volatile solvent contains at least one selected from the group consisting of surfactants, vitamins and fats and oils.
  39. 　（ｅ）工程（ｄ）で得られた医薬製剤に薬学的に許容可能な添加剤を加えて造粒して、顆粒状の製剤を得る工程をさらに含む、請求項３１～３８のいずれか一項に記載の製造方法。 (E) Any one of claims 31 to 38, further comprising a step of adding a pharmaceutically acceptable additive to the pharmaceutical preparation obtained in step (d) and granulating to obtain a granular preparation. The manufacturing method described in the section.
  40. 　（ｅ’）工程（ｄ）で得られた医薬製剤を、ゼラチン、または植物由来の原料からなる皮膜に封入して、カプセル状の製剤を得る工程をさらに含む、請求項３１～３８のいずれか一項に記載の製造方法。 (E') Any of claims 31 to 38, 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. The manufacturing method according to paragraph 1.
  41. 　請求項１～２９のいずれか一項に記載の医薬製剤を打錠成形して錠剤を得る工程を含んでなる、錠剤の製造方法。 A method for producing a tablet, which comprises a step of tableting and molding the pharmaceutical preparation according to any one of claims 1 to 29 to obtain a tablet.
  42. 　請求項１～２９のいずれか一項に記載の医薬製剤をカプセルに封入する工程を含んでなる、カプセル剤の製造方法。 A method for producing a capsule, which comprises a step of encapsulating the pharmaceutical preparation according to any one of claims 1 to 29.
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