WO2016051782A1 - Oral preparation in which bitter taste of bitter-tasting drug is masked - Google Patents

Oral preparation in which bitter taste of bitter-tasting drug is masked Download PDF

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Publication number
WO2016051782A1
WO2016051782A1 PCT/JP2015/004953 JP2015004953W WO2016051782A1 WO 2016051782 A1 WO2016051782 A1 WO 2016051782A1 JP 2015004953 W JP2015004953 W JP 2015004953W WO 2016051782 A1 WO2016051782 A1 WO 2016051782A1
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WIPO (PCT)
Prior art keywords
drug
masking
mass
bitter taste
particles
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PCT/JP2015/004953
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French (fr)
Japanese (ja)
Inventor
雄亮 柴田
直 丸山
Original Assignee
キッセイ薬品工業株式会社
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Priority to JP2016551546A priority Critical patent/JPWO2016051782A1/en
Publication of WO2016051782A1 publication Critical patent/WO2016051782A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • 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

Definitions

  • the present invention can reproduce a drug concentration having a bitter taste, for example, silodosin, which is a very bitter-tasting drug, without any foreign body feeling and without water, and can reproduce blood concentration effective for treating urination disorders associated with prostatic hypertrophy.
  • the present invention relates to a novel preparation for oral administration (especially a rapidly disintegrating preparation in the oral cavity) having dissolution properties.
  • a drug having a bitter taste such as silodosin
  • pharmaceutical preparations containing silodosin capsules and tablets (see, for example, Patent Documents 2 and 3) are used, but these preparations need to be taken with water.
  • a preparation especially an oral rapid disintegration preparation
  • a chemical masking method such as chemical modification or inclusion of the drug itself (see, for example, Patent Document 4), a functional function by adding a sweetener, a fragrance, etc.
  • Masking method for example, see Patent Document 5 and Non-Patent Document 1
  • physical masking method for coating a drug with a coating agent such as gastric polymer or enteric polymer (for example, see Patent Documents 6 to 9), etc. Is known (see, for example, Non-Patent Document 2).
  • the bitterness may not be sufficiently suppressed by the sensory masking method, and the physical masking method has to increase the coating amount of the coating agent. It has been difficult to achieve both suppression of bitterness and elution in various liquid properties, such as the problem of reduced elution.
  • Patent Document 6 JP 2008-231029 discloses rebamipide bitterness masking granules in which rebamipide and methylcellulose are sprayed onto partially pregelatinized starch to form a granulated product and coated with polyvinyl acetal diethylaminoacetate, which is a gastric polymer. Has been.
  • Patent Document 7 a mixture of fexofenadine and precipitated silica is granulated using Eudragit (registered trademark) E100, and then Eudragit (registered trademark) E100 further containing precipitated silica is used. Disclosed are fexofenadine coated granules obtained by coating with a polymer dispersion.
  • Patent Document 8 discloses a granulated product obtained by spraying an aminoalkyl methacrylate copolymer E on a mixture of mitiglinide and crystalline cellulose.
  • Patent Document 9 discloses amlodipine-containing particles obtained by spraying a coating liquid containing an aminoalkyl methacrylate copolymer E onto a mixture of amlodipine besylate and light anhydrous silicic acid.
  • the present invention can reproduce a drug concentration having a bitter taste, for example, silodosin, which is a very bitter taste drug, without water and without water, and can reproduce a blood concentration effective for treating urination disorder associated with prostatic hypertrophy. It is an object of the present invention to provide a novel preparation for oral administration (particularly an intraoral rapidly disintegrating preparation) having dissolution properties.
  • silodosin has a particularly strong bitter taste, and since it is a needle-like crystalline substance, many coating agents are used to suppress the bitter taste. Necessary, and thus there are problems such as a decrease in elution and a feeling of foreign matter remaining when taken without water.
  • silodosin has chemical properties that are easily degraded by excipients and the like that are widely used as pharmaceutical additives, and there are various points to be overcome due to the characteristics of silodosin.
  • a therapeutic agent for dysuria associated with benign prostatic hyperplasia it must be a preparation that can appropriately reproduce the blood concentration at which the already used silodosin preparations are effective.
  • the present inventors have intensively studied to solve the above problems while overcoming these points.
  • sensory masking techniques such as cocoa powder and calcium lactate
  • chemical masking techniques such as carrageenan could not mask the intense bitter taste of silodosin.
  • enteric base enteric polymer
  • enteric base enteric polymer
  • the present invention has been completed by finding that an oral administration preparation exhibiting extremely desirable performance can be obtained. Further, the present invention was completed by finding that the rapidly disintegrating preparation in the oral cavity using the masking particles of the present invention rapidly disintegrates in the oral cavity without water without feeling a strong bitter taste and has desired dissolution characteristics. .
  • the present invention [1] Masking particles obtained by granulating or coating drug particles containing a drug having a bitter taste with a coating agent containing methyl methacrylate-diethylaminoethyl methacrylate copolymer, the content of the copolymer Masking particles, wherein the amount is from 80 parts by mass to 400 parts by mass with respect to 100 parts by mass of the drug having a bitter taste; [2] The masking particle according to the above [1], wherein the drug having a bitter taste is silodosin; [3] The masking particles according to the above [2], wherein the orally administered preparation containing the masking particles has an elution rate after 15 minutes at pH 6.8 of 85% or more; [4] The masking particle according to any one of the above [1] to [3], wherein the time when the oral bitterness-containing preparation containing the masking particle starts to feel bitterness in the human bitterness sensory test is 30 seconds or longer; [5] The masking particle according to [1]
  • Dosage formulation [18] The oral administration preparation according to any of [12] to [17], wherein the oral administration preparation is an intraoral rapidly disintegrating preparation; [19] The oral administration preparation of [18], wherein the intraoral rapidly disintegrating preparation is a tablet; [20] The oral administration preparation of [19], wherein the oral disintegration time is within 40 seconds; [21] The oral administration preparation of [20] above, wherein the time until the bitter taste is started is longer than the oral disintegration time; [22] The oral administration preparation described in any of [12] to [21] above, wherein the dissolution rate after 15 minutes at pH 6.8 is 85% or more; [23] (a) a step of preparing a drug particle by mixing or granulating a drug having a bitter taste and an additive, and (b) methyl methacrylate-diethylaminoethyl methacrylate in the drug particle obtained in step (a) Granulated or coated with a coating agent containing a copolymer, the methyl methacrylate
  • examples of the “methyl methacrylate-diethylaminoethyl methacrylate copolymer” include Kollicoat (registered trademark) Smart Seal 30D.
  • methyl methacrylate-diethylaminoethyl methacrylate copolymer used in the present invention may be used in combination with a non-enteric polymer, if necessary.
  • a non-enteric polymer refers to a water-insoluble polymer other than the enteric polymer, such as a gastric polymer or a water-insoluble polymer.
  • gastric soluble polymer examples include methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer such as aminoalkyl methacrylate copolymer E (for example, Eudragit (registered trademark) EPO, Eudragit (registered trademark) E100), Examples thereof include gastric soluble polyvinyl derivatives such as polyvinyl acetal diethylaminoacetate (for example, AEA (registered trademark)).
  • AEA registered trademark
  • water-insoluble polymer examples include ethyl acrylate-methyl methacrylate copolymer such as ethyl acrylate-methyl methacrylate copolymer dispersion (for example, Eudragit (registered trademark) NE30D), aminoalkyl methacrylate copolymer RS (for example, Eudragit (R) RS100, Eudragit (R) RSPO, Eudragit (R) RL, Eudragit (R) RLPO), and aminoalkyl methacrylate copolymer RS aqueous dispersions (e.g.
  • ethyl acrylate-methyl methacrylate copolymer dispersion for example, Eudragit (registered trademark) NE30D
  • aminoalkyl methacrylate copolymer RS for example, Eudragit (R) RS100, Eudragit (R) RSPO, Eudragit (R) RL, Eudragit (R) RLPO
  • Eudragit (R) RS30D Eudragit ( Water-insoluble acrylic copolymer such as ethyl acrylate-methyl methacrylate-methacrylated trimethylammonium ethyl copolymer such as (registered trademark) RL30D)), ethyl cellulose
  • water-insoluble cellulose ether such as etosel (registered trademark), aqueous dispersion of ethyl cellulose (for example, Aquacoat (registered trademark)), vinyl acetate resin (for example, Kollicoat (registered trademark) SR, Kollicoat (registered trademark) SR30D) Etc.
  • the coating agent containing methyl methacrylate-diethylaminoethyl methacrylate copolymer used in the present invention may contain additives, water-soluble polymers, etc., if necessary, in addition to the non-enteric polymer. Good. When the water-soluble polymer is used, the ratio of the mass of the water-soluble polymer to the total mass of the non-enteric polymer and the water-soluble polymer is preferably 20% or less.
  • the additive include a plasticizer, a lubricant, a surfactant, and an antioxidant.
  • plasticizer examples include stearic acid, triacetin, triethyl citrate, macrogol, glycerin, glycerin fatty acid ester, castor oil, diethyl sebacate, dibutyl sebacate and the like.
  • lubricant examples include talc, stearic acid, magnesium stearate, calcium stearate and the like.
  • surfactant examples include sodium lauryl sulfate and polysorbate.
  • water-soluble polymer examples include hypromellose, methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, povidone, carmellose sodium, sodium alginate and the like.
  • antioxidant examples include dibutylhydroxytoluene, butylhydroxyanisole, vitamin E (tocopherol) and the like. These additives and water-soluble polymers can be used in combination of two or more.
  • the content of methyl methacrylate-diethylaminoethyl methacrylate copolymer is, for example, 80 to 400 parts by mass, 80 to 300 parts by mass with respect to 100 parts by mass of the drug having a bitter taste (for example, silodosin). 80 to 200 parts by mass, 100 to 400 parts by mass, 100 to 300 parts by mass, 100 to 200 parts by mass, and more preferably 100 to 200 parts by mass.
  • the content of the methyl methacrylate-diethylaminoethyl methacrylate copolymer in the masking particles of the present invention is preferably 10 to 30% by mass, more preferably 15 to 25% by mass.
  • the content of the methyl methacrylate-diethylaminoethyl methacrylate copolymer is, for example, generally 20 to 50 parts by mass, preferably 20 to 40 parts by mass with respect to 100 parts by mass of the drug particles.
  • the amount is preferably 30 to 40 parts by mass.
  • average particle diameter means 50% particle diameter (mass-based median diameter).
  • the 50% particle size can be measured with a sieve-type particle size distribution analyzer (eg, Gilsonic Auto Seeber GA-6, manufactured by Gilson).
  • the average particle size of the masking particles of the present invention is, for example, about 300 ⁇ m or less, and preferably about 100 to 250 ⁇ m.
  • the “drug having a bitter taste” is used as an active ingredient for treatment or prevention of a disease, and may have any unpleasant taste such as a bitter taste.
  • any unpleasant taste such as a bitter taste.
  • silodosin mitiglinide, acetaminophen, Aminophylline, ecabapid, ethionamide, epilysole, caffeine, chloramphenicol, diphenhydramine, cimetidine, sulpyrine, theophylline, nizatidine, pyrazinamide, famotidine, phenylbutazone, phenobarbital, metoclopramide and their pharmacologically acceptable salts, etc.
  • silodosin is preferred.
  • the drug having a bitter taste is not limited to this.
  • silodosin can be used, or can be produced by a method described in the literature (for example, see Patent Document 1) or a method analogous thereto.
  • silodosin used in the present invention may be particles having no aggregated mass, and may be crushed, pulverized, or the like, if necessary.
  • the average particle size of silodosin is preferably about 50 ⁇ m or less, more preferably about 1 to 30 ⁇ m.
  • the “drug particles containing a drug having a bitter taste” used in the present invention is preferably a drug having a bitter taste, for example, in the case of silodosin, it is desirable to use an appropriate additive in addition to silodosin.
  • additives which do not cause a change in composition with a drug having a bitter taste for example, silodosin
  • a disintegrant for example, a disintegrant, an excipient, a binder, a lubricant.
  • Sweetening agents, sour agents, foaming agents, flavoring agents, coloring agents, and the like can be used as appropriate.
  • disintegrants include low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, carmellose sodium, rice starch, corn starch, potato starch, carboxymethyl starch sodium, carmellose, partially pregelatinized starch, and pregelatinized.
  • Examples include starch, crospovidone, crystalline cellulose and the like.
  • Excipients include, for example, rice starch, corn starch, potato starch, partially pregelatinized starch, pregelatinized starch, trehalose, crystalline cellulose, magnesium aluminate metasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate Lactose, fructose, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol and the like.
  • binder examples include starches, crystalline cellulose, hydroxypropyl cellulose, hypromellose, povidone, dextrin, gelatin, pullulan, polyvinyl alcohol, sodium alginate, polyethylene glycol and the like.
  • lubricant examples include magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous silicic acid, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, glyceryl monostearate and the like.
  • sweetener examples include aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, acesulfame potassium, sucralose and the like.
  • sour agents include citric acid, tartaric acid, malic acid, ascorbic acid and the like.
  • foaming agent examples include sodium bicarbonate, sodium carbonate, calcium carbonate and the like.
  • corrigent examples include L-aspartic acid, sodium chloride, magnesium chloride, sodium citrate, calcium citrate, sodium L-glutamate, sodium bicarbonate and the like.
  • fragrances include strawberry, yogurt, banana, pineapple, orange, lemon, menthol, peach, apple, chocolate, cocoa, vanilla, black tea, matcha tea and the like.
  • colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, yellow iron sesquioxide, iron sesquioxide, caramel pigment, and titanium oxide.
  • sugar or sugar alcohol and starches are preferable, and starches are more preferable.
  • sugar or sugar alcohol include D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol and the like, and D-mannitol is more preferable.
  • starches include corn starch, rice starch, potato starch, partially pregelatinized starch, pregelatinized starch, and the like. Partially pregelatinized starch and pregelatinized starch are more preferable.
  • lubricant for example, magnesium stearate, calcium stearate, talc and the like are preferable, and talc is more preferable.
  • binder for example, starches, hydroxypropylcellulose, hypromellose, povidone, dextrin, gelatin, pullulan, polyvinyl alcohol, sodium alginate, polyethylene glycol and the like are preferable, and hydroxypropylcellulose and hypromellose are more preferable. You may use these additives in combination of 2 or more as needed.
  • the content of the drug having a bitter taste (for example, silodosin) in the masking particles of the present invention is preferably 30% by mass or less, more preferably 5 to 25% by mass, and further preferably 5 to 16% by mass.
  • the content of the drug (for example, silodosin) having a bitter taste in the drug particles used in the present invention is preferably 50% by mass or less, for example, 10 to 40% by mass, 10 to 30% by mass, 20 to 27% by mass, etc. is there.
  • the masking particles of the present invention can be produced by a method generally used for producing masking particles such as a nuclear granule coating method, a granulation matrix method, and a granulation coating method.
  • drug particles obtained by mixing or granulating silodosin and additives can be produced by granulating or coating with a coating agent containing a non-enteric polymer.
  • granulation or coating methods include high-speed mixing and stirring granulation method, rolling fluidized bed granulation method, fluidized bed granulation method and the like, and fluidized bed granulation method is preferable.
  • crystalline cellulose for example, in the nuclear granule coating method, commercially available or granulated crystalline cellulose, D-mannitol, corn starch, magnesium hydroxide, magnesium carbonate, sucrose, etc. are dispersed into a dispersion containing silodosin and non-coated particles.
  • Masking particles can also be produced by sequentially coating with a solution or dispersion of a coating agent containing an enteric polymer, or coating with a mixture thereof.
  • a mixture of silodosin and an additive for example, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.
  • an additive for example, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.
  • Masking particles can also be produced by granulating or coating while spraying a solution or dispersion of the agent.
  • a mixture of silodosin and an additive for example, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.
  • an additive for example, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.
  • the obtained granulated product is coated while spraying a solution or dispersion of a coating agent containing a non-enteric polymer, whereby masking particles can be produced.
  • the water-soluble binder hydroxypropylcellulose and hypromellose are preferable.
  • the granulation matrix method or the granulation coating method is preferable, and the granulation coating method is more preferable.
  • the solvent used for dissolving or dispersing the non-enteric polymer is not particularly limited, and examples thereof include alcohols such as methanol, ethanol and isopropyl alcohol, acetone, toluene, methyl ethyl ketone and water, or a mixed solvent thereof. Ethanol and water are preferred, and water is more preferred.
  • Aminoalkyl methacrylate copolymer E is insoluble in water but used as an aqueous solution dissolved in acidic (pH 5 or lower) water, or selected from aminoalkyl methacrylate copolymer E from sodium lauryl sulfate and stearic acid, diethyl sebacate and dibutyl sebacate It is also possible to use an aqueous dispersion in which at least one plasticizer is mixed at an arbitrary ratio.
  • the masking particles of the present invention may be used after being overcoated with a suitable additive in order to prevent agglomeration during production.
  • the masking particles of the present invention include those that are overcoated.
  • the mass of the masking particles does not include the mass of the additive used for the overcoat.
  • the additive used for the overcoat include sugars such as lactose, glucose, sucrose, and fructose, and sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol. D-mannitol.
  • the method of overcoating is not particularly limited, but for example, it can also be produced by coating the masking particles of the present invention while spraying an aqueous solution of an additive (for example, sugar or sugar alcohol).
  • an additive for example, sugar or sugar alcohol.
  • the content of the additive used for the overcoat is usually 1 to 20 parts by weight, preferably 2 to 15 parts by weight, and more preferably 5 to 10 parts by weight with respect to 100 parts by weight of the masking particles.
  • Oral administration preparations of various dosage forms can be produced using the masking particles of the present invention.
  • Examples of the dosage form of the oral administration preparation of the present invention include granules, powders, tablets and the like.
  • intraoral rapidly disintegrating preparations such as intraoral rapidly disintegrating granules, intraoral rapidly disintegrating powder and intraoral rapidly disintegrating tablets are preferable, and intraoral rapidly disintegrating tablets are more preferable.
  • the preparation for oral administration of the present invention can be produced by a conventional method in the pharmaceutical field using the masking particles of the present invention and pharmaceutical additives generally used for intraoral quick disintegrating preparations.
  • the masking particles of the present invention are used together with pharmaceutical additives generally used for intraoral quick disintegrating preparations, and known methods such as direct powder compression (direct compression) and granulation
  • an oral administration preparation can also be manufactured by tableting by the method according to it.
  • a mixer is used without granulating a mixture containing the masking particles of the present invention and a pharmaceutical additive such as an excipient, a disintegrant, a binder, and a lubricant. And then tableting to produce a preparation for oral administration.
  • a pharmaceutical additive such as an excipient, a disintegrant, a binder, and a lubricant.
  • a mixture of an excipient, a disintegrant, and the like is granulated using water, a mixed solution of water and ethanol, or a solution or suspension of a binder or a disintegrant. Then, after mixing with the masking particles of the present invention, a lubricant and the like using a mixer, it may be tableted, or a mixture of the masking particles of the present invention and excipients, disintegrants. After granulation using a mixed solution of water and ethanol, or a solution or suspension of a binder or disintegrant, add a lubricant and mix using a mixer, then tablet and tablet for oral administration Can also be manufactured.
  • the granule can also be produced by fluidized bed granulation according to the tablet granulation method or by stirring granulation.
  • Powders and the like can also be produced by mixing pharmaceutical additives according to the direct tableting method.
  • an additive used for the drug particles can be used.
  • the disintegrating agent include partially pregelatinized starch, crospovidone, low substituted hydroxy Propyl cellulose, carmellose calcium, carmellose sodium, corn starch and the like are preferred, and crospovidone is more preferred.
  • sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol, corn starch, crystalline cellulose and the like are preferable.
  • sodium stearyl fumarate sodium stearyl fumarate, calcium stearate, talc, light anhydrous silicic acid and the like are preferable, and sodium stearyl fumarate is more preferable. You may use these pharmaceutical additives in combination of 2 or more as needed.
  • the masking particles of the present invention and sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol and xylitol, starches such as rice starch, corn starch, potato starch and partially pregelatinized starch, crystalline cellulose and crospovidone
  • sugars such as lactose and fructose
  • sugar alcohols such as D-mannitol, erythritol and xylitol
  • starches such as rice starch, corn starch, potato starch and partially pregelatinized starch
  • the powder can also be produced by mixing at least one pharmaceutical additive selected from the above using a mixer.
  • the masking particles of the present invention and sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol and xylitol, starches such as rice starch, corn starch, potato starch and partially pregelatinized starch, crystalline cellulose, crospovidone
  • sugars such as lactose and fructose
  • sugar alcohols such as D-mannitol, erythritol and xylitol
  • starches such as rice starch, corn starch, potato starch and partially pregelatinized starch, crystalline cellulose, crospovidone
  • a tablet is produced by mixing at least one pharmaceutical additive selected from sodium stearyl fumarate, calcium stearate, talc and light anhydrous silicic acid with a mixer and then compressing the mixture.
  • sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol and maltitol, starches such as corn starch, rice starch, potato starch, partially pregelatinized starch and pregelatinized starch
  • Granules (1) can also be produced by mixing at least one pharmaceutical additive selected from the group consisting of a cellulose and crystalline cellulose and granulating while spraying a solution or dispersion of partially pregelatinized starch or crospovidone .
  • a high-speed mixed stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, or the like can be used, and a fluidized bed granulation method is preferable.
  • the granule (1), and at least one lubricant selected from sodium stearyl fumarate, calcium stearate, talc and light anhydrous silicic acid using a mixer Tablets can also be produced by tableting.
  • one or two or more excipients In the mixing step, one or two or more excipients, disintegrants, binders, lubricants, foaming agents, sweeteners, corrigents, fluidizing agents, fragrances, colorants, and the like, as necessary. You may add in combination.
  • sugars such as lactose and fructose
  • sugar alcohols such as D-mannitol, erythritol, xylitol
  • maltose D-sorbitol and maltitol
  • starches such as corn starch, rice starch, potato starch
  • Granules (2) can also be produced by mixing at least one pharmaceutical additive selected from the group of polymers and crystalline cellulose, and granulating while spraying water or a mixture of water and ethanol.
  • a high-speed mixed stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, or the like can be used, and a fluidized bed granulation method is preferable.
  • the granule (2), and at least one lubricant selected from sodium stearyl fumarate, calcium stearate, talc and light anhydrous silicic acid using a mixer Tablets can also be produced by tableting.
  • one or two or more excipients In the mixing step, one or two or more excipients, disintegrants, binders, lubricants, foaming agents, sweeteners, corrigents, fluidizing agents, fragrances, colorants, and the like, as necessary. You may add in combination.
  • the masking particle of the present invention and the granule (1) or the granule (2) can be mixed using a mixer to produce a granule.
  • an excipient, a lubricant, a foaming agent, a sweetening agent, a corrigent, a fluidizing agent, a fragrance, a coloring agent, etc. may be added in combination of one or more. Good.
  • a mixture of D-mannitol and crystalline cellulose is mixed using a fluidized bed granulator / dryer, granulated while spraying a water dispersion of crospovidone, and then adjusted using a granulator.
  • Granules (3) can also be produced.
  • the said granule (3), and a sodium stearyl fumarate using a mixer it can also manufacture a tablet by tableting.
  • an excipient, a lubricant, a foaming agent, a sweetening agent, a corrigent, a fluidizing agent, a fragrance, a coloring agent, etc. may be added in combination of one or more. Good.
  • “granulation”, “coating”, “mixing”, and “tableting” may be performed by using a conventional method in the pharmaceutical technical field.
  • “granulation” and “coating” for example, a fluidized bed granulator, a rolling fluidized bed granulation method, a high-speed mixing and agitation granulator or the like can be used.
  • “mixing”, for example, a V-type mixer, a bore container, or the like can be used.
  • a single tableting machine or a rotary tableting machine can be used for the “tablet”.
  • the tableting pressure is, for example, 1 to 20 kN, and preferably 2 to 15 kN.
  • the masking particles of the present invention and the preparation for oral administration containing the same exhibit a good bitter taste masking effect.
  • the bitter taste masking effect can be quantitatively evaluated by a bitter taste sensory test described later.
  • the average bitterness score is preferably 2 or less, more preferably 1 or less.
  • the time until the bitterness starts to be felt is preferably 30 seconds or longer, and is preferably longer, such as 40 seconds or longer, or 60 seconds or longer.
  • the preparation for oral administration of the present invention exhibits rapid dissolution without depending on the pH in the digestive tract. That is, the orally administered preparation of the present invention shows an elution rate of 80% or more after 15 minutes in the first solution (pH about 1.2) and the second solution (pH about 6.8) of the Japanese Pharmacopoeia dissolution test.
  • the dissolution rate after 15 minutes is 85% or more, and more preferably, the Japanese Pharmacopoeia dissolution test second solution (pH about 6). 8)
  • the elution rate after 15 minutes is 85% or more.
  • the dissolution property can be quantitatively evaluated by a dissolution test described later.
  • the oral dosage form of the present invention is preferably one that disintegrates in the oral cavity in a short time in order to be taken without water.
  • the average oral disintegration time may be adjusted to be shorter than the time until bitterness begins to be felt, and is usually within 60 seconds, preferably within 40 seconds, more preferably What is necessary is just to adjust so that it may become within 30 second.
  • the preparation for oral administration of the present invention preferably has an appropriate hardness from the viewpoint of convenience of production and transportation.
  • it is usually adjusted to 20 N or more, preferably 30 N or more, and more preferably 40 N or more.
  • Oral disintegration time and hardness can be appropriately adjusted by selecting the type and amount of pharmaceutical additives, production method (eg, granulation method), production conditions (eg, tableting pressure, etc.) and the like. .
  • production method eg, granulation method
  • production conditions eg, tableting pressure, etc.
  • the silodosin content per unit preparation is usually 2 to 8 mg, preferably 2 mg, 4 mg or 8 mg.
  • Examples of the preparation for oral administration of the present invention include, in the case of tablets, 50 to 500 mg, 50 to 300 mg, 100 to 250 mg, 100 to 200 mg and the like as the mass per tablet. 0.4 to 16% can be mentioned.
  • the mass per dose may include 200 to 3000 mg, 500 to 2000 mg, 500 to 1000 mg, etc.
  • the silodosin content at that time is 0.06 to 4%. Can be mentioned.
  • the dose of the active ingredient is appropriately determined depending on the sex, age, weight, degree of disease, etc. of the patient, but when the drug having a bitter taste is silodosin,
  • the dose can be generally in the range of 1 to 16 mg per adult day. Preferably, 2 to 8 mg per day for an adult is orally administered once or twice a day.
  • the masking particle of the present invention is pharmaceutically stable, suppresses the extremely intense bitterness of a drug (for example, silodosin), and has a rapid dissolution property similar to that of a commercially available tablet (for example, Urief (registered trademark) tablet). Therefore, even without water, it can be used for an orally-administered preparation that can be taken without a foreign body feeling.
  • a drug for example, silodosin
  • Urief registered trademark
  • the orally administered preparation of the present invention suppresses the bitterness peculiar to silodosin and has the same rapid dissolution property as a commercially available silodosin tablet (Urief (registered trademark) tablet), so it can be taken without any foreign body feeling even without water.
  • the masking particle of the present invention has a long time until it begins to feel a bitter taste. Therefore, by using the technique of an orally disintegrating tablet, an excellent oral disintegrating preparation can be provided.
  • Example 1 4400 g of silodosin, 16192 g of partially pregelatinized starch (manufactured by Nippon Colorcon) and 1100 g of talc (manufactured by Matsumura Sangyo) were mixed using a fluidized bed granulator / dryer (NFLO-30SJC, manufactured by Freund Sangyo Co., Ltd.). Granulation was performed while spraying a solution obtained by adding 308 g of cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water with a spray nozzle. The obtained granulated product was sized using a sizing machine (Milmist, manufactured by Freund Sangyo Co., Ltd.) with a screen size of ⁇ 1.0 mm to obtain drug particles.
  • NFLO-30SJC fluidized bed granulator / dryer
  • methyl methacrylate-diethylaminoethyl methacrylate copolymer (manufactured by BASF) 985.0 g (295.5 g as a solid content), sodium lauryl sulfate (manufactured by Kao Corporation) 53.18 g, triethyl citrate (manufactured by Morimura Corporation) ) 44.63 g and talc (manufactured by Matsumura Sangyo Co., Ltd.) 236.4 g were added to purified water to obtain a coating solution (c-1).
  • a granulated product was obtained according to a conventional method using 19326 g of D-mannitol (Freund Sangyo), 4080 g of crystalline cellulose (Asahi Kasei Chemicals) and 1700 g of crospovidone (ISP) (b-1).
  • This mixed powder for tableting was tableted using a rotary tableting machine (VELA-5, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a milling die of 8 mm and a tableting pressure of about 6 kN, and each tablet contained 4 mg of silodosin in a mass of 200 mg. Tablets were obtained.
  • a rotary tableting machine (VELA-5, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a milling die of 8 mm and a tableting pressure of about 6 kN, and each tablet contained 4 mg of silodosin in a mass of 200 mg. Tablets were obtained.
  • Example 2 20000 g of silodosin, 73600 g of partially pregelatinized starch (manufactured by Nippon Colorcon Co., Ltd.) and 5000 g of talc (manufactured by Matsumura Sangyo) were mixed using a fluid bed granulator / dryer (FL-120U, manufactured by Freund Sangyo Co., Ltd.). Granulation was performed while spraying a solution obtained by adding 1400 g of cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water with a spray nozzle. The obtained granulated product was sized using a sizing machine (Milmist, manufactured by Freund Sangyo Co., Ltd.) with a screen size of ⁇ 1.0 mm to obtain drug particles.
  • a sizing machine Malmist, manufactured by Freund Sangyo Co., Ltd.
  • methyl methacrylate-diethylaminoethyl methacrylate copolymer (manufactured by BASF) 806.6 g (242.0 g as solid content), sodium lauryl sulfate (manufactured by Kao) 87.12 g, triethyl citrate (manufactured by Morimura Corporation) 36.54 g and 193.6 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were added to purified water to obtain a coating solution (c-2).
  • This mixed powder for tableting was tableted using a rotary tableting machine (VELA-5, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a milling die of 8 mm and a tableting pressure of about 6 kN, and each tablet contained 4 mg of silodosin in a mass of 200 mg. Tablets were obtained.
  • a rotary tableting machine (VELA-5, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a milling die of 8 mm and a tableting pressure of about 6 kN, and each tablet contained 4 mg of silodosin in a mass of 200 mg. Tablets were obtained.
  • Example 3 20000 g of silodosin, 73600 g of partially pregelatinized starch (manufactured by Nippon Colorcon Co., Ltd.) and 5000 g of talc (manufactured by Matsumura Sangyo) were mixed using a fluid bed granulator / dryer (FL-120U, manufactured by Freund Sangyo Co., Ltd.). Granulation was performed while spraying a solution obtained by adding 1400 g of cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water with a spray nozzle. The obtained granulated product was sized using a sizing machine (Milmist, manufactured by Freund Sangyo Co., Ltd.) with a screen size of ⁇ 1.0 mm to obtain drug particles.
  • a sizing machine Malmist, manufactured by Freund Sangyo Co., Ltd.
  • methyl methacrylate-diethylaminoethyl methacrylate copolymer (manufactured by BASF) 982.6 g (294.8 g as solid content), sodium lauryl sulfate (manufactured by Kao) 53.07 g, triethyl citrate (manufactured by Morimura Shoji Co., Ltd.) ) 44.52 g, 7.37 g of 2,6-di-t-butyl-4-methylphenol (Wako Pure Chemical Industries, Ltd.) and 235.9 g of talc (Matsumura Sangyo Co., Ltd.) were added to purified water, and the coating solution was added. (C-3) was obtained.
  • This mixed powder for tableting was tableted using a rotary tableting machine (VELA-2, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a milling die of 8 mm and a tableting pressure of about 6 kN, and each tablet contained 4 mg of silodosin in a mass of 200 mg. Tablets were obtained.
  • a rotary tableting machine (VELA-2, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a milling die of 8 mm and a tableting pressure of about 6 kN, and each tablet contained 4 mg of silodosin in a mass of 200 mg. Tablets were obtained.
  • Table 2 shows the average particle diameter of the masking particles measured in Test Examples 1 to 5, and the bitterness of the tablets containing the masking particles, the time to start feeling bitterness, the oral disintegration time, the hardness, and the dissolution rate.
  • Table 3 shows the respective masses of silodosin, drug particles, methyl methacrylate-diethylaminoethyl methacrylate copolymer and masking particles contained in the unit preparation, and the total mass per unit preparation.
  • the oral dosage formulation containing the masking particles of the present invention can be rapidly disintegrated without feeling a strong bitter taste, can be taken without water, and has an elution property that can reproduce blood concentration effective for treatment, It was confirmed to be useful as an internal fast disintegrating preparation.
  • a drug having a bitter taste for example, silodosin, a drug having a very strong bitter taste
  • a novel preparation for oral administration especially an intraoral rapidly disintegrating preparation having a dissolution property capable of being dissolved.

Abstract

Provided is a novel oral preparation (specifically, an intraoral quickly-disintegrating preparation) that allows a bitter-tasting drug such as silodosin, which has a very strong bitter taste, to be taken without an uncomfortable feeling and even without water, and that has solubility sufficient for reproducing a blood concentration effective for treating dysuria accompanying benign prostatic hyperplasia. The present invention pertains to masking particles and a novel oral preparation containing said masking particles. The masking particles are obtained by granulating or coating drug particles containing a bitter-tasting drug (e.g. silodosin) with a coating agent containing a methyl methacrylate-diethylaminoethyl methacrylate copolymer, wherein the content of said copolymer is 80-400 parts by mass relative to 100 parts by mass of the bitter-tasting drug (e.g. silodosin).

Description

苦味を有する薬剤の苦味をマスキングした経口投与製剤Orally administered preparations masking the bitterness of drugs with bitterness
　本発明は、苦味を有する薬物、例えば、極めて苦味の強い薬剤であるシロドシンを、異物感なく水なしでも服用でき、かつ前立腺肥大症に伴う排尿障害等の治療に有効な血中濃度を再現できる溶出性を備えた、新規な経口投与製剤（特には口腔内速崩壊製剤）に関するものである。 INDUSTRIAL APPLICABILITY The present invention can reproduce a drug concentration having a bitter taste, for example, silodosin, which is a very bitter-tasting drug, without any foreign body feeling and without water, and can reproduce blood concentration effective for treating urination disorders associated with prostatic hypertrophy. The present invention relates to a novel preparation for oral administration (especially a rapidly disintegrating preparation in the oral cavity) having dissolution properties.
　苦味を有する薬剤、例えば、シロドシンは、選択的な尿道平滑筋収縮抑制作用を有し、強力な血圧低下作用を惹起することのない排尿障害治療薬であり（例えば、特許文献１参照）、前立腺肥大症に伴う排尿障害の治療剤として、広く用いられている。シロドシンを含有する医薬品製剤としては、カプセル剤及び錠剤（例えば、特許文献２及び３参照）が使用されているが、これらの製剤は、水と共に服用することが必要である。近年、高齢者などの嚥下困難な患者等でも服用し易い製剤として、水なしでも簡便に服用できる製剤（特には口腔内速崩壊製剤）の開発が求められている。 A drug having a bitter taste, such as silodosin, is a therapeutic agent for dysuria that has a selective urethral smooth muscle contraction inhibitory action and does not cause a strong blood pressure lowering action (see, for example, Patent Document 1), and prostate Widely used as a therapeutic agent for dysuria associated with hypertrophy. As pharmaceutical preparations containing silodosin, capsules and tablets (see, for example, Patent Documents 2 and 3) are used, but these preparations need to be taken with water. In recent years, there has been a demand for the development of a preparation (especially an oral rapid disintegration preparation) that can be easily taken without water as a preparation that can be easily taken even by patients who have difficulty swallowing such as elderly people.
　薬物が苦味を有する場合、その苦味を抑制する方法としては、薬物自体の化学修飾や包接化といった化学的マスキング手法（例えば、特許文献４参照）、甘味剤、香料などを添加することによる官能的マスキング手法（例えば、特許文献５及び非特許文献１参照）、胃溶性高分子又は腸溶性高分子等のコーティング剤により薬物をコーティングする物理的マスキング手法（例えば、特許文献６～９参照）等が知られている（例えば、非特許文献２参照）。 When the drug has a bitter taste, as a method for suppressing the bitter taste, a chemical masking method such as chemical modification or inclusion of the drug itself (see, for example, Patent Document 4), a functional function by adding a sweetener, a fragrance, etc. Masking method (for example, see Patent Document 5 and Non-Patent Document 1), physical masking method for coating a drug with a coating agent such as gastric polymer or enteric polymer (for example, see Patent Documents 6 to 9), etc. Is known (see, for example, Non-Patent Document 2).
　しかしながら、苦味の強い薬剤の場合、官能的マスキング手法では苦味を十分抑制できない場合があり、物理的マスキング手法ではコーティング剤の被覆量を多くしなければならず、それにより、消化管内での薬物の溶出性が低下するという問題が生じるなど、苦味の抑制と種々の液性における溶出性との両立が困難であった。 However, in the case of drugs with a strong bitter taste, the bitterness may not be sufficiently suppressed by the sensory masking method, and the physical masking method has to increase the coating amount of the coating agent. It has been difficult to achieve both suppression of bitterness and elution in various liquid properties, such as the problem of reduced elution.
　さらに、極めて苦味の強い薬剤を口腔内速崩壊製剤とするためには、上記に加えて、苦味を感じ始めるまでの時間を口腔内崩壊時間よりも長くする必要があり、かかる苦味抑制時間と溶出性との両立が困難であった。 Furthermore, in order to make a drug with a very strong bitter taste into a rapidly disintegrating preparation in the oral cavity, in addition to the above, it is necessary to make the time until the bitter taste starts to be longer than the oral disintegration time. It was difficult to achieve compatibility with sex.
　特開２００８－２３１０２９（特許文献６）には、部分アルファー化デンプンにレバミピド及びメチルセルロースを噴霧して造粒物とし、胃溶性高分子であるポリビニルアセタールジエチルアミノアセテートでコーティングしたレバミピドの苦味マスキング顆粒が開示されている。 JP 2008-231029 (Patent Document 6) discloses rebamipide bitterness masking granules in which rebamipide and methylcellulose are sprayed onto partially pregelatinized starch to form a granulated product and coated with polyvinyl acetal diethylaminoacetate, which is a gastric polymer. Has been.
　特表２００５－５１３００８（特許文献７）には、フェキソフェナジン及び沈降シリカの混合物を、オイドラギット（登録商標）Ｅ１００を用いて顆粒化した後、更に沈降シリカを含有するオイドラギット（登録商標）Ｅ１００のポリマー分散物で被覆して得られる、フェキソフェナジンの被覆された顆粒が開示されている。 In JP-T-2005-513008 (Patent Document 7), a mixture of fexofenadine and precipitated silica is granulated using Eudragit (registered trademark) E100, and then Eudragit (registered trademark) E100 further containing precipitated silica is used. Disclosed are fexofenadine coated granules obtained by coating with a polymer dispersion.
　ＷＯ２００８／０１８３７１（特許文献８）には、ミチグリニド及び結晶セルロースの混合物にアミノアルキルメタクリレートコポリマーEを噴霧して得られる造粒物が開示されている。 WO 2008/018371 (Patent Document 8) discloses a granulated product obtained by spraying an aminoalkyl methacrylate copolymer E on a mixture of mitiglinide and crystalline cellulose.
　特開２００７－６３２６３（特許文献９）には、ベシル酸アムロジピンと軽質無水ケイ酸の混合物に、アミノアルキルメタクリレートコポリマーEを含有するコーティング液を噴霧して得られるアムロジピン含有粒子が開示されている。 JP 2007-63263 (Patent Document 9) discloses amlodipine-containing particles obtained by spraying a coating liquid containing an aminoalkyl methacrylate copolymer E onto a mixture of amlodipine besylate and light anhydrous silicic acid.
　しかしながら、いずれの文献にも、シロドシンの苦味抑制と、種々の液性における溶出性を両立した水なしでも服用できる製剤は記載されておらず、新たな製剤開発が望まれていた。 However, none of the documents describes a preparation that can be taken without water that achieves both the suppression of the bitter taste of silodosin and the dissolution properties of various liquids, and the development of a new preparation has been desired.
特開平６－２２００１５号公報Japanese Unexamined Patent Publication No. Hei 6-222005 国際公開第２００４／０５４５７４号International Publication No. 2004/054544 特開２００８－４４９６０号公報JP 2008-44960 A 特開２００８－４４８７０号公報JP 2008-44870 A 特開２００８－９４８３７号公報JP 2008-94837 A 特開２００８－２３１０２９号公報JP 2008-231029 特表２００５－５１３００８号公報JP 2005-513008 A 国際公開第２００８／０１８３７１号International Publication No. 2008/018371 特開２００７－６３２６３号公報JP 2007-63263 A
　本発明は、苦味を有する薬剤、例えば、極めて苦味の強い薬剤であるシロドシンを、異物感なく水なしでも服用でき、かつ前立腺肥大症に伴う排尿障害等の治療に有効な血中濃度を再現できる溶出性を備えた、新規な経口投与製剤（特には口腔内速崩壊製剤）を提供することを課題とする。 INDUSTRIAL APPLICABILITY The present invention can reproduce a drug concentration having a bitter taste, for example, silodosin, which is a very bitter taste drug, without water and without water, and can reproduce a blood concentration effective for treating urination disorder associated with prostatic hypertrophy. It is an object of the present invention to provide a novel preparation for oral administration (particularly an intraoral rapidly disintegrating preparation) having dissolution properties.
　本発明の経口投与製剤を作製する上において、苦味を有する薬剤の中でも、特にシロドシンは極めて強い苦味を有する上、針状結晶性の物質であるため、苦味を抑制するために多くのコーティング剤を必要とし、それにより溶出性が低下したり、水なしで服用した際に異物感が残るなどの問題がある。また、シロドシンは、医薬品添加物として汎用される賦形剤等により分解しやすい化学的性質を有しており、シロドシンの特性上、様々な克服すべき点があった。更に、前立腺肥大症に伴う排尿障害の治療剤として、既に使用されているシロドシン製剤が有効性を発揮する血中濃度を、適切に再現できる製剤でなければならない。 Among the drugs having a bitter taste in producing the preparation for oral administration of the present invention, silodosin has a particularly strong bitter taste, and since it is a needle-like crystalline substance, many coating agents are used to suppress the bitter taste. Necessary, and thus there are problems such as a decrease in elution and a feeling of foreign matter remaining when taken without water. In addition, silodosin has chemical properties that are easily degraded by excipients and the like that are widely used as pharmaceutical additives, and there are various points to be overcome due to the characteristics of silodosin. Furthermore, as a therapeutic agent for dysuria associated with benign prostatic hyperplasia, it must be a preparation that can appropriately reproduce the blood concentration at which the already used silodosin preparations are effective.
　本発明者らは、これらの点を克服しつつ上記課題を解決すべく、鋭意検討を行った。例えば、ココアパウダーや乳酸カルシウムなどによる官能的マスキング手法、カラギーナンなどによる化学的マスキング手法では、シロドシンの強烈な苦味をマスキングすることができなかった。また、一般に物理的マスキング手法に用いられる腸溶性基剤（腸溶性高分子）は、シロドシンと配合変化を起こし、使用できないことが判明した。更に種々検討を行った結果、本発明のマスキング粒子を用いることにより、驚くべきことに、強い苦味を感じることなく水なしでも服用でき、所望の溶出特性によりヒトでの有効な血中濃度を実現し得ること等、極めて望ましい性能を発揮する経口投与製剤が得られることを見出し、本発明を完成した。さらに、本発明のマスキング粒子を用いた口腔内速崩壊製剤が、強い苦味を感じることなく、水なしでも口腔内で速やかに崩壊し、所望の溶出特性を有することを見出し、本発明を完成した。 The present inventors have intensively studied to solve the above problems while overcoming these points. For example, sensory masking techniques such as cocoa powder and calcium lactate, and chemical masking techniques such as carrageenan could not mask the intense bitter taste of silodosin. Moreover, it became clear that the enteric base (enteric polymer) generally used for the physical masking technique cannot be used due to a change in formulation with silodosin. As a result of various investigations, by using the masking particles of the present invention, it is surprisingly possible to take it without water without feeling a strong bitter taste, and achieve an effective blood concentration in humans with desired elution characteristics The present invention has been completed by finding that an oral administration preparation exhibiting extremely desirable performance can be obtained. Further, the present invention was completed by finding that the rapidly disintegrating preparation in the oral cavity using the masking particles of the present invention rapidly disintegrates in the oral cavity without water without feeling a strong bitter taste and has desired dissolution characteristics. .
　即ち、本発明は、
〔１〕苦味を有する薬剤を含有する薬物粒子を、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体を含有するコーティング剤で造粒又は被覆して得られるマスキング粒子であって、該共重合体含量が、苦味を有する薬剤１００質量部に対して８０質量部～４００質量部である、マスキング粒子；
〔２〕苦味を有する薬剤がシロドシンである、前記〔１〕記載のマスキング粒子；
〔３〕該マスキング粒子を含有する経口投与製剤のｐＨ６．８における１５分後の溶出率が、８５％以上である、前記〔２〕記載のマスキング粒子；
〔４〕該マスキング粒子を含有する経口投与製剤のヒト苦味官能試験における苦味を感じ始める時間が、３０秒以上である、前記〔１〕～〔３〕のいずれかに記載のマスキング粒子；
〔５〕苦味を有する薬剤を含有する薬物粒子が、シロドシンと添加剤との混合物である、前記〔１〕記載のマスキング粒子；
〔６〕苦味を有する薬剤を含有する薬物粒子が、シロドシンと添加剤との造粒物である、前記〔５〕記載のマスキング粒子；
〔７〕添加剤が、糖又は糖アルコール及びデンプン類から選択される少なくとも１つの添加剤である、前記〔５〕又は〔６〕記載のマスキング粒子；
〔８〕該共重合体含量が、苦味を有する薬剤１００質量部に対して１００質量部～２００質量部である、前記〔１〕～〔７〕のいずれかに記載のマスキング粒子；
〔９〕該マスキング粒子中の苦味を有する薬剤含量が、５～２５質量％である、前記〔１〕～〔８〕のいずれかに記載のマスキング粒子；
〔１０〕該マスキング粒子中のメタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体含量が、１０～３０質量％である、前記〔１〕～〔９〕のいずれかに記載のマスキング粒子；
〔１１〕メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体含量が、薬物粒子１００質量部に対して２０質量部～４０質量部である、前記〔１〕～〔１０〕のいずれかに記載のマスキング粒子；
〔１２〕前記〔１〕～〔１１〕のいずれかに記載のマスキング粒子を含有する経口投与製剤；
〔１３〕該マスキング粒子以外の成分として、さらに賦形剤、崩壊剤及び滑沢剤を含有してなる、前記〔１２〕記載の経口投与製剤；
〔１４〕該賦形剤及び崩壊剤が、少なくともこれらを含有する顆粒状で含有されることを特徴とする、前記〔１３〕記載の経口投与製剤；
〔１５〕賦形剤が、乳糖、果糖、Ｄ－マンニトール、エリスリトール、キシリトール、マルトース、Ｄ－ソルビトール、マルチトール、コメデンプン、トウモロコシデンプン、バレイショデンプン、結晶セルロース及び無水リン酸カルシウムから選択される1つ又は2つ以上である、前記〔１３〕記載の経口投与製剤；
〔１６〕崩壊剤が、部分アルファー化デンプン、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、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、カルメロース、カルメロースカルシウム及びカルメロースナトリウムから選択される1つ又は2つ以上である、前記〔１３〕記載の経口投与製剤；
〔１７〕滑沢剤が、フマル酸ステアリルナトリウム、ステアリン酸マグネシウム、ステアリン酸カルシウム、蔗糖脂肪酸エステル、タルク及び軽質無水ケイ酸から選択される1つ又は2つ以上である、前記〔１３〕記載の経口投与製剤；
〔１８〕経口投与製剤が口腔内速崩壊製剤である、前記〔１２〕～〔１７〕のいずれかに記載の経口投与製剤；
〔１９〕口腔内速崩壊製剤が錠剤である、前記〔１８〕記載の経口投与製剤；
〔２０〕口腔内崩壊時間が４０秒以内である、前記〔１９〕記載の経口投与製剤；
〔２１〕苦味を感じ始めるまでの時間が口腔内崩壊時間より長いことを特徴とする、前記〔２０〕記載の経口投与製剤；
〔２２〕ｐＨ６．８における１５分後の溶出率が８５％以上である、前記〔１２〕～〔２１〕のいずれかに記載の経口投与製剤；
〔２３〕（ａ）苦味を有する薬剤と添加剤を混合又は造粒して薬物粒子を調製する工程、及び（ｂ）工程（ａ）で得られた薬物粒子にメタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体を含有するコーティング剤で造粒又は被覆して、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体含量が、苦味を有する薬剤１００質量部に対して８０質量部～４００質量部である、マスキング粒子を調製する工程を包含することを特徴とする、マスキング粒子を製造する方法；
〔２４〕苦味を有する薬剤がシロドシンである、前記〔２３〕記載のマスキング粒子を製造する方法；等に関するものである。 That is, the present invention
[1] Masking particles obtained by granulating or coating drug particles containing a drug having a bitter taste with a coating agent containing methyl methacrylate-diethylaminoethyl methacrylate copolymer, the content of the copolymer Masking particles, wherein the amount is from 80 parts by mass to 400 parts by mass with respect to 100 parts by mass of the drug having a bitter taste;
[2] The masking particle according to the above [1], wherein the drug having a bitter taste is silodosin;
[3] The masking particles according to the above [2], wherein the orally administered preparation containing the masking particles has an elution rate after 15 minutes at pH 6.8 of 85% or more;
[4] The masking particle according to any one of the above [1] to [3], wherein the time when the oral bitterness-containing preparation containing the masking particle starts to feel bitterness in the human bitterness sensory test is 30 seconds or longer;
[5] The masking particle according to [1], wherein the drug particle containing a drug having a bitter taste is a mixture of silodosin and an additive;
[6] The masking particles according to the above [5], wherein the drug particles containing a drug having a bitter taste are a granulated product of silodosin and an additive;
[7] The masking particle according to [5] or [6], wherein the additive is at least one additive selected from sugar or sugar alcohol and starches;
[8] The masking particles according to any one of [1] to [7], wherein the copolymer content is 100 to 200 parts by mass with respect to 100 parts by mass of the drug having a bitter taste;
[9] The masking particle according to any one of the above [1] to [8], wherein the content of the drug having a bitter taste in the masking particle is 5 to 25% by mass;
[10] The masking particles according to any one of [1] to [9], wherein the content of methyl methacrylate-diethylaminoethyl methacrylate copolymer in the masking particles is 10 to 30% by mass;
[11] The masking according to any one of [1] to [10], wherein the content of methyl methacrylate-diethylaminoethyl methacrylate copolymer is 20 to 40 parts by mass with respect to 100 parts by mass of the drug particles. particle;
[12] An oral administration preparation containing the masking particles according to any one of [1] to [11];
[13] The preparation for oral administration according to the above [12], further comprising an excipient, a disintegrant and a lubricant as components other than the masking particles;
[14] The oral administration preparation of [13] above, wherein the excipient and disintegrant are contained in the form of granules containing at least these;
[15] One or more excipients selected from lactose, fructose, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol, rice starch, corn starch, potato starch, crystalline cellulose and anhydrous calcium phosphate Two or more oral preparations according to [13] above;
[16] One or two disintegrating agents selected from partially pregelatinized starch, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, carmellose, carmellose calcium and carmellose sodium Orally administered preparation according to the above [13];
[17] The oral administration according to [13], wherein the lubricant is one or more selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, talc and light anhydrous silicic acid. Dosage formulation;
[18] The oral administration preparation according to any of [12] to [17], wherein the oral administration preparation is an intraoral rapidly disintegrating preparation;
[19] The oral administration preparation of [18], wherein the intraoral rapidly disintegrating preparation is a tablet;
[20] The oral administration preparation of [19], wherein the oral disintegration time is within 40 seconds;
[21] The oral administration preparation of [20] above, wherein the time until the bitter taste is started is longer than the oral disintegration time;
[22] The oral administration preparation described in any of [12] to [21] above, wherein the dissolution rate after 15 minutes at pH 6.8 is 85% or more;
[23] (a) a step of preparing a drug particle by mixing or granulating a drug having a bitter taste and an additive, and (b) methyl methacrylate-diethylaminoethyl methacrylate in the drug particle obtained in step (a) Granulated or coated with a coating agent containing a copolymer, the methyl methacrylate-diethylaminoethyl methacrylate copolymer content is 80 to 400 parts by mass with respect to 100 parts by mass of the drug having a bitter taste. A method for producing masking particles, comprising the step of preparing masking particles;
[24] The method for producing masking particles according to [23], wherein the drug having a bitter taste is silodosin.
　本発明において、「メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体」としては、例えば、コリコート（登録商標）スマートシール３０Ｄ等が挙げられる。 In the present invention, examples of the “methyl methacrylate-diethylaminoethyl methacrylate copolymer” include Kollicoat (registered trademark) Smart Seal 30D.
　本発明に用いられるメタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体は、必要に応じて、非腸溶性高分子と組み合わせて使用してもよい。 The methyl methacrylate-diethylaminoethyl methacrylate copolymer used in the present invention may be used in combination with a non-enteric polymer, if necessary.
　「非腸溶性高分子」とは、腸溶性高分子以外の水に不溶な高分子をいい、例えば、胃溶性高分子又は水不溶性高分子が挙げられる。 “A non-enteric polymer” refers to a water-insoluble polymer other than the enteric polymer, such as a gastric polymer or a water-insoluble polymer.
　胃溶性高分子としては、例えば、アミノアルキルメタクリレートコポリマーＥ（例えば、オイドラギット（登録商標）ＥＰＯ、オイドラギット（登録商標）Ｅ１００）等のメタクリル酸メチル－メタクリル酸ブチル－メタクリル酸ジメチルアミノエチル共重合体、ポリビニルアセタールジエチルアミノアセテート（例えば、ＡＥＡ（登録商標））等の胃溶性ポリビニル誘導体等が挙げられる。 Examples of the gastric soluble polymer include methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer such as aminoalkyl methacrylate copolymer E (for example, Eudragit (registered trademark) EPO, Eudragit (registered trademark) E100), Examples thereof include gastric soluble polyvinyl derivatives such as polyvinyl acetal diethylaminoacetate (for example, AEA (registered trademark)).
　水不溶性高分子としては、例えば、アクリル酸エチル－メタクリル酸メチルコポリマー分散液（例えば、オイドラギット（登録商標）ＮＥ３０Ｄ）等のアクリル酸エチル－メタクリル酸メチル共重合体、アミノアルキルメタクリレートコポリマーＲＳ（例えば、オイドラギット（登録商標）ＲＳ１００、オイドラギット（登録商標）ＲＳＰＯ、オイドラギット（登録商標）ＲＬ、オイドラギット（登録商標）ＲＬＰＯ）、及びアミノアルキルメタクリレートコポリマーＲＳ水分散液（例えば、オイドラギット（登録商標）ＲＳ３０Ｄ、オイドラギット（登録商標）ＲＬ３０Ｄ））等のアクリル酸エチル－メタクリル酸メチル－メタクリル酸塩化トリメチルアンモニウムエチル共重合体等の水不溶性アクリル酸系共重合体、エチルセルロース（例えば、エトセル（登録商標））、エチルセルロース水分散液（例えば、アクアコート（登録商標））等の水不溶性セルロースエーテル、酢酸ビニル樹脂（例えば、コリコート（登録商標）ＳＲ、コリコート（登録商標）ＳＲ３０Ｄ）等が挙げられる。 Examples of the water-insoluble polymer include ethyl acrylate-methyl methacrylate copolymer such as ethyl acrylate-methyl methacrylate copolymer dispersion (for example, Eudragit (registered trademark) NE30D), aminoalkyl methacrylate copolymer RS (for example, Eudragit (R) RS100, Eudragit (R) RSPO, Eudragit (R) RL, Eudragit (R) RLPO), and aminoalkyl methacrylate copolymer RS aqueous dispersions (e.g. Eudragit (R) RS30D, Eudragit ( Water-insoluble acrylic copolymer such as ethyl acrylate-methyl methacrylate-methacrylated trimethylammonium ethyl copolymer such as (registered trademark) RL30D)), ethyl cellulose For example, water-insoluble cellulose ether such as etosel (registered trademark), aqueous dispersion of ethyl cellulose (for example, Aquacoat (registered trademark)), vinyl acetate resin (for example, Kollicoat (registered trademark) SR, Kollicoat (registered trademark) SR30D) Etc.
　本発明に用いられるメタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体を含有するコーティング剤は、上記非腸溶性高分子のほか、必要に応じて、添加剤、水溶性高分子等を含んでいてもよい。水溶性高分子を用いる場合、非腸溶性高分子及び水溶性高分子の合計質量に対する水溶性高分子の質量の割合は２０％以下が好ましい。添加剤としては、例えば、可塑剤、滑沢剤、界面活性剤、酸化防止剤等が挙げられる。可塑剤としては、例えば、ステアリン酸、トリアセチン、クエン酸トリエチル、マクロゴール、グリセリン、グリセリン脂肪酸エステル、ヒマシ油、セバシン酸ジエチル、セバシン酸ジブチル等が挙げられる。滑沢剤としては、例えば、タルク、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等が挙げられる。界面活性剤としては、例えば、ラウリル硫酸ナトリウム、ポリソルベート等が挙げられる。水溶性高分子としては、例えば、ヒプロメロース、メチルセルロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、ポビドン、カルメロースナトリウム、アルギン酸ナトリウム等が挙げられる。酸化防止剤としては、例えば、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、ビタミンE（トコフェロール）等が挙げられる。これらの添加剤及び水溶性高分子は、２つ以上を組み合わせて使用することもできる。 The coating agent containing methyl methacrylate-diethylaminoethyl methacrylate copolymer used in the present invention may contain additives, water-soluble polymers, etc., if necessary, in addition to the non-enteric polymer. Good. When the water-soluble polymer is used, the ratio of the mass of the water-soluble polymer to the total mass of the non-enteric polymer and the water-soluble polymer is preferably 20% or less. Examples of the additive include a plasticizer, a lubricant, a surfactant, and an antioxidant. Examples of the plasticizer include stearic acid, triacetin, triethyl citrate, macrogol, glycerin, glycerin fatty acid ester, castor oil, diethyl sebacate, dibutyl sebacate and the like. Examples of the lubricant include talc, stearic acid, magnesium stearate, calcium stearate and the like. Examples of the surfactant include sodium lauryl sulfate and polysorbate. Examples of the water-soluble polymer include hypromellose, methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, povidone, carmellose sodium, sodium alginate and the like. Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, vitamin E (tocopherol) and the like. These additives and water-soluble polymers can be used in combination of two or more.
　本発明において、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体の含量は、例えば、苦味を有する薬剤（例えば、シロドシン）１００質量部に対して、例えば、８０～４００質量部、８０～３００質量部、８０～２００質量部、１００～４００質量部、１００～３００質量部、１００～２００質量部等を挙げることができ、より好ましくは１００～２００質量部である。 In the present invention, the content of methyl methacrylate-diethylaminoethyl methacrylate copolymer is, for example, 80 to 400 parts by mass, 80 to 300 parts by mass with respect to 100 parts by mass of the drug having a bitter taste (for example, silodosin). 80 to 200 parts by mass, 100 to 400 parts by mass, 100 to 300 parts by mass, 100 to 200 parts by mass, and more preferably 100 to 200 parts by mass.
　本発明のマスキング粒子中のメタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体の含量は、好ましくは、１０～３０質量％であり、より好ましくは１５～２５質量％である。 The content of the methyl methacrylate-diethylaminoethyl methacrylate copolymer in the masking particles of the present invention is preferably 10 to 30% by mass, more preferably 15 to 25% by mass.
　本発明において、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体の含量は、例えば、薬物粒子１００質量部に対して、概ね２０～５０質量部であり、好ましくは２０～４０質量部であり、より好ましくは３０～４０質量部である。 In the present invention, the content of the methyl methacrylate-diethylaminoethyl methacrylate copolymer is, for example, generally 20 to 50 parts by mass, preferably 20 to 40 parts by mass with respect to 100 parts by mass of the drug particles. The amount is preferably 30 to 40 parts by mass.
　また、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体と非腸溶性高分子を組み合わせて使用する場合、これらの総含量は、前記と同じである。 Further, when a methyl methacrylate-diethylaminoethyl methacrylate copolymer and a non-enteric polymer are used in combination, the total content thereof is the same as described above.
　本発明において、「平均粒子径」とは、５０％粒子径（質量基準メジアン径）を意味する。この５０％粒子径は、篩式粒度分布測定装置（例えば、ギルソニックオートシーバーＧＡ－６、Ｇｉｌｓｏｎ社製）により測定することができる。 In the present invention, “average particle diameter” means 50% particle diameter (mass-based median diameter). The 50% particle size can be measured with a sieve-type particle size distribution analyzer (eg, Gilsonic Auto Seeber GA-6, manufactured by Gilson).
　本発明のマスキング粒子の平均粒子径は、例えば、概ね３００μｍ以下であり、好ましくは、約１００～２５０μｍである。 The average particle size of the masking particles of the present invention is, for example, about 300 μm or less, and preferably about 100 to 250 μm.
　本発明において、「苦味を有する薬剤」は、活性成分として疾患の治療又は予防に用いられるもので、苦味等の不快な味を有するものであればよく、例えば、シロドシン、ミチグリニド、アセトアミノフェン、アミノフィリン、エカバピド、エチオナミド、エピリゾール、カフェイン、クロラムフェニコール、ジフェンヒドラミン、シメチジン、スルピリン、テオフィリン、ニザチジン、ピラジナミド、ファモチジン、フェニルブタゾン、フェノバルビタール、メトクロプラミド及びそれらの薬理学的に許容される塩等が挙げられ、シロドシンが好ましい。 In the present invention, the “drug having a bitter taste” is used as an active ingredient for treatment or prevention of a disease, and may have any unpleasant taste such as a bitter taste. For example, silodosin, mitiglinide, acetaminophen, Aminophylline, ecabapid, ethionamide, epilysole, caffeine, chloramphenicol, diphenhydramine, cimetidine, sulpyrine, theophylline, nizatidine, pyrazinamide, famotidine, phenylbutazone, phenobarbital, metoclopramide and their pharmacologically acceptable salts, etc. And silodosin is preferred.
　なお、苦味を有する薬剤は、これに限定されるものではない。 Note that the drug having a bitter taste is not limited to this.
　例えば、シロドシンは、市販のものを使用することもでき、又は文献記載の方法（例えば、特許文献１参照）もしくはそれに準じた方法により製造することもできる。 For example, commercially available silodosin can be used, or can be produced by a method described in the literature (for example, see Patent Document 1) or a method analogous thereto.
　本発明に用いられる「シロドシン」は、凝集した塊がない程度の粒子であればよく、必要に応じて、解砕、粉砕等してもよい。シロドシンの平均粒子径は、５０μｍ程度以下のものが好ましく、１～３０μｍ程度のものがより好ましい。 The “silodosin” used in the present invention may be particles having no aggregated mass, and may be crushed, pulverized, or the like, if necessary. The average particle size of silodosin is preferably about 50 μm or less, more preferably about 1 to 30 μm.
　本発明に用いられる「苦味を有する薬剤を含有する薬物粒子」は、苦味を有する薬剤、例えば、シロドシンの場合、シロドシンのほかに、適当な添加剤を使用するのが望ましく、シロドシンと適当な添加剤との混合物、シロドシンと適当な添加剤との造粒物及び適当な添加剤をシロドシンで被覆したもの等が挙げられる。 The “drug particles containing a drug having a bitter taste” used in the present invention is preferably a drug having a bitter taste, for example, in the case of silodosin, it is desirable to use an appropriate additive in addition to silodosin. A mixture with an agent, a granulated product of silodosin and an appropriate additive, and an appropriate additive coated with silodosin.
　薬物粒子に用いられる添加剤としては、苦味を有する薬剤（例えば、シロドシン）と配合変化を起こさない種々の添加剤が用いることができ、例えば、崩壊剤、賦形剤、結合剤、滑沢剤、甘味剤、酸味剤、発泡剤、香料、着色剤等を適宜用いることができる。崩壊剤としては、例えば、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、カルメロースカルシウム、カルメロースナトリウム、コメデンプン、トウモロコシデンプン、バレイショデンプン、カルボキシメチルスターチナトリウム、カルメロース、部分アルファー化デンプン、アルファー化デンプン、クロスポビドン、結晶セルロース等が挙げられる。賦形剤としては、例えば、コメデンプン、トウモロコシデンプン、バレイショデンプン、部分アルファー化デンプン、アルファー化デンプン、トレハロース、結晶セルロース、メタケイ酸アルミン酸マグネシウム、無水リン酸カルシウム、沈降炭酸カルシウム、ケイ酸カルシウム、乳酸カルシウム、乳糖、果糖、Ｄ－マンニトール、エリスリトール、キシリトール、マルトース、Ｄ－ソルビトール、マルチトール等が挙げられる。結合剤としては、例えば、デンプン類、結晶セルロース、ヒドロキシプロピルセルロース、ヒプロメロース、ポビドン、デキストリン、ゼラチン、プルラン、ポリビニルアルコール、アルギン酸ナトリウム、ポリエチレングリコール等が挙げられる。滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸、タルク、軽質無水ケイ酸、蔗糖脂肪酸エステル、フマル酸ステアリルナトリウム、ポリエチレングリコール、モノステアリン酸グリセリン等が挙げられる。甘味料としては、例えば、アスパルテーム、サッカリン、サッカリンナトリウム、グリチルリチン酸ジカリウム、ステビア、ソーマチン、アセスルファムカリウム、スクラロース等が挙げられる。酸味剤としては、例えば、クエン酸、酒石酸、リンゴ酸、アスコルビン酸等が挙げられる。発泡剤としては、例えば、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カルシウム等が挙げられる。矯味剤としては、例えば、Ｌ－アスパラギン酸、塩化ナトリウム、塩化マグネシウム、クエン酸ナトリウム、クエン酸カルシウム、Ｌ－グルタミン酸ナトリウム、炭酸水素ナトリウム等が挙げられる。香料としては、例えば、ストロベリー、ヨーグルト、バナナ、パイナップル、オレンジ、レモン、メントール、ピーチ、アップル、チョコレート、ココア、バニラ、紅茶、抹茶等が挙げられる。着色剤としては、例えば、食用黄色５号、食用赤色２号、食用青色２号等の食用色素、黄色三二酸化鉄、三二酸化鉄、カラメル色素、酸化チタン等が挙げられる。 As the additive used for the drug particles, various additives which do not cause a change in composition with a drug having a bitter taste (for example, silodosin) can be used, for example, a disintegrant, an excipient, a binder, a lubricant. Sweetening agents, sour agents, foaming agents, flavoring agents, coloring agents, and the like can be used as appropriate. Examples of disintegrants include low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, carmellose sodium, rice starch, corn starch, potato starch, carboxymethyl starch sodium, carmellose, partially pregelatinized starch, and pregelatinized. Examples include starch, crospovidone, crystalline cellulose and the like. Excipients include, for example, rice starch, corn starch, potato starch, partially pregelatinized starch, pregelatinized starch, trehalose, crystalline cellulose, magnesium aluminate metasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate Lactose, fructose, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol and the like. Examples of the binder include starches, crystalline cellulose, hydroxypropyl cellulose, hypromellose, povidone, dextrin, gelatin, pullulan, polyvinyl alcohol, sodium alginate, polyethylene glycol and the like. Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous silicic acid, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, glyceryl monostearate and the like. Examples of the sweetener include aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, acesulfame potassium, sucralose and the like. Examples of sour agents include citric acid, tartaric acid, malic acid, ascorbic acid and the like. Examples of the foaming agent include sodium bicarbonate, sodium carbonate, calcium carbonate and the like. Examples of the corrigent include L-aspartic acid, sodium chloride, magnesium chloride, sodium citrate, calcium citrate, sodium L-glutamate, sodium bicarbonate and the like. Examples of the fragrances include strawberry, yogurt, banana, pineapple, orange, lemon, menthol, peach, apple, chocolate, cocoa, vanilla, black tea, matcha tea and the like. Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, yellow iron sesquioxide, iron sesquioxide, caramel pigment, and titanium oxide.
　本発明において薬物粒子に用いられる添加剤としては、賦形剤又は崩壊剤として、例えば、糖又は糖アルコール及びデンプン類等が好ましく、デンプン類がより好ましい。糖又は糖アルコールとしては、例えば、Ｄ－マンニトール、エリスリトール、キシリトール、マルトース、Ｄ－ソルビトール、マルチトール等が挙げられ、Ｄ－マンニトールがより好ましい。デンプン類としては、例えば、トウモロコシデンプン、コメデンプン、バレイショデンプン、部分アルファー化デンプン、アルファー化デンプン等が挙げられ、部分アルファー化デンプン、アルファー化デンプンがより好ましい。滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク等が好ましく、タルクがより好ましい。結合剤としては、例えば、デンプン類、ヒドロキシプロピルセルロース、ヒプロメロース、ポビドン、デキストリン、ゼラチン、プルラン、ポリビニルアルコール、アルギン酸ナトリウム、ポリエチレングリコール等が好ましく、ヒドロキシプロピルセルロース、ヒプロメロースがより好ましい。これらの添加剤は、必要に応じて、２つ以上を組み合わせて使用してもよい。 As the additive used for the drug particles in the present invention, as an excipient or a disintegrant, for example, sugar or sugar alcohol and starches are preferable, and starches are more preferable. Examples of the sugar or sugar alcohol include D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol and the like, and D-mannitol is more preferable. Examples of the starches include corn starch, rice starch, potato starch, partially pregelatinized starch, pregelatinized starch, and the like. Partially pregelatinized starch and pregelatinized starch are more preferable. As the lubricant, for example, magnesium stearate, calcium stearate, talc and the like are preferable, and talc is more preferable. As the binder, for example, starches, hydroxypropylcellulose, hypromellose, povidone, dextrin, gelatin, pullulan, polyvinyl alcohol, sodium alginate, polyethylene glycol and the like are preferable, and hydroxypropylcellulose and hypromellose are more preferable. You may use these additives in combination of 2 or more as needed.
　本発明のマスキング粒子中の苦味を有する薬剤（例えば、シロドシン）の含量は、３０質量％以下が好ましく、５～２５質量％がより好ましく、５～１６質量％が更に好ましい。 The content of the drug having a bitter taste (for example, silodosin) in the masking particles of the present invention is preferably 30% by mass or less, more preferably 5 to 25% by mass, and further preferably 5 to 16% by mass.
　本発明に用いられる薬物粒子中の苦味を有する薬剤（例えば、シロドシン）の含量は、５０質量％以下が好ましく、例えば、１０～４０質量％、１０～３０質量％、２０～２７質量％等である。 The content of the drug (for example, silodosin) having a bitter taste in the drug particles used in the present invention is preferably 50% by mass or less, for example, 10 to 40% by mass, 10 to 30% by mass, 20 to 27% by mass, etc. is there.
（マスキング粒子の製造方法）
　以下、マスキング粒子の製造方法をシロドシンを例に説明するが、苦味を有する薬剤はこれに限定されるものではない。 (Manufacturing method of masking particles)
Hereinafter, although the manufacturing method of masking particle | grains is demonstrated to an example for silodosin, the chemical | medical agent which has a bitter taste is not limited to this.
　本発明のマスキング粒子は、核顆粒コーティング法、造粒マトリックス法、造粒コーティング法等のマスキング粒子を製造する際に一般的に用いられる方法により、製造することができる。例えば、シロドシンと添加剤を混合又は造粒して得られる薬物粒子を、非腸溶性高分子を含有するコーティング剤で造粒又は被覆することにより製造することもできる。これら一連の製造において、造粒又は被覆する方法として、高速混合撹拌造粒法、転動流動層造粒法、流動層造粒法等が挙げられ、流動層造粒法が好ましい。 The masking particles of the present invention can be produced by a method generally used for producing masking particles such as a nuclear granule coating method, a granulation matrix method, and a granulation coating method. For example, drug particles obtained by mixing or granulating silodosin and additives can be produced by granulating or coating with a coating agent containing a non-enteric polymer. In these series of production, granulation or coating methods include high-speed mixing and stirring granulation method, rolling fluidized bed granulation method, fluidized bed granulation method and the like, and fluidized bed granulation method is preferable.
　具体的には、例えば、核顆粒コーティング法では、市販又は造粒した結晶セルロース、Ｄ－マンニトール、トウモロコシデンプン、水酸化マグネシウム、炭酸マグネシウム、白糖等の核粒子を、シロドシンを含有する分散液及び非腸溶性高分子を含有するコーティング剤の溶液又は分散液で順次被覆、又はこれらの混合液で被覆して、マスキング粒子を製造することもできる。 Specifically, for example, in the nuclear granule coating method, commercially available or granulated crystalline cellulose, D-mannitol, corn starch, magnesium hydroxide, magnesium carbonate, sucrose, etc. are dispersed into a dispersion containing silodosin and non-coated particles. Masking particles can also be produced by sequentially coating with a solution or dispersion of a coating agent containing an enteric polymer, or coating with a mixture thereof.
　また、例えば、造粒マトリックス法では、シロドシンと添加剤（例えば、Ｄ－マンニトール、部分アルファー化デンプン、アルファー化デンプン、軽質無水ケイ酸等）との混合物を、非腸溶性高分子を含有するコーティング剤の溶液又は分散液を噴霧しながら造粒又は被覆することにより、マスキング粒子を製造することもできる。 For example, in the granulation matrix method, a mixture of silodosin and an additive (for example, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.) is coated with a coating containing a non-enteric polymer. Masking particles can also be produced by granulating or coating while spraying a solution or dispersion of the agent.
　また、例えば、造粒コーティング法では、シロドシンと添加剤（例えば、Ｄ－マンニトール、部分アルファー化デンプン、アルファー化デンプン、軽質無水ケイ酸等）との混合物を、水溶性結合剤の溶液を噴霧しながら造粒した後、得られた造粒物を、非腸溶性高分子を含有するコーティング剤の溶液又は分散液を噴霧しながら被覆することにより、マスキング粒子を製造することもできる。水溶性結合剤としては、ヒドロキシプロピルセルロース、ヒプロメロースが好ましい。 For example, in the granulation coating method, a mixture of silodosin and an additive (for example, D-mannitol, partially pregelatinized starch, pregelatinized starch, light anhydrous silicic acid, etc.) is sprayed with a solution of a water-soluble binder. Then, after granulation, the obtained granulated product is coated while spraying a solution or dispersion of a coating agent containing a non-enteric polymer, whereby masking particles can be produced. As the water-soluble binder, hydroxypropylcellulose and hypromellose are preferable.
　上記の方法において、造粒マトリックス法又は造粒コーティング法が好ましく、造粒コーティング法がより好ましい。 In the above method, the granulation matrix method or the granulation coating method is preferable, and the granulation coating method is more preferable.
　非腸溶性高分子を溶解又は分散させるために用いられる溶媒は、特に限定されず、メタノール、エタノール、イソプロピルアルコール等のアルコール類、アセトン、トルエン、メチルエチルケトン及び水、又はこれらの混合溶媒等が挙げられ、エタノール及び水が好ましく、水がより好ましい。アミノアルキルメタクリレートコポリマーEは水に不溶であるが、酸性（ｐＨ５以下）の水に溶解した水溶液として用いるか、アミノアルキルメタクリレートコポリマーEにラウリル硫酸ナトリウムとステアリン酸、セバシン酸ジエチル及びセバシン酸ジブチルから選択される少なくとも１つの可塑剤を任意の割合で混合した水分散液として用いることもできる。 The solvent used for dissolving or dispersing the non-enteric polymer is not particularly limited, and examples thereof include alcohols such as methanol, ethanol and isopropyl alcohol, acetone, toluene, methyl ethyl ketone and water, or a mixed solvent thereof. Ethanol and water are preferred, and water is more preferred. Aminoalkyl methacrylate copolymer E is insoluble in water but used as an aqueous solution dissolved in acidic (pH 5 or lower) water, or selected from aminoalkyl methacrylate copolymer E from sodium lauryl sulfate and stearic acid, diethyl sebacate and dibutyl sebacate It is also possible to use an aqueous dispersion in which at least one plasticizer is mixed at an arbitrary ratio.
　本発明のマスキング粒子は、製造時の凝集を防ぐため、さらに適当な添加剤でオーバーコートしてから用いてもよく、本発明のマスキング粒子にはオーバーコートしたものも含まれる。ただし、本明細書において、マスキング粒子の質量には、オーバーコートに用いられる添加剤の質量は含まない。オーバーコートに用いられる添加剤としては、例えば、乳糖、グルコース、蔗糖、果糖等の糖、Ｄ－マンニトール、エリスリトール、キシリトール、マルトース、Ｄ－ソルビトール、マルチトール等の糖アルコールが挙げられ、好ましくは、Ｄ－マンニトールである。 The masking particles of the present invention may be used after being overcoated with a suitable additive in order to prevent agglomeration during production. The masking particles of the present invention include those that are overcoated. However, in the present specification, the mass of the masking particles does not include the mass of the additive used for the overcoat. Examples of the additive used for the overcoat include sugars such as lactose, glucose, sucrose, and fructose, and sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol. D-mannitol.
　オーバーコートする方法は、特に限定されないが、例えば、本発明のマスキング粒子に添加剤（例えば、糖又は糖アルコール）の水溶液を噴霧しながら被覆することにより製造することもできる。オーバーコートに用いられる添加剤の含量は、マスキング粒子100質量部に対して、通常１～２０質量部、好ましくは２～１５質量部であり、さらに好ましくは５～１０質量部である。 The method of overcoating is not particularly limited, but for example, it can also be produced by coating the masking particles of the present invention while spraying an aqueous solution of an additive (for example, sugar or sugar alcohol). The content of the additive used for the overcoat is usually 1 to 20 parts by weight, preferably 2 to 15 parts by weight, and more preferably 5 to 10 parts by weight with respect to 100 parts by weight of the masking particles.
（経口投与製剤）
　本発明のマスキング粒子を用いて種々の剤形の経口投与製剤を製造することができる。本発明の経口投与製剤の剤形としては、例えば、顆粒剤、散剤、錠剤等が挙げられる。 (Oral administration)
Oral administration preparations of various dosage forms can be produced using the masking particles of the present invention. Examples of the dosage form of the oral administration preparation of the present invention include granules, powders, tablets and the like.
　本発明の経口投与製剤としては、例えば、口腔内速崩壊顆粒、口腔内速崩壊散、口腔内速崩壊錠剤等の口腔内速崩壊製剤が好ましく、口腔内速崩壊錠剤がより好ましい。 As the preparation for oral administration of the present invention, for example, intraoral rapidly disintegrating preparations such as intraoral rapidly disintegrating granules, intraoral rapidly disintegrating powder and intraoral rapidly disintegrating tablets are preferable, and intraoral rapidly disintegrating tablets are more preferable.
　本発明の経口投与製剤は、本発明のマスキング粒子と口腔内速崩壊製剤に一般的に使用される医薬品添加物を用いて、製剤分野において慣用の方法により製造することができる。 The preparation for oral administration of the present invention can be produced by a conventional method in the pharmaceutical field using the masking particles of the present invention and pharmaceutical additives generally used for intraoral quick disintegrating preparations.
　例えば、錠剤の場合には、本発明のマスキング粒子を、口腔内速崩壊製剤に一般的に使用される医薬品添加物と共に、直接粉末圧縮法（直打法）、造粒法等の公知の方法又はそれに準じた方法で錠剤化することにより、経口投与製剤を製造することもできる。 For example, in the case of tablets, the masking particles of the present invention are used together with pharmaceutical additives generally used for intraoral quick disintegrating preparations, and known methods such as direct powder compression (direct compression) and granulation Or an oral administration preparation can also be manufactured by tableting by the method according to it.
　具体的には、例えば、直打法では、本発明のマスキング粒子と、賦形剤、崩壊剤、結合剤、滑沢剤等の医薬品添加物を含有する混合物を造粒せずに、混合機を用いて混合した後、打錠して経口投与製剤を製造することもできる。 Specifically, for example, in the direct hitting method, a mixer is used without granulating a mixture containing the masking particles of the present invention and a pharmaceutical additive such as an excipient, a disintegrant, a binder, and a lubricant. And then tableting to produce a preparation for oral administration.
　また、例えば、造粒法では、賦形剤、崩壊剤等の混合物を、水、水とエタノールの混合液又は結合剤もしくは崩壊剤の溶液もしくは懸濁液等を用いて造粒し、顆粒とした後、本発明のマスキング粒子、滑沢剤等と混合機を用いて混合した後、打錠してもよいし、本発明のマスキング粒子と賦形剤、崩壊剤等の混合物を、水、水とエタノールの混合液又は結合剤もしくは崩壊剤の溶液もしくは懸濁液等を用いて造粒後、さらに滑沢剤を添加して混合機を用いて混合した後、打錠して経口投与製剤を製造することもできる。 Further, for example, in the granulation method, a mixture of an excipient, a disintegrant, and the like is granulated using water, a mixed solution of water and ethanol, or a solution or suspension of a binder or a disintegrant. Then, after mixing with the masking particles of the present invention, a lubricant and the like using a mixer, it may be tableted, or a mixture of the masking particles of the present invention and excipients, disintegrants, After granulation using a mixed solution of water and ethanol, or a solution or suspension of a binder or disintegrant, add a lubricant and mix using a mixer, then tablet and tablet for oral administration Can also be manufactured.
　また、顆粒剤においても、錠剤の造粒方法に準じて流動層造粒を行うか、撹拌造粒を行うことにより製造することもできる。散剤等も錠剤の直打法に準じて医薬品添加物を混合することにより製造することもできる。 In addition, the granule can also be produced by fluidized bed granulation according to the tablet granulation method or by stirring granulation. Powders and the like can also be produced by mixing pharmaceutical additives according to the direct tableting method.
　口腔内速崩壊製剤に一般的に使用される医薬品添加物としては、前記薬物粒子に用いられる添加剤を用いることができるが、崩壊剤としては、部分アルファー化デンプン、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、カルメロースカルシウム、カルメロースナトリウム、トウモロコシデンプン等が好ましく、クロスポビドンがさらに好ましい。賦形剤としては、Ｄ－マンニトール、エリスリトール、キシリトール、マルトース、Ｄ－ソルビトール、マルチトール等の糖アルコール、トウモロコシデンプン、結晶セルロース等が好ましい。滑沢剤としては、フマル酸ステアリルナトリウム、ステアリン酸カルシウム、タルク、軽質無水ケイ酸等が好ましく、フマル酸ステアリルナトリウムがさらに好ましい。これらの医薬品添加物は、必要に応じて、２つ以上を組み合わせて使用してもよい。 As a pharmaceutical additive generally used for an intraoral quick disintegrating preparation, an additive used for the drug particles can be used. Examples of the disintegrating agent include partially pregelatinized starch, crospovidone, low substituted hydroxy Propyl cellulose, carmellose calcium, carmellose sodium, corn starch and the like are preferred, and crospovidone is more preferred. As the excipient, sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol, maltitol, corn starch, crystalline cellulose and the like are preferable. As the lubricant, sodium stearyl fumarate, calcium stearate, talc, light anhydrous silicic acid and the like are preferable, and sodium stearyl fumarate is more preferable. You may use these pharmaceutical additives in combination of 2 or more as needed.
（経口投与製剤の製造例）
　以下、本発明の経口投与製剤の製造方法を例示するが、これに限られるものではない。 (Manufacturing example of oral preparation)
Hereinafter, although the manufacturing method of the oral administration formulation of this invention is illustrated, it is not restricted to this.
〔製造例１〕
　例えば、本発明のマスキング粒子と乳糖、果糖等の糖、Ｄ－マンニトール、エリスリトール、キシリトール等の糖アルコール、コメデンプン、トウモロコシデンプン、バレイショデンプン、部分アルファー化デンプン等のデンプン類、結晶セルロース及びクロスポビドンから選択される少なくとも１つの医薬品添加物とを、混合機を用いて混合することにより、散剤を製造することもできる。前記混合工程において、必要に応じて、さらに賦形剤、崩壊剤、結合剤、滑沢剤、発泡剤、甘味剤、矯味剤、流動化剤、香料、着色剤等を１つ又は２つ以上組み合せて添加してもよい。 [Production Example 1]
For example, the masking particles of the present invention and sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol and xylitol, starches such as rice starch, corn starch, potato starch and partially pregelatinized starch, crystalline cellulose and crospovidone The powder can also be produced by mixing at least one pharmaceutical additive selected from the above using a mixer. In the mixing step, one or two or more excipients, disintegrants, binders, lubricants, foaming agents, sweeteners, corrigents, fluidizing agents, fragrances, colorants, and the like, as necessary. You may add in combination.
〔製造例２〕
　例えば、本発明のマスキング粒子と乳糖、果糖等の糖、Ｄ－マンニトール、エリスリトール、キシリトール等の糖アルコール、コメデンプン、トウモロコシデンプン、バレイショデンプン、部分アルファー化デンプン等のデンプン類、結晶セルロース、クロスポビドン、フマル酸ステアリルナトリウム、ステアリン酸カルシウム、タルク及び軽質無水ケイ酸から選択される少なくとも１つの医薬品添加物とを、混合機を用いて混合した後、その混合物を打錠することにより、錠剤を製造することもできる。前記混合工程において、必要に応じて、さらに賦形剤、崩壊剤、結合剤、滑沢剤、発泡剤、甘味剤、矯味剤、流動化剤、香料、着色剤等を１つ又は２つ以上組み合せて添加してもよい。 [Production Example 2]
For example, the masking particles of the present invention and sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol and xylitol, starches such as rice starch, corn starch, potato starch and partially pregelatinized starch, crystalline cellulose, crospovidone A tablet is produced by mixing at least one pharmaceutical additive selected from sodium stearyl fumarate, calcium stearate, talc and light anhydrous silicic acid with a mixer and then compressing the mixture. You can also In the mixing step, one or two or more excipients, disintegrants, binders, lubricants, foaming agents, sweeteners, corrigents, fluidizing agents, fragrances, colorants, and the like, as necessary. You may add in combination.
〔製造例３〕
　例えば、乳糖、果糖等の糖、Ｄ－マンニトール、エリスリトール、キシリトール、マルトース、Ｄ－ソルビトール、マルチトール等の糖アルコール、トウモロコシデンプン、コメデンプン、バレイショデンプン、部分アルファー化デンプン、アルファー化デンプン等のデンプン類及び結晶セルロースから選択される少なくとも１つの医薬品添加物を混合し、部分アルファー化デンプン又はクロスポビドンの溶液又は分散液を噴霧しながら造粒することにより、顆粒（１）を製造することもできる。前記混合、造粒工程は、高速混合撹拌造粒法、転動流動層造粒法、流動層造粒法等を用いることができ、好適には流動層造粒法である。次いで、本発明のマスキング粒子、前記顆粒（１）、さらにフマル酸ステアリルナトリウム、ステアリン酸カルシウム、タルク及び軽質無水ケイ酸から選択される少なくとも１つの滑沢剤を、混合機を用いて混合した後、打錠することにより、錠剤を製造することもできる。前記混合工程において、必要に応じて、さらに賦形剤、崩壊剤、結合剤、滑沢剤、発泡剤、甘味剤、矯味剤、流動化剤、香料、着色剤等を１つ又は２つ以上組み合せて添加してもよい。 [Production Example 3]
For example, sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol and maltitol, starches such as corn starch, rice starch, potato starch, partially pregelatinized starch and pregelatinized starch Granules (1) can also be produced by mixing at least one pharmaceutical additive selected from the group consisting of a cellulose and crystalline cellulose and granulating while spraying a solution or dispersion of partially pregelatinized starch or crospovidone . In the mixing and granulating step, a high-speed mixed stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, or the like can be used, and a fluidized bed granulation method is preferable. Next, after mixing the masking particles of the present invention, the granule (1), and at least one lubricant selected from sodium stearyl fumarate, calcium stearate, talc and light anhydrous silicic acid using a mixer, Tablets can also be produced by tableting. In the mixing step, one or two or more excipients, disintegrants, binders, lubricants, foaming agents, sweeteners, corrigents, fluidizing agents, fragrances, colorants, and the like, as necessary. You may add in combination.
〔製造例４〕
　例えば、乳糖、果糖等の糖、Ｄ－マンニトール、エリスリトール、キシリトール、マルトース、Ｄ－ソルビトール、マルチトール等の糖アルコール、トウモロコシデンプン、コメデンプン、バレイショデンプン、部分アルファー化デンプン、アルファー化デンプン等のデンプン類及び結晶セルロースから選択される少なくとも１つの医薬品添加物を混合し、水又は水とエタノールの混合液を噴霧しながら造粒することにより、顆粒（２）を製造することもできる。前記混合、造粒工程は、高速混合撹拌造粒法、転動流動層造粒法、流動層造粒法等を用いることができ、好適には流動層造粒法である。次いで、本発明のマスキング粒子、前記顆粒（２）、さらにフマル酸ステアリルナトリウム、ステアリン酸カルシウム、タルク及び軽質無水ケイ酸から選択される少なくとも１つの滑沢剤を、混合機を用いて混合した後、打錠することにより錠剤を製造することもできる。前記混合工程において、必要に応じて、さらに賦形剤、崩壊剤、結合剤、滑沢剤、発泡剤、甘味剤、矯味剤、流動化剤、香料、着色剤等を１つ又は２つ以上組み合せて添加してもよい。 [Production Example 4]
For example, sugars such as lactose and fructose, sugar alcohols such as D-mannitol, erythritol, xylitol, maltose, D-sorbitol and maltitol, starches such as corn starch, rice starch, potato starch, partially pregelatinized starch and pregelatinized starch Granules (2) can also be produced by mixing at least one pharmaceutical additive selected from the group of polymers and crystalline cellulose, and granulating while spraying water or a mixture of water and ethanol. In the mixing and granulating step, a high-speed mixed stirring granulation method, a rolling fluidized bed granulation method, a fluidized bed granulation method, or the like can be used, and a fluidized bed granulation method is preferable. Then, after mixing the masking particles of the present invention, the granule (2), and at least one lubricant selected from sodium stearyl fumarate, calcium stearate, talc and light anhydrous silicic acid using a mixer, Tablets can also be produced by tableting. In the mixing step, one or two or more excipients, disintegrants, binders, lubricants, foaming agents, sweeteners, corrigents, fluidizing agents, fragrances, colorants, and the like, as necessary. You may add in combination.
〔製造例５〕
　例えば、本発明のマスキング粒子及び前記顆粒（１）又は前記顆粒（２）を、混合機を用いて混合し、顆粒剤を製造することもできる。前記混合工程において、必要に応じて、さらに賦形剤、滑沢剤、発泡剤、甘味剤、矯味剤、流動化剤、香料、着色剤等を１つ又は２つ以上組み合せて添加してもよい。 [Production Example 5]
For example, the masking particle of the present invention and the granule (1) or the granule (2) can be mixed using a mixer to produce a granule. In the mixing step, if necessary, an excipient, a lubricant, a foaming agent, a sweetening agent, a corrigent, a fluidizing agent, a fragrance, a coloring agent, etc. may be added in combination of one or more. Good.
〔製造例６〕
　例えば、Ｄ－マンニトール及び結晶セルロースの混合物を、流動層造粒乾燥機を用いて混合し、これにクロスポビドンの水分散液を噴霧しながら造粒を行った後に、整粒機を用いて整粒し、顆粒（３）を製造することもできる。次いで、本発明のマスキング粒子、前記顆粒（３）及びフマル酸ステアリルナトリウムを、混合機を用いて混合した後、打錠することにより錠剤を製造することもできる。前記混合工程において、必要に応じて、さらに賦形剤、滑沢剤、発泡剤、甘味剤、矯味剤、流動化剤、香料、着色剤等を１つ又は２つ以上組み合せて添加してもよい。 [Production Example 6]
For example, a mixture of D-mannitol and crystalline cellulose is mixed using a fluidized bed granulator / dryer, granulated while spraying a water dispersion of crospovidone, and then adjusted using a granulator. Granules (3) can also be produced. Subsequently, after mixing the masking particle | grains of this invention, the said granule (3), and a sodium stearyl fumarate using a mixer, it can also manufacture a tablet by tableting. In the mixing step, if necessary, an excipient, a lubricant, a foaming agent, a sweetening agent, a corrigent, a fluidizing agent, a fragrance, a coloring agent, etc. may be added in combination of one or more. Good.
〔製造例７〕
　例えば、Ｄ－マンニトール、結晶セルロース及びクロスポビドンの混合物を、流動層造粒乾燥機を用いて混合し、これに水を噴霧しながら造粒を行った後に、整粒機を用いて整粒し、顆粒（４）を製造することもできる。次いで、本発明のマスキング粒子、前記顆粒（４）及びフマル酸ステアリルナトリウムを、混合機を用いて混合した後、打錠することにより錠剤を製造することもできる。前記混合工程において、必要に応じて、さらに賦形剤、滑沢剤、発泡剤、甘味剤、矯味剤、流動化剤、香料、着色剤等を１つ又は２つ以上組み合せて添加してもよい。 [Production Example 7]
For example, a mixture of D-mannitol, crystalline cellulose and crospovidone is mixed using a fluidized bed granulation dryer, granulated while spraying water thereto, and then sized using a granulator. Granules (4) can also be produced. Subsequently, after mixing the masking particle | grains of this invention, the said granule (4), and a sodium stearyl fumarate using a mixer, it can also manufacture a tablet by tableting. In the mixing step, if necessary, an excipient, a lubricant, a foaming agent, a sweetening agent, a corrigent, a fluidizing agent, a fragrance, a coloring agent, etc. may be added in combination of one or more. Good.
〔製造例８〕
　上記製造例６又は７において、結晶セルロースの代わりにトウモロコシデンプン、クロスポビドンの代わりに部分アルファー化デンプンを用いて、製造例６又は７と同様の方法により、錠剤を製造することもできる。 [Production Example 8]
In the above Production Example 6 or 7, tablets can be produced in the same manner as in Production Example 6 or 7 using corn starch instead of crystalline cellulose and partially pregelatinized starch instead of crospovidone.
　本発明のマスキング粒子又は経口投与製剤を製造する工程において、「造粒」、「被覆」、「混合」、「打錠」は、製剤技術分野における慣用の方法を用いて行えばよい。「造粒」及び「被覆」には、例えば、流動層造粒機、転動流動層造粒法、高速混合攪拌造粒機等を用いることもできる。「混合」には、例えば、Ｖ型混合機、ボーレコンテナ等を用いることもできる。「打錠」は、例えば、単発打錠機、ロータリー打錠機等を用いることもできる。打錠圧は、例えば、１～２０ｋＮであり、好適には２～１５ｋＮである。 In the process of producing the masking particles or the oral administration preparation of the present invention, “granulation”, “coating”, “mixing”, and “tableting” may be performed by using a conventional method in the pharmaceutical technical field. For "granulation" and "coating", for example, a fluidized bed granulator, a rolling fluidized bed granulation method, a high-speed mixing and agitation granulator or the like can be used. For “mixing”, for example, a V-type mixer, a bore container, or the like can be used. For example, a single tableting machine or a rotary tableting machine can be used for the “tablet”. The tableting pressure is, for example, 1 to 20 kN, and preferably 2 to 15 kN.
　本発明のマスキング粒子及びこれを含有する経口投与製剤は、良好な苦味マスキング効果を示す。苦味マスキング効果は、後述する苦味官能試験により定量的に評価することができる。苦味スコアの平均点が２以下であるものが好ましく、１以下であるものがより好ましい。また、苦味を感じ始めるまでの時間は、３０秒以上が好ましく、４０秒以上、又は６０秒以上のように、より長いほうが好ましい。 The masking particles of the present invention and the preparation for oral administration containing the same exhibit a good bitter taste masking effect. The bitter taste masking effect can be quantitatively evaluated by a bitter taste sensory test described later. The average bitterness score is preferably 2 or less, more preferably 1 or less. The time until the bitterness starts to be felt is preferably 30 seconds or longer, and is preferably longer, such as 40 seconds or longer, or 60 seconds or longer.
　本発明の経口投与製剤は、消化管内のｐＨに依存せずに速やかな溶出性を示す。即ち、本発明の経口投与製剤は、日本薬局方溶出試験第１液（ｐＨ約１．２）及び第２液（ｐＨ約６．８）において、１５分後の溶出率が８０％以上を示し、好ましくは、日本薬局方溶出試験第１液（ｐＨ約１．２）において、１５分後の溶出率が８５％以上であり、より好ましくは、日本薬局方溶出試験第２液（ｐＨ約６．８）においても、１５分後の溶出率が８５％以上である。溶出性は、後述する溶出試験により定量的に評価することができる。 The preparation for oral administration of the present invention exhibits rapid dissolution without depending on the pH in the digestive tract. That is, the orally administered preparation of the present invention shows an elution rate of 80% or more after 15 minutes in the first solution (pH about 1.2) and the second solution (pH about 6.8) of the Japanese Pharmacopoeia dissolution test. Preferably, in the Japanese Pharmacopoeia dissolution test first solution (pH about 1.2), the dissolution rate after 15 minutes is 85% or more, and more preferably, the Japanese Pharmacopoeia dissolution test second solution (pH about 6). 8), the elution rate after 15 minutes is 85% or more. The dissolution property can be quantitatively evaluated by a dissolution test described later.
　本発明の経口投与製剤は、水なしで服用するために、口腔内において短時間で崩壊するものが好ましい。例えば、後述する口腔内崩壊試験において、平均口腔内崩壊時間が、苦味を感じ始めるまでの時間よりも短くなるように調整すればよく、通常、６０秒以内、好ましくは４０秒以内、さらに好ましくは３０秒以内となるように調整すればよい。 The oral dosage form of the present invention is preferably one that disintegrates in the oral cavity in a short time in order to be taken without water. For example, in the oral disintegration test described below, the average oral disintegration time may be adjusted to be shorter than the time until bitterness begins to be felt, and is usually within 60 seconds, preferably within 40 seconds, more preferably What is necessary is just to adjust so that it may become within 30 second.
　本発明の経口投与製剤は、錠剤の場合、製造や輸送の利便性等から、適度な硬度を有するものが好ましい。例えば、後述する硬度試験において、通常、２０Ｎ以上、好ましくは３０Ｎ以上、さらに好ましくは４０Ｎ以上となるように調整すればよい。 In the case of a tablet, the preparation for oral administration of the present invention preferably has an appropriate hardness from the viewpoint of convenience of production and transportation. For example, in a hardness test to be described later, it is usually adjusted to 20 N or more, preferably 30 N or more, and more preferably 40 N or more.
　口腔内崩壊時間や硬度は、適宜、医薬品添加物の種類や量、製造方法（例えば、造粒方法等）、製造条件（例えば、打錠圧等）等を選択することにより調整することもできる。 Oral disintegration time and hardness can be appropriately adjusted by selecting the type and amount of pharmaceutical additives, production method (eg, granulation method), production conditions (eg, tableting pressure, etc.) and the like. .
　本発明の経口投与製剤において、苦味を有する薬剤がシロドシンの場合、単位製剤当たりのシロドシン含量は、通常、２～８ｍｇであり、好ましくは、２ｍｇ、４ｍｇ又は８ｍｇである。 In the oral administration preparation of the present invention, when the drug having a bitter taste is silodosin, the silodosin content per unit preparation is usually 2 to 8 mg, preferably 2 mg, 4 mg or 8 mg.
　本発明の経口投与製剤は、例えば、錠剤の場合、1錠当たりの質量として５０～５００ｍｇ、５０～３００ｍｇ、１００～２５０ｍｇ、１００～２００ｍｇ等を挙げることができ、その際のシロドシン含量としては、０．４～１６％を挙げることができる。顆粒剤、散剤等の場合、１回投与量当たりの質量として、２００～３０００ｍｇ、５００～２０００ｍｇ、５００～１０００ｍｇ等を挙げることができ、その際のシロドシン含量としては、０．０６～４％を挙げることができる。 Examples of the preparation for oral administration of the present invention include, in the case of tablets, 50 to 500 mg, 50 to 300 mg, 100 to 250 mg, 100 to 200 mg and the like as the mass per tablet. 0.4 to 16% can be mentioned. In the case of granules, powders, etc., the mass per dose may include 200 to 3000 mg, 500 to 2000 mg, 500 to 1000 mg, etc. The silodosin content at that time is 0.06 to 4%. Can be mentioned.
　本発明の経口投与製剤を実際の治療に使用する場合、活性成分の投与量は、患者の性別、年齢、体重、疾患の程度等によって適宜決定されるが、苦味を有する薬剤がシロドシンの場合、概ね成人１日あたり、１～１６ｍｇの範囲で投薬することができる。好ましくは、成人１日あたり、２～８ｍｇを１日１回又は２回に分けて経口投与する。 When the oral administration preparation of the present invention is used for actual treatment, the dose of the active ingredient is appropriately determined depending on the sex, age, weight, degree of disease, etc. of the patient, but when the drug having a bitter taste is silodosin, The dose can be generally in the range of 1 to 16 mg per adult day. Preferably, 2 to 8 mg per day for an adult is orally administered once or twice a day.
　本発明のマスキング粒子は、製剤学的に安定であり、薬剤（例えばシロドシン）の極めて強烈な苦味を抑制し、市販の錠剤（例えば、ユリーフ（登録商標）錠）と同様の速やかな溶出性を有するので、水なしでも、異物感がなく服用できる経口投与製剤に用いることができる。また本発明の経口投与製剤は、シロドシン特有の苦味を抑制し、市販のシロドシンの錠剤（ユリーフ（登録商標）錠）と同様の速やかな溶出性を有することから、水なしでも異物感がなく服用できるシロドシン含有製剤として有用である。本発明のマスキング粒子は、上記に加え、苦味を感じ始めるまでの時間が長いことから、口腔内崩壊錠の技術を用いることにより、優れた口腔内速崩壊製剤を提供することができる。 The masking particle of the present invention is pharmaceutically stable, suppresses the extremely intense bitterness of a drug (for example, silodosin), and has a rapid dissolution property similar to that of a commercially available tablet (for example, Urief (registered trademark) tablet). Therefore, even without water, it can be used for an orally-administered preparation that can be taken without a foreign body feeling. In addition, the orally administered preparation of the present invention suppresses the bitterness peculiar to silodosin and has the same rapid dissolution property as a commercially available silodosin tablet (Urief (registered trademark) tablet), so it can be taken without any foreign body feeling even without water. It is useful as a silodosin-containing preparation. In addition to the above, the masking particle of the present invention has a long time until it begins to feel a bitter taste. Therefore, by using the technique of an orally disintegrating tablet, an excellent oral disintegrating preparation can be provided.
　本発明の内容を以下の試験例及び実施例によりさらに詳細に説明するが、本発明の内容はこれに限定されるものではない。 The content of the present invention will be described in more detail with reference to the following test examples and examples, but the content of the present invention is not limited thereto.
〔試験例１〕
苦味官能試験
　健常人男性１～３名において、実施例１～３で調製した錠剤１錠をそれぞれ口腔内に含み、苦味を感じた時の苦味を表１に従い点数を付け、平均を求めた。また、錠剤については、錠剤を口腔内に含み、舌で軽く転がしながら錠剤を崩壊させ、苦味を感じ始めるまでの時間も評価した。 [Test Example 1]
Bitter taste sensory test In 1 to 3 healthy males, one tablet prepared in Examples 1 to 3 was included in the oral cavity, and the bitterness when bitterness was felt was scored according to Table 1, and the average was obtained. For the tablets, the time until the tablets were included in the oral cavity, disintegrated while being gently rolled with the tongue, and starting to feel bitter was also evaluated.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
〔試験例２〕
口腔内崩壊試験
　健常人男性１～３名において、実施例１～３で調製した錠剤１錠をそれぞれ口腔内に含み、舌で軽く転がしながら錠剤を崩壊させ、口腔内で錠剤が崩壊した時間を測定し、平均を求めた。 [Test Example 2]
Oral disintegration test In 1 to 3 healthy males, each of the tablets prepared in Examples 1 to 3 was included in the oral cavity, and the tablet was disintegrated while gently rolling with the tongue. Measured and averaged.
〔試験例３〕
硬度試験
　実施例１～３で調製した錠剤の硬度を、全自動錠剤測定装置（ＷＨＴ、ＰＨＡＲＭＡ ＴＥＳＴ社製）を用いて測定した。 [Test Example 3]
Hardness Test The hardness of the tablets prepared in Examples 1 to 3 was measured using a fully automatic tablet measuring device (WHT, manufactured by PHARMA TEST).
〔試験例４〕
溶出試験方法
　実施例１～３で調製した錠剤について、第16改正日本薬局方記載の溶出試験法パドル法に従い、パドル回転数５０ｒｐｍ、試験液として日本薬局方溶出試験第２液を用いて溶出試験を行い、サンプリング液中のシロドシンを高速液体クロマトグラフ法で定量して溶出率を求めた。なお、溶出率は、各製剤について、無作為に2～3個抽出して試験を行い、その平均値を求めた。
　　検出器：紫外吸光光度計（測定波長：２７０ｎｍ） [Test Example 4]
Dissolution test method For tablets prepared in Examples 1 to 3, dissolution test using paddle rotation speed 50rpm and Japanese Pharmacopoeia Dissolution Test 2 as test solution according to the 16th revised Japanese Pharmacopoeia Then, silodosin in the sampling solution was quantified by high performance liquid chromatography to determine the elution rate. For the dissolution rate, 2 to 3 samples were randomly extracted and tested, and the average value was determined.
Detector: UV absorptiometer (measurement wavelength: 270 nm)
〔試験例５〕
粒度分布測定
　篩式粒度分布測定装置（ギルソニックオートシーバーＧＡ－６、Ｇｉｌｓｏｎ社製）を用いて、ふるい分けにより粒度分布を測定し、５０％粒子径（質量基準メジアン径）を求めた。 [Test Example 5]
Particle size distribution measurement The particle size distribution was measured by sieving using a sieve-type particle size distribution measuring device (Gilsonic Auto Seeber GA-6, manufactured by Gilson) to obtain a 50% particle size (mass-based median size).
〔実施例１〕
　シロドシン４４００ｇ、部分アルファー化デンプン（日本カラコン社製）１６１９２ｇ及びタルク（松村産業製）１１００ｇを、流動層造粒乾燥機（ＮＦＬＯ－３０ＳＪＣ、フロイント産業社製）を用いて混合し、ここへヒドロキシプロピルセルロース（日本曹達社製）３０８ｇを精製水に添加した溶液をスプレーノズルで噴霧しながら造粒を行った。得られた造粒物を、整粒機（ミルマイスト、フロイント産業社製）を用いて、スクリーンサイズΦ１．０ｍｍにて整粒し、薬物粒子を得た。 [Example 1]
4400 g of silodosin, 16192 g of partially pregelatinized starch (manufactured by Nippon Colorcon) and 1100 g of talc (manufactured by Matsumura Sangyo) were mixed using a fluidized bed granulator / dryer (NFLO-30SJC, manufactured by Freund Sangyo Co., Ltd.). Granulation was performed while spraying a solution obtained by adding 308 g of cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water with a spray nozzle. The obtained granulated product was sized using a sizing machine (Milmist, manufactured by Freund Sangyo Co., Ltd.) with a screen size of Φ1.0 mm to obtain drug particles.
　一方、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体（ＢＡＳＦ社製）９８５．０ｇ（固形分として２９５．５ｇ）、ラウリル硫酸ナトリウム（花王社製）５３．１８ｇ、クエン酸トリエチル（森村商事社製）４４．６３ｇ及びタルク（松村産業社製）２３６．４ｇを精製水に添加し、コーティング液を得た（ｃ－１）。 On the other hand, methyl methacrylate-diethylaminoethyl methacrylate copolymer (manufactured by BASF) 985.0 g (295.5 g as a solid content), sodium lauryl sulfate (manufactured by Kao Corporation) 53.18 g, triethyl citrate (manufactured by Morimura Corporation) ) 44.63 g and talc (manufactured by Matsumura Sangyo Co., Ltd.) 236.4 g were added to purified water to obtain a coating solution (c-1).
　得られた薬物粒子１０００ｇを流動層造粒乾燥機（ＦＬＯ－５Ｍ、フロイント産業社製）に入れ、コーティング液（ｃ－１）をスプレーし、シロドシン１００質量部に対して、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体として９８．５質量部を被膜し、マスキング粒子を得た（ａ－１）。 1000 g of the obtained drug particles are placed in a fluidized bed granulator / dryer (FLO-5M, manufactured by Freund Sangyo Co., Ltd.), sprayed with coating liquid (c-1), and 100 parts by mass of silodosin with methyl methacrylate-methacrylic acid. As a diethylaminoethyl acid copolymer, 98.5 parts by mass were coated to obtain masking particles (a-1).
　Ｄ－マンニトール（フロイント産業社製）１９３２６ｇ、結晶セルロース（旭化成ケミカルズ社製）４０８０ｇ及びクロスポビドン（ＩＳＰ社製）１７００ｇを用いて、常法に従い造粒物を得た（ｂ－１）。 A granulated product was obtained according to a conventional method using 19326 g of D-mannitol (Freund Sangyo), 4080 g of crystalline cellulose (Asahi Kasei Chemicals) and 1700 g of crospovidone (ISP) (b-1).
　マスキング粒子（ａ－１）１１３．６ｇ、造粒物（ｂ－１）６１４．４ｇ、トウモロコシデンプン（日本食品化工社製）５６ｇ、フマル酸ステアリルナトリウム（丸善油化商事社製）１６ｇを、Ｖ形混合機（Ｓ－３－Ｓ、筒井理化学器械社製）を用いて混合し、打錠用混合物を得た。この打錠用混合末を、ロータリー打錠機（ＶＥＬＡ－５、菊水製作所社製）を用い、杵臼８ｍｍ、打錠圧約６ｋＮの条件で打錠し、１錠当たり、シロドシン４ｍｇ含有する質量２００ｍｇの錠剤を得た。 113.6 g of masking particles (a-1), 614.4 g of granulated product (b-1), 56 g of corn starch (manufactured by Nippon Shokuhin Kako), 16 g of sodium stearyl fumarate (manufactured by Maruzen Oil Chemical Co., Ltd.) The mixture was mixed using a shape mixer (S-3-S, manufactured by Tsutsui Riken Kikai Co., Ltd.) to obtain a tableting mixture. This mixed powder for tableting was tableted using a rotary tableting machine (VELA-5, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a milling die of 8 mm and a tableting pressure of about 6 kN, and each tablet contained 4 mg of silodosin in a mass of 200 mg. Tablets were obtained.
〔実施例２〕
　シロドシン２００００ｇ、部分アルファー化デンプン（日本カラコン社製）７３６００ｇ及びタルク（松村産業製）５０００ｇを、流動層造粒乾燥機（ＦＬ－１２０Ｕ、フロイント産業社製）を用いて混合し、ここへヒドロキシプロピルセルロース（日本曹達社製）１４００ｇを精製水に添加した溶液をスプレーノズルで噴霧しながら造粒を行った。得られた造粒物を、整粒機（ミルマイスト、フロイント産業社製）を用いて、スクリーンサイズΦ１．０ｍｍにて整粒し、薬物粒子を得た。 [Example 2]
20000 g of silodosin, 73600 g of partially pregelatinized starch (manufactured by Nippon Colorcon Co., Ltd.) and 5000 g of talc (manufactured by Matsumura Sangyo) were mixed using a fluid bed granulator / dryer (FL-120U, manufactured by Freund Sangyo Co., Ltd.). Granulation was performed while spraying a solution obtained by adding 1400 g of cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water with a spray nozzle. The obtained granulated product was sized using a sizing machine (Milmist, manufactured by Freund Sangyo Co., Ltd.) with a screen size of Φ1.0 mm to obtain drug particles.
　一方、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体（ＢＡＳＦ社製）８０６．６ｇ（固形分として２４２．０ｇ）、ラウリル硫酸ナトリウム（花王社製）８７．１２ｇ、クエン酸トリエチル（森村商事社製）３６．５４ｇ及びタルク（松村産業社製）１９３．６ｇを精製水に添加し、コーティング液を得た（ｃ－２）。 On the other hand, methyl methacrylate-diethylaminoethyl methacrylate copolymer (manufactured by BASF) 806.6 g (242.0 g as solid content), sodium lauryl sulfate (manufactured by Kao) 87.12 g, triethyl citrate (manufactured by Morimura Corporation) 36.54 g and 193.6 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) were added to purified water to obtain a coating solution (c-2).
　得られた薬物粒子１０００ｇを流動層造粒乾燥機（ＦＬＯ－５Ｍ、フロイント産業社製）に入れ、コーティング液（ｃ－２）をスプレーし、シロドシン１００質量部に対して、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体として１０６質量部を被膜し、マスキング粒子を得た（ａ－２）。 1000 g of the obtained drug particles are put in a fluidized bed granulator / dryer (FLO-5M, manufactured by Freund Sangyo Co., Ltd.), sprayed with coating liquid (c-2), and 100 parts by mass of silodosin with methyl methacrylate-methacrylic acid. As a diethylaminoethyl acid copolymer, 106 parts by mass were coated to obtain masking particles (a-2).
　Ｄ－マンニトール（フロイント産業社製）１９３２６ｇ、結晶セルロース（旭化成ケミカルズ社製）４０８０ｇ及びクロスポビドン（ＩＳＰ社製）１７００ｇを用いて、常法に従い造粒物を得た（ｂ－２）。 Using 19326 g of D-mannitol (manufactured by Freund Sangyo), 4080 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals) and 1700 g of crospovidone (manufactured by ISP), a granulated product was obtained according to a conventional method (b-2).
　マスキング粒子（ａ－２）１１９ｇ、造粒物（ｂ－２）６０９ｇ、トウモロコシデンプン（日本食品化工社製）５６ｇ、フマル酸ステアリルナトリウム（丸善油化商事社製）１６ｇを、V形混合機（Ｓ－３－Ｓ、筒井理化学器械社製）を用いて混合し、打錠用混合物を得た。この打錠用混合末を、ロータリー打錠機（ＶＥＬＡ－５、菊水製作所社製）を用い、杵臼８ｍｍ、打錠圧約６ｋＮの条件で打錠し、１錠当たり、シロドシン４ｍｇ含有する質量２００ｍｇの錠剤を得た。 119 g of masking particles (a-2), 609 g of granulated product (b-2), 56 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), 16 g of sodium stearyl fumarate (manufactured by Maruzen Oil Chemical Co., Ltd.) S-3-S, manufactured by Tsutsui Rika Instruments Co., Ltd.) to obtain a tableting mixture. This mixed powder for tableting was tableted using a rotary tableting machine (VELA-5, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a milling die of 8 mm and a tableting pressure of about 6 kN, and each tablet contained 4 mg of silodosin in a mass of 200 mg. Tablets were obtained.
〔実施例３〕
　シロドシン２００００ｇ、部分アルファー化デンプン（日本カラコン社製）７３６００ｇ及びタルク（松村産業製）５０００ｇを、流動層造粒乾燥機（ＦＬ－１２０Ｕ、フロイント産業社製）を用いて混合し、ここへヒドロキシプロピルセルロース（日本曹達社製）１４００ｇを精製水に添加した溶液をスプレーノズルで噴霧しながら造粒を行った。得られた造粒物を、整粒機（ミルマイスト、フロイント産業社製）を用いて、スクリーンサイズΦ１．０ｍｍにて整粒し、薬物粒子を得た。 Example 3
20000 g of silodosin, 73600 g of partially pregelatinized starch (manufactured by Nippon Colorcon Co., Ltd.) and 5000 g of talc (manufactured by Matsumura Sangyo) were mixed using a fluid bed granulator / dryer (FL-120U, manufactured by Freund Sangyo Co., Ltd.). Granulation was performed while spraying a solution obtained by adding 1400 g of cellulose (manufactured by Nippon Soda Co., Ltd.) to purified water with a spray nozzle. The obtained granulated product was sized using a sizing machine (Milmist, manufactured by Freund Sangyo Co., Ltd.) with a screen size of Φ1.0 mm to obtain drug particles.
　一方、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体（ＢＡＳＦ社製）９８２．６ｇ（固形分として２９４．８ｇ）、ラウリル硫酸ナトリウム（花王社製）５３．０７ｇ、クエン酸トリエチル（森村商事社製）４４．５２ｇ、２，６－ジ－ｔ－ブチル－４－メチルフェノール（和光純薬工業社製）７．３７ｇ及びタルク（松村産業社製）２３５．９ｇを精製水に添加し、コーティング液を得た（ｃ－３）。 On the other hand, methyl methacrylate-diethylaminoethyl methacrylate copolymer (manufactured by BASF) 982.6 g (294.8 g as solid content), sodium lauryl sulfate (manufactured by Kao) 53.07 g, triethyl citrate (manufactured by Morimura Shoji Co., Ltd.) ) 44.52 g, 7.37 g of 2,6-di-t-butyl-4-methylphenol (Wako Pure Chemical Industries, Ltd.) and 235.9 g of talc (Matsumura Sangyo Co., Ltd.) were added to purified water, and the coating solution was added. (C-3) was obtained.
　得られた薬物粒子１０００ｇを流動層造粒乾燥機（ＦＬＯ－５Ｍ、フロイント産業社製）に入れ、コーティング液（ｃ－３）をスプレーし、シロドシン１００質量部に対して、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体として１５３質量部を被膜し、マスキング粒子を得た（ａ－３）。 1000 g of the obtained drug particles are put into a fluidized bed granulator / dryer (FLO-5M, Freund Sangyo Co., Ltd.), sprayed with coating liquid (c-3), and 100 parts by mass of silodosin with methyl methacrylate-methacrylic acid. As a diethylaminoethyl acid copolymer, 153 parts by mass was coated to obtain masking particles (a-3).
　Ｄ－マンニトール（フロイント産業社製）１９３２６ｇ、結晶セルロース（旭化成ケミカルズ社製）４０８０ｇ及びクロスポビドン（ＩＳＰ社製）１７００ｇを用いて、常法に従い造粒物を得た（ｂ－３）。 Using 19326 g of D-mannitol (manufactured by Freund Sangyo), 4080 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals) and 1700 g of crospovidone (manufactured by ISP), a granulated product was obtained according to a conventional method (b-3).
　マスキング粒子（ａ－３）１３２．６ｇ、造粒物（ｂ－３）５９５．４ｇ、トウモロコシデンプン（日本食品化工社製）５６ｇ、フマル酸ステアリルナトリウム（丸善油化商事社製）１６ｇを、Ｖ形混合機（Ｓ－３－Ｓ、筒井理化学器械社製）を用いて混合し、打錠用混合物を得た。この打錠用混合末を、ロータリー打錠機（ＶＥＬＡ－２、菊水製作所社製）を用い、杵臼８ｍｍ、打錠圧約６ｋＮの条件で打錠し、１錠当たり、シロドシン４ｍｇ含有する質量２００ｍｇの錠剤を得た。 132.6 g of masking particles (a-3), 595.4 g of the granulated product (b-3), 56 g of corn starch (manufactured by Nippon Shokuhin Kako), 16 g of sodium stearyl fumarate (manufactured by Maruzen Oil Chemical Co., Ltd.) The mixture was mixed using a shape mixer (S-3-S, manufactured by Tsutsui Riken Kikai Co., Ltd.) to obtain a tableting mixture. This mixed powder for tableting was tableted using a rotary tableting machine (VELA-2, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a milling die of 8 mm and a tableting pressure of about 6 kN, and each tablet contained 4 mg of silodosin in a mass of 200 mg. Tablets were obtained.
　試験例１～５で測定したマスキング粒子の平均粒子径及びマスキング粒子を含有する錠剤の苦味、苦味を感じ始めるまでの時間、口腔内崩壊時間、硬度及び溶出率の結果を表２に示す。 Table 2 shows the average particle diameter of the masking particles measured in Test Examples 1 to 5, and the bitterness of the tablets containing the masking particles, the time to start feeling bitterness, the oral disintegration time, the hardness, and the dissolution rate.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　単位製剤中に含まれるシロドシン、薬物粒子、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体及びマスキング粒子の各質量及び単位製剤当たりの総質量を表３に示す。 Table 3 shows the respective masses of silodosin, drug particles, methyl methacrylate-diethylaminoethyl methacrylate copolymer and masking particles contained in the unit preparation, and the total mass per unit preparation.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　以上の通り、実施例１～３の製剤はいずれも強い苦味が抑制され、かつ苦味を感じ始めるまでの時間が口腔内崩壊時間よりも長かった。更に、日本薬局方（第１６改正）溶出試験液第２液において１５分後の溶出率が８５%以上であった。 As described above, in all of the preparations of Examples 1 to 3, strong bitterness was suppressed, and the time until the bitterness began to be felt was longer than the oral disintegration time. Furthermore, the dissolution rate after 15 minutes in the Japanese Pharmacopoeia (16th revision) dissolution test solution 2 was 85% or more.
　以上から、本発明のマスキング粒子を含有する経口投与製剤は、強い苦味を感じることなく速やかに崩壊して水なしで服用でき、治療に有効な血中濃度を再現できる溶出性を備えた、口腔内速崩壊製剤として有用であることが確認された。 From the above, the oral dosage formulation containing the masking particles of the present invention can be rapidly disintegrated without feeling a strong bitter taste, can be taken without water, and has an elution property that can reproduce blood concentration effective for treatment, It was confirmed to be useful as an internal fast disintegrating preparation.
　本発明により、苦味を有する薬剤、例えば、極めて苦味の強い薬剤であるシロドシンを、異物感なく、水なしでも服用でき、かつ前立腺肥大症に伴う排尿障害等の治療に有効な血中濃度を再現できる溶出性を備えた、新規な経口投与製剤（特には、口腔内速崩壊製剤）を提供することができる。 According to the present invention, a drug having a bitter taste, for example, silodosin, a drug having a very strong bitter taste, can be taken without a foreign body feeling and without water, and reproduces a blood concentration effective for treating urination disorder associated with prostatic hypertrophy. It is possible to provide a novel preparation for oral administration (especially an intraoral rapidly disintegrating preparation) having a dissolution property capable of being dissolved.

Claims (21)

  1. 　苦味を有する薬剤を含有する薬物粒子を、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体を含有するコーティング剤で造粒又は被覆して得られるマスキング粒子であって、該共重合体含量が、苦味を有する薬剤１００質量部に対して８０質量部～４００質量部である、マスキング粒子。 Masking particles obtained by granulating or coating drug particles containing a drug having a bitter taste with a coating agent containing methyl methacrylate-diethylaminoethyl methacrylate copolymer, wherein the copolymer content is bitter Masking particles which are 80 to 400 parts by mass with respect to 100 parts by mass of the drug having
  2. 　苦味を有する薬剤がシロドシンである、請求項１記載のマスキング粒子。 The masking particle according to claim 1, wherein the drug having a bitter taste is silodosin.
  3. 　該マスキング粒子を含有する経口投与製剤のｐＨ６．８における１５分後の溶出率が、８５％以上である、請求項２記載のマスキング粒子。 The masking particles according to claim 2, wherein the orally administered preparation containing the masking particles has an elution rate after 15 minutes at pH 6.8 of 85% or more.
  4. 　該マスキング粒子を含有する経口投与製剤のヒト苦味官能試験における苦味を感じ始める時間が、３０秒以上である、請求項１～３のいずれかに記載のマスキング粒子。 The masking particle according to any one of claims 1 to 3, wherein a time when the oral bitterness preparation containing the masking particle starts to feel bitterness in a human bitterness sensory test is 30 seconds or more.
  5. 　苦味を有する薬剤を含有する薬物粒子が、シロドシンと添加剤との混合物である、請求項１記載のマスキング粒子。 The masking particle according to claim 1, wherein the drug particle containing a drug having a bitter taste is a mixture of silodosin and an additive.
  6. 　苦味を有する薬剤を含有する薬物粒子が、シロドシンと添加剤との造粒物である、請求項５記載のマスキング粒子。 6. The masking particle according to claim 5, wherein the drug particle containing a drug having a bitter taste is a granulated product of silodosin and an additive.
  7. 　添加剤が、糖又は糖アルコール及びデンプン類から選択される少なくとも１つの添加剤である、請求項５又は６記載のマスキング粒子。 The masking particle according to claim 5 or 6, wherein the additive is at least one additive selected from sugar or sugar alcohol and starches.
  8. 　該共重合体含量が、苦味を有する薬剤１００質量部に対して１００質量部～２００質量部である、請求項１～７のいずれかに記載のマスキング粒子。 The masking particles according to any one of claims 1 to 7, wherein the copolymer content is 100 to 200 parts by mass with respect to 100 parts by mass of the drug having a bitter taste.
  9. 　該マスキング粒子中の苦味を有する薬剤含量が、５～２５質量％である、請求項１～８のいずれかに記載のマスキング粒子。 The masking particles according to any one of claims 1 to 8, wherein the content of the drug having a bitter taste in the masking particles is 5 to 25% by mass.
  10. 　該マスキング粒子中のメタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体含量が、１０～３０質量％である、請求項１～９のいずれかに記載のマスキング粒子。 The masking particles according to any one of claims 1 to 9, wherein the content of methyl methacrylate-diethylaminoethyl methacrylate copolymer in the masking particles is 10 to 30% by mass.
  11. 　メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体含量が、薬物粒子１００質量部に対して２０質量部～４０質量部である、請求項１～１０のいずれかに記載のマスキング粒子。 The masking particles according to any one of claims 1 to 10, wherein the content of methyl methacrylate-diethylaminoethyl methacrylate copolymer is 20 to 40 parts by mass with respect to 100 parts by mass of the drug particles.
  12. 　請求項１～１１のいずれかに記載のマスキング粒子を含有する経口投与製剤。 An oral administration preparation containing the masking particles according to any one of claims 1 to 11.
  13. 　該マスキング粒子以外の成分として、さらに賦形剤、崩壊剤及び滑沢剤を含有してなる、請求項１２に記載の経口投与製剤。 The orally administered preparation according to claim 12, further comprising an excipient, a disintegrant and a lubricant as components other than the masking particles.
  14. 　該賦形剤及び崩壊剤が、少なくともこれらを含有する顆粒状であることを特徴とする、請求項１３に記載の経口投与製剤。 The orally administered preparation according to claim 13, wherein the excipient and disintegrant are in the form of granules containing at least these.
  15. 　経口投与製剤が口腔内速崩壊製剤である、請求項１２～１４のいずれかに記載の経口投与製剤。 The oral administration preparation according to any one of claims 12 to 14, wherein the oral administration preparation is an intraoral rapidly disintegrating preparation.
  16. 　口腔内速崩壊製剤が錠剤である、請求項１５記載の経口投与製剤。 The orally administered preparation according to claim 15, wherein the intraoral rapidly disintegrating preparation is a tablet.
  17. 　口腔内崩壊時間が４０秒以内である、請求項１６記載の経口投与製剤。 The oral administration preparation according to claim 16, wherein the oral disintegration time is within 40 seconds.
  18. 　苦味を感じ始めるまでの時間が口腔内崩壊時間より長いことを特徴とする、請求項１７記載の経口投与製剤。 The oral administration preparation according to claim 17, wherein the time until the bitter taste is started is longer than the disintegration time in the oral cavity.
  19. 　ｐH６．８における１５分後の溶出率が８５％以上である、請求項１２～１８のいずれかに記載の経口投与製剤。 The oral administration preparation according to any one of claims 12 to 18, wherein the dissolution rate after 15 minutes at pH 6.8 is 85% or more.
  20. 　（ａ）苦味を有する薬剤と添加剤を混合又は造粒して薬物粒子を調製する工程、及び（ｂ）工程（ａ）で得られた薬物粒子にメタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体を含有するコーティング剤で造粒又は被覆して、メタクリル酸メチル－メタクリル酸ジエチルアミノエチル共重合体含量が、苦味を有する薬剤１００質量部に対して８０質量部～４００質量部である、マスキング粒子を調製する工程を包含することを特徴とする、マスキング粒子を製造する方法。 (A) a step of preparing a drug particle by mixing or granulating a drug having a bitter taste and an additive; and (b) a methyl methacrylate-diethylaminoethyl methacrylate copolymer on the drug particle obtained in step (a). A masking particle having a methyl methacrylate-diethylaminoethyl methacrylate copolymer content of 80 to 400 parts by mass with respect to 100 parts by mass of the drug having a bitter taste. A method for producing masking particles, comprising the step of preparing.
  21. 　苦味を有する薬剤がシロドシンである、請求項２０記載のマスキング粒子を製造する方法。 The method for producing masking particles according to claim 20, wherein the drug having a bitter taste is silodosin.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017048174A (en) * 2015-09-01 2017-03-09 大原薬品工業株式会社 Orally disintegrable tablet containing chemically stable coated particles containing drug substance
JP2018150287A (en) * 2017-03-15 2018-09-27 武田テバファーマ株式会社 Oral pharmaceutical composition with discomfort taste masked
JP6427634B1 (en) * 2017-06-30 2018-11-21 キッセイ薬品工業株式会社 An oral solid preparation containing silodosin excellent in light stability
JP2019011379A (en) * 2017-06-30 2019-01-24 キッセイ薬品工業株式会社 Silodosin-containing oral solid preparation excellent in light stability
CN112933084A (en) * 2019-12-10 2021-06-11 广东东阳光药业有限公司 Silodosin composition
US11951095B2 (en) 2018-03-23 2024-04-09 Pharmajor International Non-hormonal compositions and methods for male contraception

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004175796A (en) * 2002-11-13 2004-06-24 Asahi Kasei Pharma Kk Intraoral disintegrating preparation for treating dysuria
WO2006085497A1 (en) * 2005-02-09 2006-08-17 Kissei Pharmaceutical Co., Ltd. Tablet disintegrating in the oral cavity
JP2010535261A (en) * 2007-08-02 2010-11-18 ビーエーエスエフ ソシエタス・ヨーロピア Aqueous polymer dispersions based on N, N-diethylaminoethyl methacrylate, their preparation and use
JP2013532651A (en) * 2010-07-23 2013-08-19 ラティオファルム ゲー・エム・ベー・ハー Pharmaceuticals for oral administration containing a mixture of silodosin and basic copolymer
WO2014157137A1 (en) * 2013-03-26 2014-10-02 キッセイ薬品工業株式会社 Oral administration preparation with masked bitterness of silodosin

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004175796A (en) * 2002-11-13 2004-06-24 Asahi Kasei Pharma Kk Intraoral disintegrating preparation for treating dysuria
WO2006085497A1 (en) * 2005-02-09 2006-08-17 Kissei Pharmaceutical Co., Ltd. Tablet disintegrating in the oral cavity
JP2010535261A (en) * 2007-08-02 2010-11-18 ビーエーエスエフ ソシエタス・ヨーロピア Aqueous polymer dispersions based on N, N-diethylaminoethyl methacrylate, their preparation and use
JP2013532651A (en) * 2010-07-23 2013-08-19 ラティオファルム ゲー・エム・ベー・ハー Pharmaceuticals for oral administration containing a mixture of silodosin and basic copolymer
WO2014157137A1 (en) * 2013-03-26 2014-10-02 キッセイ薬品工業株式会社 Oral administration preparation with masked bitterness of silodosin

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017048174A (en) * 2015-09-01 2017-03-09 大原薬品工業株式会社 Orally disintegrable tablet containing chemically stable coated particles containing drug substance
JP2018150287A (en) * 2017-03-15 2018-09-27 武田テバファーマ株式会社 Oral pharmaceutical composition with discomfort taste masked
JP7062368B2 (en) 2017-03-15 2022-05-06 武田テバファーマ株式会社 Oral pharmaceutical composition masked with unpleasant taste
JP6427634B1 (en) * 2017-06-30 2018-11-21 キッセイ薬品工業株式会社 An oral solid preparation containing silodosin excellent in light stability
JP2019011379A (en) * 2017-06-30 2019-01-24 キッセイ薬品工業株式会社 Silodosin-containing oral solid preparation excellent in light stability
JP2019011295A (en) * 2017-06-30 2019-01-24 キッセイ薬品工業株式会社 Silodosin-containing oral solid preparation excellent in light stability
JP7316777B2 (en) 2017-06-30 2023-07-28 キッセイ薬品工業株式会社 Silodosin-containing oral solid dosage form with excellent photostability
US11951095B2 (en) 2018-03-23 2024-04-09 Pharmajor International Non-hormonal compositions and methods for male contraception
CN112933084A (en) * 2019-12-10 2021-06-11 广东东阳光药业有限公司 Silodosin composition

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