WO2018124260A1 - Composition médicinale comprenant une dispersion solide de ed-71 et une dispersion d'huile - Google Patents

Composition médicinale comprenant une dispersion solide de ed-71 et une dispersion d'huile 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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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 KR1020227004397A priority Critical patent/KR102583517B1/ko
Priority to JP2018559626A priority patent/JP6905538B2/ja
Priority to KR1020197019067A priority patent/KR102366186B1/ko
Priority to CN201780081610.0A priority patent/CN110121348A/zh
Publication of WO2018124260A1 publication Critical patent/WO2018124260A1/fr

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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
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    • 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
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
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    • 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
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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
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof
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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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    • 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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    • A61K9/14—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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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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    • 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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    • 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.

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Abstract

L'invention concerne : un procédé d'inhibition de l'oxydation du (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-sécocholesta-5,7,10(19)-triène-1,3,25-triol (ED-71), ledit procédé comprenant une étape de préparation d'une solution d'un mélange contenant ED-71 et un polymère hydrosoluble ou un composé basique dans un solvant et une étape d'élimination du solvant depuis la solution ainsi obtenue du mélange; et un procédé d'inhibition de la dégradation de ED-71, ledit procédé comprenant une étape de préparation d'une émulsion de type huile dans l'eau comprenant une solution huileuse de ED-71 et une solution aqueuse d'un polymère soluble dans l'eau, le polymère soluble dans l'eau étant choisi parmi l'hydroxypropylméthylcellulose et l'hydroxypropylcellulose.
PCT/JP2017/047156 2016-12-28 2017-12-28 Composition médicinale comprenant une dispersion solide de ed-71 et une dispersion d'huile WO2018124260A1 (fr)

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KR1020227004397A KR102583517B1 (ko) 2016-12-28 2017-12-28 Ed-71의 고체 분산체 및 유분 분산체를 포함하는 의약 조성물
JP2018559626A JP6905538B2 (ja) 2016-12-28 2017-12-28 Ｅｄ−７１の固体分散体および油分分散体を含む医薬組成物
KR1020197019067A KR102366186B1 (ko) 2016-12-28 2017-12-28 Ed-71의 고체 분산체 및 유분 분산체를 포함하는 의약 조성물
CN201780081610.0A CN110121348A (zh) 2016-12-28 2017-12-28 包含ed－71的固体分散体及油分散体的药物组合物

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WO2020004541A1 (fr) * 2018-06-27 2020-01-02 中外製薬株式会社 Composition pharmaceutique comprenant une dispersion à constituante lipidique contenant ed -71 et sa forme époxy dans le corps gras
CN110946837A (zh) * 2019-12-11 2020-04-03 正大制药（青岛）有限公司 用于治疗骨质疏松症的艾地骨化醇片及其制备方法
CN112770750A (zh) * 2018-07-30 2021-05-07 中外制药株式会社 乙内酰脲衍生物的固体分散体

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