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WO2016051782A1 - Préparation pour voie orale dans laquelle le goût amer d'un médicament au goût amer est masqué - Google Patents

Préparation pour voie orale dans laquelle le goût amer d'un médicament au goût amer est masqué 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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WO
WIPO (PCT)
Prior art keywords
drug
masking
mass
bitter taste
particles
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2015/004953
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English (en)
Japanese (ja)
Inventor
雄亮 柴田
直 丸山
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kissei Pharmaceutical Co Ltd
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Kissei Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Kissei Pharmaceutical Co Ltd filed Critical Kissei Pharmaceutical Co Ltd
Priority to JP2016551546A priority Critical patent/JPWO2016051782A1/ja
Publication of WO2016051782A1 publication Critical patent/WO2016051782A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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.

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Abstract

L'invention concerne une nouvelle préparation destinée à une utilisation par voie orale (spécifiquement, une préparation à désintégration rapide à l'intérieur de la bouche) qui permet qu'un médicament au goût amer tel que la silodosine, qui présente un très fort goût amer, puisse être pris sans sensation inconfortable et même sans eau, et qui présente une solubilité suffisante pour obtenir une concentration sanguine efficace pour traiter la dysurie accompagnant une hypertrophie bénigne de la prostate. La présente invention concerne des particules de masquage et une nouvelle préparation destinée à une utilisation par voie orale contenant lesdites particules de masquage. Les particules de masquage sont obtenues par granulation ou recouvrement des particules de médicament contenant un médicament au goût amer (par exemple la silodosine) avec un agent de recouvrement contenant un copolymère de méthacrylate de méthyle-méthacrylate de diéthylaminoéthyle, la quantité dudit copolymère étant de 80-400 parties en masse par rapport à 100 parties en masse du médicament au goût amer (par exemple la silodosine).
PCT/JP2015/004953 2014-09-30 2015-09-29 Préparation pour voie orale dans laquelle le goût amer d'un médicament au goût amer est masqué Ceased WO2016051782A1 (fr)

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JP2017048174A (ja) * 2015-09-01 2017-03-09 大原薬品工業株式会社 化学的に安定な原薬含有被覆粒子を含む口腔内崩壊錠剤
JP2018150287A (ja) * 2017-03-15 2018-09-27 武田テバファーマ株式会社 不快な味がマスキングされた経口医薬組成物
JP2019011379A (ja) * 2017-06-30 2019-01-24 キッセイ薬品工業株式会社 光安定性に優れたシロドシン含有経口固形製剤
JP2019011295A (ja) * 2017-06-30 2019-01-24 キッセイ薬品工業株式会社 光安定性に優れたシロドシン含有経口固形製剤
CN112933084A (zh) * 2019-12-10 2021-06-11 广东东阳光药业有限公司 一种赛洛多辛组合物
US11951095B2 (en) 2018-03-23 2024-04-09 Pharmajor International Non-hormonal compositions and methods for male contraception

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JP2004175796A (ja) * 2002-11-13 2004-06-24 Asahi Kasei Pharma Kk 排尿障害治療用口腔内崩壊製剤
WO2006085497A1 (fr) * 2005-02-09 2006-08-17 Kissei Pharmaceutical Co., Ltd. Comprimé à désintégration orale
JP2010535261A (ja) * 2007-08-02 2010-11-18 ビーエーエスエフ ソシエタス・ヨーロピア Ｎ，ｎ−ジエチルアミノエチルメタクリラートをベースとする水性ポリマーディスパージョン、その調製及び使用
JP2013532651A (ja) * 2010-07-23 2013-08-19 ラティオファルム ゲー・エム・ベー・ハー シロドシンと塩基性コポリマーとの混合物を含む経口投与用医薬品
WO2014157137A1 (fr) * 2013-03-26 2014-10-02 キッセイ薬品工業株式会社 Préparation pour l'administration orale avec l'amertume de la silodosine masquée

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JP2004175796A (ja) * 2002-11-13 2004-06-24 Asahi Kasei Pharma Kk 排尿障害治療用口腔内崩壊製剤
WO2006085497A1 (fr) * 2005-02-09 2006-08-17 Kissei Pharmaceutical Co., Ltd. Comprimé à désintégration orale
JP2010535261A (ja) * 2007-08-02 2010-11-18 ビーエーエスエフ ソシエタス・ヨーロピア Ｎ，ｎ−ジエチルアミノエチルメタクリラートをベースとする水性ポリマーディスパージョン、その調製及び使用
JP2013532651A (ja) * 2010-07-23 2013-08-19 ラティオファルム ゲー・エム・ベー・ハー シロドシンと塩基性コポリマーとの混合物を含む経口投与用医薬品
WO2014157137A1 (fr) * 2013-03-26 2014-10-02 キッセイ薬品工業株式会社 Préparation pour l'administration orale avec l'amertume de la silodosine masquée

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017048174A (ja) * 2015-09-01 2017-03-09 大原薬品工業株式会社 化学的に安定な原薬含有被覆粒子を含む口腔内崩壊錠剤
JP2018150287A (ja) * 2017-03-15 2018-09-27 武田テバファーマ株式会社 不快な味がマスキングされた経口医薬組成物
JP7062368B2 (ja) 2017-03-15 2022-05-06 武田テバファーマ株式会社 不快な味がマスキングされた経口医薬組成物
JP2019011379A (ja) * 2017-06-30 2019-01-24 キッセイ薬品工業株式会社 光安定性に優れたシロドシン含有経口固形製剤
JP2019011295A (ja) * 2017-06-30 2019-01-24 キッセイ薬品工業株式会社 光安定性に優れたシロドシン含有経口固形製剤
JP7316777B2 (ja) 2017-06-30 2023-07-28 キッセイ薬品工業株式会社 光安定性に優れたシロドシン含有経口固形製剤
US11951095B2 (en) 2018-03-23 2024-04-09 Pharmajor International Non-hormonal compositions and methods for male contraception
CN112933084A (zh) * 2019-12-10 2021-06-11 广东东阳光药业有限公司 一种赛洛多辛组合物

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