WO2020218517A1 - 医薬製剤およびその製造方法 - Google Patents

医薬製剤およびその製造方法 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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English (en)
French (fr)
Japanese (ja)
Inventor
俊行 稲田
隆樹 下平
良成 金山
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Fuji Pharma Co Ltd
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Fuji Pharma Co Ltd
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Priority to JP2021516265A priority Critical patent/JP7640453B2/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • 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
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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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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WO2022091442A1 (ja) * 2020-10-28 2022-05-05 株式会社キノファーマ ウイルス性腟周辺部疾患の予防又は治療のための医薬組成物

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WO2010095494A1 (ja) * 2009-02-19 2010-08-26 アサヒビール株式会社 難溶性物質を含有する顆粒、錠剤、及び難溶性物質の可溶化方法
JP2011520774A (ja) * 2008-05-15 2011-07-21 大塚製薬株式会社 固形医薬製剤
JP2015048315A (ja) * 2013-08-30 2015-03-16 旭化成ケミカルズ株式会社 セルロース系核粒子及びその製造方法
JP2018118936A (ja) * 2017-01-27 2018-08-02 日本ケミファ株式会社 腸溶層破損防止用組成物
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JP2011520774A (ja) * 2008-05-15 2011-07-21 大塚製薬株式会社 固形医薬製剤
WO2010095494A1 (ja) * 2009-02-19 2010-08-26 アサヒビール株式会社 難溶性物質を含有する顆粒、錠剤、及び難溶性物質の可溶化方法
JP2015048315A (ja) * 2013-08-30 2015-03-16 旭化成ケミカルズ株式会社 セルロース系核粒子及びその製造方法
JP2018118936A (ja) * 2017-01-27 2018-08-02 日本ケミファ株式会社 腸溶層破損防止用組成物
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WO2022091442A1 (ja) * 2020-10-28 2022-05-05 株式会社キノファーマ ウイルス性腟周辺部疾患の予防又は治療のための医薬組成物
JPWO2022091442A1 (https=) * 2020-10-28 2022-05-05
JP7606239B2 (ja) 2020-10-28 2024-12-25 株式会社キノファーマ ウイルス性腟周辺部疾患の予防又は治療のための医薬組成物

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