WO2018124260A1 - Medicinal composition comprising ed-71 solid dispersion and oil dispersion - Google Patents

Medicinal composition comprising ed-71 solid dispersion and oil dispersion Download PDF

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WO2018124260A1
WO2018124260A1 PCT/JP2017/047156 JP2017047156W WO2018124260A1 WO 2018124260 A1 WO2018124260 A1 WO 2018124260A1 JP 2017047156 W JP2017047156 W JP 2017047156W WO 2018124260 A1 WO2018124260 A1 WO 2018124260A1
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water
oil
soluble polymer
solution
pharmaceutical composition
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PCT/JP2017/047156
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French (fr)
Japanese (ja)
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和貴 倉崎
隆介 ▲高▼野
慶宏 松岡
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中外製薬株式会社
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Priority to KR1020197019067A priority Critical patent/KR102366186B1/en
Priority to JP2018559626A priority patent/JP6905538B2/en
Priority to KR1020227004397A priority patent/KR102583517B1/en
Priority to CN201780081610.0A priority patent/CN110121348A/en
Publication of WO2018124260A1 publication Critical patent/WO2018124260A1/en

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    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • 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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to (5Z, 7E)-(1R, 2R, 3R) -2- (3-hydroxypropoxy) -9,10-secocholesta 5,7,10 (19) -triene-1,3,25-triol (Hereinafter also referred to as ED-71) and a method for producing the same, and a method for inhibiting oxidation or decomposition of ED-71.
  • ED-71 (generic name: eldecalcitol) is a synthetic derivative of active vitamin D 3 having a bone forming action, and is manufactured and sold as a therapeutic agent for osteoporosis by oral administration.
  • ED-71 can be formulated as a soft capsule, like other vitamin D derivatives.
  • Patent Document 1 discloses a seamless soft capsule in which a medium chain fatty acid triglyceride (hereinafter also referred to as MCT) solution of ED-71 is enclosed in a gelatin coating.
  • MCT medium chain fatty acid triglyceride
  • Patent Document 1 also discloses that the addition of an anti-oxidant such as dl- ⁇ -tocopherol to the solution suppresses the production of taxol and isomers, which are degradation products of ED-71. ing.
  • Patent Document 2 discloses a combination of a strontium salt and a vitamin D derivative that can be applied to osteoporosis. Eldecalcitol is mentioned as an example of the vitamin D derivative. Patent Document 2 describes that the mixture can be made into a tablet. However, the description is merely a description as a general tablet, and the effect when a specific additive other than the strontium salt is added to the ED-71 preparation is not disclosed.
  • Patent Document 3 for example, 1 ⁇ - (OH) -D 3 and after dissolving the polyvinylpyrrolidone in ethanol, was added anhydrous lactose, after stirring, the reaction product obtained by distilling off ethanol under reduced pressure, further ground The 1 ⁇ - (OH) -D 3 composition obtained by doing so is described.
  • Edirol (registered trademark) capsules 0.5 ⁇ g and 0.75 ⁇ g marketed as osteoporosis treatment agents are only spherical soft capsules, and the development of functionally superior ED-71 preparations by new formulations is required. It was done. In addition, there has been a demand for usability such that a spherical soft capsule is made non-spherical so that it becomes easier to pinch and is difficult to roll. For the convenience of patients who need to administer ED-71, development of non-spherical ED-71 formulations other than soft capsules has been sought.
  • the inventors of the present invention formed a preparation produced from a solid dispersion in which solid ED-71 and a solid additive were mixed, and particles of an oil and fat solution of ED-71 as such a preparation.
  • a preparation produced from an oil dispersion dispersed in an agent was promoted, the following problems were found.
  • the present invention has been made in view of such circumstances, and an object of the present invention is to provide means for suppressing degradation of ED-71 in ED-71 preparations of various dosage forms other than soft capsules.
  • oil dispersion by using hydroxypropylmethylcellulose or hydroxypropylcellulose which is a water-soluble polymer as an additive, it becomes possible to produce a preparation (especially a tablet) of sufficient quality. It was found that there was no decrease in stability.
  • the present invention more specifically provides the following [1] to [12].
  • [1] (5Z, 7E)-(1R, 2R, 3R) -2- (3-hydroxypropoxy) -9,10-secocholesta 5,7,10 (19) -triene-1,3,25-triol ( A step of preparing a mixed solution containing ED-71) and a water-soluble polymer or a basic compound in a solvent, and a step of removing the solvent from the obtained mixed solution; A method for inhibiting oxidation of ED-71.
  • [2] The method according to [1], wherein the weight ratio of ED-71 to the additive is 1:50 to 1: 5000.
  • the water-soluble polymer is hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, sulfobutyl ether- ⁇ -cyclodextrin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, hydroxypropylcellulose, ethylcellulose, sucrose fatty acid ester, polyvinylpyrrolidone, polyvinylpyrrolidone, copovidone, polyoxyethylene hydrogenated castor oil, 2-hydroxypropyl- ⁇ -cyclodextrin , D- ⁇ -tocopheryl polyethylene Recall succinic acid, polyoxyethylene hydrogenated castor oil dextrin, gum arabic, hydroxypropyl methylcellulose-acetate succin
  • a pharmaceutical composition comprising ED-71, It is produced by preparing a mixed solution containing ED-71 and a water-soluble polymer or basic compound in a solvent, and removing the solvent from the mixed solution.
  • the water-soluble polymer is hydroxypropylmethylcellulose, polyoxyethylene.
  • Polyoxypropylene glycol polyethylene glycol, polyoxyethylene polyoxypropylene glycol, sulfobutyl ether- ⁇ -cyclodextrin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, hydroxy Propyl cellulose, ethyl cellulose, sucrose fatty acid ester, polyvinyl pyrrolidone, polyvinyl pyrrolidone, copobi Don, polyoxyethylene hydrogenated castor oil, 2-hydroxypropyl- ⁇ -cyclodextrin, D- ⁇ -tocopheryl polyethylene glycol succinic acid, polyoxyethylene hydrogenated castor oil dextrin, gum arabic, hydroxypropyl methylcellulose-acetate succinate, alkali treatment Selected from gelatin, methyl cellulose, polyvinyl
  • [7] The method according to [6], wherein the weight ratio between the oil-in-water emulsion and the excipient is 1: 4 to 1:20.
  • a pharmaceutical composition comprising ED-71, Comprising particles coated with a coating containing a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose in or on the surface of the excipient; The pharmaceutical composition, wherein the particle comprises an oil / fat solution of ED-71.
  • the pharmaceutical composition according to [9] which is a coated tablet coated with an HPMC film.
  • [11] including a step of preparing an oil-in-water emulsion comprising an oil / fat solution of ED-71 and an aqueous solution of a water-soluble polymer,
  • the water-soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropylcellulose.
  • a method for suppressing the decomposition of ED-71 [12] The method according to [11], further comprising a step of drying the obtained oil-in-water emulsion.
  • ED-71 decomposition of ED-71 can be suppressed in the solid dispersion and the oil dispersion.
  • ED-71 formulations of various dosage forms other than soft capsules can be produced using solid dispersion and oil dispersion.
  • FIG. 2 is a schematic view of a production flow for producing a tablet containing an oil dispersion of ED-71.
  • 2 is a photograph showing an emulsified state when a 2% aqueous solution of a water-soluble polymer is mixed with a medium-chain fatty acid triglyceride. From the left, HPMC, HPC, PVP, and POVA-COAT.
  • ED-71 is a compound represented by the following formula (I).
  • ED-71 is prepared, for example, according to the method described in JP-A-10-72432 (1R, 2R, 3R) -2- (3-hydroxypropoxy) cholesta-5,7-diene-1,3,25- Using triol as a starting material, it can be obtained by ultraviolet irradiation and thermal isomerization, followed by purification by reverse phase HPLC, concentration, and crystallization with ethyl acetate.
  • Solid dispersion of ED-71 I-1 Method for inhibiting oxidation of ED-71
  • the solid dispersion of ED-71 refers to a composition in which solid ED-71 and a solid additive are mixed. As shown in Examples described later, it was revealed that ED-71 decomposes by oxidation during storage.
  • the present invention provides a method for suppressing such degradation of ED-71 due to oxidation. This method prepares a mixed solution containing ED-71 and a water-soluble polymer or basic compound in a solvent as a step of mixing ED-71 with an additive selected from a water-soluble polymer and a basic compound. And a step of removing the solvent from the mixed solution. By mixing ED-71 with the additive, oxidation of ED-71 is suppressed.
  • Inhibition of the oxidation of ED-71 is carried out by examining the residual ratio of ED-71 after the solid dispersion of ED-71 obtained by carrying out the method of the present invention is shielded from light and stored at 60 ° C. for 7 days or 14 days. It is confirmed by this. If the residual ratio of ED-71 in the solid dispersion is higher than that of the standard ED-71 containing no additive, it is judged that the oxidation of ED-71 is suppressed.
  • the residual ratio of ED-71 was determined by using ED-71 and its isomer (chemical name: 6Z- (1R, 2R, 3R) by high performance liquid chromatography (measurement wavelength: 265 nm) for the storage sample and the initial sample.
  • the water-soluble polymer used in the present invention may not have been conventionally known to have an antioxidant action, such as hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyoxyethylene.
  • the water-soluble polymer comprises sulfobutyl ether- ⁇ -cyclodextrin, polyethylene glycol, sucrose fatty acid ester (F-160), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, D- ⁇ -tocopheryl polyethylene glycol succinate.
  • hydroxypropylmethylcellulose-acetate succinate polyvinyl acetate, polyoxyethylene hydrogenated castor oil, dextrin, polyvinylpyrrolidone K90, hydroxypropylmethylcellulose, hydroxyethylcellulose, 2-hydroxypropyl- ⁇ -cyclodextrin, hydroxypropylcellulose, polyoxyethylene Polyoxypropylene glycol, copovidone, ethyl cellulose, amino acid Selected from alkyl methacrylate copolymer, methylcellulose, and polyvinylpyrrolidone K30.
  • the water-soluble polymer is hydroxypropylmethylcellulose-acetate succinate, polyvinyl acetate, polyoxyethylene hydrogenated castor oil 40, dextrin, polyvinylpyrrolidone K90, hydroxypropylmethylcellulose, hydroxyethylcellulose, 2-hydroxypropyl- ⁇ - Selected from cyclodextrin, polyoxyethylene polyoxypropylene glycol 101, hydroxypropylcellulose, polyoxyethylene polyoxypropylene glycol F68, copovidone, ethylcellulose, aminoalkyl methacrylate copolymer E100, methylcellulose, and polyvinylpyrrolidone K30. You may use these individually or in combination of 2 or more types.
  • the basic compound used in the present invention may not have been conventionally known to have an antioxidative action, for example, a pharmaceutically acceptable base such as meglumine, L-arginine, and tetrapotassium pyrophosphate. Compound.
  • the basic compound is meglumine or L-arginine. You may use these individually or in combination of 2 or more types.
  • the additive used in the above embodiment is preferably a water-soluble polymer.
  • ED-71 and additives can be mixed by a method generally used in the pharmaceutical field.
  • a method generally used in the pharmaceutical field examples include a method of dissolving or suspending ED-71 and additives in a solvent such as water or an organic solvent, and then removing the solvent, a melt-kneading method, and the like.
  • These blends often form a solid dispersion in which the additive is uniformly present in ED-71 or ED-71 is uniformly present in the additive.
  • a solid dispersion in which ED-71 is uniformly present in the additive is used in the present invention.
  • At least one of ED-71 and the additive may be suspended without dissolving in the solvent, but both ED-71 and the additive are dissolved in the solvent.
  • the mixing is performed by preparing a mixed solution in which ED-71 and a water-soluble polymer or basic compound are dissolved in a solvent, and removing the solvent from the mixed solution.
  • the solvent used in the present invention may be any one that is pharmaceutically acceptable.
  • the solvent is 1-butanol, 2-butanol, ethanol, 2-ethoxyethanol, ethylene glycol, methanol, 2-methoxyethanol, isopentanol, 2-methyl-1-propanol, pentanol, propanol, and An alcohol such as isopropanol, more preferably ethanol. You may use these individually or in combination of 2 or more types.
  • the alcohol may be a hydrous alcohol (for example, hydrous ethanol) mixed with water.
  • the removal of the solvent can be performed by a method generally used in the pharmaceutical field.
  • a method generally used in the pharmaceutical field examples include vacuum distillation, freeze drying, spray drying, fluidized bed drying, heat drying, precipitation in a poor solvent, blast drying, natural drying, and the like. is there.
  • the weight ratio of ED-71 to the additive in the blend is from 1: 0.01 to 1: 100000, preferably from 1: 0.1 to 1: 10000, more preferably 1: 1 to 1: 8000, even more preferably 1:50 to 1: 5000.
  • the weight ratio of ED-71 to additive in the blend is 1: 1 to 1: 10000, such as 1:10 to 1: 10000, 1: 100 to 1: 10000, or 1: 1000.
  • ⁇ 1: 10000 Specific examples of the weight ratio of ED-71 to the additive in the blend include, for example, 1: 1, 1:10, 1: 100, 1: 1000, 1: 4000, and 1: 10000, preferably 1: 1000 and 1: 4000. Another preferred specific example is 1: 10000. In an embodiment in which the weight of ED-71 is less than the weight of the additive, ED-71 is often dispersed in the solid additive.
  • composition containing ED-71 Pharmaceutical composition containing ED-71 using an admixture in which oxidation of ED-71 is suppressed by mixing ED-71 with an additive by the above method (ie, solid dispersion) Can be manufactured. Accordingly, the present invention provides a pharmaceutical composition containing ED-71, comprising preparing a mixed solution containing ED-71 and a water-soluble polymer or basic compound in a solvent, and removing the solvent from the mixed solution. The pharmaceutical composition manufactured by is provided. In one embodiment of the invention, ED-71 is dispersed in an additive selected from water soluble polymers and basic compounds. In the pharmaceutical composition of the present invention, the oxidation of ED-71 is suppressed by mixing ED-71 with an additive.
  • the content of ED-71 in the pharmaceutical composition of the present invention is not particularly limited, but in one embodiment, the amount of ED-71 per unit preparation is 0.05 to 5 ⁇ g, preferably 0.5 to 0.75 ⁇ g. It is.
  • An admixture of ED-71 and an additive is prepared by the method described in I-1 above.
  • the water-soluble polymer and the basic compound in the present invention are as described in I-1.
  • the weight ratio of ED-71 and the additive in the pharmaceutical composition of the present invention is, in one aspect, 1: 0.01 to 1: 100000, preferably 1: 0.1 to 1: 10000, More preferably, it is 1: 1 to 1: 8000, and still more preferably 1:50 to 1: 5000.
  • the weight ratio of ED-71 to additive in the blend is 1: 1 to 1: 10000, such as 1:10 to 1: 10000, 1: 100 to 1: 10000, or 1: 1000. ⁇ 1: 10000.
  • weight ratio of ED-71 to the additive in the blend include, for example, 1: 1, 1:10, 1: 100, 1: 1000, 1: 4000, and 1: 10000, preferably 1: 1000 and 1: 4000. Another preferred specific example is 1: 10000.
  • the pharmaceutical composition of the present invention can be made into oral preparations such as tablets, capsules, granules and powders. These oral preparations can be produced by methods used in the pharmaceutical field. For example, as a tablet production method, the following methods i), ii) and iii) can be mentioned.
  • Tablets are produced by mixing an admixture of ED-71 and additives with additional additives such as excipients, disintegrants, lubricants, and then compression molding.
  • a solvent eg, purified water, ethanol, or a mixture thereof
  • a tablet is manufactured by adding an appropriate amount of lubricant and, if necessary, a disintegrant to the granulated product, mixing, and then compression-molding. iii) after admixture of ED-71 and additive is mixed with excipients, then binder and optionally other additives are dispersed in a solvent (eg purified water, ethanol, or a mixture thereof) or Granulate while adding or spraying the solution obtained by dissolution.
  • a solvent eg purified water, ethanol, or a mixture thereof
  • An appropriate amount of a lubricant and, if necessary, a disintegrant and the like are added to and mixed with the obtained granulated product, and then compression-molded to produce a tablet.
  • Additional additives other than water-soluble polymers and basic compounds include excipients, disintegrants, binders, and lubricants, for example, surfactants and pH for the purpose of improving drug release. Adjusting agent, fluidizing agent for the purpose of improving fluidity in the process, stabilizer for the purpose of improving stability, flavoring agent for the purpose of adding taste and odor, and coloring agent for the purpose of adding color. , Can be used respectively. The amount of these used is usually 0 to 99.999 parts by weight, preferably 50 to 99.5 parts by weight, and more preferably 90 to 99 parts by weight with respect to 100 parts by weight of the preparation.
  • excipients examples include corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch, lactose hydrate, fructose, glucose, mannitol, sorbitol, etc. Sugars or sugar alcohols, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate and the like. In a preferred embodiment, the excipient is starches, lactose hydrate, crystalline cellulose, or anhydrous calcium hydrogen phosphate.
  • disintegrant examples include sodium starch glycolate, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like.
  • the amount of disintegrant used is preferably 0.5 to 25 parts by weight, more preferably 1 to 15 parts by weight, based on 100 parts by weight of the preparation.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), gum arabic powder and the like.
  • the amount of the binder used is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight with respect to 100 parts by weight of the preparation.
  • lubricant examples include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, and light anhydrous silicic acid.
  • surfactant examples include polysorbate 80, polyoxyl 40 stearate, lauromacrogol and the like.
  • pH adjuster examples include acetic acid, lactic acid, citric acid, malic acid, succinic acid, fumaric acid, tartaric acid, phosphoric acid, and any salt thereof.
  • Examples of the fluidizing agent include light anhydrous silicic acid, silicon dioxide such as hydrous silicon dioxide, and talc.
  • specific examples of light anhydrous silicic acid include, for example, Silicia 320 (trade name, Fuji Silysia Chemical Co., Ltd.), Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.), and the like.
  • Stabilizers include, for example, paraoxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; Examples include sorbic acid.
  • flavoring agents include sweeteners, acidulants, and fragrances that are commonly used in the pharmaceutical field.
  • Any colorant may be used as long as it is permitted to be added to a pharmaceutical product.
  • Food Yellow No. 5 (Sunset Yellow, US Food Yellow No. 6), Food Red No. 2, Food Blue
  • edible pigments such as No. 2, edible lake pigments, and iron sesquioxide.
  • the tablet may further contain an antioxidant as an additional additive.
  • Antioxidants can be added at any step in the processes of i), ii) and iii). For example, in the case of the production method i), an antioxidant is mixed with an admixture together with other additives and then compression-molded to produce a tablet.
  • antioxidant examples include nitrite (for example, sodium nitrite), sulfite (for example, sodium sulfite, dry sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite), thiosulfate (for example, sodium thiosulfate), and alpha thioglycerin.
  • nitrite for example, sodium nitrite
  • sulfite for example, sodium sulfite, dry sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite
  • thiosulfate for example, sodium thiosulfate
  • alpha thioglycerin alpha thioglycerin.
  • 1,3-butylene glycol 1,3-butylene glycol, thioglycolic acid and its salts (for example, sodium thioglycolate), thiomalate (for example, sodium thiomalate), thiourea, thiolactic acid, edetate (for example, sodium edetate), dichloro Isocyanurates (eg potassium dichloroisocyanurate), citric acid, cysteine and its salts (eg cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (eg sodium erythorbate) ), Ascorbic acid and its ester compounds (eg L-ascorbic acid stearate, palmitic acid ascorbic acid), phospholipids (eg soy lecithin), metal chelators and their salts (eg ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid calcium diacetate)
  • tocopherol acetate, dibutylhydroxytren, natural vitamin E, dl- ⁇ -tocopherol, d- ⁇ -tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, L-ascorbic acid stearate, butylhydroxyanisole, propyl gallate Dl- ⁇ -tocopherol, dibutylhydroxytoluene, butylhydroxyanisole and gallic acid are more preferred, and dl- ⁇ -tocopherol is even more preferred.
  • the amount of the antioxidant used is preferably 0.001 to 10 parts by weight, more preferably 0.01 to 1 part by weight per 100 parts by weight of the preparation.
  • the above-mentioned additional additives may be used by mixing two or more kinds at an appropriate ratio.
  • sugar-coated tablets or film-coated tablets can also be obtained using a suitable coating additive.
  • suitable coating additive include sugar coating base, coating agent, enteric film coating base, sustained-release film coating base and the like.
  • sugar coating base examples include sugars such as sucrose and erythritol or sugar alcohols, and further, one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like are used in combination. Also good.
  • the coating agent examples include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.
  • enteric film coating bases include cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Acrylic polymers such as Evonik Degussa], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Evonik Degussa], and methacrylic acid copolymer S [Eudragit S (trade name), Evonik Degussa]; Examples include natural products such as shellac.
  • sustained-release film coating bases include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Evonik Degussa), ethyl acrylate / methyl methacrylate copolymer suspension Acrylic polymers such as suspensions (Eudragit NE (trade name), Evonik Degussa); cellulose acetate and the like.
  • cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Evonik Degussa), ethyl acrylate / methyl methacrylate copolymer suspension
  • Acrylic polymers such as suspensions (Eudragit NE (trade name), Evonik Degussa); cellulose acetate and the like.
  • Two or more of the above coating additives may be mixed at an appropriate ratio.
  • Water-soluble substances, plasticizers, etc. may be added to the coating additives as needed to adjust the dissolution rate.
  • Water-soluble substances include water-soluble polymers such as hydroxypropylmethylcellulose, sugar alcohols such as mannitol, saccharides such as sucrose and anhydrous maltose, sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, polysorbate, sodium lauryl sulfate
  • surfactants such as can be used.
  • Plasticizers include acetylated monoglycerides, triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium chain triglycerides, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, dibutyl adipate, oleic acid, oleinol
  • acetylated monoglycerides triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium chain triglycerides, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, dibutyl adipate, oleic acid, oleinol
  • acetylated monoglycerides triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate
  • a general method in the pharmaceutical field can be used, for example, pan coating method, fluid coating method, rolling coating method, A fluid rolling coating method may be mentioned.
  • the coating solution used in these methods is obtained by mixing the coating additive, talc, and a solvent (preferably ethanol or a mixture of ethanol and water).
  • the solid content concentration of such a coating solution is preferably in the range of 5 to 15% by weight with respect to the total weight of the coating solution.
  • granulation is performed in addition to the principle and apparatus described in the examples, extrusion granulation, pulverization / regulation, rotary granulation, dry granulation, wet high shear granulation, And fluidized bed granulation.
  • Examples of granulation equipment based on extrusion granulation include Twin Dome Gran, Basket Reuser, Semi-dry / low moisture granulator disk pelleter, Semi-dry / small-diameter granulator fine disk pelleter, and pelleter double. , Basketreuser, and multi-gran (above Dalton), and KEX extruder and KRC kneader (above Kurimoto).
  • granulators based on the principle of crushing and sizing, for example, power mill (Dalton), granulator Fiore F and Randel mill (above, manufactured by Tokuju Kosakusho), no screen granulator Nebula Sizer (manufactured by Nara Machinery Co., Ltd.) ), Quick Mill QMY (manufactured by Seishin Company), Roll Granulator (manufactured by Matsubo), New Speed Mill (manufactured by Okada Seiko), MF Granulator Oscillator and Crushing Granulator Conibit (above, Swiss Frevit) Manufactured and sold by Earth Technica).
  • power mill Dalton
  • granulator Fiore F and Randel mill above, manufactured by Tokuju Kosakusho
  • no screen granulator Nebula Sizer manufactured by Nara Machinery Co., Ltd.
  • Quick Mill QMY manufactured by Seishin Company
  • Roll Granulator manufactured by Matsubo
  • New Speed Mill manufactured by
  • Examples of the granulating apparatus based on the principle of rotary granulation include a Malmerizer (manufactured by Dalton), a centrifugal fluidized coating granulator CF, and Granurex GX (manufactured by Freund Sangyo).
  • Examples of the granulation apparatus based on dry granulation include a roller compactor (manufactured by Freund Industries), a pharmapactor (manufactured by Hosokawa Micron), an RCP roller compactor (manufactured by Kurimoto Steel Works), and a pharmacompactor (manufactured by Matsubo).
  • a roller compactor manufactured by Freund Industries
  • a pharmapactor manufactured by Hosokawa Micron
  • an RCP roller compactor manufactured by Kurimoto Steel Works
  • a pharmacompactor manufactured by Matsubo
  • granulators based on wet high shear granulation for example, SP granulator and Spartan Luther (from Dalton), vertical granulator (from Paul Lec), GEA Aeromatic Fielder Multiprocessor R & D PharmaConnect ( Eurotechno), Mixer & Granulator (NMG) (Nara Machinery Co., Ltd.), Crushing and rolling Newgramachine SEG (Seishin Enterprise), New Speed Kneader (Okada Seiko), High Speed Mixer (Advanced Series), Dynamic Examples thereof include dryers, high flex glals, and microwave granulator dryers (manufactured by Fukae Pautech, sold by Earth Technica), and TM granulation mixers (manufactured by Nippon Coke Industries).
  • Examples of granulators based on fluidized bed granulation include, for example, a pneumaticizer, a swirling fluidized bed, a micro fluidized bed, and a swing processor (Gluton), a flow coater containment, a flow coater universal, and a flow coater FLO.
  • a pneumaticizer for example, a pneumaticizer, a swirling fluidized bed, a micro fluidized bed, and a swing processor (Gluton), a flow coater containment, a flow coater universal, and a flow coater FLO.
  • Spiraflow SFC above, manufactured by Freund Corporation
  • Agromaster manufactured by Hosokawa Micron
  • GEA Aeromatic Fielder Flexstream manufactured by Eurotechno
  • Sprued Okawara Seisakusho
  • the mixing is performed according to each principle of convection type (mechanical stirring type), diffusion type (container rotation type), and Kazuwa / kneader.
  • Mixing devices based on the convection type include, for example, mixing stirrer NDM type, mixing stirrer XDM type, mixing stirrer DM type, prototype / research mixing stirrer AM / XDM / DM type, laboratory mixing stirrer twin Mix, Pug mixer, Ribbon mixer, Spartan mixer, Paste mixer (above Dalton), Cyclomix, Nauta mixer (Osokawa Micron), ⁇ mounting MAG-NEO seal mixer (Magneno Giken), Bottom super Mag mixer, S mixer supermix (above, Satake Chemical Machinery Co., Ltd.), Julia mixer, ribbon mixer (above, Deoksugaku Kosakusho), PX mixer (made by Seishin Enterprise), Ladige mixer (made by Matsubo) , FM mixer RC type, and MP mixer (Nippon Coke Industries, Ltd.) Ribocone (Okawara Seisakusho Co., Ltd.) and the like in beauty.
  • mixing stirrer NDM type mixing stirrer XDM type
  • Examples of mixing devices based on the diffusion type include GEA book system IBC blender, IBC blender with GEA book system NIR measuring device (Eurotechno), V-type mixer, and W-type mixing.
  • Machine above, manufactured by Tokuju Factory
  • V-type mixer made by Nara Machinery Co., Ltd.
  • W-type mixer SCM made by Nara Machinery Co., Ltd.
  • V-type mixer SVM above, made by Seishin Enterprise
  • capsule locking mixer made by Aichi Electric
  • Boule container mixer PM manufactured by Kotobuki Industries
  • Examples of mixing devices based on Kazuwa and Kneader include continuous kneader, batch kneader (made by Dalton), TK Hibismix, and TK Hibis Dispermix (made by Primex), Leistritz Extruder. (Manufactured by Nara Machinery Co., Ltd.) and planetary mixer (manufactured by Iwata Iron Works).
  • mixing devices include, for example, Conti-TDS (manufactured by Dalton), mixing torque meter ST-3000II process reactor DDL • 3000, and stirring simulation MixSim (manufactured by Satake Chemical Machinery Co., Ltd.).
  • mixing can be performed according to principles such as a fluid stirring method, a non-stirring method, and a high-speed shearing method.
  • Tableting is performed according to the principles of single-punch tableting and rotary tableting, but rotary tableting is preferable from the viewpoint of efficiency.
  • the names of the tableting devices based on the principle of rotary tableting include, in addition to those described in the examples, for example, a detachable high-speed tableting machine Fette (manufactured by Bosch Packaging Technology), a high-speed tableting machine COMPRIMA, and a high-speed tableting SYNTHESIS machine (Mutual), Rotary press MZ400 (Mori Machinery), GEA Coltor module type tablet P, S, D, and GEA Pharma system performer P (Eurotechno) Small rotary tablet machine for research and development, small high-speed rotary tablet machine, medium high-speed rotary tablet machine, dual high-speed rotary tablet machine, rotary disk detachable water washing rotary tablet machine, and containment tablet machine (above, manufactured by Kikusui Seisakusho) ), BX type HX type high pressure tableting machine, CVX type rotary table removable tableting machine, X type ⁇ AP type small tableting machine, X type AP type medium size tableting machine, AP type large
  • a single-layer tablet can be obtained.
  • a multi-layer tablet can be obtained using a GEA Coltor module type double-layer tablet press D type (manufactured by Eurotechno) and a multi-layer tablet machine (manufactured by Kikusui Seisakusho).
  • Nucleated tablets can also be produced by using a tableted tablet machine (manufactured by Kikusui Seisakusho) or an AP / MS type C-type nucleated tableting machine (manufactured by Hata Seiko).
  • Coating is performed according to the principles of pan coating (horizontal pan), pan coating (tilted pan), and air floating type (fluidized bed) in addition to the principle and apparatus described in the examples.
  • Examples of the coating apparatus based on the principle of pan coating include a high coater FZ, an aqua coater AQC ⁇ containment, and an aqua coater AQC (hereinafter, Freund Sangyo).
  • pan coating examples include, for example, POWREC COATER PRC and DORIA COATER DRC (hereinafter, POWREC).
  • Examples of the coating apparatus based on the air floating type (fluidized bed) include, for example, Glatt Powder Coater “GPCG” SPC, Multiplex, and Composite Fluidized Bed “SFP” (hereinafter, “Powrec”).
  • GPCG Glatt Powder Coater
  • SFP Composite Fluidized Bed
  • coating apparatuses include, for example, a hybridization system (manufactured by Nara Machinery Co., Ltd.) and a mechano hybrid (manufactured by Nippon Coke Industries).
  • the pharmaceutical composition of the present invention is useful for treating or preventing a disease or symptom (for example, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.
  • a disease or symptom for example, osteoporosis
  • the treatment or prevention of a disease or symptom includes prevention of onset of the disease, suppression or inhibition of progression or progression, reduction of one or more symptoms exhibited by an individual suffering from the disease, or suppression of progression or progression. , Treatment or prevention of secondary diseases and the like.
  • the subject to which the pharmaceutical composition of the present invention is administered is a mammal.
  • the mammal is preferably a human.
  • the pharmaceutical composition of the present invention is administered to a subject in an amount effective for treatment or prevention.
  • “Amount effective for treatment or prevention” means an amount that exhibits a therapeutic or prophylactic effect for a specific disease, administration form, and administration route. The species, type of disease, symptom, sex, age, chronic disease, etc. It is determined appropriately according to the factors. The route of administration is usually oral.
  • the dosage of the pharmaceutical composition of the present invention is appropriately determined according to the species of the subject, the type of disease, symptoms, sex, age, disease, and other factors, and is usually ED-71 for human adults. 0.01 to 10 ⁇ g per day, preferably 0.5 to 0.75 ⁇ g can be administered.
  • the present invention also relates to a method for the treatment or prevention of a disease or symptom comprising administering to a subject in need thereof a therapeutic or prophylactically effective amount of the pharmaceutical composition of the present invention.
  • the “therapeutically or prophylactically effective amount” in the present invention means an amount having a therapeutic or prophylactic effect for a specific disease or symptom, administration form and administration route, and includes the species of the subject, the type of disease or symptom, symptom, sex, It is determined as appropriate according to age, chronic illness, and other factors.
  • the “subject” in the present invention is, for example, a mammal, preferably a human.
  • administering in the present invention usually means oral administration.
  • the “disease or symptom” in the present invention includes a disease or symptom (for example, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.
  • a disease or symptom for example, osteoporosis
  • Oil dispersion of ED-71 II-1 Oil dispersion of ED-71 II-1.
  • Pharmaceutical Composition Containing ED-71 and Method for Producing the Same A second aspect of the present invention relates to an oil dispersion of ED-71.
  • the oil dispersion of ED-71 refers to a composition in which particles of an oil and fat solution of ED-71 are dispersed in an excipient.
  • the present invention provides a pharmaceutical composition comprising such an ED-71 oil dispersion.
  • a pharmaceutical composition comprising ED-71, which is coated with a coating agent containing a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose in or on the surface of the excipient Providing said pharmaceutical composition, wherein said particle comprises a fat solution of ED-71.
  • the present invention also provides a method for producing such a pharmaceutical composition.
  • a method for producing a pharmaceutical composition containing ED-71 comprising the steps of: (i) preparing an oil-in-water emulsion containing an oil / fat solution of ED-71 and an aqueous solution of a water-soluble polymer; ii) attaching or adsorbing an oil-in-water emulsion to an excipient, and (iii) drying the oil-in-water emulsion, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose and hydroxypropyl
  • the method is provided selected from cellulose.
  • the particles of the ED-71 oil / fat solution are coated with the water-soluble polymer in the excipient, and a preparation (especially a tablet) using the ED-71 oil dispersion can be produced.
  • a preparation especially a tablet
  • a preparation using the ED-71 oil dispersion can be produced.
  • a method of impregnating an excipient with an oil / fat solution containing an active ingredient is already known, but after using an oil-in-water emulsion instead of an oil / fat solution and adhering or adsorbing to an excipient.
  • a method for drying an oil-in-water emulsion and coating an oil / fat solution with components in an aqueous layer has not been known.
  • the oils and fats used in the present invention include medium chain fatty acid triglycerides (hereinafter also referred to as “MCT”), tricaprylin, caproic acid, caprylic acid, capric acid, oleic acid, linoleic acid, linolenic acid, vegetable oil.
  • MCT medium chain fatty acid triglycerides
  • examples of the vegetable oil include coconut oil, olive oil, rapeseed oil, falling raw oil, corn oil, soybean oil, cottonseed oil, grape oil, safflower oil, and the like.
  • MCT medium chain fatty acid triglycerides
  • tricaprylin caproic acid
  • caprylic acid capric acid
  • oleic acid linoleic acid
  • linolenic acid vegetable oil.
  • examples of the vegetable oil include coconut oil, olive oil, rapeseed oil, falling raw oil, corn oil, soybean oil, cottonseed oil, grape oil, safflower oil, and the like
  • the concentration of ED-71 in the oil / fat solution in the step (i) can be appropriately determined according to the target disease or symptom, administration form, administration route, etc., for example, 0.001 to 0.3% by weight Preferably, it is 0.005 to 0.1% by weight, and more preferably 0.01 to 0.05% by weight.
  • An antioxidant may be further added to the oil / fat solution in step (i).
  • the antioxidant in the present invention include nitrite (for example, sodium nitrite), sulfite (for example, sodium sulfite, dry sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite), thiosulfate (for example, sodium thiosulfate), Alpha thioglycerin, 1,3-butylene glycol, thioglycolic acid and its salts (eg sodium thioglycolate), thiomalate (eg sodium thiomalate), thiourea, thiolactic acid, edetate (eg sodium edetate) Dichloroisocyanurate (eg potassium dichloroisocyanurate), citric acid, cysteine and its salts (eg cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (
  • tocopherol acetate, dibutylhydroxytren, natural vitamin E, dl- ⁇ -tocopherol, d- ⁇ -tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, L-ascorbic acid stearate, butylhydroxyanisole, propyl gallate Dl- ⁇ -tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, or gallic acid is more preferred, and dl- ⁇ -tocopherol or dibutylhydroxytoluene is even more preferred.
  • the amount of the antioxidant added to the oil / fat solution is not particularly limited, but the amount described below is the maximum use amount that can be used as the antioxidant (for example, the approval listed in the Pharmaceutical Additives Encyclopedia (Pharmaceutical Daily), 2000) Below the maximum use amount of the previous example, the amount of use limit amount or less described in the Food Additives Official Document (Japan Food Additives Association, 1999) can be usually used.
  • dl- ⁇ -tocopherol is added to the oil / fat solution at a concentration of 0.01% by weight or more (for example, 1% by weight or more) and 10% by weight or less (for example, 5% by weight or less).
  • concentration of 0.01% by weight or more for example, 1% by weight or more
  • 10% by weight or less for example, 5% by weight or less.
  • the addition amount of dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate and the like is the same as that of the above dl- ⁇ -tocopherol.
  • the coating agent used in the present invention contains a water-soluble polymer.
  • the water soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropylcellulose.
  • Many additives reduce the stability of ED-71 when added to an ED-71 oil solution, whereas hydroxypropylmethylcellulose and hydroxypropylcellulose do not reduce the stability of ED-71.
  • hydroxypropylmethylcellulose and hydroxypropylcellulose are used, the emulsified state of the oil-in-water emulsion can be maintained for a long time.
  • the fact that the stability of ED-71 does not decrease in the pharmaceutical composition of the present invention is that a tablet is produced from the pharmaceutical composition of the present invention and stored at 40 ° C. for 1, 3, or 6 months while being shielded from light. This is confirmed by examining the residual ratio of ED-71.
  • the residual ratio of ED-71 was determined by using ED-71 and its isomer (chemical name: 6Z- (1R, 2R, 3R) by high performance liquid chromatography (measurement wavelength: 265 nm) for the storage sample and the initial sample.
  • Hydroxypropylmethylcellulose and hydroxypropylcellulose may be of any grade acceptable for pharmaceutical preparations.
  • the hydroxypropyl methylcellulose in the present invention can be purchased from Shin-Etsu Chemical Co., Ltd. under the trade name TC-5.
  • hydroxypropylcellulose is a component in the Pharmaceutical Additives Encyclopedia 2016 (edited by Japan Pharmaceutical Additives Association; published by Yakuji Nippo Inc .; ISBN978-4-8408-1329-7). This refers to hydroxypropylcellulose listed as number 002303, which is different from the low-substituted hydroxypropylcellulose listed as component number 002440 in the same encyclopedia.
  • the molar substitution degree (MS) (representing the ratio of the hydroxy group of the HPC repeating unit (glucose ring) being substituted with a hydroxypropoxy group) is usually 2 to 3, preferably 2. 5 to 3, more preferably 3.
  • the molar substitution degree in the low-substituted hydroxypropyl cellulose is 0.2 to 0.4.
  • the hydroxypropylcellulose in the present invention can be purchased, for example, from Ice Pee Japan under the trade name Klucel and from Nippon Soda as the trade name hydroxypropylcellulose.
  • the coating agent in the present invention may contain an additive other than the water-soluble polymer, and may contain, for example, a stabilizer or an antioxidant.
  • the concentration of the water-soluble polymer in the aqueous solution in step (i) is appropriately determined according to the amount of ED-71, and is, for example, 1 to 15% by weight, preferably 2 to 10% by weight, It is preferably 3 to 6% by weight, more preferably 4 to 6% by weight, and even more preferably 5 to 6% by weight.
  • the aqueous solution in step (i) may contain an additive other than the water-soluble polymer, and may contain, for example, a stabilizer or an antioxidant.
  • the oil-in-water emulsion can be prepared by a method generally used in the pharmaceutical field, but is preferably prepared by a mechanical emulsification method.
  • Mechanical emulsification methods include, for example, chemical stirrers, vortex mixers, homomixers, homogenizers, hydro shears, colloid mills, flow jet mixers, ultrasonic generators, wet pulverizers using glass beads, membrane emulsifiers using porous membranes, A method using an electric emulsifier using electric energy or the like can be mentioned.
  • a homogenizer for example, T-50 Ultra Turrax (manufactured by IKA) can be used.
  • the ratio (weight ratio, o / w ratio) of the oil / fat solution of ED-71 to the aqueous solution of the water-soluble polymer may be within a range in which an oil-in-water emulsion can be prepared. To 1:20, preferably 1: 2 to 1:20, or 1: 2 to 1: 4.
  • the concentration of the water-soluble polymer in the aqueous solution of the water-soluble polymer is 3 to 6% by weight, 4 to 6% by weight, or 5 to 6% by weight
  • the oil / fat solution of ED-71 and the water-soluble polymer The ratio of the polymer to the aqueous solution is 1: 1.5 to 1:20, 1: 2 to 1:20, or 1: 2 to 1: 4.
  • the ratio (weight ratio) between the oil / fat solution of ED-71 and the water-soluble polymer may be in a range that allows the particles of the oil / fat solution of ED-71 to be covered with the water-soluble polymer.
  • the concentration of the water-soluble polymer in the aqueous solution of the water-soluble polymer is 3 to 6% by weight, 4 to 6% by weight, or 5 to 6% by weight
  • the oil / fat solution of ED-71 and the water-soluble polymer The ratio (weight ratio) to the polymer is 1: 0.05 to 1:10, 1: 0.1 to 1: 1, or 1: 0.1 to 1: 0.3.
  • the particles are preferably spherical.
  • the particle size is usually from 0.01 to 100 ⁇ m, preferably from 0.1 to 10 ⁇ m.
  • the excipients used in the present invention include, for example, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch and other starches, anhydrous lactose, Examples include lactose hydrate, fructose, glucose, mannitol, sorbitol, erythritol and other sugars or sugar alcohols, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc., preferably sugars or sugar alcohols More preferred is mannitol, anhydrous lactose, lactose hydrate, and more preferred is mannitol.
  • the ratio (weight ratio) between the oil-in-water emulsion and the excipient used in step (ii) may vary depending on the type of excipient, etc., but is usually 1: 1 to 1: 100, preferably 1: 4 to The range is 1:20.
  • the excipient is mannitol
  • a preferred granulated powder that can be used in the preparation of a preparation such as a tablet can be obtained if the weight ratio is usually in the range of 1: 4 to 1:20.
  • Adhesion or adsorption of an oil-in-water emulsion to an excipient can be performed by a method generally used in the pharmaceutical field. For example, granulation while spraying an emulsion on an excipient, shaping Examples include a method of adding an emulsified liquid to the agent and mixing and stirring. Such a method can be performed using, for example, a high speed stirring granulator (VG-600CT manufactured by POWREX), a mixing stirrer (DM type manufactured by Shinagawa Kogyo) or the like.
  • the adhesion or adsorption includes impregnation (infiltration of an oil-in-water emulsion in the pores in a porous excipient).
  • the oil dispersion obtained in this way contains particles containing an ED-71 oil-and-fat solution and exhibits good manufacturability (for example, fluidity and compression moldability) when used in the production of tablets and the like. .
  • the oil-in-water emulsion can be dried by a method generally used in the pharmaceutical field, for example, fluid drying, freeze drying, aeration drying, spray drying, stationary drying, stirring drying, airflow drying, vacuum drying. , Microwave drying, infrared / far infrared drying, and the like. Moreover, you may perform drying with a heating or cooling. Drying can be performed using, for example, a fluidized bed granulator / dryer (WSG-200pro manufactured by POWREX), a vacuum dryer (conical dryer manufactured by Nippon Dryer), or the like.
  • the pharmaceutical composition of the present invention can be made into oral preparations such as tablets, capsules, granules and powders. These oral preparations can be produced by methods used in the pharmaceutical field. For example, as a tablet production method, the following methods i), ii) and iii) can be mentioned.
  • Tablets are produced by mixing an oil dispersion of ED-71 with additional additives (excipients, disintegrants, lubricants, etc.) and then compression molding.
  • ii) After mixing the oil dispersion of ED-71 with additional additives (excipients, binders, etc.), granulation while adding or spraying a solvent (eg purified water, ethanol, or a mixture thereof) To do.
  • a solvent eg purified water, ethanol, or a mixture thereof
  • a tablet is manufactured by adding an appropriate amount of lubricant and, if necessary, a disintegrant to the granulated product, mixing, and then compression-molding.
  • the binder and optionally other additives are mixed with a solvent (eg purified water, ethanol, or a mixture thereof) And granulated while adding or spraying a liquid obtained by dispersing or dissolving in the above.
  • a solvent eg purified water, ethanol, or a mixture thereof
  • An appropriate amount of a lubricant and, if necessary, a disintegrant and the like are added to and mixed with the obtained granulated product, and then compression-molded to produce a tablet.
  • Additional additives include, for example, surfactants and pH adjusters for the purpose of improving drug release, fluidizing agents for the purpose of improving fluidity during the process, and stabilization for the purpose of increasing stability.
  • the agent can be used as a flavoring agent for the purpose of adding taste and odor, and the colorant can be used for the purpose of adding color.
  • the tablet may further contain an antioxidant as an additional additive.
  • Antioxidants can be added at any step in the processes of i), ii) and iii).
  • a tablet can be produced by mixing an antioxidant with an oil dispersion together with other additives, followed by compression molding. It is also possible to produce a tablet by preparing an oil dispersion using an ED-71 oil solution in which an antioxidant is dissolved in advance, mixing this with other additives, and then compression molding. .
  • Excipients, disintegrants, binders, lubricants, surfactants, pH adjusters, fluidizers, stabilizers, flavoring agents, and colorants should be those described in I-2 above. Can do. Moreover, the above-mentioned thing can be used for an antioxidant.
  • the above-mentioned additional additives may be used by mixing two or more kinds at an appropriate ratio.
  • sugar-coated tablets or film-coated tablets can also be obtained using a suitable coating additive.
  • a suitable coating additive those described in I-2 above can be used.
  • the pharmaceutical composition of the present invention is a coated tablet coated with an HPMC film.
  • the pharmaceutical composition of the present invention is useful for treating or preventing a disease or symptom (for example, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.
  • a disease or symptom for example, osteoporosis
  • the treatment or prevention of a disease or symptom includes prevention of onset of the disease, suppression or inhibition of progression or progression, reduction of one or more symptoms exhibited by an individual suffering from the disease, or suppression of progression or progression. , Treatment or prevention of secondary diseases and the like.
  • the subject to which the pharmaceutical composition of the present invention is administered is a mammal.
  • the mammal is preferably a human.
  • the pharmaceutical composition of the present invention is administered to a subject in an amount effective for treatment or prevention.
  • “Amount effective for treatment or prevention” means an amount that exhibits a therapeutic or prophylactic effect for a specific disease, administration form, and administration route. The species, type of disease, symptom, sex, age, chronic disease, etc. It is determined appropriately according to the factors. The route of administration is usually oral.
  • the dosage of the pharmaceutical composition of the present invention is appropriately determined according to the species of the subject, the type of disease, symptoms, sex, age, disease, and other factors, and is usually ED-71 for human adults. 0.01 to 10 ⁇ g per day, preferably 0.5 to 0.75 ⁇ g can be administered.
  • the present invention also relates to a method for the treatment or prevention of a disease or symptom comprising administering to a subject in need thereof a therapeutic or prophylactically effective amount of the pharmaceutical composition of the present invention.
  • the “therapeutically or prophylactically effective amount” in the present invention means an amount having a therapeutic or prophylactic effect for a specific disease or symptom, administration form and administration route, and includes the species of the subject, the type of disease or symptom, symptom, sex, It is determined as appropriate according to age, chronic illness, and other factors.
  • the “subject” in the present invention is, for example, a mammal, preferably a human.
  • administering in the present invention usually means oral administration.
  • the “disease or symptom” in the present invention includes a disease or symptom (for example, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.
  • a disease or symptom for example, osteoporosis
  • the present invention further comprises a step of preparing an oil-in-water emulsion comprising an oil / fat solution of ED-71 and an aqueous solution of a water-soluble polymer, wherein the water-soluble polymer is A method for inhibiting the degradation of ED-71, selected from hydroxypropylmethylcellulose and hydroxypropylcellulose.
  • the step of preparing an oil-in-water emulsion comprising an ED-71 oil / fat solution and an aqueous solution of a water-soluble polymer in the present invention is a step in the method for producing a pharmaceutical composition containing ED-71 described in II-1 above. Same as (i).
  • the oil / fat solution of ED-71 is considered to be covered with a water-soluble polymer in an oil-in-water emulsion.
  • This method is useful in that an oil dispersion of ED-71 and a pharmaceutical composition using the same can be produced without reducing the stability of ED-71 in the oil / fat solution.
  • EtOH ethanol
  • HPMC Hydroxypropyl methylcellulose
  • THF tetrahydrofuran
  • BHT Dibutylhydroxytoluene
  • MCT Medium chain fatty acid triglyceride
  • HPC Hydroxypropyl cellulose
  • PVP Polyvinylpyrrolidone
  • PVA copolymer Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer
  • Solid dispersion Reference examples A1 to A3 ED-71 was dissolved in EtOH (ethanol (99.5) reagent special grade, Imazu Pharmaceutical Co., Ltd.) to prepare an EtOH solution (0.1 mg / mL). 100 ⁇ L of this was dispensed into a glass tube, and the solvent was distilled off under reduced pressure to obtain dried ED-71.
  • EtOH ethanol (99.5) reagent special grade, Imazu Pharmaceutical Co., Ltd.
  • control example A1 This alone (control example A1) or in the presence of an oxygen scavenger (Pharmace Keep KD-20, Mitsubishi Gas Chemical) (reference example A1), a hygroscopic agent (silica gel (medium granular (blue), manufactured by Wako Pure Chemical Industries, Ltd.) )
  • reference Example A2 In the presence of air
  • Reference Example A3 In the presence of an oxygen scavenger and hygroscopic agent
  • the residual ratio of ED-71 was measured by the following method.
  • a sample solution was prepared by dispensing 100 ⁇ L of EtOH and 400 ⁇ L of acetonitrile into the glass tube containing ED-71 and stirring by pipetting. Separately, 100 ⁇ L of ED-71 EtOH solution (0.1 mg / mL) used for sample preparation was dispensed into an empty glass tube, 400 ⁇ L of acetonitrile was added, and the mixture was stirred by pipetting was used as a standard solution. The sample solution and the standard solution were measured by high performance liquid chromatography (Waters Alliance, measurement wavelength 265 nm), and the ED-71 peak area and the pre-ED-71 peak area of the sample solution were determined.
  • Example A1 15 mg ED-71 was dissolved in 100 mL EtOH (HPLC grade, Wako Pure Chemical Industries). Weigh 375 mg of water-soluble polymer HPMC (TC-5R, Shin-Etsu Chemical Co., Ltd.) in a sample container and dissolve in 10 mL of 70v / v% EtOH (mixed water and EtOH at a volume ratio of 30:70). To prepare an additive solution. 20 ⁇ L of ED-71 ethanol solution and 80 ⁇ L of additive solution were mixed in a 1 mL glass tube, and then the solvent was distilled off under reduced pressure and dried to obtain the composition of Example A1.
  • EtOH HPLC grade, Wako Pure Chemical Industries
  • This composition is placed in a 96-well tube stand together with the tube, placed in an aluminum pouch in the presence of air, shielded from light, and stored in a thermostatic chamber adjusted to 60 ° C. After 7 days and 14 days, the residual ratio of ED-71 Examined.
  • Control Example A2 was prepared in the same manner as in Example A1 except that 70 v / v% EtOH was used instead of the additive solution, and the residual ratio of ED-71 was examined in the same manner as in Example A1.
  • Example A2 to A6 Using the water-soluble polymer described in Table A3 instead of HPMC of Example A1, an ED-71 composition was produced in the same manner as in Example A1, and stability at 60 ° C. was obtained as in Example A1. And compared with Control A2. The results are shown in Table A3. All of the compositions of Examples A2 to A6 were shown to be more stable under higher temperature conditions than Control A2.
  • Example A7 to A19 In the same manner as in Example A1, except that EtOH was used instead of 70 v / v% EtOH of Example A1 and water-soluble polymers shown in Table A4 were used instead of HPMC, the ED- of Examples A7 to A19 71 compositions were obtained. In the same manner as in Control A2, Control A3 containing no water-soluble polymer was prepared. The stability of ED-71 in these samples at 60 ° C. was examined in the same manner as in Example A1. The results are shown in Table A4. All of the compositions of Examples A7 to A19 were shown to be more stable under higher temperature conditions than the control.
  • Examples A20 to A28 Instead of 70 v / v% EtOH of Example A1, 50 v / v% EtOH (mixed water and EtOH at a volume ratio of 50:50) and water-soluble polymer shown in Table A5 instead of HPMC were used.
  • the ED-71 compositions of Examples A20 to A28 were obtained in the same manner as in Example A1.
  • Control A4 containing no water-soluble polymer was prepared.
  • the stability of ED-71 in these samples at 60 ° C. was examined in the same manner as in Example A1. The results are shown in Table A5. All of the compositions of Examples A7 to A19 were shown to be more stable under higher temperature conditions than the control.
  • Example A29 In the same manner as in Example A1, using THF (HPLC grade, Wako Pure Chemical Industries) instead of 70v / v% EtOH of Example A1 and using lecithin powder (chemical, Nacalai Tesque) instead of HPMC The ED-71 composition of Example A29 was obtained. In the same manner as in Control A2, Control A5 containing no water-soluble polymer was prepared. The stability of ED-71 in these samples at 60 ° C. was examined in the same manner as in Example A1. The results are shown in Table A6. The composition of Example A29 was shown to be more stable under higher temperature conditions than the control.
  • THF HPLC grade, Wako Pure Chemical Industries
  • Examples A30 and A31 ED-71 compositions of Examples A30 and A31 were obtained in the same manner as in Example A1, using the basic compounds shown in Table A7 instead of HPMC of Example A1.
  • the stability of the prepared ED-71 composition at 60 ° C. was examined in the same manner as in Example A1, and compared with Control A2. The results are shown in Table A7.
  • the compositions of Examples A30 and A31 were both shown to be more stable under higher temperature conditions than the control.
  • Example A32 Same as Example A1 using 50 v / v% EtOH instead of 70 v / v% EtOH of Example A1, and tetrapotassium pyrophosphate (food additive grade, Taihei Chemical Industry) as the basic compound instead of HPMC Thus, an ED-71 composition of Example A32 was obtained. The stability of the prepared ED-71 composition at 60 ° C. was examined in the same manner as in Example A1, and compared with Control A4. The results are shown in Table A8. The composition of Example A32 was shown to be more stable under higher temperature conditions than the control.
  • Examples A33 to A38 15 mg of ED-71 was dissolved in 100 mL of EtOH (HPLC grade, Wako Pure Chemical Industries) to prepare an ED-71-dissolved EtOH solution.
  • EtOH HPLC grade, Wako Pure Chemical Industries
  • 750 mg of water-soluble polymer hydroxypropylmethylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.) and basic compound meglumine (Merck) were weighed in each sample container, and 20 mL of 70v / v% EtOH (water and EtOH) Were mixed in a volume ratio of 30:70) and diluted to a concentration of 37.5 mg / mL to 0.0375 mg / mL to prepare an additive solution.
  • the ED-71-dissolved additive solution was prepared by dispensing the ED-71-dissolved EtOH solution and additive solution into the centrifuge tube so that the ratio of the ED-71 drug substance amount to the additive amount was as shown in Table A9. Dispense the prepared ED-71 dissolution additive solution into a 1 mL glass tube each to make the amount of ED-71 drug substance 3 ⁇ g, then distill off the solvent under reduced pressure and vacuum dry the composition. (Examples A33 to A38). The composition was placed in a 96-well tube stand together with the tube, placed in an aluminum pouch in the presence of air, shielded from light, and stored in a thermostatic chamber adjusted to 60 ° C., and the residual ratio of ED-71 was examined after 7 days.
  • the residual ratio of ED-71 was determined by the following calculation formula.
  • Examples A39 to A41 In Examples A33 to A38, EtOH was used instead of 70v / v% EtOH, and polyvinylpyrrolidone (K-30, BASF), which is a water-soluble polymer, was used as an additive instead of hydroxypropylmethylcellulose or meglumine.
  • ED-71 compositions were obtained in the same manner as A33 to A38 (Examples A39 to A41). The stability of ED-71 in these samples at 60 ° C. was examined in the same manner as in Examples A33 to A38. The results are shown in Table A11. ED-71 was more stable in the coexistence with polyvinylpyrrolidone than in the case of ED-71 at any addition ratio under high temperature conditions. In addition, there was a tendency for the residual ratio of ED-71 to increase as the additive ratio increased.
  • Oil dispersion Example B1 Formulation change 1 50 mg of ED-71 was dissolved in 2.5 mL of EtOH to prepare an ethanol solution of ED-71.
  • Dissolve BHT Merck
  • dl- ⁇ -tocopherol special purpose, Wako Pure Chemical Industries
  • MCT MCT
  • ODOC Nisshin Oilio
  • Example B1 To 150 mg of the prepared ED-71 oil / fat solution, 300 mg of hydroxypropylmethylcellulose was added to prepare an ED-71 composition (Example B1). The prepared ED-71 composition was stored in a thermostat adjusted to 60 ° C. in the presence of air, and the residual ratio (%) of ED-71 was examined after 14 and 28 days.
  • control example B1 As the control, the above ED-71 oil / fat solution alone (control example B1) was used.
  • Example B1 using the additive (300 mg) described in Table B1 instead of the hydroxypropylmethylcellulose of Example B1, an ED-71 composition was produced in the same manner as in Example B1, and the stability at 60 ° C. was improved. The examination was performed in the same manner as in Example B1.
  • Example B1 is as stable as or higher than the fat solution of Control B1 alone, and more stable at higher temperatures than the compositions of Controls B2-B34. It was.
  • Example B2 Mixture change 2 Using the additives described in Table B2 in place of the hydroxypropylmethylcellulose of Example B1, the ED-71 compositions of Example B2 and Control B35 were prepared in the same manner as in Example B1, and at 60 ° C. Stability was examined as in Example B1 and compared to Control B1. The results are shown in Table B2. The composition of Example B2 was shown to be as stable or better than Control B1 and more stable under high temperature conditions than the compositions of Controls B2-B34 shown in Table B1. Although the stability of ED-71 was not decreased in the composition of Comparative Example B35, when meglumine was used as an additive, the emulsified state required in the oil dispersion tablet manufacturing process described later was obtained. It has been found that meglumine is not suitable as an additive for the production of oil dispersion tablets, for example because it cannot be maintained.
  • HPMC TC-5R, Shin-Etsu Chemical
  • HPC HPC
  • SSL Shin-Etsu Chemical
  • PVP K90, BASF
  • POVA-COAT F, manufactured by Daido Kasei Kogyo
  • An aqueous solution was prepared. 20 mL of each solution was added to a 50 mL centrifuge tube made of plastic. Thereto was added 10 mL each of medium-chain fatty acid triglycerides dissolved in red at a rate of 0.1 g / L of oil red (Oil Red O, Nacalai Tesque).
  • FIG. 2 shows the emulsified state (photo) in the centrifuge tube after 24 hours when a 2% aqueous solution of a water-soluble polymer was used.
  • HPMC, HPC, and PVA-copolymer did not cause separation of the water and oil layers, whereas PVP caused separation.
  • Examples B3 to B11 Stability of ED-71 during preparation of emulsion 100 mg of ED-71 was dissolved in 5.0 mL of EtOH to prepare an ethanol solution of ED-71.
  • Dissolve BHT Merck
  • dl- ⁇ -tocopherol special purpose, Wako Pure Chemical Industries
  • MCT MCT
  • ODOC Nisshin Oilio
  • the ED-71-dissolved MCT solution and the water-soluble polymer solution were mixed at the ratio shown in Table B5 and emulsified by stirring at 5400 rpm for 1 minute using a homogenizer to prepare an ED-71-containing emulsion.
  • the prepared ED-71-containing emulsion was weighed so that the amount of ED-71 drug substance was about 1 ⁇ g, and distilled off under reduced pressure with a vacuum dryer, and the obtained sample was used for residual rate measurement (Example B3 ⁇ B11).
  • the sample was stored in a thermostat adjusted to 60 ° C. in the presence of air, and the ED-71 content value immediately after preparation, the content value of ED-71 after 14 days and 25 days, and the residual rate (%) were examined.
  • each content value was calculated so that the sample which weighed ED-71 melt
  • the content value and the residual rate of ED-71 were obtained by the following calculation formula.
  • ED-71 residual rate (%) average content of accelerated samples / average content of samples immediately after preparation
  • the concentration of the water-soluble polymer solution containing 1% to 15% HPMC or HPC is preferably 5 to 6% for stabilization in the ED-71 emulsion.
  • Oil dispersion tablet dl- ⁇ -tocopherol (Wako Pure Chemical Industries) 0.142 kg and BHT (Merck) 0.284 kg were dissolved in MCT (Nisshin Oilio) 9.025 kg, where eldecalcitol (ED-71 After adding 1.1813 g of ethanol (99.5%) (Imazu Pharmaceutical Co., Ltd.) (0.078 kg) solution, ethanol was distilled off under reduced pressure (Solution 1).
  • Emulsified liquid is sprayed while stirring 165.6 kg of mannitol (Merck) sieved with a vibrating sieve with an opening of 850 ⁇ m in a high-speed stirring granulator (VG-600CT made by POWREX) under the conditions of blade 56 rpm and cross screw 1500 rpm. The mixture was added and kneaded for 15 minutes to obtain a granulated powder.
  • mannitol mannitol
  • VG-600CT made by POWREX
  • the obtained granulated powder is sieved while operating a wet granulator (UWR made by POWREX) with a 9.5 mm (square hole) screen at 300 mm rpm. Transfer to POWREX WSG-200pro) and dry.
  • UWR wet granulator
  • the dried granulated powder was sized by operating a dry granulator (POWREX U-20) set with a 2 mm diameter screen at 800 mm rpm.
  • the sized product was mixed with a mixture of mannitol (3.0 ⁇ ⁇ ⁇ kg) and croscarmellose sodium (DFE pharma) (3.6 kg) that had been sieved with a sieve having an opening of 850 ⁇ m for 15 minutes.
  • DFE pharma croscarmellose sodium
  • the mixture was tableted with a tableting machine (COMPRIMA manufactured by IMA) at a pressure of about 7.5 kgk to obtain tablets. During tableting, the tablet weight was adjusted so that the content of eldecalcitol per tablet was 0.75 ⁇ g.
  • All the obtained tablets were put into a coating machine (PRC-450 manufactured by POWREC), and dried at 60 ° C by spraying a solution of HPMC (6.480 kg) with water (74.520 kg), and further, 4.950 kg of hypromellose, talc ( Merck) 1.350 kg, titanium oxide (Ishihara Sangyo) 2.664 kg, and iron sesquioxide ( ⁇ ⁇ ) 0.036 kg water (65.167 kg) suspension is spray-dried and the tablets coated with two layers of film Obtained (Eldecalcitol content per tablet was 0.75 ⁇ g).
  • PRC-450 manufactured by POWREC
  • the second layer is 4.950 kg of hypromellose, 1.350 kg of talc, 2.502 kg of titanium oxide (Ishihara Sangyo), iron sesquioxide ( ⁇ ⁇ Chemical conversion) 0.018 kg and yellow iron sesquioxide (Chemical conversion) 0.180 kg water (65.167 kg) were spray coated.
  • FIG. 1 A schematic diagram of the manufacturing flow is shown in FIG. 1
  • the residual ratio of ED-71 was measured by the following method.
  • ED-71 residual rate (%) Ratio of ED-71 content in accelerated sample to displayed amount (%) / Ratio of ED-71 content in unaccelerated sample to displayed amount (%) x 100
  • the indicated amount refers to the weight (0.5 ⁇ g or 0.75 ⁇ g) of ED-71 that is intended to be contained per tablet.
  • an ED-71 preparation having a dosage form other than soft capsules, in which decomposition of ED-71 is suppressed.

Abstract

Provided are: a method for inhibiting oxidation of (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol (ED-71), said method comprising a step for preparing a solution of a mixture containing ED-71 and a water-soluble polymer or basic compound in a solvent and a step for removing the solvent from the thus obtained solution of the mixture; and a method for inhibiting degradation of ED-71, said method comprising a step for preparing an oil-in-water type emulsion comprising an oily solution of ED-71 and an aqueous solution of a water-soluble polymer, wherein the water-soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose.

Description

ＥＤ－７１の固体分散体および油分分散体を含む医薬組成物Pharmaceutical composition comprising a solid dispersion of ED-71 and an oil dispersion
　本発明は、（５Ｚ，７Ｅ）－（１Ｒ，２Ｒ，３Ｒ）－２－（３－ヒドロキシプロポキシ）－９，１０－セココレスタ５，７，１０（１９）－トリエン－１，３，２５－トリオール（以下、ＥＤ－７１とも称する）を含む医薬組成物およびその製造方法、ＥＤ－７１の酸化または分解を抑制する方法などに関する。 The present invention relates to (5Z, 7E)-(1R, 2R, 3R) -2- (3-hydroxypropoxy) -9,10-secocholesta 5,7,10 (19) -triene-1,3,25-triol (Hereinafter also referred to as ED-71) and a method for producing the same, and a method for inhibiting oxidation or decomposition of ED-71.
　ＥＤ－７１（一般名：エルデカルシトール）は、骨形成作用を有する活性型ビタミンＤ３の合成誘導体であり、経口投与による骨粗鬆症治療剤として製造販売されている。 ED-71 (generic name: eldecalcitol) is a synthetic derivative of active vitamin D 3 having a bone forming action, and is manufactured and sold as a therapeutic agent for osteoporosis by oral administration.
　ＥＤ－７１は、他のビタミンＤ誘導体と同様に、ソフトカプセル剤として製剤化することができる。特許文献１には、ＥＤ－７１の中鎖脂肪酸トリグリセリド（以下ＭＣＴとも称する）溶液をゼラチン剤皮内に封入したシームレスソフトカプセルが開示されている。また特許文献１には、当該溶液にｄｌ－α－トコフェロールなどの抗酸化剤を添加することにより、ＥＤ－７１の分解物であるタキステロール体およびトランス体の生成が抑制されることも開示されている。 ED-71 can be formulated as a soft capsule, like other vitamin D derivatives. Patent Document 1 discloses a seamless soft capsule in which a medium chain fatty acid triglyceride (hereinafter also referred to as MCT) solution of ED-71 is enclosed in a gelatin coating. Patent Document 1 also discloses that the addition of an anti-oxidant such as dl-α-tocopherol to the solution suppresses the production of taxol and isomers, which are degradation products of ED-71. ing.
　現在のところ、ソフトカプセル以外のＥＤ－７１製剤として市販されているものは知られていない。特許文献２には、骨粗鬆症に適用できるストロンチウム塩とビタミンＤ誘導体との合剤が開示されており、ビタミンＤ誘導体の一例としてエルデカルシトールが挙げられている。また特許文献２には、当該合剤を錠剤とすることができることが記載されている。しかしながら、その記載は一般的な錠剤としての記載に過ぎず、ストロンチウム塩以外の特定の添加剤をＥＤ－７１製剤に配合した場合の効果については開示されていない。 At present, there are no known commercially available ED-71 preparations other than soft capsules. Patent Document 2 discloses a combination of a strontium salt and a vitamin D derivative that can be applied to osteoporosis. Eldecalcitol is mentioned as an example of the vitamin D derivative. Patent Document 2 describes that the mixture can be made into a tablet. However, the description is merely a description as a general tablet, and the effect when a specific additive other than the strontium salt is added to the ED-71 preparation is not disclosed.
　特許文献３には、例えば、１α－（ＯＨ）－Ｄ３およびポリビニルピロリドンをエタノールに溶解後、無水乳糖を添加し、撹拌後、エタノールを減圧留去して得られる反応生成物を、さらに粉砕することで得られた１α－（ＯＨ）－Ｄ３組成物が記載されている。 Patent Document 3, for example, 1α- (OH) -D 3 and after dissolving the polyvinylpyrrolidone in ethanol, was added anhydrous lactose, after stirring, the reaction product obtained by distilling off ethanol under reduced pressure, further ground The 1α- (OH) -D 3 composition obtained by doing so is described.
ＷＯ２００５／０７４９４３Ａ１WO2005 / 074943A1 ＣＮ１０２６８８２４９ＡCN10268249A ＷＯ９０／０９７９６ＡWO90 / 09796A
　骨粗鬆症治療剤として市販されているエディロール（登録商標）カプセル０．５μｇおよび同０．７５μｇは、球形のソフトカプセル剤のみであり、新たな製剤による機能的に優れたＥＤ－７１製剤の開発が求められていた。また、球形のソフトカプセル剤を非球形にすることで、よりつまみ易くなり、また、転がりにくくなるといった使用性に関する需要が存在した。ＥＤ－７１の投与が必要な患者の利便性のため、ソフトカプセル以外の剤形の非球形のＥＤ－７１製剤の開発が求められていた。 Edirol (registered trademark) capsules 0.5 μg and 0.75 μg marketed as osteoporosis treatment agents are only spherical soft capsules, and the development of functionally superior ED-71 preparations by new formulations is required. It was done. In addition, there has been a demand for usability such that a spherical soft capsule is made non-spherical so that it becomes easier to pinch and is difficult to roll. For the convenience of patients who need to administer ED-71, development of non-spherical ED-71 formulations other than soft capsules has been sought.
　本発明者らは、そのような製剤として、固体のＥＤ－７１と固体の添加剤とを混和させた固体分散体（solid dispersion）から製造した製剤およびＥＤ－７１の油脂溶液の粒子を賦形剤中に分散させた油分分散体（oil dispersion）から製造した製剤の開発を進めたところ、以下の課題が見出された。 The inventors of the present invention formed a preparation produced from a solid dispersion in which solid ED-71 and a solid additive were mixed, and particles of an oil and fat solution of ED-71 as such a preparation. When the development of a preparation produced from an oil dispersion dispersed in an agent was promoted, the following problems were found.
　まず固体分散体から製造する製剤の開発においては、固体のＥＤ－７１の安定性が低く、その安定性を高める必要があるという課題が見出された。 First, in the development of a preparation produced from a solid dispersion, a problem has been found that the stability of solid ED-71 is low and the stability needs to be increased.
　また油分分散体から製造する製剤の開発においては、ＥＤ－７１の油脂溶液をそのまま用いて調製した油分分散体を用いると、充分な品質の製剤を製造することができないという課題が見出された。さらにこの課題を解決するために研究を重ねた結果、ＥＤ－７１の油脂溶液の粒子を特定の添加剤によって被覆するとの着想を得たが、用いる添加剤の多くにより、ＥＤ－７１の安定性が低下するという新たな課題が見出された。 Further, in the development of a preparation produced from an oil dispersion, a problem has been found that a preparation of sufficient quality cannot be produced if an oil dispersion prepared using an ED-71 oil and fat solution as it is is used. . Furthermore, as a result of repeated studies to solve this problem, the idea of coating the particles of the ED-71 oil and fat solution with a specific additive was obtained, but the stability of ED-71 depends on many of the additives used. A new problem has been found to be reduced.
　本発明はこのような状況に鑑みてなされたものであり、その目的は、ソフトカプセル以外の種々の剤形のＥＤ－７１製剤において、ＥＤ－７１の分解を抑制する手段を提供することにある。 The present invention has been made in view of such circumstances, and an object of the present invention is to provide means for suppressing degradation of ED-71 in ED-71 preparations of various dosage forms other than soft capsules.
　本発明者らは、上記目的を解決するために鋭意研究した結果、固体分散体に関しては、固体のＥＤ－７１の分解が酸化によるものであることを見出し、さらにこの酸化が、抗酸化作用を持たないとされているヒドロキシプロピルメチルセルロースなどの水溶性高分子またはメグルミン、Ｌ－アルギニン、およびピロリン酸四カリウムなどの塩基性化合物を添加剤として用いることによって顕著に抑制されることを見出した。 As a result of diligent research to solve the above-mentioned object, the present inventors have found that for solid dispersions, the decomposition of solid ED-71 is due to oxidation, and this oxidation has an antioxidant effect. It has been found that water-soluble polymers such as hydroxypropylmethylcellulose, which are considered not to have, or basic compounds such as meglumine, L-arginine, and tetrapotassium pyrophosphate are significantly suppressed by using as additives.
　また油分分散体に関しては、添加剤として水溶性高分子であるヒドロキシプロピルメチルセルロースまたはヒドロキシプロピルセルロースを用いることにより、充分な品質の製剤（特に錠剤）を製造することが可能となり、さらにＥＤ－７１の安定性の低下が起こらないことを見出した。 As for the oil dispersion, by using hydroxypropylmethylcellulose or hydroxypropylcellulose which is a water-soluble polymer as an additive, it becomes possible to produce a preparation (especially a tablet) of sufficient quality. It was found that there was no decrease in stability.
　本発明者らは、これらの発見に基づきさらに研究を重ね、本発明を完成した。 The inventors have further studied based on these findings and completed the present invention.
　すなわち本発明は、より具体的には以下の［１］～［１２］を提供するものである。
［１］（５Ｚ，７Ｅ）－（１Ｒ，２Ｒ，３Ｒ）－２－（３－ヒドロキシプロポキシ）－９，１０－セココレスタ５，７，１０（１９）－トリエン－１，３，２５－トリオール（ＥＤ－７１）と水溶性高分子または塩基性化合物とを溶媒中に含む混合溶液を調製する工程、および
得られた混合溶液から溶媒を除去する工程、
を含む、ＥＤ－７１の酸化を抑制する方法。
［２］ＥＤ－７１と添加剤との重量比が、１：５０～１：５０００である、［１］に記載の方法。
［３］水溶性高分子が、ヒドロキシプロピルメチルセルロース、ポリオキシエチレンポリオキシプロピレングリコール、ポリエチレングリコール、ポリオキシエチレンポリオキシプロピレングリコール、スルホブチルエーテル-β-シクロデキストリン、ポリビニルカプロラクタム－ポリビニル酢酸－ポリエチレングリコールグラフトコポリマーアミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、ヒドロキシプロピルセルロース、エチルセルロース、ショ糖脂肪酸エステル、ポリビニルピロリドン、ポリビニルピロリドン、コポビドン、ポリオキシエチレン硬化ヒマシ油、２－ヒドロキシプロピル－β－シクロデキストリン、Ｄ－α－トコフェリル ポリエチレン グリコールコハク酸、ポリオキシエチレン硬化ヒマシ油デキストリン、アラビアガム、ヒドロキシプロピルメチルセルロース－アセテートサクシネート、アルカリ処理ゼラチン、メチルセルロース、ポリビニルアセテート、ポリビニルアセテート・アクリル酸・メタクリル酸コポリマー、α化でんぷん、ヒドロキシエチルセルロース、およびレシチン粉末から選択され、塩基性化合物が、メグルミン、Ｌ－アルギニン、およびピロリン酸四カリウムから選択される、［１］または［２］に記載の方法。
［４］ＥＤ－７１を含む医薬組成物であって、
ＥＤ－７１と水溶性高分子または塩基性化合物とを溶媒中に含む混合溶液を調製し、当該混合溶液から溶媒を除去することにより製造され、水溶性高分子が、ヒドロキシプロピルメチルセルロース、ポリオキシエチレンポリオキシプロピレングリコール、ポリエチレングリコール、ポリオキシエチレンポリオキシプロピレングリコール、スルホブチルエーテル-β-シクロデキストリン、ポリビニルカプロラクタム－ポリビニル酢酸－ポリエチレングリコールグラフトコポリマーアミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、ヒドロキシプロピルセルロース、エチルセルロース、ショ糖脂肪酸エステル、ポリビニルピロリドン、ポリビニルピロリドン、コポビドン、ポリオキシエチレン硬化ヒマシ油、２－ヒドロキシプロピル－β－シクロデキストリン、Ｄ－α－トコフェリル ポリエチレン グリコールコハク酸、ポリオキシエチレン硬化ヒマシ油デキストリン、アラビアガム、ヒドロキシプロピルメチルセルロース－アセテートサクシネート、アルカリ処理ゼラチン、メチルセルロース、ポリビニルアセテート、ポリビニルアセテート・アクリル酸・メタクリル酸コポリマー、α化でんぷん、ヒドロキシエチルセルロース、およびレシチン粉末から選択され、塩基性化合物が、メグルミン、Ｌ－アルギニン、およびピロリン酸四カリウムから選択される、前記医薬組成物。
［５］ＥＤ－７１と添加剤との重量比が、１：５０～１：５０００である、［４］に記載の医薬組成物。
［６］ＥＤ－７１を含む医薬組成物の製造方法であって、
ＥＤ－７１の油脂溶液と水溶性高分子の水溶液とを含む水中油型乳化液を調製する工程、
水中油型乳化液を賦形剤に付着または吸着させる工程、および
水中油型乳化液を乾燥させる工程、
を含み、
ここで前記水溶性高分子は、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される、前記方法。
［７］水中油型乳化液と賦形剤との重量比が、１：４～１：２０である、［６］に記載の方法。
［８］賦形剤が、糖または糖アルコール類から選択される、［６］または［７］に記載の方法。
［９］ＥＤ－７１を含む医薬組成物であって、
賦形剤中または賦形剤の表面に、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される水溶性高分子を含む被覆剤で被覆された粒子を含み、
当該粒子は、ＥＤ－７１の油脂溶液を含む、前記医薬組成物。
［１０］ＨＰＭＣフィルムでコーティングされたコーティング錠である、［９］に記載の医薬組成物。
［１１］ＥＤ－７１の油脂溶液と水溶性高分子の水溶液とからなる水中油型乳化液を調製する工程を含み、
ここで前記水溶性高分子は、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される、
ＥＤ－７１の分解を抑制する方法。
［１２］得られた水中油型乳化液を乾燥する工程をさらに含む、［１１］に記載の方法。 That is, the present invention more specifically provides the following [1] to [12].
[1] (5Z, 7E)-(1R, 2R, 3R) -2- (3-hydroxypropoxy) -9,10-secocholesta 5,7,10 (19) -triene-1,3,25-triol ( A step of preparing a mixed solution containing ED-71) and a water-soluble polymer or a basic compound in a solvent, and a step of removing the solvent from the obtained mixed solution;
A method for inhibiting oxidation of ED-71.
[2] The method according to [1], wherein the weight ratio of ED-71 to the additive is 1:50 to 1: 5000.
[3] The water-soluble polymer is hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, sulfobutyl ether-β-cyclodextrin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, hydroxypropylcellulose, ethylcellulose, sucrose fatty acid ester, polyvinylpyrrolidone, polyvinylpyrrolidone, copovidone, polyoxyethylene hydrogenated castor oil, 2-hydroxypropyl-β-cyclodextrin , D-α-tocopheryl polyethylene Recall succinic acid, polyoxyethylene hydrogenated castor oil dextrin, gum arabic, hydroxypropyl methylcellulose-acetate succinate, alkali-treated gelatin, methylcellulose, polyvinyl acetate, polyvinyl acetate / acrylic acid / methacrylic acid copolymer, pregelatinized starch, hydroxyethyl cellulose, and The method according to [1] or [2], wherein the basic compound is selected from lecithin powder and the basic compound is selected from meglumine, L-arginine, and tetrapotassium pyrophosphate.
[4] A pharmaceutical composition comprising ED-71,
It is produced by preparing a mixed solution containing ED-71 and a water-soluble polymer or basic compound in a solvent, and removing the solvent from the mixed solution. The water-soluble polymer is hydroxypropylmethylcellulose, polyoxyethylene. Polyoxypropylene glycol, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, sulfobutyl ether-β-cyclodextrin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, hydroxy Propyl cellulose, ethyl cellulose, sucrose fatty acid ester, polyvinyl pyrrolidone, polyvinyl pyrrolidone, copobi Don, polyoxyethylene hydrogenated castor oil, 2-hydroxypropyl-β-cyclodextrin, D-α-tocopheryl polyethylene glycol succinic acid, polyoxyethylene hydrogenated castor oil dextrin, gum arabic, hydroxypropyl methylcellulose-acetate succinate, alkali treatment Selected from gelatin, methyl cellulose, polyvinyl acetate, polyvinyl acetate / acrylic acid / methacrylic acid copolymer, pregelatinized starch, hydroxyethyl cellulose, and lecithin powder, the basic compound selected from meglumine, L-arginine, and tetrapotassium pyrophosphate The said pharmaceutical composition.
[5] The pharmaceutical composition according to [4], wherein the weight ratio of ED-71 to the additive is 1:50 to 1: 5000.
[6] A method for producing a pharmaceutical composition comprising ED-71,
Preparing an oil-in-water emulsion containing an ED-71 oil and fat solution and an aqueous solution of a water-soluble polymer;
Attaching or adsorbing the oil-in-water emulsion to the excipient, and drying the oil-in-water emulsion,
Including
Wherein the water soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropylcellulose.
[7] The method according to [6], wherein the weight ratio between the oil-in-water emulsion and the excipient is 1: 4 to 1:20.
[8] The method according to [6] or [7], wherein the excipient is selected from sugars or sugar alcohols.
[9] A pharmaceutical composition comprising ED-71,
Comprising particles coated with a coating containing a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose in or on the surface of the excipient;
The pharmaceutical composition, wherein the particle comprises an oil / fat solution of ED-71.
[10] The pharmaceutical composition according to [9], which is a coated tablet coated with an HPMC film.
[11] including a step of preparing an oil-in-water emulsion comprising an oil / fat solution of ED-71 and an aqueous solution of a water-soluble polymer,
Here, the water-soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropylcellulose.
A method for suppressing the decomposition of ED-71.
[12] The method according to [11], further comprising a step of drying the obtained oil-in-water emulsion.
　本発明によれば、固体分散体および油分分散体においてＥＤ－７１の分解を抑制することができる。また固体分散体および油分分散体を用いてソフトカプセル以外の種々の剤形のＥＤ－７１製剤を製造することができる。 According to the present invention, decomposition of ED-71 can be suppressed in the solid dispersion and the oil dispersion. In addition, ED-71 formulations of various dosage forms other than soft capsules can be produced using solid dispersion and oil dispersion.
ＥＤ－７１の油分分散体を含む錠剤を製造する製造フローの概略図である。FIG. 2 is a schematic view of a production flow for producing a tablet containing an oil dispersion of ED-71. 水溶性高分子の2%水溶液を中鎖脂肪酸トリグリセリドと混合した際の乳化状態を示す写真である。左から、HPMC、HPC、PVP、およびPOVA-COAT。2 is a photograph showing an emulsified state when a 2% aqueous solution of a water-soluble polymer is mixed with a medium-chain fatty acid triglyceride. From the left, HPMC, HPC, PVP, and POVA-COAT.
　本発明において、ＥＤ－７１は下記式（Ｉ）で表される化合物である。 In the present invention, ED-71 is a compound represented by the following formula (I).
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　ＥＤ-７１は、例えば特開平10-72432号に記載された方法に従い、（１Ｒ，２Ｒ，３Ｒ）－２－（３－ヒドロキシプロボキシ）コレスタ－５，７－ジエン－１，３，２５－トリオールを出発物質として、紫外線照射及び熱異性化反応後、逆相HPLCで精製し、濃縮後、酢酸エチルで結晶化させることにより得ることができる。 ED-71 is prepared, for example, according to the method described in JP-A-10-72432 (1R, 2R, 3R) -2- (3-hydroxypropoxy) cholesta-5,7-diene-1,3,25- Using triol as a starting material, it can be obtained by ultraviolet irradiation and thermal isomerization, followed by purification by reverse phase HPLC, concentration, and crystallization with ethyl acetate.
Ｉ．ＥＤ－７１の固体分散体
Ｉ－１．ＥＤ－７１の酸化を抑制する方法
　本発明の第一の態様は、ＥＤ－７１の固体分散体に関する。本明細書中、ＥＤ－７１の固体分散体とは、固体のＥＤ－７１と固体の添加剤とを混和させた組成物をいう。後述の実施例に示す通り、ＥＤ－７１は、保存中に酸化により分解することが明らかとなった。本発明は、そのようなＥＤ－７１の酸化による分解を抑制する方法を提供する。本方法は、ＥＤ－７１を水溶性高分子および塩基性化合物から選択される添加剤と混和する工程として、ＥＤ－７１と水溶性高分子または塩基性化合物とを溶媒中に含む混合溶液を調製し、当該混合溶液から溶媒を除去する工程を含む。ＥＤ－７１を添加剤と混和することにより、ＥＤ－７１の酸化が抑制される。 I. Solid dispersion of ED-71
I-1. Method for inhibiting oxidation of ED-71 A first aspect of the present invention relates to a solid dispersion of ED-71. In the present specification, the solid dispersion of ED-71 refers to a composition in which solid ED-71 and a solid additive are mixed. As shown in Examples described later, it was revealed that ED-71 decomposes by oxidation during storage. The present invention provides a method for suppressing such degradation of ED-71 due to oxidation. This method prepares a mixed solution containing ED-71 and a water-soluble polymer or basic compound in a solvent as a step of mixing ED-71 with an additive selected from a water-soluble polymer and a basic compound. And a step of removing the solvent from the mixed solution. By mixing ED-71 with the additive, oxidation of ED-71 is suppressed.
　ＥＤ－７１の酸化の抑制は、本発明の方法の実施により得られるＥＤ－７１の固体分散体を遮光して７日または１４日間６０℃で保存した後の、ＥＤ－７１の残存率を調べることにより確認される。添加剤を含まないＥＤ－７１の標準品と比較して、当該固体分散体におけるＥＤ－７１の残存率が高ければ、ＥＤ－７１の酸化が抑制されたと判断される。ＥＤ－７１の残存率は、保存試料と初期試料について、高速液体クロマトグラフィー法（測定波長265nm）によりＥＤ－７１とその異性体であるプレ体（化学名：６Ｚ－（１Ｒ，２Ｒ，３Ｒ）－２－（３－ヒドロキシプロポキシ）－９，１０－セココレスタ－５（１０），６，８（９）－トリエン－１，３，２５－トリオール；本明細書中、pre ED-71とも称する）のピーク面積を測定し、以下の計算式により算出される。
ED-71の残存率(%)＝保存試料中のED-71ピーク面積合計／初期試料中のED-71ピーク面積合計×100
（ED-71ピーク面積合計＝ED-71ピーク面積＋1.98×pre ED-71のピーク面積） Inhibition of the oxidation of ED-71 is carried out by examining the residual ratio of ED-71 after the solid dispersion of ED-71 obtained by carrying out the method of the present invention is shielded from light and stored at 60 ° C. for 7 days or 14 days. It is confirmed by this. If the residual ratio of ED-71 in the solid dispersion is higher than that of the standard ED-71 containing no additive, it is judged that the oxidation of ED-71 is suppressed. The residual ratio of ED-71 was determined by using ED-71 and its isomer (chemical name: 6Z- (1R, 2R, 3R) by high performance liquid chromatography (measurement wavelength: 265 nm) for the storage sample and the initial sample. -2- (3-hydroxypropoxy) -9,10-secocholesta-5 (10), 6,8 (9) -triene-1,3,25-triol; also referred to herein as pre ED-71) The peak area is measured and calculated by the following formula.
ED-71 residual rate (%) = total ED-71 peak area in the stored sample / total ED-71 peak area in the initial sample x 100
(Total ED-71 peak area = ED-71 peak area + 1.98 x pre ED-71 peak area)
　本発明に用いる水溶性高分子は、抗酸化作用を有することが従来知られていなかったものであってもよく、例えば、ヒドロキシプロピルメチルセルロース、ポリオキシエチレンポリオキシプロピレングリコール、ポリエチレングリコール、ポリオキシエチレンポリオキシプロピレングリコール、スルホブチルエーテル-β-シクロデキストリン、ポリビニルカプロラクタム－ポリビニル酢酸－ポリエチレングリコールグラフトコポリマーアミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、ヒドロキシプロピルセルロース、エチルセルロース、ショ糖脂肪酸エステル、ポリビニルピロリドン、ポリビニルピロリドン、コポビドン、ポリオキシエチレン硬化ヒマシ油、２－ヒドロキシプロピル－β－シクロデキストリン、Ｄ－α－トコフェリル ポリエチレン グリコールコハク酸、ポリオキシエチレン硬化ヒマシ油デキストリン、アラビアガム、ヒドロキシプロピルメチルセルロース－アセテートサクシネート、アルカリ処理ゼラチン、メチルセルロース、ポリビニルアセテート、ポリビニルアセテート・アクリル酸・メタクリル酸コポリマー、α化でんぷん、ヒドロキシエチルセルロース、およびレシチン粉末などの製剤上許容される水溶性高分子が挙げられる。好ましい態様において、水溶性高分子は、スルホブチルエーテル－β－シクロデキストリン、ポリエチレングリコール、ショ糖脂肪酸エステル（Ｆ－１６０）、ポリビニルカプロラクタム－ポリビニル酢酸－ポリエチレングリコールグラフトコポリマー、Ｄ－α－トコフェリル ポリエチレン グリコールコハク酸、ヒドロキシプロピルメチルセルロース－アセテートサクシネート、ポリビニルアセテート、ポリオキシエチレン硬化ヒマシ油、デキストリン、ポリビニルピロリドンＫ９０、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、２－ヒドロキシプロピル－β－シクロデキストリン、ヒドロキシプロピルセルロース、ポリオキシエチレンポリオキシプロピレングリコール、コポビドン、エチルセルロース、アミノアルキルメタクリレートコポリマー、メチルセルロース、およびポリビニルピロリドンＫ３０から選択される。より好ましい態様において、水溶性高分子は、ヒドロキシプロピルメチルセルロース－アセテートサクシネート、ポリビニルアセテート、ポリオキシエチレン硬化ヒマシ油４０、デキストリン、ポリビニルピロリドンＫ９０、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、２－ヒドロキシプロピル－β－シクロデキストリン、ポリオキシエチレンポリオキシプロピレングリコール１０１、ヒドロキシプロピルセルロース、ポリオキシエチレンポリオキシプロピレングリコールＦ６８、コポビドン、エチルセルロース、アミノアルキルメタクリレートコポリマーＥ１００、メチルセルロース、およびポリビニルピロリドンＫ３０から選択される。これらを単独でまたは２種以上を組み合わせて用いてもよい。 The water-soluble polymer used in the present invention may not have been conventionally known to have an antioxidant action, such as hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyoxyethylene. Polyoxypropylene glycol, sulfobutyl ether-β-cyclodextrin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, hydroxypropyl cellulose, ethyl cellulose, sucrose fatty acid ester, polyvinyl Pyrrolidone, polyvinylpyrrolidone, copovidone, polyoxyethylene hydrogenated castor oil 2-hydroxypropyl-β-cyclodextrin, D-α-tocopheryl フ ェ polyethylene glycol succinic acid, polyoxyethylene hydrogenated castor oil dextrin, gum arabic, hydroxypropyl methylcellulose-acetate succinate, alkali-treated gelatin, methylcellulose, polyvinyl acetate, polyvinyl Examples of the water-soluble polymers that are acceptable in pharmaceutical preparations include acetate / acrylic acid / methacrylic acid copolymers, pregelatinized starch, hydroxyethyl cellulose, and lecithin powder. In a preferred embodiment, the water-soluble polymer comprises sulfobutyl ether-β-cyclodextrin, polyethylene glycol, sucrose fatty acid ester (F-160), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, D-α-tocopheryl polyethylene glycol succinate. Acid, hydroxypropylmethylcellulose-acetate succinate, polyvinyl acetate, polyoxyethylene hydrogenated castor oil, dextrin, polyvinylpyrrolidone K90, hydroxypropylmethylcellulose, hydroxyethylcellulose, 2-hydroxypropyl-β-cyclodextrin, hydroxypropylcellulose, polyoxyethylene Polyoxypropylene glycol, copovidone, ethyl cellulose, amino acid Selected from alkyl methacrylate copolymer, methylcellulose, and polyvinylpyrrolidone K30. In a more preferred embodiment, the water-soluble polymer is hydroxypropylmethylcellulose-acetate succinate, polyvinyl acetate, polyoxyethylene hydrogenated castor oil 40, dextrin, polyvinylpyrrolidone K90, hydroxypropylmethylcellulose, hydroxyethylcellulose, 2-hydroxypropyl-β- Selected from cyclodextrin, polyoxyethylene polyoxypropylene glycol 101, hydroxypropylcellulose, polyoxyethylene polyoxypropylene glycol F68, copovidone, ethylcellulose, aminoalkyl methacrylate copolymer E100, methylcellulose, and polyvinylpyrrolidone K30. You may use these individually or in combination of 2 or more types.
　本発明に用いる塩基性化合物は、抗酸化作用を有することが従来知られていなかったものであってもよく、例えば、メグルミン、Ｌ－アルギニン、およびピロリン酸四カリウムなどの製剤上許容される塩基性化合物が挙げられる。好ましい態様において、塩基性化合物は、メグルミンまたはＬ－アルギニンである。これらを単独でまたは２種以上を組み合わせて用いてもよい。 The basic compound used in the present invention may not have been conventionally known to have an antioxidative action, for example, a pharmaceutically acceptable base such as meglumine, L-arginine, and tetrapotassium pyrophosphate. Compound. In a preferred embodiment, the basic compound is meglumine or L-arginine. You may use these individually or in combination of 2 or more types.
　上記態様において使用する添加剤としては、水溶性高分子が好ましい。 The additive used in the above embodiment is preferably a water-soluble polymer.
　ＥＤ－７１と添加剤との混和は、製剤分野において一般的に用いられる方法で行うことができる。そのような方法としては、例えば、水または有機溶媒などの溶媒にＥＤ－７１および添加剤を溶解させるかまたは懸濁させた後、溶媒を除去する方法、溶融混練法などが挙げられる。これらの混和により、多くの場合、ＥＤ－７１中に添加剤が均一に存在するか、または添加剤中にＥＤ－７１が均一に存在する固体分散体を形成する。好ましくは、添加剤中にＥＤ－７１が均一に存在する固体分散体が本発明に用いられる。 ED-71 and additives can be mixed by a method generally used in the pharmaceutical field. Examples of such a method include a method of dissolving or suspending ED-71 and additives in a solvent such as water or an organic solvent, and then removing the solvent, a melt-kneading method, and the like. These blends often form a solid dispersion in which the additive is uniformly present in ED-71 or ED-71 is uniformly present in the additive. Preferably, a solid dispersion in which ED-71 is uniformly present in the additive is used in the present invention.
　溶媒を用いる方法において、ＥＤ－７１および添加剤の少なくとも１種が当該溶媒に溶解せずに懸濁した状態であってもよいが、ＥＤ－７１および添加剤の両方を当該溶媒に溶解させることが好ましい。すなわち、好ましい態様において、混和は、ＥＤ－７１と水溶性高分子または塩基性化合物とを溶媒に溶解させた混合溶液を調製し、当該混合溶液から溶媒を除去することによりなされる。 In the method using a solvent, at least one of ED-71 and the additive may be suspended without dissolving in the solvent, but both ED-71 and the additive are dissolved in the solvent. Is preferred. That is, in a preferred embodiment, the mixing is performed by preparing a mixed solution in which ED-71 and a water-soluble polymer or basic compound are dissolved in a solvent, and removing the solvent from the mixed solution.
　本発明に用いる溶媒は、製剤上許容されるものであればよく、例えば酢酸、アセトン、アセトニトリル、アニソール、ベンゼン、１－ブタノール、２－ブタノール、酢酸ブチル、ｔ－ブチルメチルエーテル、四塩化炭素、クロロベンゼン、クロロホルム、クメン、シクロヘキサン、１，２－ジクロロエタン、１，２－ジクロロエテン、ジクロロメタン、１，２－ジメトキシエタン、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、１，４－ジオキサン、エタノール、２－エトキシエタノール、酢酸エチル、エチレングリコール、エチルエーテル、ギ酸エチル、ホルムアミド、ギ酸、ヘプタン、ヘキサン、酢酸イソブチル、酢酸イソプロピル、メタノール、２－メトキシエタノール、酢酸メチル、イソペンタノール、メチルブチルケトン、メチルシクロヘキサン、ヘキサン－２－オン、酢酸イソペンチル、メチルエチルケトン、メチルイソブチルケトン、２－メチル－１－プロパノール、Ｎ－メチルピロリドン、ニトロメタン、ペンタン、ペンタノール、プロパノール、イソプロパノール、酢酸プロピル、ピリジン、スルホラン、テトラヒドロフラン、テトラリン、トルエン、１，１，１－トリクロロエタン、１，１，２－トリクロロエテン、およびキシレンが挙げられる。好ましい態様において、溶媒は、１－ブタノール、２－ブタノール、エタノール、２－エトキシエタノール、エチレングリコール、メタノール、２－メトキシエタノール、イソペンタノール、２－メチル－１－プロパノール、ペンタノール、プロパノール、およびイソプロパノールなどのアルコールであり、より好ましくはエタノールである。これらを単独でまたは２種以上を組み合わせて用いてもよい。またアルコールは、水と混合された含水アルコール（例えば含水エタノール）であってもよい。 The solvent used in the present invention may be any one that is pharmaceutically acceptable. For example, acetic acid, acetone, acetonitrile, anisole, benzene, 1-butanol, 2-butanol, butyl acetate, t-butyl methyl ether, carbon tetrachloride, Chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethane, 1,2-dichloroethane, dichloromethane, 1,2-dimethoxyethane, N, N-dimethylacetamide, N, N-dimethylformamide, dimethyl sulfoxide, 1,4 -Dioxane, ethanol, 2-ethoxyethanol, ethyl acetate, ethylene glycol, ethyl ether, ethyl formate, formamide, formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, methanol, 2-methoxyethanol, methyl acetate, ethyl Pentanol, methyl butyl ketone, methyl cyclohexane, hexane-2-one, isopentyl acetate, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, N-methylpyrrolidone, nitromethane, pentane, pentanol, propanol, isopropanol, acetic acid Examples include propyl, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,1-trichloroethane, 1,1,2-trichloroethene, and xylene. In a preferred embodiment, the solvent is 1-butanol, 2-butanol, ethanol, 2-ethoxyethanol, ethylene glycol, methanol, 2-methoxyethanol, isopentanol, 2-methyl-1-propanol, pentanol, propanol, and An alcohol such as isopropanol, more preferably ethanol. You may use these individually or in combination of 2 or more types. The alcohol may be a hydrous alcohol (for example, hydrous ethanol) mixed with water.
　溶媒の除去は、製剤分野において一般的に用いられる方法で行うことができる。そのような方法としては、例えば、減圧留去、凍結乾燥、噴霧乾燥、流動層乾燥、加熱乾燥、貧溶媒中への沈殿法、送風乾燥、自然乾燥などが挙げられ、好ましくは減圧留去である。 The removal of the solvent can be performed by a method generally used in the pharmaceutical field. Examples of such a method include vacuum distillation, freeze drying, spray drying, fluidized bed drying, heat drying, precipitation in a poor solvent, blast drying, natural drying, and the like. is there.
　このようにして得られる混和物中では、多くの場合、ＥＤ－７１が固体の添加剤中に分散した状態か、固体の添加剤がＥＤ－７１中に分散した状態となっている。ここで分散した状態とは、母材となる成分中に他の成分がほぼ均一に存在する状態をいう。一態様において、混和物中のＥＤ－７１と添加剤との重量比は１：０．０１～１：１０００００であり、好ましくは１：０．１～１：１００００であり、より好ましくは１：１～１：８０００であり、さらにより好ましくは１：５０～１：５０００である。別の態様において、混和物中のＥＤ－７１と添加剤との重量比は１：１～１：１００００、例えば、１：１０～１：１００００、１：１００～１：１００００、または１：１０００～１：１００００である。混和物中のＥＤ－７１と添加剤との重量比の具体例としては、例えば１：１、１：１０、１：１００、１：１０００、１：４０００および1：１００００が挙げられ、好ましくは、１：１０００および１：４０００である。別の好ましい具体例としては1：１００００が挙げられる。ＥＤ－７１の重量が添加剤の重量よりも少ない態様においては、多くの場合、ＥＤ－７１が固体の添加剤中に分散した状態となっている。 In the mixture obtained in this way, in many cases, ED-71 is dispersed in a solid additive or a solid additive is dispersed in ED-71. Here, the dispersed state refers to a state in which other components are present almost uniformly in the component as a base material. In one embodiment, the weight ratio of ED-71 to the additive in the blend is from 1: 0.01 to 1: 100000, preferably from 1: 0.1 to 1: 10000, more preferably 1: 1 to 1: 8000, even more preferably 1:50 to 1: 5000. In another embodiment, the weight ratio of ED-71 to additive in the blend is 1: 1 to 1: 10000, such as 1:10 to 1: 10000, 1: 100 to 1: 10000, or 1: 1000. ~ 1: 10000. Specific examples of the weight ratio of ED-71 to the additive in the blend include, for example, 1: 1, 1:10, 1: 100, 1: 1000, 1: 4000, and 1: 10000, preferably 1: 1000 and 1: 4000. Another preferred specific example is 1: 10000. In an embodiment in which the weight of ED-71 is less than the weight of the additive, ED-71 is often dispersed in the solid additive.
Ｉ－２．ＥＤ－７１を含む医薬組成物
　上記方法によりＥＤ－７１を添加剤と混和することによりＥＤ－７１の酸化が抑制された混和物（すなわち固体分散体）を用いて、ＥＤ－７１を含む医薬組成物を製造することができる。したがって本発明は、ＥＤ－７１を含む医薬組成物であって、ＥＤ－７１と水溶性高分子または塩基性化合物とを溶媒中に含む混合溶液を調製し、当該混合溶液から溶媒を除去することにより製造される医薬組成物を提供する。本発明の一態様において、ＥＤ－７１は水溶性高分子および塩基性化合物から選択される添加剤中に分散している。本発明の医薬組成物においては、ＥＤ－７１を添加剤と混和することにより、ＥＤ－７１の酸化が抑制されている。 I-2. Pharmaceutical composition containing ED-71 Pharmaceutical composition containing ED-71 using an admixture in which oxidation of ED-71 is suppressed by mixing ED-71 with an additive by the above method (ie, solid dispersion) Can be manufactured. Accordingly, the present invention provides a pharmaceutical composition containing ED-71, comprising preparing a mixed solution containing ED-71 and a water-soluble polymer or basic compound in a solvent, and removing the solvent from the mixed solution. The pharmaceutical composition manufactured by is provided. In one embodiment of the invention, ED-71 is dispersed in an additive selected from water soluble polymers and basic compounds. In the pharmaceutical composition of the present invention, the oxidation of ED-71 is suppressed by mixing ED-71 with an additive.
　本発明の医薬組成物中のＥＤ－７１の含有量は特に限定されないが、一態様において、単位製剤あたりのＥＤ－７１量として０．０５～５μｇであり、好ましくは０．５～０．７５μｇである。 The content of ED-71 in the pharmaceutical composition of the present invention is not particularly limited, but in one embodiment, the amount of ED-71 per unit preparation is 0.05 to 5 μg, preferably 0.5 to 0.75 μg. It is.
　ＥＤ－７１と添加剤との混和物（ＥＤ－７１の固体分散体）は、上記Ｉ－１に記載した方法により調製される。本発明における水溶性高分子および塩基性化合物は、Ｉ－１に記載した通りである。また本発明の医薬組成物中のＥＤ－７１と添加剤との重量比は、一態様において１：０．０１～１：１０００００であり、好ましくは１：０．１～１：１００００であり、より好ましくは１：１～１：８０００であり、さらにより好ましくは１：５０～１：５０００である。別の態様において、混和物中のＥＤ－７１と添加剤との重量比は１：１～１：１００００、例えば、１：１０～１：１００００、１：１００～１：１００００、または１：１０００～１：１００００である。混和物中のＥＤ－７１と添加剤との重量比の具体例としては、例えば１：１、１：１０、１：１００、１：１０００、１：４０００および1：１００００が挙げられ、好ましくは、１：１０００および１：４０００である。別の好ましい具体例としては1：１００００が挙げられる。 An admixture of ED-71 and an additive (a solid dispersion of ED-71) is prepared by the method described in I-1 above. The water-soluble polymer and the basic compound in the present invention are as described in I-1. The weight ratio of ED-71 and the additive in the pharmaceutical composition of the present invention is, in one aspect, 1: 0.01 to 1: 100000, preferably 1: 0.1 to 1: 10000, More preferably, it is 1: 1 to 1: 8000, and still more preferably 1:50 to 1: 5000. In another embodiment, the weight ratio of ED-71 to additive in the blend is 1: 1 to 1: 10000, such as 1:10 to 1: 10000, 1: 100 to 1: 10000, or 1: 1000. ~ 1: 10000. Specific examples of the weight ratio of ED-71 to the additive in the blend include, for example, 1: 1, 1:10, 1: 100, 1: 1000, 1: 4000, and 1: 10000, preferably 1: 1000 and 1: 4000. Another preferred specific example is 1: 10000.
　本発明の医薬組成物は、錠剤、カプセル剤、顆粒剤、散剤などの経口剤とすることができる。これらの経口剤は、製剤分野において用いられる方法により製造することができる。例えば錠剤の製造方法としては、以下のｉ）、ｉｉ）およびｉｉｉ）の方法が挙げられる。
　ｉ）ＥＤ－７１と添加剤との混和物を賦形剤、崩壊剤、滑沢剤などの追加の添加剤と共に混合した後、圧縮成形することによって、錠剤を製造する。
　ｉｉ）ＥＤ－７１と添加剤との混和物を賦形剤、結合剤などの追加の添加剤と混合した後、溶媒（例えば、精製水、エタノール、またはその混合液）を添加または噴霧しながら造粒する。得られた造粒物に、適量の滑沢剤、必要に応じて崩壊剤などを加えて混合後、圧縮成形することによって、錠剤を製造する。
　ｉｉｉ）ＥＤ－７１と添加剤との混和物を賦形剤と混合した後、結合剤および必要に応じて他の添加剤を溶媒（例えば、精製水、エタノール、またはその混合液）に分散または溶解して得られる液を添加または噴霧しながら造粒する。得られた造粒物に、適量の滑沢剤、必要に応じて崩壊剤など加えて混合した後、圧縮成形することによって、錠剤を製造する。 The pharmaceutical composition of the present invention can be made into oral preparations such as tablets, capsules, granules and powders. These oral preparations can be produced by methods used in the pharmaceutical field. For example, as a tablet production method, the following methods i), ii) and iii) can be mentioned.
i) Tablets are produced by mixing an admixture of ED-71 and additives with additional additives such as excipients, disintegrants, lubricants, and then compression molding.
ii) While admixture of ED-71 and additives is mixed with additional additives such as excipients, binders, etc., while adding or spraying a solvent (eg, purified water, ethanol, or a mixture thereof) Granulate. A tablet is manufactured by adding an appropriate amount of lubricant and, if necessary, a disintegrant to the granulated product, mixing, and then compression-molding.
iii) after admixture of ED-71 and additive is mixed with excipients, then binder and optionally other additives are dispersed in a solvent (eg purified water, ethanol, or a mixture thereof) or Granulate while adding or spraying the solution obtained by dissolution. An appropriate amount of a lubricant and, if necessary, a disintegrant and the like are added to and mixed with the obtained granulated product, and then compression-molded to produce a tablet.
　水溶性高分子および塩基性化合物以外の追加の添加剤としては、賦形剤、崩壊剤、結合剤、および滑沢剤の他、例えば、薬物の放出性を向上させる目的で界面活性剤やｐＨ調整剤を、工程中の流動性を良くする目的で流動化剤を、安定性を上げる目的で安定化剤を、味や臭いを加える目的で矯味矯臭剤を、色を加える目的で着色剤を、それぞれ用いることができる。これらの使用量は、製剤１００重量部に対して、通常０～９９．９９９重量部であり、好ましくは５０～９９．５重量部、より好ましくは９０～９９重量部である。 Additional additives other than water-soluble polymers and basic compounds include excipients, disintegrants, binders, and lubricants, for example, surfactants and pH for the purpose of improving drug release. Adjusting agent, fluidizing agent for the purpose of improving fluidity in the process, stabilizer for the purpose of improving stability, flavoring agent for the purpose of adding taste and odor, and coloring agent for the purpose of adding color. , Can be used respectively. The amount of these used is usually 0 to 99.999 parts by weight, preferably 50 to 99.5 parts by weight, and more preferably 90 to 99 parts by weight with respect to 100 parts by weight of the preparation.
　賦形剤としては、例えば、トウモロコシデンプン、馬鈴薯デンプン、コムギコデンプン、コメデンプン、部分アルファー化デンプン、アルファー化デンプン、有孔デンプンなどのデンプン類、乳糖水和物、果糖、ブドウ糖、マンニトール、ソルビトールなどの糖または糖アルコール類、無水リン酸水素カルシウム、結晶セルロース、沈降炭酸カルシウム、ケイ酸カルシウムなどが挙げられる。好ましい態様において、賦形剤は、デンプン類、乳糖水和物、結晶セルロース、または無水リン酸水素カルシウムである。 Examples of excipients include corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch, lactose hydrate, fructose, glucose, mannitol, sorbitol, etc. Sugars or sugar alcohols, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate and the like. In a preferred embodiment, the excipient is starches, lactose hydrate, crystalline cellulose, or anhydrous calcium hydrogen phosphate.
　崩壊剤としては、例えば、デンプングリコール酸ナトリウム、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルスターチなどが挙げられる。崩壊剤の使用量は、製剤１００重量部に対して、好ましくは０．５～２５重量部、さらに好ましくは１～１５重量部である。 Examples of the disintegrant include sodium starch glycolate, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like. The amount of disintegrant used is preferably 0.5 to 25 parts by weight, more preferably 1 to 15 parts by weight, based on 100 parts by weight of the preparation.
　結合剤としては、例えば、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、メチルセルロース、ポビドン（ポリビニルピロリドン）、アラビアゴム末などが挙げられる。結合剤の使用量は、製剤１００重量部に対して、好ましくは０．１～５０重量部、さらに好ましくは０．５～４０重量部である。 Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), gum arabic powder and the like. The amount of the binder used is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight with respect to 100 parts by weight of the preparation.
　滑沢剤としては、例えば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、蔗糖脂肪酸エステル、フマル酸ステアリルナトリウム、軽質無水ケイ酸などが挙げられる。 Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, and light anhydrous silicic acid.
　界面活性剤としては、例えば、ポリソルベート８０、ステアリン酸ポリオキシル４０、ラウロマクロゴールなどが挙げられる。 Examples of the surfactant include polysorbate 80, polyoxyl 40 stearate, lauromacrogol and the like.
　ｐＨ調整剤としては、例えば、酢酸、乳酸、クエン酸、リンゴ酸、コハク酸、フマル酸、酒石酸、リン酸、およびそれらのいずれかの塩が挙げられる。 Examples of the pH adjuster include acetic acid, lactic acid, citric acid, malic acid, succinic acid, fumaric acid, tartaric acid, phosphoric acid, and any salt thereof.
　流動化剤としては、例えば、軽質無水ケイ酸、含水二酸化ケイ素などの二酸化ケイ素、タルクなどが挙げられる。ここで、軽質無水ケイ酸の具体例としては、例えばサイリシア３２０（商品名、富士シリシア化学（株））、アエロジル２００（商品名、日本アエロジル（株））等が挙げられる。 Examples of the fluidizing agent include light anhydrous silicic acid, silicon dioxide such as hydrous silicon dioxide, and talc. Here, specific examples of light anhydrous silicic acid include, for example, Silicia 320 (trade name, Fuji Silysia Chemical Co., Ltd.), Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.), and the like.
　安定化剤としては、例えばメチルパラベン、プロピルパラベンなどのパラオキシ安息香酸エステル；クロロブタノール、ベンジルアルコール、フェニルエチルアルコールなどのアルコール；塩化ベンザルコニウム；フェノール、クレゾールなどのフェノール類；チメロサール；デヒドロ酢酸；およびソルビン酸が挙げられる。 Stabilizers include, for example, paraoxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; Examples include sorbic acid.
　矯味矯臭剤としては、例えば、製剤分野において通常使用される甘味料、酸味料、香料などが挙げられる。 Examples of flavoring agents include sweeteners, acidulants, and fragrances that are commonly used in the pharmaceutical field.
　着色剤としては、医薬品に添加することが許可されているものであれば、いかなるものでもよく、例えば食用黄色５号（サンセットイエロー、米国の食用黄色６号）、食用赤色２号、食用青色２号などの食用色素、食用レーキ色素、三二酸化鉄などが挙げられる。 Any colorant may be used as long as it is permitted to be added to a pharmaceutical product. For example, Food Yellow No. 5 (Sunset Yellow, US Food Yellow No. 6), Food Red No. 2, Food Blue Examples include edible pigments such as No. 2, edible lake pigments, and iron sesquioxide.
　また錠剤は、追加の添加剤としてさらに抗酸化剤を含んでいてもよい。抗酸化剤は、ｉ）、ｉｉ）およびｉｉｉ）の製造法における任意の工程で添加できる。例えば、ｉ）の製造法の場合、抗酸化剤を、他の添加剤と共に混和物と混合した後、圧縮成形することによって、錠剤を製造することができる。 The tablet may further contain an antioxidant as an additional additive. Antioxidants can be added at any step in the processes of i), ii) and iii). For example, in the case of the production method i), an antioxidant is mixed with an admixture together with other additives and then compression-molded to produce a tablet.
　抗酸化剤としては、例えば、亜硝酸塩（例えば亜硝酸ナトリウム）、亜硫酸塩（例えば亜硫酸ナトリウム、乾燥亜硫酸ナトリウム、亜硫酸水素ナトリウム、ピロ亜硫酸ナトリウム）、チオ硫酸塩（例えばチオ硫酸ナトリウム）、アルファチオグリセリン、１，３－ブチレングリコール、チオグリコール酸およびその塩（例えばチオグリコール酸ナトリウム）、チオリンゴ酸塩（例えばチオリンゴ酸ナトリウム）、チオ尿素、チオ乳酸、エデト酸塩（例えばエデト酸ナトリウム）、ジクロルイソシアヌール酸塩（例えばジクロルイシアヌール酸カリウム）、クエン酸、システイン及びその塩（例えば塩酸システイン）、ベンゾトリアゾール、２－メルカプトベンズイミダゾール、エリソルビン酸およびその塩（例えばエリソルビン酸ナトリウム）、アスコルビン酸およびそのエステル化合物（例えばＬ－アスコルビン酸ステアリン酸エステル、パルミチン酸アスコルビン酸）、リン脂質（例えば大豆レシチン）、金属キレート剤およびその塩（例えば、エチレンジアミン四酢酸、エチレンジアミン四酢酸カルシウム二ナトリウム、エチレンジアミン四酢酸二ナトリウム）、酒石酸およびその塩（例えばロッシェル塩）、ポリフェノール類（例えばカテキン）、グルタチオン、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、没食子酸プロピル、天然ビタミンＥ、酢酸トコフェロール、濃縮混合トコフェロール、トコフェロール同族体（例えばｄ－α－トコフェロール、ｄｌ－α－トコフェロール、５，８－ジメチルトコール、７，８－ジメチルトコール、δ－メチルトコール、５，７，８－トリメチルトコトリエノール、５，８－ジメチルトコトリエノール、７，８－ジメチルトコトリエノール、８－メチルトコトリエノール）などが挙げられる。この中でも、酢酸トコフェロール、ジブチルヒドロキシトレン、天然ビタミンＥ、ｄｌ－α－トコフェロール、ｄ－α－トコフェロール、濃縮混合トコフェロール、パルミチン酸アスコルビン酸、Ｌ－アスコルビン酸ステアリン酸エステル、ブチルヒドロキシアニソール、没食子酸プロピルが好ましく、ｄｌ－α－トコフェロール、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、没食子酸がより好ましく、ｄｌ－α－トコフェロールがさらにより好ましい。 Examples of the antioxidant include nitrite (for example, sodium nitrite), sulfite (for example, sodium sulfite, dry sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite), thiosulfate (for example, sodium thiosulfate), and alpha thioglycerin. 1,3-butylene glycol, thioglycolic acid and its salts (for example, sodium thioglycolate), thiomalate (for example, sodium thiomalate), thiourea, thiolactic acid, edetate (for example, sodium edetate), dichloro Isocyanurates (eg potassium dichloroisocyanurate), citric acid, cysteine and its salts (eg cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (eg sodium erythorbate) ), Ascorbic acid and its ester compounds (eg L-ascorbic acid stearate, palmitic acid ascorbic acid), phospholipids (eg soy lecithin), metal chelators and their salts (eg ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid calcium diacetate) Sodium, disodium ethylenediaminetetraacetate), tartaric acid and its salts (eg Rochelle salt), polyphenols (eg catechin), glutathione, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, natural vitamin E, tocopherol acetate, concentrated mixed tocopherol , Tocopherol homologues (eg d-α-tocopherol, dl-α-tocopherol, 5,8-dimethyltocol, 7,8-dimethyltocol, δ-methyltocole) Le, 5,7,8- trimethyl-tocotrienol, 5,8-dimethyl-tocotrienol, 7,8-dimethyl-tocotrienol, 8-methyl-tocotrienol), and the like. Among them, tocopherol acetate, dibutylhydroxytren, natural vitamin E, dl-α-tocopherol, d-α-tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, L-ascorbic acid stearate, butylhydroxyanisole, propyl gallate Dl-α-tocopherol, dibutylhydroxytoluene, butylhydroxyanisole and gallic acid are more preferred, and dl-α-tocopherol is even more preferred.
　抗酸化剤の使用量は、製剤１００重量部に対して、好ましくは０．００１～１０重量部、さらに好ましくは０．０１～１重量部である。 The amount of the antioxidant used is preferably 0.001 to 10 parts by weight, more preferably 0.01 to 1 part by weight per 100 parts by weight of the preparation.
　上記追加の添加剤は、２種以上を適宜の割合で混合して用いてもよい。 The above-mentioned additional additives may be used by mixing two or more kinds at an appropriate ratio.
　錠剤から、さらに適当なコーティング用添加剤を用いて、糖衣コーティング錠あるいはフィルムコーティング錠を得ることもできる。コーティング用添加剤としては、糖衣基剤、コーティング剤、腸溶性フィルムコーティング基剤、徐放性フィルムコーティング基剤などが挙げられる。 From the tablets, sugar-coated tablets or film-coated tablets can also be obtained using a suitable coating additive. Examples of the coating additive include sugar coating base, coating agent, enteric film coating base, sustained-release film coating base and the like.
　糖衣基剤としては、例えば白糖、エリスリトールなどの糖あるいは糖アルコールが挙げられ、さらに、タルク、沈降炭酸カルシウム、ゼラチン、アラビアゴム、プルラン、カルナバロウなどから選ばれる１種または２種以上を併用してもよい。 Examples of the sugar coating base include sugars such as sucrose and erythritol or sugar alcohols, and further, one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like are used in combination. Also good.
　コーティング剤としては、例えば、エチルセルロース、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、セラック、タルク、カルナウバロウ、パラフィンなどが挙げられる。 Examples of the coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.
　腸溶性フィルムコーティング基剤としては、例えばヒドロキシプロピルメチルセルロース フタレート、ヒドロキシプロピルメチルセルロース アセテートサクシネート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロースなどのセルロース系高分子；メタアクリル酸コポリマーＬ〔オイドラギットＬ（商品名）、エボニックデグサ社〕、メタアクリル酸コポリマーＬＤ〔オイドラギットＬ－３０Ｄ５５（商品名）、エボニックデグサ社〕、メタアクリル酸コポリマーＳ〔オイドラギットＳ（商品名）、エボニックデグサ社〕などのアクリル酸系高分子；セラックなどの天然物などが挙げられる。 Examples of enteric film coating bases include cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Acrylic polymers such as Evonik Degussa], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Evonik Degussa], and methacrylic acid copolymer S [Eudragit S (trade name), Evonik Degussa]; Examples include natural products such as shellac.
　徐放性フィルムコーティング基剤としては、例えばエチルセルロースなどのセルロース系高分子；アミノアルキルメタアクリレートコポリマーＲＳ〔オイドラギットＲＳ（商品名）、エボニックデグサ社〕、アクリル酸エチル・メタアクリル酸メチル共重合体懸濁液〔オイドラギットＮＥ（商品名）、エボニックデグサ社〕などのアクリル酸系高分子；酢酸セルロースなどが挙げられる。 Examples of sustained-release film coating bases include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Evonik Degussa), ethyl acrylate / methyl methacrylate copolymer suspension Acrylic polymers such as suspensions (Eudragit NE (trade name), Evonik Degussa); cellulose acetate and the like.
　上記したコーティング用添加剤は、その２種以上を適宜の割合で混合して用いてもよい。 Two or more of the above coating additives may be mixed at an appropriate ratio.
　コーティング用添加剤には、溶出速度調節のために、水溶性物質、可塑剤などを必要に応じて加えても良い。水溶性物質には、ヒドロキシプロピルメチルセルロースなどの水溶性高分子類、マンニトールなどの糖アルコール類、白糖や無水マルトースなどの糖類、ショ糖脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、ポリソルベート、ラウリル硫酸ナトリウムなどの界面活性剤などから選択される１種以上を用いることができる。可塑剤には、アセチル化モノグリセリド、クエン酸トリエチル、トリアセチン、セバシン酸ジブチル、セバシン酸ジメチル、中鎖脂肪酸トリグリセリド、クエン酸アセチルトリエチル、クエン酸トリブチル、クエン酸アセチルトリブチル、アジピン酸ジブチル、オレイン酸、オレイノールなどから選択される１種以上を用いることができる。 水溶 Water-soluble substances, plasticizers, etc. may be added to the coating additives as needed to adjust the dissolution rate. Water-soluble substances include water-soluble polymers such as hydroxypropylmethylcellulose, sugar alcohols such as mannitol, saccharides such as sucrose and anhydrous maltose, sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, polysorbate, sodium lauryl sulfate One or more selected from surfactants such as can be used. Plasticizers include acetylated monoglycerides, triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium chain triglycerides, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, dibutyl adipate, oleic acid, oleinol One or more selected from the above can be used.
　また、錠剤を前記コーティング用添加剤でコーティングしてコーティング層を形成する方法としては、製剤分野において一般的な方法を用いることができ、例えば、パンコーティング法、流動コーティング法、転動コーティング法、流動転動コーティング法が挙げられる。これらの方法に用いるコーティング液は、前記コーティング用添加剤と、タルクと、溶媒（好ましくは、エタノール、またはエタノールと水との混合物）とを混合することにより得られる。このようなコーティング液の固形分濃度は、コーティング液全体の重量に対して５～１５重量％の範囲であることが好ましい。 In addition, as a method of forming a coating layer by coating a tablet with the coating additive, a general method in the pharmaceutical field can be used, for example, pan coating method, fluid coating method, rolling coating method, A fluid rolling coating method may be mentioned. The coating solution used in these methods is obtained by mixing the coating additive, talc, and a solvent (preferably ethanol or a mixture of ethanol and water). The solid content concentration of such a coating solution is preferably in the range of 5 to 15% by weight with respect to the total weight of the coating solution.
　本発明の医薬組成物の製剤化において、造粒は、実施例に記載した原理・装置に加え、押出し造粒、解砕・整粒、回転造粒、乾式造粒、湿式高剪断造粒、および流動層造粒の各原理により行うことができる。 In the formulation of the pharmaceutical composition of the present invention, granulation is performed in addition to the principle and apparatus described in the examples, extrusion granulation, pulverization / regulation, rotary granulation, dry granulation, wet high shear granulation, And fluidized bed granulation.
　押出し造粒を原理とする造粒装置としては、例えばツインドームグラン、バスケットリューザー、半乾式/低水分造粒機ディスクペレッター、半乾式/小径造粒機ファイン・ディスクペレッター、ペレッターダブル、バスケットリューザー、およびマルチグラン（以上、ダルトン製）、ならびにKEXエクストルーダおよびKRCニーダ（以上、栗本鐵工所）が挙げられる。 Examples of granulation equipment based on extrusion granulation include Twin Dome Gran, Basket Reuser, Semi-dry / low moisture granulator disk pelleter, Semi-dry / small-diameter granulator fine disk pelleter, and pelleter double. , Basketreuser, and multi-gran (above Dalton), and KEX extruder and KRC kneader (above Kurimoto).
　解砕・整粒を原理とする造粒装置としては、例えばパワーミル（ダルトン製）、整粒機フィオーレＦおよびランデルミル（以上、徳寿工作所製）、ノースクリーン整粒機ネビュラサイザー（奈良機械製作所製）、クイックミルQMY（セイシン企業製）、ロールグラニュレーター（マツボー製）、ニュースピードミル（岡田精工製）、ならびにMF型整粒機オシュレーターおよび解砕整粒機コニビット（以上、スイス・フレビット社製、アーステクニカにて販売）が挙げられる。 As granulators based on the principle of crushing and sizing, for example, power mill (Dalton), granulator Fiore F and Randel mill (above, manufactured by Tokuju Kosakusho), no screen granulator Nebula Sizer (manufactured by Nara Machinery Co., Ltd.) ), Quick Mill QMY (manufactured by Seishin Company), Roll Granulator (manufactured by Matsubo), New Speed Mill (manufactured by Okada Seiko), MF Granulator Oscillator and Crushing Granulator Conibit (above, Swiss Frevit) Manufactured and sold by Earth Technica).
　回転造粒を原理とする造粒装置としては、例えばマルメライザー（ダルトン製）、ならびに遠心流動コーティング造粒機CFおよびグラニュレックスGX（以上、フロイント産業製）が挙げられる。 Examples of the granulating apparatus based on the principle of rotary granulation include a Malmerizer (manufactured by Dalton), a centrifugal fluidized coating granulator CF, and Granurex GX (manufactured by Freund Sangyo).
　乾式造粒を原理とする造粒装置としては、例えばローラーコンパクター（フロイント産業製）、ファーマパクタ（ホソカワミクロン製）、RCPローラーコンパクタ（栗本鐵工所製）、およびファーマコンパクター（マツボー製）が挙げられる。 Examples of the granulation apparatus based on dry granulation include a roller compactor (manufactured by Freund Industries), a pharmapactor (manufactured by Hosokawa Micron), an RCP roller compactor (manufactured by Kurimoto Steel Works), and a pharmacompactor (manufactured by Matsubo).
　湿式高剪断造粒を原理とする造粒装置としては、例えばSPグラニュレーターおよびスパルタンリューザー（以上、ダルトン製）、バーチカルグラニュレーター（パウレック製）、GEAエアロマティックフィールダーマルチプロセッサー研究開発用ファーマコネクト（ユーロテクノ製）、ミキサー&グラニュレーター(NMG)（奈良機械製作所製）、破砕転動式ニューグラマシンSEG（セイシン企業製）、ニュースピードニーダー（岡田精工製）、ハイスピードミキサー(アドバンスシリーズ)、ダイナミックドライヤー、ハイフレックスグラル、およびマイクロウェーブグラニュレータードライヤー（以上、深江パウテック製、アーステクニカにて販売）、ならびにTM型造粒ミキサ（日本コークス工業製）が挙げられる。 As granulators based on wet high shear granulation, for example, SP granulator and Spartan Luther (from Dalton), vertical granulator (from Paul Lec), GEA Aeromatic Fielder Multiprocessor R & D PharmaConnect ( Eurotechno), Mixer & Granulator (NMG) (Nara Machinery Co., Ltd.), Crushing and rolling Newgramachine SEG (Seishin Enterprise), New Speed Kneader (Okada Seiko), High Speed Mixer (Advanced Series), Dynamic Examples thereof include dryers, high flex glals, and microwave granulator dryers (manufactured by Fukae Pautech, sold by Earth Technica), and TM granulation mixers (manufactured by Nippon Coke Industries).
　流動層造粒を原理とする造粒装置としては、例えばニューマルメライザー、旋回流動層、微少量流動層、およびスイングプロセッサー（以上、グルトン製）、フローコーターコンテインメント、フローコーターUniversal、フローコーターFLO、およびスパイラフローSFC（以上、フロイント産業製）、アグロマスタ（ホソカワミクロン製）、GEAエアロマテイックフィールダーフレックスストリーム（ユーロテクノ製）、ならびにスプリュード（大川原製作所）が挙げられる。 Examples of granulators based on fluidized bed granulation include, for example, a pneumaticizer, a swirling fluidized bed, a micro fluidized bed, and a swing processor (Gluton), a flow coater containment, a flow coater universal, and a flow coater FLO. And Spiraflow SFC (above, manufactured by Freund Corporation), Agromaster (manufactured by Hosokawa Micron), GEA Aeromatic Fielder Flexstream (manufactured by Eurotechno), and Sprued (Okawara Seisakusho).
　混合は、実施例に記載した原理・装置に加え、対流式(機械攪拌式)、拡散式(容器回転式)、および捏和・ニーダーの各原理により行われる。 In addition to the principle and apparatus described in the examples, the mixing is performed according to each principle of convection type (mechanical stirring type), diffusion type (container rotation type), and Kazuwa / kneader.
　対流式(機械攪拌式)を原理とする混合装置としては、例えば混合攪拌機NDMタイプ、混合攪拌機XDMタイプ、混合攪拌機DMタイプ、試作・研究用混合攪拌機AM・XDM・DMタイプ、ラボ用混合攪拌機ツインミックス、パグミキサー、リボンミキサー、スパルタンミキサー、およびペーストミキサー（以上、ダルトン製）、サイクロミックス、およびナウタミキサー（以上、ホソカワミクロン製）、竪取付MAG-NEOシールミキサー（マグネオ技研製）、底面型スーパーマグミキサー、およびSミキサースーパーミックス（以上、佐竹化学機械工業製）、ジュリアミキサー、およびリボン混合機（以上、徳寿工作所製）、PXミキサー（セイシン企業製）、レーディゲミキサー（マツボー製）、FMミキサRCタイプ、およびMPミキサ（以上、日本コークス工業製）、ならびにリボコーン（大川原製作所製）が挙げられる。 Mixing devices based on the convection type (mechanical stirring type) include, for example, mixing stirrer NDM type, mixing stirrer XDM type, mixing stirrer DM type, prototype / research mixing stirrer AM / XDM / DM type, laboratory mixing stirrer twin Mix, Pug mixer, Ribbon mixer, Spartan mixer, Paste mixer (above Dalton), Cyclomix, Nauta mixer (Osokawa Micron), 竪 mounting MAG-NEO seal mixer (Magneno Giken), Bottom super Mag mixer, S mixer supermix (above, Satake Chemical Machinery Co., Ltd.), Julia mixer, ribbon mixer (above, Deoksugaku Kosakusho), PX mixer (made by Seishin Enterprise), Ladige mixer (made by Matsubo) , FM mixer RC type, and MP mixer (Nippon Coke Industries, Ltd.) Ribocone (Okawara Seisakusho Co., Ltd.) and the like in beauty.
　拡散式(容器回転式)を原理とする混合装置としては、例えばGEAブックシステムIBCブレンダー、およびGEAブックシステムNIR測定装置付IBCブレンダー（以上、ユーロテクノ製）、V型混合機、およびW型混合機（以上、徳寿工作所製）、V型ミキサー（奈良機械製作所製）、W型混合機SCM、およびV型混合機SVM（以上、セイシン企業製）、カプセルロッキングミキサー（愛知電機製）、ならびにボーレコンテナミキサーPM（寿工業製）が挙げられる。 Examples of mixing devices based on the diffusion type (container rotation type) include GEA book system IBC blender, IBC blender with GEA book system NIR measuring device (Eurotechno), V-type mixer, and W-type mixing. Machine (above, manufactured by Tokuju Factory), V-type mixer (made by Nara Machinery Co., Ltd.), W-type mixer SCM, V-type mixer SVM (above, made by Seishin Enterprise), capsule locking mixer (made by Aichi Electric), and Boule container mixer PM (manufactured by Kotobuki Industries) can be mentioned.
　捏和・ニーダーを原理とする混合装置としては、例えばコンティーニュアースニーダー、およびバッチニーダー（以上、ダルトン製）、T.K.ハイビスミックス、およびT.K.ハイビスディスパーミックス（以上、プライミクス製）、ライストリッツ・エクストルーダー（奈良機械製作所製）、ならびにプラネタリーミキサー（淺田鉄工製）が挙げられる。 Examples of mixing devices based on Kazuwa and Kneader include continuous kneader, batch kneader (made by Dalton), TK Hibismix, and TK Hibis Dispermix (made by Primex), Leistritz Extruder. (Manufactured by Nara Machinery Co., Ltd.) and planetary mixer (manufactured by Iwata Iron Works).
　その他の混合装置としては、例えばConti-TDS（ダルトン製）、ならびにミキシングトルクメーターST-3000II プロセスリアクターDDL・3000、および攪拌シミュレーションMixSim（以上、佐竹化学機械工業製）が挙げられる。 Other mixing devices include, for example, Conti-TDS (manufactured by Dalton), mixing torque meter ST-3000II process reactor DDL • 3000, and stirring simulation MixSim (manufactured by Satake Chemical Machinery Co., Ltd.).
　上記の各原理の他、流動撹拌式、無撹拌式、および高速剪断式などの原理により混合することもできる。 In addition to the above-mentioned principles, mixing can be performed according to principles such as a fluid stirring method, a non-stirring method, and a high-speed shearing method.
　打錠は、単発式打錠および回転式打錠の各原理により行われるが、回転式打錠が効率性の観点で好ましい。 Tableting is performed according to the principles of single-punch tableting and rotary tableting, but rotary tableting is preferable from the viewpoint of efficiency.
　回転式打錠を原理とする打錠装置名としては、実施例に記載のものに加え、例えば脱着式高速打錠機フェッテ（ボッシュパッケージングテクノロジー製）、高速打錠機COMPRIMA、および高速打錠機SYNTHESIS（以上、ミューチュアル製）、ロータリープレスMZ400（モリマシナリー製）、GEAコルトアモジュール型打錠機P型、S型、Ｄ型、およびGEAフアーマシステムパフォーマP（以上、ユーロテクノ製）、研究開発用小型回転式錠剤機、小型高速回転式錠剤機、中型高速回転式錠剤機、複式高速回転式錠剤機、回転盤脱着水洗回転式錠剤機、およびコンテインメント錠剤機（以上、菊水製作所製）、ならびにＢＸ型 ＨＸ型強圧打錠機、CVX型回転盤着脱式打錠機、X型 AP型小型打錠機、X型 AP型中型打錠機、AP型大型打錠機、およびX型 AP型大型複式打錠機（以上、畑鐵工所製）が挙げられる。 The names of the tableting devices based on the principle of rotary tableting include, in addition to those described in the examples, for example, a detachable high-speed tableting machine Fette (manufactured by Bosch Packaging Technology), a high-speed tableting machine COMPRIMA, and a high-speed tableting SYNTHESIS machine (Mutual), Rotary press MZ400 (Mori Machinery), GEA Coltor module type tablet P, S, D, and GEA Pharma system performer P (Eurotechno) Small rotary tablet machine for research and development, small high-speed rotary tablet machine, medium high-speed rotary tablet machine, dual high-speed rotary tablet machine, rotary disk detachable water washing rotary tablet machine, and containment tablet machine (above, manufactured by Kikusui Seisakusho) ), BX type HX type high pressure tableting machine, CVX type rotary table removable tableting machine, X type 型 AP type small tableting machine, X type AP type medium size tableting machine, AP type large type tableting machine, and X type AP type large compound tableting (Manufactured by HataTetsuko office), and the like.
　上記の打錠装置では単層錠が得られるが、例えばGEAコルトアモジュール型二層錠打錠機D型（ユーロテクノ製）、および多層錠剤機（菊水製作所製）などを用いて多層錠を製造することや、有核錠剤機（菊水製作所製）、およびAP・MS型 C型有核打錠機（畑鐵工所製）などを用いて有核錠を製造することもできる。 In the above tableting device, a single-layer tablet can be obtained. For example, a multi-layer tablet can be obtained using a GEA Coltor module type double-layer tablet press D type (manufactured by Eurotechno) and a multi-layer tablet machine (manufactured by Kikusui Seisakusho). Nucleated tablets can also be produced by using a tableted tablet machine (manufactured by Kikusui Seisakusho) or an AP / MS type C-type nucleated tableting machine (manufactured by Hata Seiko).
　コーティングは、実施例に記載した原理・装置に加え、パンコーティング(水平パン)、パンコーティング（傾斜パン）、および空気浮遊式（流動層）の各原理により行われる。 Coating is performed according to the principles of pan coating (horizontal pan), pan coating (tilted pan), and air floating type (fluidized bed) in addition to the principle and apparatus described in the examples.
　パンコーティング(水平パン)を原理とするコーティング装置としては、例えばハイコーターFZ、アクアコーターAQC コンテインメント、およびアクアコーターAQC（以上、フロイント産業製）が挙げられる。 Examples of the coating apparatus based on the principle of pan coating (horizontal panning) include a high coater FZ, an aqua coater AQC テ containment, and an aqua coater AQC (hereinafter, Freund Sangyo).
　パンコーティング（傾斜パン）を原理とするコーティング装置としては、例えばパウレックコーター PRC、およびドリアコーター DRC（以上、パウレック製）が挙げられる。 Examples of the coating apparatus based on pan coating (tilted pan) include, for example, POWREC COATER PRC and DORIA COATER DRC (hereinafter, POWREC).
　空気浮遊式（流動層）を原理とするコーティング装置としては、例えばグラットパウダーコータ GPCG SPC、マルチプレックス、および複合型流動層 SFP（以上、パウレック製）が挙げられる。 Examples of the coating apparatus based on the air floating type (fluidized bed) include, for example, Glatt Powder Coater “GPCG” SPC, Multiplex, and Composite Fluidized Bed “SFP” (hereinafter, “Powrec”).
　その他のコーティング装置としては、例えばハイブリダイゼーシヨンシステム（奈良機械製作所製）、およびメカノハイブリッド（日本コークスエ業製）が挙げられる。 Other coating apparatuses include, for example, a hybridization system (manufactured by Nara Machinery Co., Ltd.) and a mechano hybrid (manufactured by Nippon Coke Industries).
　本発明の医薬組成物は、骨代謝回転を抑制して骨密度および骨強度を改善することにより治療または予防し得る疾患または症状（例えば骨粗鬆症）の治療または予防に有用である。 The pharmaceutical composition of the present invention is useful for treating or preventing a disease or symptom (for example, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.
　本発明において、疾患または症状の治療または予防には、該疾患の発症の予防、増悪または進行の抑制または阻害、該疾患に罹患した個体が呈する一つ以上の症状の軽減または増悪もしくは進行の抑制、二次性疾患の治療または予防などが含まれる。 In the present invention, the treatment or prevention of a disease or symptom includes prevention of onset of the disease, suppression or inhibition of progression or progression, reduction of one or more symptoms exhibited by an individual suffering from the disease, or suppression of progression or progression. , Treatment or prevention of secondary diseases and the like.
　本発明の医薬組成物が投与される対象は哺乳動物である。哺乳動物は、好ましくはヒトである。 The subject to which the pharmaceutical composition of the present invention is administered is a mammal. The mammal is preferably a human.
　本発明の医薬組成物は、治療または予防に有効な量で対象に投与される。「治療または予防に有効な量」とは、特定の疾患、投与形態および投与経路につき治療または予防効果を奏する量を意味し、対象の種、疾患の種類、症状、性別、年齢、持病、その他の要素に応じて適宜決定される。投与経路は、通常は経口投与である。 The pharmaceutical composition of the present invention is administered to a subject in an amount effective for treatment or prevention. “Amount effective for treatment or prevention” means an amount that exhibits a therapeutic or prophylactic effect for a specific disease, administration form, and administration route. The species, type of disease, symptom, sex, age, chronic disease, etc. It is determined appropriately according to the factors. The route of administration is usually oral.
　本発明の医薬組成物の投与量は、対象の種、疾患の種類、症状、性別、年齢、持病、その他の要素に応じて適宜決定され、ヒトの成人に対しては、通常、ＥＤ－７１として１日あたり０．０１～１０μｇ、好適には０．５～０．７５μｇを投与することができる。 The dosage of the pharmaceutical composition of the present invention is appropriately determined according to the species of the subject, the type of disease, symptoms, sex, age, disease, and other factors, and is usually ED-71 for human adults. 0.01 to 10 μg per day, preferably 0.5 to 0.75 μg can be administered.
　また本発明は、本発明の医薬組成物の治療または予防有効量を、それを必要とする対象に投与することを含む、疾患または症状の治療または予防のための方法に関する。 The present invention also relates to a method for the treatment or prevention of a disease or symptom comprising administering to a subject in need thereof a therapeutic or prophylactically effective amount of the pharmaceutical composition of the present invention.
　本発明における「治療または予防有効量」とは、特定の疾患または症状、投与形態および投与経路につき治療または予防効果を奏する量を意味し、対象の種、疾患または症状の種類、症状、性別、年齢、持病、その他の要素に応じて適宜決定される。 The “therapeutically or prophylactically effective amount” in the present invention means an amount having a therapeutic or prophylactic effect for a specific disease or symptom, administration form and administration route, and includes the species of the subject, the type of disease or symptom, symptom, sex, It is determined as appropriate according to age, chronic illness, and other factors.
　本発明における「対象」は、例えば、哺乳動物であり、好ましくはヒトである。 The “subject” in the present invention is, for example, a mammal, preferably a human.
　本発明における「投与すること」は、通常、経口投与を意味する。 “Administering” in the present invention usually means oral administration.
　本発明における「疾患または症状」としては、骨代謝回転を抑制して骨密度および骨強度を改善することにより治療または予防し得る疾患または症状（例えば骨粗鬆症）が挙げられる。 The “disease or symptom” in the present invention includes a disease or symptom (for example, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.
ＩＩ．ＥＤ－７１の油分分散体
ＩＩ－１．ＥＤ－７１を含む医薬組成物およびその製造方法
　本発明の第二の態様は、ＥＤ－７１の油分分散体に関する。本明細書中、ＥＤ－７１の油分分散体とは、ＥＤ－７１の油脂溶液の粒子が賦形剤中に分散した組成物をいう。 II. Oil dispersion of ED-71
II-1. Pharmaceutical Composition Containing ED-71 and Method for Producing the Same A second aspect of the present invention relates to an oil dispersion of ED-71. In the present specification, the oil dispersion of ED-71 refers to a composition in which particles of an oil and fat solution of ED-71 are dispersed in an excipient.
　本発明は、そのようなＥＤ－７１の油分分散体を含む医薬組成物を提供する。具体的には、ＥＤ－７１を含む医薬組成物であって、賦形剤中または賦形剤の表面に、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される水溶性高分子を含む被覆剤で被覆された粒子を含み、当該粒子は、ＥＤ－７１の油脂溶液を含む、前記医薬組成物を提供する。 The present invention provides a pharmaceutical composition comprising such an ED-71 oil dispersion. Specifically, a pharmaceutical composition comprising ED-71, which is coated with a coating agent containing a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose in or on the surface of the excipient Providing said pharmaceutical composition, wherein said particle comprises a fat solution of ED-71.
　また本発明は、そのような医薬組成物の製造方法を提供する。具体的には、ＥＤ－７１を含む医薬組成物の製造方法であって、（ｉ）ＥＤ－７１の油脂溶液と水溶性高分子の水溶液とを含む水中油型乳化液を調製する工程、（ｉｉ）水中油型乳化液を賦形剤に付着または吸着させる工程、および（ｉｉｉ）水中油型乳化液を乾燥させる工程、を含み、ここで前記水溶性高分子は、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される、前記方法を提供する。この方法により、賦形剤中でＥＤ－７１の油脂溶液の粒子が水溶性高分子に被覆された状態となり、ＥＤ－７１の油分分散体を用いた製剤（特に錠剤）の製造が可能となる。製剤分野において、有効成分を含む油脂溶液を賦形剤に含浸させる方法は既に知られているが、油脂溶液ではなく水中油型乳化液を用いること、また賦形剤に付着または吸着させた後に水中油型乳化液を乾燥させ、水層中の成分で油脂溶液を被覆する方法は従来知られていなかった。 The present invention also provides a method for producing such a pharmaceutical composition. Specifically, a method for producing a pharmaceutical composition containing ED-71, comprising the steps of: (i) preparing an oil-in-water emulsion containing an oil / fat solution of ED-71 and an aqueous solution of a water-soluble polymer; ii) attaching or adsorbing an oil-in-water emulsion to an excipient, and (iii) drying the oil-in-water emulsion, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose and hydroxypropyl The method is provided selected from cellulose. By this method, the particles of the ED-71 oil / fat solution are coated with the water-soluble polymer in the excipient, and a preparation (especially a tablet) using the ED-71 oil dispersion can be produced. . In the formulation field, a method of impregnating an excipient with an oil / fat solution containing an active ingredient is already known, but after using an oil-in-water emulsion instead of an oil / fat solution and adhering or adsorbing to an excipient. A method for drying an oil-in-water emulsion and coating an oil / fat solution with components in an aqueous layer has not been known.
　工程（ｉ）に関して、本発明に用いる油脂としては、中鎖脂肪酸トリグリセリド（以下、「ＭＣＴ」とも記す）、トリカプリリン、カプロン酸、カプリル酸、カプリン酸、オレイン酸、リノール酸、リノレン酸、植物油などが挙げられる。ここで、植物油としては、ヤシ油、オリーブ油、菜種油、落下生油、コーン油、大豆油、綿実油、ぶどう油、紅花油などが挙げられる。これらのうち、不飽和脂肪酸を含んでいない、ＭＣＴ、トリカプリリン、カプロン酸、カプリル酸、またはカプリン酸が好ましく、ＭＣＴが特に好ましい。 Regarding step (i), the oils and fats used in the present invention include medium chain fatty acid triglycerides (hereinafter also referred to as “MCT”), tricaprylin, caproic acid, caprylic acid, capric acid, oleic acid, linoleic acid, linolenic acid, vegetable oil. Etc. Here, examples of the vegetable oil include coconut oil, olive oil, rapeseed oil, falling raw oil, corn oil, soybean oil, cottonseed oil, grape oil, safflower oil, and the like. Of these, MCT, tricaprylin, caproic acid, caprylic acid, or capric acid that do not contain unsaturated fatty acids are preferred, and MCT is particularly preferred.
　工程（ｉ）における油脂溶液中のＥＤ－７１の濃度は、対象とする疾患または症状、投与形態、投与経路などに応じて適宜決定することができるが、例えば０．００１～０．３重量％であり、好ましくは０．００５～０．１重量％であり、より好ましくは０．０１～０．０５重量％である。 The concentration of ED-71 in the oil / fat solution in the step (i) can be appropriately determined according to the target disease or symptom, administration form, administration route, etc., for example, 0.001 to 0.3% by weight Preferably, it is 0.005 to 0.1% by weight, and more preferably 0.01 to 0.05% by weight.
　工程（ｉ）における油脂溶液には、さらに抗酸化剤を添加してもよい。本発明における抗酸化剤としては、例えば、亜硝酸塩（例えば亜硝酸ナトリウム）、亜硫酸塩（例えば亜硫酸ナトリウム、乾燥亜硫酸ナトリウム、亜硫酸水素ナトリウム、ピロ亜硫酸ナトリウム）、チオ硫酸塩（例えばチオ硫酸ナトリウム）、アルファチオグリセリン、１，３－ブチレングリコール、チオグリコール酸およびその塩（例えばチオグリコール酸ナトリウム）、チオリンゴ酸塩（例えばチオリンゴ酸ナトリウム）、チオ尿素、チオ乳酸、エデト酸塩（例えばエデト酸ナトリウム）、ジクロルイソシアヌール酸塩（例えばジクロルイシアヌール酸カリウム）、クエン酸、システイン及びその塩（例えば塩酸システイン）、ベンゾトリアゾール、２－メルカプトベンズイミダゾール、エリソルビン酸およびその塩（例えばエリソルビン酸ナトリウム）、アスコルビン酸およびそのエステル化合物（例えばＬ－アスコルビン酸ステアリン酸エステル、パルミチン酸アスコルビン酸）、リン脂質（例えば大豆レシチン）、金属キレート剤およびその塩（例えば、エチレンジアミン四酢酸、エチレンジアミン四酢酸カルシウム二ナトリウム、エチレンジアミン四酢酸二ナトリウム）、酒石酸およびその塩（例えばロッシェル塩）、ポリフェノール類（例えばカテキン）、グルタチオン、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、没食子酸プロピル、天然ビタミンＥ、酢酸トコフェロール、濃縮混合トコフェロール、トコフェロール同族体（例えばｄ－α－トコフェロール、ｄｌ－α－トコフェロール、５，８－ジメチルトコール、７，８－ジメチルトコール、δ－メチルトコール、５，７，８－トリメチルトコトリエノール、５，８－ジメチルトコトリエノール、７，８－ジメチルトコトリエノール、８－メチルトコトリエノール）などが挙げられる。この中でも、酢酸トコフェロール、ジブチルヒドロキシトレン、天然ビタミンＥ、ｄｌ－α－トコフェロール、ｄ－α－トコフェロール、濃縮混合トコフェロール、パルミチン酸アスコルビン酸、Ｌ－アスコルビン酸ステアリン酸エステル、ブチルヒドロキシアニソール、没食子酸プロピルが好ましく、ｄｌ－α－トコフェロール、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、または没食子酸がより好ましく、ｄｌ－α－トコフェロールまたはジブチルヒドロキシトルエンがさらにより好ましい。 An antioxidant may be further added to the oil / fat solution in step (i). Examples of the antioxidant in the present invention include nitrite (for example, sodium nitrite), sulfite (for example, sodium sulfite, dry sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite), thiosulfate (for example, sodium thiosulfate), Alpha thioglycerin, 1,3-butylene glycol, thioglycolic acid and its salts (eg sodium thioglycolate), thiomalate (eg sodium thiomalate), thiourea, thiolactic acid, edetate (eg sodium edetate) Dichloroisocyanurate (eg potassium dichloroisocyanurate), citric acid, cysteine and its salts (eg cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (eg erythorbide) Acid sodium), ascorbic acid and its ester compounds (eg L-ascorbic acid stearate, palmitic acid ascorbic acid), phospholipids (eg soybean lecithin), metal chelators and their salts (eg ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid) Calcium disodium, ethylenediaminetetraacetic acid disodium), tartaric acid and its salts (eg Rochelle salt), polyphenols (eg catechin), glutathione, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, natural vitamin E, tocopherol acetate, concentrated Mixed tocopherols, tocopherol homologues (eg d-α-tocopherol, dl-α-tocopherol, 5,8-dimethyltocol, 7,8-dimethyltocol, δ Methyl DOO call, 5,7,8- trimethyl-tocotrienol, 5,8-dimethyl-tocotrienol, 7,8-dimethyl-tocotrienol, 8-methyl-tocotrienol), and the like. Among them, tocopherol acetate, dibutylhydroxytren, natural vitamin E, dl-α-tocopherol, d-α-tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, L-ascorbic acid stearate, butylhydroxyanisole, propyl gallate Dl-α-tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, or gallic acid is more preferred, and dl-α-tocopherol or dibutylhydroxytoluene is even more preferred.
　油脂溶液への抗酸化剤の添加量は、特に限定されないが、抗酸化剤として使用可能な最大使用量以下の量（例えば、医薬品添加物事典（薬事日報社，２０００）に記載されている承認前例の最大使用量以下、食品添加物公定書（日本食品添加物協会，１９９９）に記載されている使用制限量以下の量など）を通常用いることができる。 The amount of the antioxidant added to the oil / fat solution is not particularly limited, but the amount described below is the maximum use amount that can be used as the antioxidant (for example, the approval listed in the Pharmaceutical Additives Encyclopedia (Pharmaceutical Daily), 2000) Below the maximum use amount of the previous example, the amount of use limit amount or less described in the Food Additives Official Document (Japan Food Additives Association, 1999) can be usually used.
　好ましい態様において、ｄｌ－α－トコフェロールは、油脂溶液中に０．０１重量％以上（例えば１重量％以上）、１０重量％以下（例えば５重量％以下）の濃度で添加される。ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、没食子酸プロピル等の添加量についても、上記のｄｌ－α－トコフェロールと同様である。 In a preferred embodiment, dl-α-tocopherol is added to the oil / fat solution at a concentration of 0.01% by weight or more (for example, 1% by weight or more) and 10% by weight or less (for example, 5% by weight or less). The addition amount of dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate and the like is the same as that of the above dl-α-tocopherol.
　本発明に用いる被覆剤は、水溶性高分子を含む。水溶性高分子は、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される。多くの添加剤は、ＥＤ－７１の油脂溶液に添加するとＥＤ－７１の安定性を低下させるが、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースは、ＥＤ－７１の安定性を低下させない。またヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースを用いた場合、水中油型乳化液の乳化状態を長期にわたり維持することができる。 The coating agent used in the present invention contains a water-soluble polymer. The water soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropylcellulose. Many additives reduce the stability of ED-71 when added to an ED-71 oil solution, whereas hydroxypropylmethylcellulose and hydroxypropylcellulose do not reduce the stability of ED-71. When hydroxypropylmethylcellulose and hydroxypropylcellulose are used, the emulsified state of the oil-in-water emulsion can be maintained for a long time.
　ここで本発明の医薬組成物においてＥＤ－７１の安定性が低下しないことは、本発明の医薬組成物から錠剤を製造し、これを遮光して１、３、または６箇月間４０℃で保存した後の、ＥＤ－７１の残存率を調べることにより確認される。ＥＤ－７１の残存率は、保存試料と初期試料について、高速液体クロマトグラフィー法（測定波長265nm）によりＥＤ－７１とその異性体であるプレ体（化学名：６Ｚ－（１Ｒ，２Ｒ，３Ｒ）－２－（３－ヒドロキシプロポキシ）－９，１０－セココレスタ－５（１０），６，８（９）－トリエン－１，３，２５－トリオール；本明細書中、pre ED-71とも称する）のピーク面積を測定し、以下の計算式により算出される。
ED-71の表示量に対する含有量の比（%）＝（ED-71標準品の秤取量／ED-71標準品中のED-71ピーク面積合計）×初期試料または保存試料中のED-71ピーク面積合計×（初期試料または保存試料全体の重量／測定に使用した試料の重量）／表示量×100
（ED-71ピーク面積合計＝ED-71ピーク面積＋1.98×pre ED-71のピーク面積）
ED-71の残存率(%)＝保存試料中のED-71の表示量に対する含有量の比（%）／初期試料中のED-71の表示量に対する含有量の比（%）×100 Here, the fact that the stability of ED-71 does not decrease in the pharmaceutical composition of the present invention is that a tablet is produced from the pharmaceutical composition of the present invention and stored at 40 ° C. for 1, 3, or 6 months while being shielded from light. This is confirmed by examining the residual ratio of ED-71. The residual ratio of ED-71 was determined by using ED-71 and its isomer (chemical name: 6Z- (1R, 2R, 3R) by high performance liquid chromatography (measurement wavelength: 265 nm) for the storage sample and the initial sample. -2- (3-hydroxypropoxy) -9,10-secocholesta-5 (10), 6,8 (9) -triene-1,3,25-triol; also referred to herein as pre ED-71) The peak area is measured and calculated by the following formula.
Ratio of content to display amount of ED-71 (%) = (Weighed amount of ED-71 standard product / Total ED-71 peak area in ED-71 standard product) x ED- in initial sample or stored sample 71 Peak area total x (weight of initial sample or whole stored sample / weight of sample used for measurement) / display amount x 100
(Total ED-71 peak area = ED-71 peak area + 1.98 x pre ED-71 peak area)
Residual rate of ED-71 (%) = Ratio of content to the displayed amount of ED-71 in the stored sample (%) / Ratio of content to the displayed amount of ED-71 in the initial sample (%) x 100
　なお、上記式における各用語の意味は以下の通りである。
・「表示量」：１錠あたりの理論含量
・「ED-71標準品」:ED-71の原薬
・「ED-71標準品の秤取量／ED-71標準品中のED-71ピーク面積合計」:単位ピーク面積あたりのED-71標準品の重量（ピーク面積から測定試料中のED-71の含有量を算出するための値） In addition, the meaning of each term in the said formula is as follows.
・ "Indication amount": Theoretical content per tablet ・ "ED-71 standard product": ED-71 drug substance "Weighed amount of ED-71 standard product / ED-71 peak in ED-71 standard product Total area ”: Weight of ED-71 standard product per unit peak area (value for calculating the content of ED-71 in the measurement sample from the peak area)
　ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースは、製剤上許容されるグレードのものであればよい。 Hydroxypropylmethylcellulose and hydroxypropylcellulose may be of any grade acceptable for pharmaceutical preparations.
　本発明におけるヒドロキシプロピルメチルセルロースは、例えば、商品名ＴＣ－５として信越化学工業から購入できる。 The hydroxypropyl methylcellulose in the present invention can be purchased from Shin-Etsu Chemical Co., Ltd. under the trade name TC-5.
　また本発明において、ヒドロキシプロピルセルロース（ＨＰＣ）とは、医薬品添加物事典２０１６（編集：日本医薬品添加物協会；発行：（株）薬事日報社；ISBN978-4-8408-1329-7）において、成分番号００２３０３として収載されているヒドロキシプロピルセルロースを指し、同事典において成分番号００２４４０として収載されている低置換度ヒドロキシプロピルセルロースとは異なる物である。本発明に用いるヒドロキシプロピルセルロースでは、モル置換度（ＭＳ）（ＨＰＣの繰り返し単位（グルコース環）のヒドロキシ基がヒドロキシプロポキシ基に置換された割合を示す）が、通常２～３、好ましくは２．５～３、より好ましくは３である。一方、低置換度ヒドロキシプロピルセルロースにおけるモル置換度は、０．２～０．４である。本発明におけるヒドロキシプロピルセルロースは、例えば、商品名Ｋｌｕｃｅｌとしてアイスピー・ジャパンから、および商品名ヒドロキシプロピルセルロースとして日本曹達から、それぞれ購入できる。 In the present invention, hydroxypropylcellulose (HPC) is a component in the Pharmaceutical Additives Encyclopedia 2016 (edited by Japan Pharmaceutical Additives Association; published by Yakuji Nippo Inc .; ISBN978-4-8408-1329-7). This refers to hydroxypropylcellulose listed as number 002303, which is different from the low-substituted hydroxypropylcellulose listed as component number 002440 in the same encyclopedia. In the hydroxypropyl cellulose used in the present invention, the molar substitution degree (MS) (representing the ratio of the hydroxy group of the HPC repeating unit (glucose ring) being substituted with a hydroxypropoxy group) is usually 2 to 3, preferably 2. 5 to 3, more preferably 3. On the other hand, the molar substitution degree in the low-substituted hydroxypropyl cellulose is 0.2 to 0.4. The hydroxypropylcellulose in the present invention can be purchased, for example, from Ice Pee Japan under the trade name Klucel and from Nippon Soda as the trade name hydroxypropylcellulose.
　本発明における被覆剤は、水溶性高分子以外の添加剤を含んでもよく、例えば、安定化剤や抗酸化剤を含んでもよい。 The coating agent in the present invention may contain an additive other than the water-soluble polymer, and may contain, for example, a stabilizer or an antioxidant.
　工程（ｉ）における水溶液中の水溶性高分子の濃度は、ＥＤ－７１の量に応じて適宜決定されるが、例えば１～１５重量％であり、好ましくは２～１０重量％であり、より好ましくは３～６重量％、より好ましくは４～６重量％、さらにより好ましくは５～６重量％である。工程（ｉ）における水溶液は、水溶性高分子以外の添加剤を含んでもよく、例えば、安定化剤や抗酸化剤を含んでもよい。 The concentration of the water-soluble polymer in the aqueous solution in step (i) is appropriately determined according to the amount of ED-71, and is, for example, 1 to 15% by weight, preferably 2 to 10% by weight, It is preferably 3 to 6% by weight, more preferably 4 to 6% by weight, and even more preferably 5 to 6% by weight. The aqueous solution in step (i) may contain an additive other than the water-soluble polymer, and may contain, for example, a stabilizer or an antioxidant.
　水中油型乳化液は、製剤分野において一般的に用いられる方法により調製することができるが、機械的乳化法により調製することが好ましい。機械的乳化法は、例えば、ケミカルスターラー、ボルテックスミキサー、ホモミクサー、ホモジナイザー、ハイドロシェア、コロイドミル、フロージェットミクサー、超音波発生機、ガラスビーズを用いる湿式粉砕機、多孔質膜を用いる膜乳化機、電気的エネルギーを用いる電気乳化装置などを用いる方法が挙げられる。ホモジナイザーとしては、例えばT-50 Ultra Turrax（IKA製）を用いることができる。 The oil-in-water emulsion can be prepared by a method generally used in the pharmaceutical field, but is preferably prepared by a mechanical emulsification method. Mechanical emulsification methods include, for example, chemical stirrers, vortex mixers, homomixers, homogenizers, hydro shears, colloid mills, flow jet mixers, ultrasonic generators, wet pulverizers using glass beads, membrane emulsifiers using porous membranes, A method using an electric emulsifier using electric energy or the like can be mentioned. As a homogenizer, for example, T-50 Ultra Turrax (manufactured by IKA) can be used.
　ＥＤ－７１の油脂溶液と水溶性高分子の水溶液との比率（重量比、o/w比）は、水中油型乳化液を調製することができる範囲であればよく、通常１：１．５～１：２０であり、好ましくは１：２～１：２０、または１：２～１：４である。好ましい態様において、水溶性高分子の水溶液中の水溶性高分子の濃度が３～６重量％、４～６重量％、または５～６重量％である場合、ＥＤ－７１の油脂溶液と水溶性高分子の水溶液との比率は１：１．５～１：２０、１：２～１：２０、または１：２～１：４である。 The ratio (weight ratio, o / w ratio) of the oil / fat solution of ED-71 to the aqueous solution of the water-soluble polymer may be within a range in which an oil-in-water emulsion can be prepared. To 1:20, preferably 1: 2 to 1:20, or 1: 2 to 1: 4. In a preferred embodiment, when the concentration of the water-soluble polymer in the aqueous solution of the water-soluble polymer is 3 to 6% by weight, 4 to 6% by weight, or 5 to 6% by weight, the oil / fat solution of ED-71 and the water-soluble polymer The ratio of the polymer to the aqueous solution is 1: 1.5 to 1:20, 1: 2 to 1:20, or 1: 2 to 1: 4.
　またＥＤ－７１の油脂溶液と水溶性高分子との比率（重量比）は、ＥＤ－７１の油脂溶液の粒子を水溶性高分子に被覆された状態とすることができる範囲であればよく、通常１：０．０５～１：１０、好ましくは１：０．１～１：１、または１：０．１～１：０．３である。好ましい態様において、水溶性高分子の水溶液中の水溶性高分子の濃度が３～６重量％、４～６重量％、または５～６重量％である場合、ＥＤ－７１の油脂溶液と水溶性高分子との比率（重量比）は、１：０．０５～１：１０、１：０．１～１：１、または１：０．１～１：０．３である。 Further, the ratio (weight ratio) between the oil / fat solution of ED-71 and the water-soluble polymer may be in a range that allows the particles of the oil / fat solution of ED-71 to be covered with the water-soluble polymer. Usually 1: 0.05 to 1:10, preferably 1: 0.1 to 1: 1, or 1: 0.1 to 1: 0.3. In a preferred embodiment, when the concentration of the water-soluble polymer in the aqueous solution of the water-soluble polymer is 3 to 6% by weight, 4 to 6% by weight, or 5 to 6% by weight, the oil / fat solution of ED-71 and the water-soluble polymer The ratio (weight ratio) to the polymer is 1: 0.05 to 1:10, 1: 0.1 to 1: 1, or 1: 0.1 to 1: 0.3.
　当該粒子は、好ましくは球形である。その粒子径は、通常０．０１～１００μｍ、好ましくは０．１～１０μｍである。 The particles are preferably spherical. The particle size is usually from 0.01 to 100 μm, preferably from 0.1 to 10 μm.
　工程（ｉｉ）に関して、本発明に用いる賦形剤としては、例えば、トウモロコシデンプン、馬鈴薯デンプン、コムギコデンプン、コメデンプン、部分アルファー化デンプン、アルファー化デンプン、有孔デンプンなどのデンプン類、無水乳糖、乳糖水和物、果糖、ブドウ糖、マンニトール、ソルビトール、エリスリトールなどの糖または糖アルコール類、無水リン酸水素カルシウム、結晶セルロース、沈降炭酸カルシウム、ケイ酸カルシウムなどが挙げられ、好ましくは糖または糖アルコール類、さらに好ましくはマンニトール、無水乳糖、乳糖水和物、さらに好ましくはマンニトールである。 Regarding the step (ii), the excipients used in the present invention include, for example, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch and other starches, anhydrous lactose, Examples include lactose hydrate, fructose, glucose, mannitol, sorbitol, erythritol and other sugars or sugar alcohols, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc., preferably sugars or sugar alcohols More preferred is mannitol, anhydrous lactose, lactose hydrate, and more preferred is mannitol.
　工程（ｉｉ）において用いる水中油型乳化液と賦形剤との比率（重量比）は、賦形剤の種類などによって変わり得るが、通常１：１～１：１００、好ましくは１：４～１：２０の範囲である。特に、賦形剤がマンニトールである場合、重量比が通常１：４～１：２０の範囲であれば、錠剤などの製剤の製造に用い得る好ましい造粒末を得ることができる。 The ratio (weight ratio) between the oil-in-water emulsion and the excipient used in step (ii) may vary depending on the type of excipient, etc., but is usually 1: 1 to 1: 100, preferably 1: 4 to The range is 1:20. In particular, when the excipient is mannitol, a preferred granulated powder that can be used in the preparation of a preparation such as a tablet can be obtained if the weight ratio is usually in the range of 1: 4 to 1:20.
　水中油型乳化液の賦形剤への付着または吸着は、製剤分野において一般的に用いられる方法により行うことができ、例えば、賦形剤に乳化液を噴霧しながら造粒する方法、賦形剤に乳化液を加えて混合撹拌する方法などが挙げられる。このような方法は、例えば、高速撹拌造粒機（POWREX製VG-600CT）、混合攪拌機（品川工業所製ＤＭ型）などを用いて行うことができる。なお、付着または吸着には、含浸（多孔質の賦形剤において、水中油型乳化液を孔内に浸潤させること）も含まれる。 Adhesion or adsorption of an oil-in-water emulsion to an excipient can be performed by a method generally used in the pharmaceutical field. For example, granulation while spraying an emulsion on an excipient, shaping Examples include a method of adding an emulsified liquid to the agent and mixing and stirring. Such a method can be performed using, for example, a high speed stirring granulator (VG-600CT manufactured by POWREX), a mixing stirrer (DM type manufactured by Shinagawa Kogyo) or the like. The adhesion or adsorption includes impregnation (infiltration of an oil-in-water emulsion in the pores in a porous excipient).
　工程（ｉｉｉ）において、賦形剤に付着または吸着した水中油型乳化液が乾燥され、それにより水溶性高分子の水溶液から水が除かれ、油脂溶液が直接水溶性高分子で被覆された粒子が形成されると考えられる。このようにして得られる油分分散体は、ＥＤ－７１の油脂溶液を含む粒子を含み、錠剤などの製剤の製造に用いた場合に良好な製造性（例えば、流動性や圧縮成形性）を示す。 Particles obtained by drying the oil-in-water emulsion adhering or adsorbing to the excipient in step (iii), thereby removing water from the aqueous solution of the water-soluble polymer, and directly coating the oil-and-fat solution with the water-soluble polymer. Is thought to be formed. The oil dispersion obtained in this way contains particles containing an ED-71 oil-and-fat solution and exhibits good manufacturability (for example, fluidity and compression moldability) when used in the production of tablets and the like. .
　水中油型乳化液の乾燥は、製剤分野において一般的に用いられる方法により行うことができ、例えば、流動乾燥、凍結乾燥、通気乾燥、噴霧乾燥、静置乾燥、撹拌乾燥、気流乾燥、真空乾燥、マイクロ波乾燥、赤外線・遠赤外線乾燥などが挙げられる。また乾燥は、加熱または冷却と共に行ってもよい。乾燥は、例えば、流動層造粒乾燥機（POWREX製WSG-200pro）、真空乾燥機（日本乾燥機製コニカルドライヤ）などを用いて行うことができる。 The oil-in-water emulsion can be dried by a method generally used in the pharmaceutical field, for example, fluid drying, freeze drying, aeration drying, spray drying, stationary drying, stirring drying, airflow drying, vacuum drying. , Microwave drying, infrared / far infrared drying, and the like. Moreover, you may perform drying with a heating or cooling. Drying can be performed using, for example, a fluidized bed granulator / dryer (WSG-200pro manufactured by POWREX), a vacuum dryer (conical dryer manufactured by Nippon Dryer), or the like.
　本発明の医薬組成物は、錠剤、カプセル剤、顆粒剤、散剤などの経口剤とすることができる。これらの経口剤は、製剤分野において用いられる方法により製造することができる。例えば錠剤の製造方法としては、以下のｉ）、ｉｉ）およびｉｉｉ）の方法が挙げられる。
　ｉ）ＥＤ－７１の油分分散体を追加の添加剤（賦形剤、崩壊剤、滑沢剤など）と共に混合した後、圧縮成形することによって、錠剤を製造する。
　ｉｉ）ＥＤ－７１の油分分散体を追加の添加剤（賦形剤、結合剤など）と混合した後、溶媒（例えば、精製水、エタノール、またはその混合液）を添加または噴霧しながら造粒する。得られた造粒物に、適量の滑沢剤、必要に応じて崩壊剤などを加えて混合後、圧縮成形することによって、錠剤を製造する。
　ｉｉｉ）ＥＤ－７１の油分分散体を追加の添加剤（賦形剤など）と混合した後、結合剤および必要に応じて他の添加剤を溶媒（例えば、精製水、エタノール、またはその混合液）に分散または溶解して得られる液を添加または噴霧しながら造粒する。得られた造粒物に、適量の滑沢剤、必要に応じて崩壊剤など加えて混合した後、圧縮成形することによって、錠剤を製造する。 The pharmaceutical composition of the present invention can be made into oral preparations such as tablets, capsules, granules and powders. These oral preparations can be produced by methods used in the pharmaceutical field. For example, as a tablet production method, the following methods i), ii) and iii) can be mentioned.
i) Tablets are produced by mixing an oil dispersion of ED-71 with additional additives (excipients, disintegrants, lubricants, etc.) and then compression molding.
ii) After mixing the oil dispersion of ED-71 with additional additives (excipients, binders, etc.), granulation while adding or spraying a solvent (eg purified water, ethanol, or a mixture thereof) To do. A tablet is manufactured by adding an appropriate amount of lubricant and, if necessary, a disintegrant to the granulated product, mixing, and then compression-molding.
iii) After mixing the oil dispersion of ED-71 with additional additives (excipients, etc.), the binder and optionally other additives are mixed with a solvent (eg purified water, ethanol, or a mixture thereof) And granulated while adding or spraying a liquid obtained by dispersing or dissolving in the above. An appropriate amount of a lubricant and, if necessary, a disintegrant and the like are added to and mixed with the obtained granulated product, and then compression-molded to produce a tablet.
　追加の添加剤としては、例えば、薬物の放出性を向上させる目的で界面活性剤やｐＨ調整剤を、工程中の流動性を良くする目的で流動化剤を、安定性を上げる目的で安定化剤を、味や臭いを加える目的で矯味矯臭剤を、色を加える目的で着色剤を、それぞれ用いることができる。 Additional additives include, for example, surfactants and pH adjusters for the purpose of improving drug release, fluidizing agents for the purpose of improving fluidity during the process, and stabilization for the purpose of increasing stability. The agent can be used as a flavoring agent for the purpose of adding taste and odor, and the colorant can be used for the purpose of adding color.
　また錠剤は、追加の添加剤としてさらに抗酸化剤を含んでいてもよい。抗酸化剤は、ｉ）、ｉｉ）およびｉｉｉ）の製造法における任意の工程で添加できる。例えば、ｉ）の製造法の場合、抗酸化剤を、他の添加剤と共に油分分散体と混合した後、圧縮成形することによって、錠剤を製造することができる。また、予め抗酸化剤が溶解されたＥＤ－７１の油脂溶液を用いて油分分散体を調製し、これを他の添加剤と混合した後、圧縮成形することによって、錠剤を製造することもできる。 The tablet may further contain an antioxidant as an additional additive. Antioxidants can be added at any step in the processes of i), ii) and iii). For example, in the case of the production method i), a tablet can be produced by mixing an antioxidant with an oil dispersion together with other additives, followed by compression molding. It is also possible to produce a tablet by preparing an oil dispersion using an ED-71 oil solution in which an antioxidant is dissolved in advance, mixing this with other additives, and then compression molding. .
　賦形剤、崩壊剤、結合剤、滑沢剤、界面活性剤、ｐＨ調整剤、流動化剤、安定化剤、矯味矯臭剤、および着色剤は、上記Ｉ－２に記載したものを用いることができる。また抗酸化剤は、上記のものを用いることができる。 Excipients, disintegrants, binders, lubricants, surfactants, pH adjusters, fluidizers, stabilizers, flavoring agents, and colorants should be those described in I-2 above. Can do. Moreover, the above-mentioned thing can be used for an antioxidant.
　上記追加の添加剤は、２種以上を適宜の割合で混合して用いてもよい。 The above-mentioned additional additives may be used by mixing two or more kinds at an appropriate ratio.
　錠剤から、さらに適当なコーティング用添加剤を用いて、糖衣コーティング錠あるいはフィルムコーティング錠を得ることもできる。コーティング用添加剤は、上記Ｉ－２に記載したものを用いることができる。好ましい態様において、本発明の医薬組成物は、ＨＰＭＣフィルムでコーティングされたコーティング錠である。 From the tablets, sugar-coated tablets or film-coated tablets can also be obtained using a suitable coating additive. As the coating additive, those described in I-2 above can be used. In a preferred embodiment, the pharmaceutical composition of the present invention is a coated tablet coated with an HPMC film.
　本発明の医薬組成物の製造における、造粒、混合、打錠、およびコーティングは、上記Ｉ－２に記載した原理・装置により行われる。 In the production of the pharmaceutical composition of the present invention, granulation, mixing, tableting, and coating are performed by the principle and apparatus described in I-2 above.
　本発明の医薬組成物は、骨代謝回転を抑制して骨密度および骨強度を改善することにより治療または予防し得る疾患または症状（例えば骨粗鬆症）の治療または予防に有用である。 The pharmaceutical composition of the present invention is useful for treating or preventing a disease or symptom (for example, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.
　本発明において、疾患または症状の治療または予防には、該疾患の発症の予防、増悪または進行の抑制または阻害、該疾患に罹患した個体が呈する一つ以上の症状の軽減または増悪もしくは進行の抑制、二次性疾患の治療または予防などが含まれる。 In the present invention, the treatment or prevention of a disease or symptom includes prevention of onset of the disease, suppression or inhibition of progression or progression, reduction of one or more symptoms exhibited by an individual suffering from the disease, or suppression of progression or progression. , Treatment or prevention of secondary diseases and the like.
　本発明の医薬組成物が投与される対象は哺乳動物である。哺乳動物は、好ましくはヒトである。 The subject to which the pharmaceutical composition of the present invention is administered is a mammal. The mammal is preferably a human.
　本発明の医薬組成物は、治療または予防に有効な量で対象に投与される。「治療または予防に有効な量」とは、特定の疾患、投与形態および投与経路につき治療または予防効果を奏する量を意味し、対象の種、疾患の種類、症状、性別、年齢、持病、その他の要素に応じて適宜決定される。投与経路は、通常は経口投与である。 The pharmaceutical composition of the present invention is administered to a subject in an amount effective for treatment or prevention. “Amount effective for treatment or prevention” means an amount that exhibits a therapeutic or prophylactic effect for a specific disease, administration form, and administration route. The species, type of disease, symptom, sex, age, chronic disease, etc. It is determined appropriately according to the factors. The route of administration is usually oral.
　本発明の医薬組成物の投与量は、対象の種、疾患の種類、症状、性別、年齢、持病、その他の要素に応じて適宜決定され、ヒトの成人に対しては、通常、ＥＤ－７１として１日あたり０．０１～１０μｇ、好適には０．５～０．７５μｇを投与することができる。  The dosage of the pharmaceutical composition of the present invention is appropriately determined according to the species of the subject, the type of disease, symptoms, sex, age, disease, and other factors, and is usually ED-71 for human adults. 0.01 to 10 μg per day, preferably 0.5 to 0.75 μg can be administered.
　また本発明は、本発明の医薬組成物の治療または予防有効量を、それを必要とする対象に投与することを含む、疾患または症状の治療または予防のための方法に関する。 The present invention also relates to a method for the treatment or prevention of a disease or symptom comprising administering to a subject in need thereof a therapeutic or prophylactically effective amount of the pharmaceutical composition of the present invention.
　本発明における「治療または予防有効量」とは、特定の疾患または症状、投与形態および投与経路につき治療または予防効果を奏する量を意味し、対象の種、疾患または症状の種類、症状、性別、年齢、持病、その他の要素に応じて適宜決定される。 The “therapeutically or prophylactically effective amount” in the present invention means an amount having a therapeutic or prophylactic effect for a specific disease or symptom, administration form and administration route, and includes the species of the subject, the type of disease or symptom, symptom, sex, It is determined as appropriate according to age, chronic illness, and other factors.
　本発明における「対象」は、例えば、哺乳動物であり、好ましくはヒトである。 The “subject” in the present invention is, for example, a mammal, preferably a human.
　本発明における「投与すること」は、通常、経口投与を意味する。 “Administering” in the present invention usually means oral administration.
　本発明における「疾患または症状」としては、骨代謝回転を抑制して骨密度および骨強度を改善することにより治療または予防し得る疾患または症状（例えば骨粗鬆症）が挙げられる。 The “disease or symptom” in the present invention includes a disease or symptom (for example, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.
ＩＩ－２．ＥＤ－７１の分解を抑制する方法
　本発明はさらに、ＥＤ－７１の油脂溶液と水溶性高分子の水溶液とからなる水中油型乳化液を調製する工程を含み、ここで前記水溶性高分子は、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される、ＥＤ－７１の分解を抑制する方法を提供する。 II-2. Method for inhibiting decomposition of ED-71 The present invention further comprises a step of preparing an oil-in-water emulsion comprising an oil / fat solution of ED-71 and an aqueous solution of a water-soluble polymer, wherein the water-soluble polymer is A method for inhibiting the degradation of ED-71, selected from hydroxypropylmethylcellulose and hydroxypropylcellulose.
　本発明におけるＥＤ－７１の油脂溶液と水溶性高分子の水溶液とからなる水中油型乳化液を調製する工程は、上記ＩＩ－１に記載のＥＤ－７１を含む医薬組成物の製造方法における工程（ｉ）と同一である。ＥＤ－７１の油脂溶液は、水中油型乳化液中で水溶性高分子に覆われた状態となっていると考えられる。本方法は、油脂溶液中のＥＤ－７１の安定性を低下させることなく、ＥＤ－７１の油分分散体やそれを用いた医薬組成物を製造することが可能となる点で有用である。 The step of preparing an oil-in-water emulsion comprising an ED-71 oil / fat solution and an aqueous solution of a water-soluble polymer in the present invention is a step in the method for producing a pharmaceutical composition containing ED-71 described in II-1 above. Same as (i). The oil / fat solution of ED-71 is considered to be covered with a water-soluble polymer in an oil-in-water emulsion. This method is useful in that an oil dispersion of ED-71 and a pharmaceutical composition using the same can be produced without reducing the stability of ED-71 in the oil / fat solution.
　なお、本明細書において引用された全ての先行技術文献は、参照により本明細書に組み入れられる。 It should be noted that all prior art documents cited in the present specification are incorporated herein by reference.
　本発明を実施例によりさらに詳しく説明する。 The present invention will be described in more detail with reference to examples.
　本実施例では、以下の略号を用いる。
EtOH：エタノール
HPMC：ヒドロキシプロピルメチルセルロース
THF：テトラヒドロフラン
BHT：ジブチルヒドロキシトルエン
MCT：中鎖脂肪酸トリグリセリド
HPC：ヒドロキシプロピルセルロース
PVP：ポリビニルピロリドン
PVA copolymer：ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体 In this example, the following abbreviations are used.
EtOH: ethanol
HPMC: Hydroxypropyl methylcellulose
THF: tetrahydrofuran
BHT: Dibutylhydroxytoluene
MCT: Medium chain fatty acid triglyceride
HPC: Hydroxypropyl cellulose
PVP: Polyvinylpyrrolidone
PVA copolymer: Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer
　Ａ．固体分散体
　参考例A1～A3
　ED-71をEtOH（エタノール（９９．５）試薬特級、今津薬品工業）に溶解させて、EtOH溶液(0.1 mg/mL)を調製した。これをガラスチューブに100μL分注し、溶媒を減圧下にて留去し、乾燥させたED-71を得た。これを、単独で(対照例A1)、または脱酸素剤(ファーマキープKD-20、三菱ガス化学)存在下(参考例A1)、吸湿剤(シリカゲル（中粒状（青色）、和光純薬工業製）存在下(参考例A2)、もしくは脱酸素剤および吸湿剤存在下(参考例A3)の条件にて、大気存在下でアルミパウチ（ラミジップ、アズワン）に入れて遮光し、60℃に調整した恒温槽内に保存し、7日後および14日後にED-71の残存率（%）を調べた。 A. Solid dispersion Reference examples A1 to A3
ED-71 was dissolved in EtOH (ethanol (99.5) reagent special grade, Imazu Pharmaceutical Co., Ltd.) to prepare an EtOH solution (0.1 mg / mL). 100 μL of this was dispensed into a glass tube, and the solvent was distilled off under reduced pressure to obtain dried ED-71. This alone (control example A1) or in the presence of an oxygen scavenger (Pharmace Keep KD-20, Mitsubishi Gas Chemical) (reference example A1), a hygroscopic agent (silica gel (medium granular (blue), manufactured by Wako Pure Chemical Industries, Ltd.) ) In the presence of air (Reference Example A2) or in the presence of an oxygen scavenger and hygroscopic agent (Reference Example A3), put in an aluminum pouch (Lami Zip, ASONE) in the presence of air and shield from light, and adjust to 60 ° C It preserve | saved in the thermostat and the residual rate (%) of ED-71 was investigated after 7 days and 14 days.
　ED-71の残存率は、以下の方法により測定した。 The residual ratio of ED-71 was measured by the following method.
　ED-71の入った上記ガラスチューブにEtOH 100μLおよびアセトニトリル400μLを分注し、ピペッティングにて撹拌を行ったものをサンプル溶液とした。別途、サンプル調製に用いたED-71 EtOH溶液(0.1 mg/mL)100μLを空のガラスチューブに分注し、アセトニトリル400μLを加え、ピペッティングにて撹拌を行ったものを標準溶液とした。サンプル溶液及び標準溶液を高速液体クロマトグラフィー法（Waters製Alliance、測定波長265nm）で測定し、サンプル溶液のED-71ピーク面積およびpre ED-71のピーク面積を求めた。 A sample solution was prepared by dispensing 100 μL of EtOH and 400 μL of acetonitrile into the glass tube containing ED-71 and stirring by pipetting. Separately, 100 μL of ED-71 EtOH solution (0.1 mg / mL) used for sample preparation was dispensed into an empty glass tube, 400 μL of acetonitrile was added, and the mixture was stirred by pipetting was used as a standard solution. The sample solution and the standard solution were measured by high performance liquid chromatography (Waters Alliance, measurement wavelength 265 nm), and the ED-71 peak area and the pre-ED-71 peak area of the sample solution were determined.
　以下の計算式によりED-71の残存率を求めた。
ED-71の残存率(%)＝加速サンプル溶液中のED-71ピーク面積合計／未加速サンプル溶液中のED-71ピーク面積合計
（ED-71ピーク面積合計＝ED-71ピーク面積＋1.98×pre ED-71のピーク面積） The residual ratio of ED-71 was obtained by the following calculation formula.
ED-71 residual rate (%) = total ED-71 peak area in the accelerated sample solution / total ED-71 peak area in the unaccelerated sample solution (ED-71 peak area total = ED-71 peak area + 1.98) X Pre ED-71 peak area)
　結果を第A1表に示す。第A1表より、ED-71の分解の原因は酸素であり、ED-71が脱酸素剤存在下にて安定化することが示された。 The results are shown in Table A1. From Table A1, it was shown that the cause of ED-71 decomposition was oxygen, and ED-71 was stabilized in the presence of an oxygen scavenger.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　実施例A1
　15 mgのED-71を100 mLのEtOH（HPLCグレード、和光純薬工業）に溶解させた。水溶性高分子であるHPMC（ＴＣ－５Ｒ、信越化学工業）を試料容器に375 mg秤量し、10 mLの70v/v% EtOH（水とEtOHを容積比30:70で混合したもの）に溶解させて、添加剤溶液を調製した。ED-71エタノール溶液20μLと添加剤溶液80μLとを1 mLガラスチューブ内で混合し、ついで溶媒を減圧下にて留去し、乾燥して実施例A1の組成物を得た。本組成物をチューブごと96穴チューブ立てに並べ、大気存在下でアルミパウチに入れて遮光し、60℃に調整した恒温槽内に保存し、7日後および14日後にED-71の残存率を調べた。 Example A1
15 mg ED-71 was dissolved in 100 mL EtOH (HPLC grade, Wako Pure Chemical Industries). Weigh 375 mg of water-soluble polymer HPMC (TC-5R, Shin-Etsu Chemical Co., Ltd.) in a sample container and dissolve in 10 mL of 70v / v% EtOH (mixed water and EtOH at a volume ratio of 30:70). To prepare an additive solution. 20 μL of ED-71 ethanol solution and 80 μL of additive solution were mixed in a 1 mL glass tube, and then the solvent was distilled off under reduced pressure and dried to obtain the composition of Example A1. This composition is placed in a 96-well tube stand together with the tube, placed in an aluminum pouch in the presence of air, shielded from light, and stored in a thermostatic chamber adjusted to 60 ° C. After 7 days and 14 days, the residual ratio of ED-71 Examined.
　添加剤溶液の代わりに70v/v% EtOHを用いたこと以外は実施例A1と同様にして対照例A2を調製し、実施例A1と同様にしてED-71の残存率を調べた。 Control Example A2 was prepared in the same manner as in Example A1 except that 70 v / v% EtOH was used instead of the additive solution, and the residual ratio of ED-71 was examined in the same manner as in Example A1.
　結果を第A2表に示す。第A2表より明らかな通り、ED-71は、高温条件下では、単独の場合よりもHPMCの存在下においてより安定であった。 The results are shown in Table A2. As is apparent from Table A2, ED-71 was more stable in the presence of HPMC under high temperature conditions than it did alone.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　実施例A2～A6
　実施例A1のHPMCの代わりに第A3表に記載の水溶性高分子を用いて、実施例A1と同様の方法でED-71組成物を製し、実施例A1と同様に60℃における安定性を調べ、対照例A2と比較した。結果を第A3表に示す。実施例A2～A6の組成物はいずれも対照例A2よりも高温条件下で安定であることが示された。 Examples A2 to A6
Using the water-soluble polymer described in Table A3 instead of HPMC of Example A1, an ED-71 composition was produced in the same manner as in Example A1, and stability at 60 ° C. was obtained as in Example A1. And compared with Control A2. The results are shown in Table A3. All of the compositions of Examples A2 to A6 were shown to be more stable under higher temperature conditions than Control A2.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　実施例A7～A19
　実施例A1の70v/v% EtOHの代わりにEtOHを、またHPMCの代わりに第A4表に示した水溶性高分子を用いて、実施例A1と同様の方法で実施例A7～A19のED-71組成物を得た。また対照例A2と同様にして、水溶性高分子を含まない対照例A3を調製した。これらの試料中のED-71の60℃における安定性を実施例A1と同様に調べた。結果を第A4表に示す。実施例A7～A19の組成物はいずれも対照よりも高温条件下で安定であることが示された。 Examples A7 to A19
In the same manner as in Example A1, except that EtOH was used instead of 70 v / v% EtOH of Example A1 and water-soluble polymers shown in Table A4 were used instead of HPMC, the ED- of Examples A7 to A19 71 compositions were obtained. In the same manner as in Control A2, Control A3 containing no water-soluble polymer was prepared. The stability of ED-71 in these samples at 60 ° C. was examined in the same manner as in Example A1. The results are shown in Table A4. All of the compositions of Examples A7 to A19 were shown to be more stable under higher temperature conditions than the control.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　実施例A20～A28
　実施例A1の70v/v% EtOHの代わりに50v/v% EtOH（水とEtOHを容積比５０：５０で混ぜたもの）を、またHPMCの代わりに第A5表に示した水溶性高分子を用いて、実施例A1と同様の方法で実施例A20～A28のED-71組成物を得た。また対照例A2と同様にして、水溶性高分子を含まない対照例A4を調製した。これらの試料中のED-71の60℃における安定性を実施例A1と同様に調べた。結果を第A5表に示す。実施例A7～A19の組成物はいずれも対照よりも高温条件下で安定であることが示された。 Examples A20 to A28
Instead of 70 v / v% EtOH of Example A1, 50 v / v% EtOH (mixed water and EtOH at a volume ratio of 50:50) and water-soluble polymer shown in Table A5 instead of HPMC were used. The ED-71 compositions of Examples A20 to A28 were obtained in the same manner as in Example A1. In the same manner as in Control A2, Control A4 containing no water-soluble polymer was prepared. The stability of ED-71 in these samples at 60 ° C. was examined in the same manner as in Example A1. The results are shown in Table A5. All of the compositions of Examples A7 to A19 were shown to be more stable under higher temperature conditions than the control.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
　実施例A29
　実施例A1の70v/v% EtOHの代わりにTHF（HPLCグレード、和光純薬工業）を、またHPMCの代わりにレシチン粉末（化学用、ナカライテスク）を用いて、実施例A1と同様の方法で実施例A29のED-71組成物を得た。また対照例A2と同様にして、水溶性高分子を含まない対照例A5を調製した。これらの試料中のED-71の60℃における安定性を実施例A1と同様に調べた。結果を第A6表に示す。実施例A29の組成物は対照よりも高温条件下で安定であることが示された。 Example A29
In the same manner as in Example A1, using THF (HPLC grade, Wako Pure Chemical Industries) instead of 70v / v% EtOH of Example A1 and using lecithin powder (chemical, Nacalai Tesque) instead of HPMC The ED-71 composition of Example A29 was obtained. In the same manner as in Control A2, Control A5 containing no water-soluble polymer was prepared. The stability of ED-71 in these samples at 60 ° C. was examined in the same manner as in Example A1. The results are shown in Table A6. The composition of Example A29 was shown to be more stable under higher temperature conditions than the control.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　実施例A30およびA31
　実施例A1のHPMCの代わりに第A7表に示した塩基性化合物を用いて、実施例A1と同様の方法で実施例A30およびA31のED-71組成物を得た。調製したED-71組成物の60℃における安定性を実施例A1と同様に調べ、対照例A2と比較した。結果を第A7表に示す。実施例A30およびA31の組成物はいずれも対照よりも高温条件下で安定であることが示された。 Examples A30 and A31
ED-71 compositions of Examples A30 and A31 were obtained in the same manner as in Example A1, using the basic compounds shown in Table A7 instead of HPMC of Example A1. The stability of the prepared ED-71 composition at 60 ° C. was examined in the same manner as in Example A1, and compared with Control A2. The results are shown in Table A7. The compositions of Examples A30 and A31 were both shown to be more stable under higher temperature conditions than the control.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　実施例A32
　実施例A1の70v/v% EtOHの代わりに50v/v% EtOHを、またHPMCの代わりに塩基性化合物としてピロリン酸四カリウム（食添グレード、太平化学産業）を用いて、実施例A1と同様の方法で実施例A32のED-71組成物を得た。調製したED-71組成物の60℃における安定性を実施例A1と同様に調べ、対照例A4と比較した。結果を第A8表に示す。実施例A32の組成物は対照よりも高温条件下で安定であることが示された。 Example A32
Same as Example A1 using 50 v / v% EtOH instead of 70 v / v% EtOH of Example A1, and tetrapotassium pyrophosphate (food additive grade, Taihei Chemical Industry) as the basic compound instead of HPMC Thus, an ED-71 composition of Example A32 was obtained. The stability of the prepared ED-71 composition at 60 ° C. was examined in the same manner as in Example A1, and compared with Control A4. The results are shown in Table A8. The composition of Example A32 was shown to be more stable under higher temperature conditions than the control.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
実施例A33～A38
　15 mgのED-71を100 mLのEtOH（HPLCグレード、和光純薬工業）に溶解させED-71溶解EtOH溶液を調製した。水溶性高分子であるヒドロキシプロピルメチルセルロース（ＴＣ－５Ｒ、信越化学工業）、塩基性化合物であるメグルミン(Merck)をそれぞれ試料容器に750 mg秤量し、20 mLの70v/v% EtOH（水とEtOHを容積比30:70で混合したもの）に溶解させ、37.5 mg/mL～0.0375 mg/mLの濃度となるようそれぞれ希釈し、添加剤溶液を調製した。ED-71原薬量と添加剤量の比が第A9表となるようにED-71溶解EtOH溶液と添加剤溶液を遠沈管に分注し、ED-71溶解添加剤溶液を調製した。調製したED-71溶解添加剤溶液を、ED-71原薬量として3μgとなるようそれぞれ1 mLガラスチューブ内に分注し、ついで溶媒を減圧下にて留去し、真空乾燥して組成物を得た（実施例A33～A38）。本組成物をチューブごと96穴チューブ立てに並べ、大気存在下でアルミパウチに入れて遮光し、60℃に調整した恒温槽内に保存し、7日後にED-71の残存率を調べた。なお、以下の計算式によりED-71の残存率を求めた。
ED-71の残存率(%)＝加速サンプル中のED-71ピーク面積合計／未加速サンプル中のED-71ピーク面積合計（ED-71ピーク面積合計＝ED-71ピーク面積＋1.98×pre ED-71のピーク面積） Examples A33 to A38
15 mg of ED-71 was dissolved in 100 mL of EtOH (HPLC grade, Wako Pure Chemical Industries) to prepare an ED-71-dissolved EtOH solution. 750 mg of water-soluble polymer hydroxypropylmethylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.) and basic compound meglumine (Merck) were weighed in each sample container, and 20 mL of 70v / v% EtOH (water and EtOH) Were mixed in a volume ratio of 30:70) and diluted to a concentration of 37.5 mg / mL to 0.0375 mg / mL to prepare an additive solution. The ED-71-dissolved additive solution was prepared by dispensing the ED-71-dissolved EtOH solution and additive solution into the centrifuge tube so that the ratio of the ED-71 drug substance amount to the additive amount was as shown in Table A9. Dispense the prepared ED-71 dissolution additive solution into a 1 mL glass tube each to make the amount of ED-71 drug substance 3 μg, then distill off the solvent under reduced pressure and vacuum dry the composition. (Examples A33 to A38). The composition was placed in a 96-well tube stand together with the tube, placed in an aluminum pouch in the presence of air, shielded from light, and stored in a thermostatic chamber adjusted to 60 ° C., and the residual ratio of ED-71 was examined after 7 days. The residual ratio of ED-71 was determined by the following calculation formula.
ED-71 residual rate (%) = total ED-71 peak area in the accelerated sample / total ED-71 peak area in the unaccelerated sample (ED-71 peak area total = ED-71 peak area + 1.98 x pre (ED-71 peak area)
　また、添加剤溶液を用いずに調製したED-71溶解EtOH溶液を、ED-71原薬量として3μgとなるようそれぞれ1 mLガラスチューブ内に分注し、ついで溶媒を減圧下にて留去し、真空乾燥して組成物を調製し（対照例A6）、実施例A33～A38と同様にED-71の残存率を調べた。 Dispense the ED-71-dissolved EtOH solution prepared without using the additive solution into a 1 mL glass tube to make the amount of the ED-71 drug substance 3 μg each, and then distill off the solvent under reduced pressure. Then, the composition was prepared by vacuum drying (Control A6), and the residual ratio of ED-71 was examined in the same manner as in Examples A33 to A38.
　結果を第A10表に示す。第A10表より明らかな通り、ED-71は、高温条件下ではいずれの添加割合であっても、単独の場合よりもヒドロキシプロピルメチルセルロースまたはメグルミンとの共存下においてより安定であった。また添加剤の添加割合が高いほど、ED-71残存率が高くなる傾向が見られた。 The results are shown in Table A10. As is apparent from Table A10, ED-71 was more stable in the presence of hydroxypropylmethylcellulose or meglumine than it was alone, at any addition ratio under high temperature conditions. In addition, there was a tendency for the residual ratio of ED-71 to increase as the additive ratio increased.
　実施例A39～A41
　実施例A33～A38の70v/v% EtOHの代わりにEtOHを、またヒドロキシプロピルメチルセルロースまたはメグルミンの代わりに水溶性高分子であるポリビニルピロリドン（K-30、BASF）を添加剤として用いて、実施例A33～A38と同様の方法でED-71組成物を得た（実施例A39～A41）。これらの試料中のED-71の60℃における安定性を実施例A33～A38と同様に調べた。結果を第A11表に示す。ED-71は、高温条件下ではいずれの添加割合であっても、単独の場合よりもポリビニルピロリドンとの共存下においてより安定であった。また添加剤の添加割合が高いほど、ED-71残存率が高くなる傾向が見られた。 Examples A39 to A41
In Examples A33 to A38, EtOH was used instead of 70v / v% EtOH, and polyvinylpyrrolidone (K-30, BASF), which is a water-soluble polymer, was used as an additive instead of hydroxypropylmethylcellulose or meglumine. ED-71 compositions were obtained in the same manner as A33 to A38 (Examples A39 to A41). The stability of ED-71 in these samples at 60 ° C. was examined in the same manner as in Examples A33 to A38. The results are shown in Table A11. ED-71 was more stable in the coexistence with polyvinylpyrrolidone than in the case of ED-71 at any addition ratio under high temperature conditions. In addition, there was a tendency for the residual ratio of ED-71 to increase as the additive ratio increased.
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
　Ｂ．油分分散体
　実施例B1：配合変化１
　50 mgのED-71を2.5 mLのEtOHに溶解させED-71のエタノール溶解液を調製した。BHT（Ｍｅｒｃｋ）を1 g、およびdl-α-tocopherol（特殊用、和光純薬工業）を2 g、97 gのMCT（Ｏ．Ｄ．Ｏ．Ｃ、日清オイリオ）中に溶解させMCT液を調製した。調製したMCT液にED-71のエタノール溶解液を0.5 mL加え、ボルテックスミキサーで撹拌した。さらに減圧下にて留去し、ED-71油脂溶液を調製した。調製したED-71油脂溶液150 mgにヒドロキシプロピルメチルセルロースを300 mg加え、ED-71組成物（実施例B1）を調製した。調製したED-71組成物を60℃に調整した恒温槽内に大気存在下で保存し、14日後および28日後にED-71の残存率（%）を調べた。 B. Oil dispersion Example B1: Formulation change 1
50 mg of ED-71 was dissolved in 2.5 mL of EtOH to prepare an ethanol solution of ED-71. Dissolve BHT (Merck) in 1 g and dl-α-tocopherol (special purpose, Wako Pure Chemical Industries) in 2 g, 97 g of MCT (ODOC, Nisshin Oilio). Was prepared. 0.5 mL of an ethanol solution of ED-71 was added to the prepared MCT solution, and the mixture was stirred with a vortex mixer. Further, it was distilled off under reduced pressure to prepare an ED-71 oil / fat solution. To 150 mg of the prepared ED-71 oil / fat solution, 300 mg of hydroxypropylmethylcellulose was added to prepare an ED-71 composition (Example B1). The prepared ED-71 composition was stored in a thermostat adjusted to 60 ° C. in the presence of air, and the residual ratio (%) of ED-71 was examined after 14 and 28 days.
　対照物としては上記のED-71油脂溶液単独（対照例B1）を用いた。 As the control, the above ED-71 oil / fat solution alone (control example B1) was used.
　また実施例B1のヒドロキシプロピルメチルセルロースの代わりに第B1表に記載した添加剤（300 mg）を用いて、実施例B1と同様の方法でED-71組成物を製し、60℃における安定性を実施例B1と同様に調べた。 Further, using the additive (300 mg) described in Table B1 instead of the hydroxypropylmethylcellulose of Example B1, an ED-71 composition was produced in the same manner as in Example B1, and the stability at 60 ° C. was improved. The examination was performed in the same manner as in Example B1.
　結果を第B1表に示す。第B1表より明らかな通り、実施例B1の組成物は対照例B1の油脂液単独と同等またはそれ以上に安定であり、また対照例B2～B34の組成物よりも高温条件下では安定であった。 The results are shown in Table B1. As is apparent from Table B1, the composition of Example B1 is as stable as or higher than the fat solution of Control B1 alone, and more stable at higher temperatures than the compositions of Controls B2-B34. It was.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
　実施例B2：配合変化２
　実施例B1のヒドロキシプロピルメチルセルロースの代わりに第B2表に記載した添加剤を用いて、実施例B1と同様の方法で実施例B2および対照例B35のED-71組成物を製し、60℃における安定性を実施例B1と同様に調べ、対照例B1と比較した。結果を第B2表に示す。実施例B2の組成物は対照例B1と同等又はそれ以上に安定であり、また第B1表に示した対照例B2～B34の組成物よりも高温条件下では安定であることが示された。なお、対照例B35の組成物ではED-71の安定性の低下は見られなかったものの、メグルミンを添加剤として使用した場合には後述する油分分散体錠剤の製造過程において必要となる乳化状態を維持することができないなどの理由から、メグルミンは油分分散体錠剤の製造のための添加剤には適さないことが判明した。 Example B2: Mixture change 2
Using the additives described in Table B2 in place of the hydroxypropylmethylcellulose of Example B1, the ED-71 compositions of Example B2 and Control B35 were prepared in the same manner as in Example B1, and at 60 ° C. Stability was examined as in Example B1 and compared to Control B1. The results are shown in Table B2. The composition of Example B2 was shown to be as stable or better than Control B1 and more stable under high temperature conditions than the compositions of Controls B2-B34 shown in Table B1. Although the stability of ED-71 was not decreased in the composition of Comparative Example B35, when meglumine was used as an additive, the emulsified state required in the oil dispersion tablet manufacturing process described later was obtained. It has been found that meglumine is not suitable as an additive for the production of oil dispersion tablets, for example because it cannot be maintained.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
　［試験例］エマルション安定化試験
　後述するように、油分分散体錠剤の製造過程においてはED-71のMCT溶液と水溶性高分子の水溶液との乳化状態を維持する必要がある。そこで、MCTと水溶性高分子との乳化液を調製し、乳化状態を調べた。 [Test Example] Emulsion Stabilization Test As described later, it is necessary to maintain the emulsified state of the MCT solution of ED-71 and the aqueous solution of the water-soluble polymer in the production process of the oil dispersion tablet. Therefore, an emulsion of MCT and water-soluble polymer was prepared and the emulsified state was examined.
　HPMC（TC-5R、信越化学）、HPC（SSL、信越化学）、PVP（K90、ＢＡＳＦ）、POVA-COAT（F、大同化成工業製）を精製水に溶解し、それぞれ2%および5%の水溶液を調製した。各液20 mLをプラスチック製の50 mL遠沈管にそれぞれ加えた。そこにオイルレッド（オイルレッドＯ、ナカライテスク）を0.1 g/Lで溶解し赤色に着色した中鎖脂肪酸トリグリセリドを各10 mL加えた。 Dissolve HPMC (TC-5R, Shin-Etsu Chemical), HPC (SSL, Shin-Etsu Chemical), PVP (K90, BASF), POVA-COAT (F, manufactured by Daido Kasei Kogyo) in purified water, 2% and 5% respectively. An aqueous solution was prepared. 20 mL of each solution was added to a 50 mL centrifuge tube made of plastic. Thereto was added 10 mL each of medium-chain fatty acid triglycerides dissolved in red at a rate of 0.1 g / L of oil red (Oil Red O, Nacalai Tesque).
　ホモジナイザーにて約10,000 rpmで1分間撹拌して乳化させた後、2時間後および24時間後の乳化液の上部への油層の分離の有無を判定した。 After stirring and emulsifying at about 10,000 rpm for 1 minute with a homogenizer, the presence or absence of separation of the oil layer on the top of the emulsion after 2 hours and 24 hours was determined.
　結果を第B3表に示す。また水溶性高分子の2%水溶液を用いた場合の24時間後の遠沈管内の乳化状態（写真）を図２に示す。HPMC、HPC、およびPVA copolymerでは水層と油層との分離が生じなかったのに対して、PVPでは分離が生じた。 The results are shown in Table B3. FIG. 2 shows the emulsified state (photo) in the centrifuge tube after 24 hours when a 2% aqueous solution of a water-soluble polymer was used. HPMC, HPC, and PVA-copolymer did not cause separation of the water and oil layers, whereas PVP caused separation.
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
　実施例B3～B11：エマルション調製時におけるED-71の安定性
　100 mgのED-71を5.0 mLのEtOHに溶解させED-71のエタノール溶解液を調製した。BHT（Merck）を1 g、およびdl-α-tocopherol（特殊用、和光純薬工業）を2 g、97 gのMCT（Ｏ．Ｄ．Ｏ．Ｃ、日清オイリオ）中に溶解させMCT液を調製した。調製したMCT液にED-71のエタノール溶解液を0.5 mL加え、ボルテックスミキサーで撹拌し、ED-71溶解MCT液とした。第B4表に示した水溶性高分子溶液をそれぞれ調製した。第B5表に記載の割合でED-71溶解MCT液および水溶性高分子溶液を混合し、ホモジナイザーを用いて5400rpmで1分間撹拌して乳化させ、ED-71含有エマルションを調製した。調製したED-71含有エマルションをED-71原薬量としておよそ1μgとなるように秤取し、真空乾燥機にて減圧留去し、得られたサンプルを残存率測定に用いた（実施例B3～B11）。サンプルを60℃に調整した恒温槽内に大気存在下で保存し、調製直後のED-71含量値、14日後および25日後のED-71の含量値および残存率（%）を調べた。なお、各含量値はED-71溶解MCT液をED-71原薬量としておよそ1μgとなるように秤取し、真空乾燥機にて減圧留去したサンプルを標準品として算出した。ED-71の含量値および残存率は、以下の計算式によりを求めた。
ED-71の含量値(%)＝サンプル中のED-71ピーク面積合計／標準品中のED-71ピーク面積合計（ED-71ピーク面積合計＝ED-71ピーク面積＋1.98×pre ED-71のピーク面積）
ED-71の残存率(%)＝加速サンプルの含量値平均／調製直後のサンプルの含量値平均 Examples B3 to B11: Stability of ED-71 during preparation of emulsion 100 mg of ED-71 was dissolved in 5.0 mL of EtOH to prepare an ethanol solution of ED-71. Dissolve BHT (Merck) in 1 g and dl-α-tocopherol (special purpose, Wako Pure Chemical Industries) in 2 g, 97 g of MCT (ODOC, Nisshin Oilio). Was prepared. To the prepared MCT solution, 0.5 mL of an ED-71 ethanol solution was added and stirred with a vortex mixer to obtain an ED-71-dissolved MCT solution. Water-soluble polymer solutions shown in Table B4 were prepared. The ED-71-dissolved MCT solution and the water-soluble polymer solution were mixed at the ratio shown in Table B5 and emulsified by stirring at 5400 rpm for 1 minute using a homogenizer to prepare an ED-71-containing emulsion. The prepared ED-71-containing emulsion was weighed so that the amount of ED-71 drug substance was about 1 μg, and distilled off under reduced pressure with a vacuum dryer, and the obtained sample was used for residual rate measurement (Example B3 ~ B11). The sample was stored in a thermostat adjusted to 60 ° C. in the presence of air, and the ED-71 content value immediately after preparation, the content value of ED-71 after 14 days and 25 days, and the residual rate (%) were examined. In addition, each content value was calculated so that the sample which weighed ED-71 melt | dissolution MCT liquid so that it might become about 1 microgram as ED-71 drug substance amount, and was depressurizingly distilled with the vacuum dryer was used as a standard product. The content value and the residual rate of ED-71 were obtained by the following calculation formula.
ED-71 content value (%) = total ED-71 peak area in the sample / total ED-71 peak area in the standard product (ED-71 peak area total = ED-71 peak area + 1.98 x pre ED- 71 peak area)
ED-71 residual rate (%) = average content of accelerated samples / average content of samples immediately after preparation
　結果を第B5表に示す。第B5表より分かる通り、水溶性高分子の濃度が低い処方(1%)ではED-71の含量値のバラつきが大きいことが分かった。これは、水溶性高分子の濃度が低い処方では調製後エマルションの分離が見られ、サンプリングしたエマルション中のED-71の秤取量にバラつきが見られたことが原因であると考えられる。水溶性高分子の濃度が5%または6%のサンプルでは結果のバラつきが小さく、かつ25日後のED-71残存率はいずれも95%以上を示した。水溶性高分子の濃度が高い処方(10%または15%)ではバラつきは小さいものの25日後のサンプルでは90%前後までED-71残存率が低下した。 The results are shown in Table B5. As can be seen from Table B5, it was found that the ED-71 content value varied greatly in the formulation with a low concentration of water-soluble polymer (1%). This is thought to be due to the fact that the pre-preparation emulsion was separated in the formulation with a low concentration of water-soluble polymer, and that the ED-71 weighed in the sampled emulsion was uneven. Samples with a water-soluble polymer concentration of 5% or 6% showed little variation, and the residual ratio of ED-71 after 25 days was 95% or more. The formulation with a high concentration of water-soluble polymer (10% or 15%) showed little variation, but the ED-71 residual rate decreased to around 90% in the sample after 25 days.
　1%～15%のHPMCまたはHPCを含有する水溶性高分子溶液の濃度としては、5～6%がED-71のエマルション中での安定化のためには好ましい。 The concentration of the water-soluble polymer solution containing 1% to 15% HPMC or HPC is preferably 5 to 6% for stabilization in the ED-71 emulsion.
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
　［製造例］油分分散体錠剤
　dl-α-トコフェロール（和光純薬工業）0.142 kgおよびBHT（Merck） 0.284 kgをMCT（日清オイリオ） 9.025 kgに溶解し、ここにエルデカルシトール（ＥＤ－７１） 1.1813 gをエタノール（99.5%）（今津薬品工業）（0.078kg）溶液を加えたのち、エタノールを減圧下留去した（溶液１）。 [Production Example] Oil dispersion tablet dl-α-tocopherol (Wako Pure Chemical Industries) 0.142 kg and BHT (Merck) 0.284 kg were dissolved in MCT (Nisshin Oilio) 9.025 kg, where eldecalcitol (ED-71 After adding 1.1813 g of ethanol (99.5%) (Imazu Pharmaceutical Co., Ltd.) (0.078 kg) solution, ethanol was distilled off under reduced pressure (Solution 1).
　ヒプロメロース（HPMC）（ＴＣ－５Ｒ、信越化学工業）1.134 kgを精製水 17.766 kgに溶解させた（溶液２）。 1.134 kg of hypromellose (HPMC) (TC-5R, Shin-Etsu Chemical Co., Ltd.) was dissolved in 17.766 kg of purified water tank (solution 2).
　３ｋｇの溶液１に６ｋｇの溶液２を加え、ホモジナイザー（IKA製T-50 Ultra Turrax；回転数9,600 rpm）で10分間撹拌した。この操作を３回繰り返して乳化液を得た。 6 kg of solution 2 was added to 3 kg of solution 1 and stirred for 10 minutes with a homogenizer (IKA T-50 UltraATurrax; rotation speed 9,600 rpm). This operation was repeated 3 times to obtain an emulsion.
　目開き850μmの振動篩で篩過したマンニトール（Merck）165.6kgを高速撹拌造粒機（POWREX製VG-600CT）中、ブレード56 rpm，クロススクリュー1500 rpmの条件で撹拌しながら、乳化液を噴霧添加し、15分間練合し、造粒末を得た。 Emulsified liquid is sprayed while stirring 165.6 kg of mannitol (Merck) sieved with a vibrating sieve with an opening of 850 μm in a high-speed stirring granulator (VG-600CT made by POWREX) under the conditions of blade 56 rpm and cross screw 1500 rpm. The mixture was added and kneaded for 15 minutes to obtain a granulated powder.
　得られた造粒末を、9.5 mm（角穴）のスクリーンがセットされた湿式整粒機（POWREX製U-20）を300 rpmで運転しながら篩過しつつ、流動層造粒乾燥機（POWREX製WSG-200pro）に移し、乾燥した。 The obtained granulated powder is sieved while operating a wet granulator (UWR made by POWREX) with a 9.5 mm (square hole) screen at 300 mm rpm. Transfer to POWREX WSG-200pro) and dry.
　乾燥された造粒末に対し、直径2 mmのスクリーンがセットされた乾式整粒機（POWREX製U-20）を800 rpmで運転し、整粒した。 The dried granulated powder was sized by operating a dry granulator (POWREX U-20) set with a 2 mm diameter screen at 800 mm rpm.
　整粒品は、それぞれ目開き850μmの篩で篩過したマンニトール3.0 kgおよびクロスカルメロースナトリウム（DFE pharma）3.6 kgの混合物と15分間混合し、さらに、それぞれ目開き850μmの篩で篩過したマンニトール6.6 kgおよびステアリン酸カルシウム（Merck）0.72 kgの混合物と3分間混合後、約7.5 kNの圧力で、打錠機（IMA製COMPRIMA）にて打錠して錠剤とした。打錠の際、１錠当たりのエルデカルシトール含量が、0.75μgとなるように錠剤重量を調整した。 The sized product was mixed with a mixture of mannitol (3.0 お よ び kg) and croscarmellose sodium (DFE pharma) (3.6 kg) that had been sieved with a sieve having an opening of 850μm for 15 minutes. After mixing with a mixture of 6.6 kg and calcium stearate (Merck) 0.72 kg for 3 minutes, the mixture was tableted with a tableting machine (COMPRIMA manufactured by IMA) at a pressure of about 7.5 kgk to obtain tablets. During tableting, the tablet weight was adjusted so that the content of eldecalcitol per tablet was 0.75 μg.
　得られた錠剤全てをコーティング機（パウレック製PRC-450）内に投入し、60℃にて、HPMC 6.480 kgの水（74.520 kg）溶液を噴霧して乾燥し、さらに、ヒプロメロース4.950 kg、タルク（Merck）1.350 kg、酸化チタン（石原産業）2.664 kg、および三二酸化鉄（癸巳化成）0.036 kgの水（65.167 kg）懸濁液を噴霧して乾燥し、２層のフィルムでコーティングされた錠剤を得た（１錠当たりのエルデカルシトール含量は0.75μg）。 All the obtained tablets were put into a coating machine (PRC-450 manufactured by POWREC), and dried at 60 ° C by spraying a solution of HPMC (6.480 kg) with water (74.520 kg), and further, 4.950 kg of hypromellose, talc ( Merck) 1.350 kg, titanium oxide (Ishihara Sangyo) 2.664 kg, and iron sesquioxide (癸巳 化成) 0.036 kg water (65.167 kg) suspension is spray-dried and the tablets coated with two layers of film Obtained (Eldecalcitol content per tablet was 0.75 μg).
　なお、１錠当たりのエルデカルシトール含量が0.5μgの錠剤を調製する際は、２層目はヒプロメロース4.950 kg、タルク（Merck）1.350 kg、酸化チタン（石原産業）2.502 kg、三二酸化鉄（癸巳化成）0.018 kgおよび黄色三二酸化鉄（癸巳化成）0.180 kgの水（65.167 kg）懸濁液を噴霧してコーティングした。 When preparing tablets with an eldecalcitol content of 0.5 μg per tablet, the second layer is 4.950 kg of hypromellose, 1.350 kg of talc, 2.502 kg of titanium oxide (Ishihara Sangyo), iron sesquioxide (二 酸化Chemical conversion) 0.018 kg and yellow iron sesquioxide (Chemical conversion) 0.180 kg water (65.167 kg) were spray coated.
　製造フロー概略図を図１に示す。 A schematic diagram of the manufacturing flow is shown in FIG.
　［試験例］加速安定性試験
　『［製造例］油分分散体錠剤』で得られた錠剤（１錠当たりのエルデカルシトール含量が0.5μg及び0.75μgの2種類）を高密度ポリエチレンボトル容器（NC-130、伸晃化学）に500錠ずつ投入した。ポリプロピレンキャップ（SK-200B、伸晃化学）でボトルを閉栓し、40℃/75%RHに調整した恒温槽内に保存し、１箇月後、３箇月後、および６箇月後にED-71の残存率を調べた。 [Test example] Accelerated stability test [Manufacturing example] Tablets obtained by "Oil dispersion tablet" (eldecalcitol content of 0.5μg and 0.75μg per tablet) were placed in high-density polyethylene bottle containers (NC -130, Shingo Chemical Co., Ltd.) were added 500 tablets each. The bottle is closed with a polypropylene cap (SK-200B, Shingo Chemical) and stored in a thermostatic chamber adjusted to 40 ° C / 75% RH, and the residual rate of ED-71 after 1, 3 and 6 months I investigated.
　ED-71の残存率は、以下の方法により測定した。 The residual ratio of ED-71 was measured by the following method.
　錠剤5錠を30mL遠沈管に投入した。水：アセトニトリル（２０：８０）を7mL加えて30分間超音波照射した。超音波照射中は10分毎に1回撹拌を行った。上澄みを孔径0.20μmのポリテトラフルオロエチレン（ＰＴＦＥ）フィルターでろ過し、最初の約1mLを廃棄し、残りのろ液をサンプル溶液とした。別途、ED-71標準品を用いて約0.6μg/mLの濃度となるように水：アセトニトリル（２０：８０）で溶解し、サンプル溶液の調製と同様の方法で標準溶液を調製した。サンプル溶液及び標準溶液を高速液体クロマトグラフィー法（Waters製Alliance、測定波長265nm）で測定し、サンプル中のED-71含有量を定量した。 5 tablets were put into a 30 mL centrifuge tube. 7 mL of water: acetonitrile (20:80) was added and sonicated for 30 minutes. During ultrasonic irradiation, stirring was performed once every 10 minutes. The supernatant was filtered through a polytetrafluoroethylene (PTFE) filter having a pore size of 0.20 μm, the first about 1 mL was discarded, and the remaining filtrate was used as a sample solution. Separately, ED-71 standard was used and dissolved in water: acetonitrile (20:80) to a concentration of about 0.6 μg / mL, and a standard solution was prepared in the same manner as the sample solution. The sample solution and the standard solution were measured by high performance liquid chromatography (Waters Alliance, measurement wavelength 265 nm), and the content of ED-71 in the sample was quantified.
　以下の計算式によりED-71の残存率を求めた。
ED-71の残存率(%)＝表示量に対する加速サンプル中のED-71含有量の比(%)／表示量に対する未加速サンプル中のED-71含有量の比(%)×100 The residual ratio of ED-71 was obtained by the following calculation formula.
ED-71 residual rate (%) = Ratio of ED-71 content in accelerated sample to displayed amount (%) / Ratio of ED-71 content in unaccelerated sample to displayed amount (%) x 100
　なお、表示量とは、一錠当たりに含有することが意図されているED-71の重量（0.5μg又は0.75μg）を指す。 The indicated amount refers to the weight (0.5 μg or 0.75 μg) of ED-71 that is intended to be contained per tablet.
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
　『［製造例］油分分散体錠剤』で得られた錠剤は、ＩＣＨガイドライン（Ｑ１Ａ）に定められた加速条件において安定であることが示された。 It was shown that the tablets obtained in “[Production Example] Oil dispersion tablets” are stable under the acceleration conditions defined in the ICH guidelines (Q1A).
　本発明により、ＥＤ－７１の分解が抑制された、ソフトカプセル以外の剤形のＥＤ－７１製剤の提供が可能となる。
  According to the present invention, it is possible to provide an ED-71 preparation having a dosage form other than soft capsules, in which decomposition of ED-71 is suppressed.

Claims (12)

  1. 　（５Ｚ，７Ｅ）－（１Ｒ，２Ｒ，３Ｒ）－２－（３－ヒドロキシプロポキシ）－９，１０－セココレスタ５，７，１０（１９）－トリエン－１，３，２５－トリオール（ＥＤ－７１）と水溶性高分子または塩基性化合物とを溶媒中に含む混合溶液を調製する工程、および
    得られた混合溶液から溶媒を除去する工程、
    を含む、ＥＤ－７１の酸化を抑制する方法。     (5Z, 7E)-(1R, 2R, 3R) -2- (3-hydroxypropoxy) -9,10-secocholesta 5,7,10 (19) -triene-1,3,25-triol (ED-71 ) And a water-soluble polymer or basic compound in a solvent, and a step of removing the solvent from the obtained mixed solution,
    A method for inhibiting oxidation of ED-71.
  2. 　ＥＤ－７１と添加剤との重量比が、１：５０～１：５０００である、請求項１に記載の方法。 The method according to claim 1, wherein the weight ratio of ED-71 to the additive is 1:50 to 1: 5000.
  3. 　水溶性高分子が、ヒドロキシプロピルメチルセルロース、ポリオキシエチレンポリオキシプロピレングリコール、ポリエチレングリコール、ポリオキシエチレンポリオキシプロピレングリコール、スルホブチルエーテル-β-シクロデキストリン、ポリビニルカプロラクタム－ポリビニル酢酸－ポリエチレングリコールグラフトコポリマーアミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、ヒドロキシプロピルセルロース、エチルセルロース、ショ糖脂肪酸エステル、ポリビニルピロリドン、ポリビニルピロリドン、コポビドン、ポリオキシエチレン硬化ヒマシ油、２－ヒドロキシプロピル－β－シクロデキストリン、Ｄ－α－トコフェリル ポリエチレン グリコールコハク酸、ポリオキシエチレン硬化ヒマシ油デキストリン、アラビアガム、ヒドロキシプロピルメチルセルロース－アセテートサクシネート、アルカリ処理ゼラチン、メチルセルロース、ポリビニルアセテート、ポリビニルアセテート・アクリル酸・メタクリル酸コポリマー、α化でんぷん、ヒドロキシエチルセルロース、およびレシチン粉末から選択され、塩基性化合物が、メグルミン、Ｌ－アルギニン、およびピロリン酸四カリウムから選択される、請求項１または２に記載の方法。 Water-soluble polymer is hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, sulfobutyl ether-β-cyclodextrin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer aminoalkyl methacrylate Copolymer, aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, hydroxypropyl cellulose, ethyl cellulose, sucrose fatty acid ester, polyvinyl pyrrolidone, polyvinyl pyrrolidone, copovidone, polyoxyethylene hydrogenated castor oil, 2-hydroxypropyl-β-cyclodextrin, D- α-tocopheryl polyethylene glycine Succinic acid, polyoxyethylene hydrogenated castor oil dextrin, gum arabic, hydroxypropyl methylcellulose-acetate succinate, alkali-treated gelatin, methylcellulose, polyvinyl acetate, polyvinyl acetate / acrylic acid / methacrylic acid copolymer, pregelatinized starch, hydroxyethyl cellulose, and lecithin 3. The method according to claim 1 or 2, wherein the basic compound is selected from powder and the basic compound is selected from meglumine, L-arginine, and tetrapotassium pyrophosphate.
  4. 　ＥＤ－７１を含む医薬組成物であって、
    ＥＤ－７１と水溶性高分子または塩基性化合物とを溶媒中に含む混合溶液を調製し、当該混合溶液から溶媒を除去することにより製造され、水溶性高分子が、ヒドロキシプロピルメチルセルロース、ポリオキシエチレンポリオキシプロピレングリコール、ポリエチレングリコール、ポリオキシエチレンポリオキシプロピレングリコール、スルホブチルエーテル-β-シクロデキストリン、ポリビニルカプロラクタム－ポリビニル酢酸－ポリエチレングリコールグラフトコポリマーアミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、アミノアルキルメタクリレートコポリマー、ヒドロキシプロピルセルロース、エチルセルロース、ショ糖脂肪酸エステル、ポリビニルピロリドン、ポリビニルピロリドン、コポビドン、ポリオキシエチレン硬化ヒマシ油、２－ヒドロキシプロピル－β－シクロデキストリン、Ｄ－α－トコフェリル ポリエチレン グリコールコハク酸、ポリオキシエチレン硬化ヒマシ油デキストリン、アラビアガム、ヒドロキシプロピルメチルセルロース－アセテートサクシネート、アルカリ処理ゼラチン、メチルセルロース、ポリビニルアセテート、ポリビニルアセテート・アクリル酸・メタクリル酸コポリマー、α化でんぷん、ヒドロキシエチルセルロース、およびレシチン粉末から選択され、塩基性化合物が、メグルミン、Ｌ－アルギニン、およびピロリン酸四カリウムから選択される、前記医薬組成物。     A pharmaceutical composition comprising ED-71,
    It is produced by preparing a mixed solution containing ED-71 and a water-soluble polymer or basic compound in a solvent, and removing the solvent from the mixed solution. The water-soluble polymer is hydroxypropylmethylcellulose, polyoxyethylene. Polyoxypropylene glycol, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, sulfobutyl ether-β-cyclodextrin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, hydroxy Propyl cellulose, ethyl cellulose, sucrose fatty acid ester, polyvinyl pyrrolidone, polyvinyl pyrrolidone, copobi Don, polyoxyethylene hydrogenated castor oil, 2-hydroxypropyl-β-cyclodextrin, D-α-tocopheryl polyethylene glycol succinic acid, polyoxyethylene hydrogenated castor oil dextrin, gum arabic, hydroxypropyl methylcellulose-acetate succinate, alkali treatment Selected from gelatin, methyl cellulose, polyvinyl acetate, polyvinyl acetate / acrylic acid / methacrylic acid copolymer, pregelatinized starch, hydroxyethyl cellulose, and lecithin powder, the basic compound selected from meglumine, L-arginine, and tetrapotassium pyrophosphate The said pharmaceutical composition.
  5. 　ＥＤ－７１と添加剤との重量比が、１：５０～１：５０００である、請求項４に記載の医薬組成物。 The pharmaceutical composition according to claim 4, wherein the weight ratio of ED-71 to the additive is 1:50 to 1: 5000.
  6. 　ＥＤ－７１を含む医薬組成物の製造方法であって、
    ＥＤ－７１の油脂溶液と水溶性高分子の水溶液とを含む水中油型乳化液を調製する工程、
    水中油型乳化液を賦形剤に付着または吸着させる工程、および
    水中油型乳化液を乾燥させる工程、
    を含み、
    ここで前記水溶性高分子は、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される、前記方法。     A method for producing a pharmaceutical composition comprising ED-71, comprising:
    Preparing an oil-in-water emulsion containing an ED-71 oil and fat solution and an aqueous solution of a water-soluble polymer;
    Attaching or adsorbing the oil-in-water emulsion to the excipient, and drying the oil-in-water emulsion,
    Including
    Wherein the water soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropylcellulose.
  7. 　水中油型乳化液と賦形剤との重量比が、１：４～１：２０である、請求項６に記載の方法。 The method according to claim 6, wherein the weight ratio of the oil-in-water emulsion to the excipient is 1: 4 to 1:20.
  8. 　賦形剤が、糖または糖アルコール類から選択される、請求項６または７に記載の方法。 The method according to claim 6 or 7, wherein the excipient is selected from sugar or sugar alcohols.
  9. 　ＥＤ－７１を含む医薬組成物であって、
    賦形剤中または賦形剤の表面に、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される水溶性高分子を含む被覆剤で被覆された粒子を含み、
    当該粒子は、ＥＤ－７１の油脂溶液を含む、前記医薬組成物。     A pharmaceutical composition comprising ED-71,
    Comprising particles coated with a coating containing a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose in or on the surface of the excipient;
    The pharmaceutical composition, wherein the particle comprises an oil / fat solution of ED-71.
  10. 　ＨＰＭＣフィルムでコーティングされたコーティング錠である、請求項９に記載の医薬組成物。 The pharmaceutical composition according to claim 9, which is a coated tablet coated with an HPMC film.
  11. 　ＥＤ－７１の油脂溶液と水溶性高分子の水溶液とからなる水中油型乳化液を調製する工程を含み、
    ここで前記水溶性高分子は、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから選択される、
    ＥＤ－７１の分解を抑制する方法。     Including the step of preparing an oil-in-water emulsion comprising an ED-71 oil and fat solution and an aqueous solution of a water-soluble polymer,
    Here, the water-soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropylcellulose.
    A method for suppressing the decomposition of ED-71.
  12. 　得られた水中油型乳化液を乾燥する工程をさらに含む、請求項１１に記載の方法。
          The method of Claim 11 which further includes the process of drying the obtained oil-in-water emulsion.
PCT/JP2017/047156 2016-12-28 2017-12-28 Medicinal composition comprising ed-71 solid dispersion and oil dispersion WO2018124260A1 (en)

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