WO2019172420A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO2019172420A1
WO2019172420A1 PCT/JP2019/009317 JP2019009317W WO2019172420A1 WO 2019172420 A1 WO2019172420 A1 WO 2019172420A1 JP 2019009317 W JP2019009317 W JP 2019009317W WO 2019172420 A1 WO2019172420 A1 WO 2019172420A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
salt
soluble
granulated product
mass
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PCT/JP2019/009317
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English (en)
Japanese (ja)
Inventor
宮本　祐司
崇郁 佐藤
Original Assignee
協和発酵キリン株式会社
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Publication of WO2019172420A1 publication Critical patent/WO2019172420A1/fr

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    • 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
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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 relates to a pharmaceutical composition.
  • the present invention relates more particularly to immediate release pharmaceutical compositions.
  • Patent Document 1 and Non-Patent Document 1 contain a solid dispersion in which a sparingly water-soluble drug is supported on a gel-forming water-soluble polymer, and a pharmaceutical composition containing a salt substance of an alkali and a weak acid or a strong acid Things are disclosed.
  • the pharmaceutical composition is said to exhibit rapid disintegration and solubility.
  • Patent Document 2 discloses a method containing a salting-out agent in order to suppress drug release delay due to drug gelation. This method is said to quickly elute the drug.
  • Patent Document 3 discloses a preparation in which a drug, granulated particles containing a water-soluble polymer, and a neutral to acidic water-soluble salt are present. The preparation is said to suppress disintegration delay due to gelation.
  • Patent Document 1 does not describe that the pharmaceutical composition contains a dry granulated product. Furthermore, in the preparations disclosed in Patent Documents 1 to 3 and Non-Patent Document 1, the pharmaceutical composition is disintegrated when the preparation contains a solid dispersion in which a poorly water-soluble drug is supported on a water-soluble polymer in a high content. Without being able to release the active ingredient in the body.
  • the problem to be solved by the present invention is to provide a pharmaceutical composition containing a poorly water-soluble drug that exhibits rapid disintegration and dissolution.
  • the inventors of the present invention rapidly disintegrate a pharmaceutical composition containing a dry granulated product having a specific configuration to release a target active ingredient.
  • the present invention has been found to be possible.
  • the present invention is as follows.
  • a pharmaceutical composition containing 30 to 90% by mass of a dry granulated product contains a solid dispersion containing a poorly water-soluble drug and a gel-forming water-soluble polymer, and a salt.
  • a pharmaceutical composition, wherein the content of the salt is 1 to 20% by mass relative to the total amount of the pharmaceutical composition.
  • the gel-forming water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone, and hypromellose.
  • the pharmaceutical composition according to [1], wherein the gel-forming water-soluble polymer is one or more gel-forming water-soluble polymers including hydroxypropylcellulose, polyvinylpyrrolidone, or hypromellose.
  • the salt comprises at least one selected from the group consisting of sodium chloride, sodium glutamate, and sodium citrate.
  • the pharmaceutical composition according to [1] or [2], wherein the salt is one or more salts containing sodium chloride, sodium glutamate, or sodium citrate.
  • a method for producing a pharmaceutical composition comprising a poorly water-soluble drug, i) a step of mixing a poorly water-soluble drug and a gel-forming water-soluble polymer to prepare a solid dispersion; ii) mixing the solid dispersion and salt, performing dry granulation to obtain a dry granulated product, iii) mixing the dry granulated product with a pharmaceutically acceptable additive to obtain a pharmaceutical composition; Manufacturing method.
  • [5] The production method according to [4], wherein the content of the dry granulated product in the pharmaceutical composition is 30 to 90% by mass.
  • the content of the salt in the pharmaceutical composition is 1 to 20% by mass based on the total amount of the pharmaceutical composition.
  • [7] The production method according to any one of [4] to [6], wherein the gel-forming water-soluble polymer contains at least one selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone, and hypromellose.
  • the gel-forming water-soluble polymer is one or more gel-forming water-soluble polymers containing hydroxypropylcellulose, polyvinylpyrrolidone, or hypromellose, according to any one of [4] to [6].
  • Production method. [8] The production method according to any one of [4] to [7], wherein the salt comprises at least one selected from the group consisting of sodium chloride, sodium glutamate, and sodium citrate.
  • the salt is one or more salts containing sodium chloride, sodium glutamate, or sodium citrate.
  • the pharmaceutical composition of the present invention is a pharmaceutical composition containing 30 to 90% by mass of a dry granulated product.
  • the dry granulated product in the present invention contains a solid dispersion containing a poorly water-soluble drug and a gel-forming water-soluble polymer, and a salt.
  • the salt content in the dry granulated product is 1 to 20% by mass with respect to the total amount of the pharmaceutical composition.
  • the solid dispersion includes a poorly water-soluble drug and a gel-forming water-soluble polymer.
  • the solid dispersion in the present invention is a composition in which a poorly water-soluble drug is dispersed in a gel-forming water-soluble polymer.
  • the poorly water-soluble drug may be dispersed in the gelation-forming water-soluble polymer in a fine particle or molecular state.
  • the solid dispersion can also be referred to as an amorphous form of a poorly water-soluble drug.
  • the poorly water-soluble drug in the present invention is a term indicating solubility in the 17th revised Japanese Pharmacopoeia. It is very soluble, easily soluble, slightly soluble, slightly soluble, hardly soluble, extremely difficult to dissolve, and hardly soluble. Of those that are, it means drugs that are classified as slightly soluble, slightly difficult to dissolve, difficult to dissolve, very difficult to dissolve, or hardly soluble.
  • the poorly water-soluble drug is not particularly limited, and examples thereof include indomethacin, carbamazepine, tolbutamide, dipyridamole, itraconazole, oxaprozin, naproxen, pranlukast hydrate, haloperidol, and benzbromarone.
  • a poorly water-soluble drug may be mix
  • the mixing ratio of the poorly water-soluble drug and the gelation-forming water-soluble polymer in the solid dispersion is not particularly limited, and the total mass of the poorly water-soluble drug and the gelation-forming water-soluble polymer is 100% by mass.
  • the content of the poorly water-soluble drug is preferably 1 to 60% by mass, more preferably 5 to 50% by mass, further preferably 10 to 40% by mass, and still more preferably 20 to 30% by mass. %.
  • the solid dispersion may contain an additive such as a surfactant as necessary.
  • the solid dispersion in the present invention contains a poorly water-soluble drug and a gel-forming water-soluble polymer as main components. It is more preferable to consist of a poorly water-soluble drug and a gel-forming water-soluble polymer.
  • the “main component” means that the proportion of the poorly water-soluble drug and the gel-forming water-soluble polymer in the solid dispersion is usually 70% by mass or more, preferably 80% by mass or more, more preferably 90%. It means that it is at least mass%.
  • the upper limit of the proportion of the poorly water-soluble drug and the gel-forming water-soluble polymer in the solid dispersion is 100% by mass.
  • the solid dispersion can be obtained by producing a poorly water-soluble drug and a gel-forming water-soluble polymer by a known method such as a spray drying method or a hot melt extrusion (HME) method.
  • a spray drying method is preferable because it can be produced at room temperature.
  • the method of mixing is not particularly limited as long as it is a method that can pharmaceutically normally mix each component uniformly.
  • a method of mixing from the viewpoint of obtaining a uniform solid dispersion, there is a method of obtaining a solid dispersion by drying a solution obtained by dissolving a poorly water-soluble drug and a gel-forming water-soluble polymer in a solvent.
  • a method of obtaining a solid dispersion by drying the solution by spray drying is more preferable.
  • Solvents used when dissolving poorly water-soluble drugs and gelation-forming water-soluble polymers in a solvent include pharmaceutically acceptable solvents that can dissolve poorly water-soluble drugs and gelation-forming water-soluble polymers. If it is, it will not restrict
  • the solid dispersion When obtaining a solid dispersion by spray drying or the like, the solid dispersion is obtained as particles.
  • the size of the particles is usually 1 ⁇ m or more and 500 ⁇ m or less, preferably 2 ⁇ m or more and 300 ⁇ m or less, more preferably 3 ⁇ m or more and 200 ⁇ m or less.
  • the conditions for spray drying that is, the temperature, the feed flow rate of the solution containing the poorly water-soluble drug and the gel-forming water-soluble polymer, and the spray pressure are the conditions for performing normal spray drying. If it is. Further, the solid dispersion obtained by spray drying may be further dried, and the drying conditions, that is, the temperature and time may be appropriately adjusted depending on the kind of the poorly water-soluble drug.
  • the gelation-forming water-soluble polymer in the present invention is not particularly limited as long as it is water-soluble and has a gelling ability.
  • “having water solubility” is a term indicating solubility in the 17th revised Japanese pharmacopoeia. It is extremely soluble, easily soluble, slightly soluble, slightly soluble, hardly soluble, extremely difficult to dissolve, almost It means that it is classified as being extremely soluble, slightly soluble, slightly difficult to dissolve, difficult to dissolve, or extremely difficult to dissolve among those that are not soluble.
  • “having gelling ability” means having the ability to form a gel by partially dissolving the water-soluble polymer.
  • a gel-forming water-soluble polymer disperses a poorly water-soluble drug in the gel-forming water-soluble polymer and suppresses the movement of the poorly water-soluble drug in a molecular state.
  • a preparation containing this gel-forming water-soluble polymer is considered to gel when it comes into contact with and dissolves in water, preventing the preparation from collapsing.
  • the pharmaceutical composition of the present invention even when the gel-forming water-soluble polymer in the composition comes into contact with and dissolves in water, the preparation rapidly disintegrates and the poorly water-soluble drug can be eluted from the preparation.
  • the gel-forming water-soluble polymer examples include cellulose derivatives such as methylcellulose, carmellose, carboxypropylcellulose, hydroxypropylcellulose, hypromellose (also referred to as hydroxypropylmethylcellulose); starch such as pregelatinized starch; polyvinyl alcohol; polyvinylpyrrolidone; A pullulan etc. are mentioned. These may be used alone or in combination of two or more.
  • cellulose derivatives such as methylcellulose, carmellose, carboxypropylcellulose, hydroxypropylcellulose, hypromellose (also referred to as hydroxypropylmethylcellulose); starch such as pregelatinized starch; polyvinyl alcohol; polyvinylpyrrolidone; A pullulan etc. are mentioned. These may be used alone or in combination of two or more.
  • the gel-forming water-soluble polymer hydroxypropylcellulose, polyvinylpyrrolidone, and hypromellose are preferable. That is, the gel-forming water-soluble poly
  • the salt in the present invention is a compound in which an anion derived from an acid and a cation derived from a base are ion-bonded.
  • the salt in the present invention preferably exhibits neutrality, weak acidity, and weak basicity from the viewpoint of safety in vivo and suppression of decomposition and modification of components in the composition.
  • the salt in the present invention is preferably an inorganic salt, an amino acid salt, and a salt of a carboxylic acid present in a living body.
  • the salt of the present invention is more preferably a sodium salt, potassium salt, calcium salt, or magnesium salt.
  • inorganic salts include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium phosphate. , Potassium phosphate, calcium phosphate, magnesium phosphate and the like.
  • amino acid salts include sodium glutamate, potassium glutamate, calcium glutamate, magnesium glutamate, sodium aspartate, potassium aspartate, calcium aspartate, and magnesium aspartate.
  • carboxylic acid salts present in living bodies include sodium citrate, potassium citrate, calcium citrate, magnesium citrate, sodium ascorbate, potassium ascorbate, calcium ascorbate, magnesium ascorbate, sodium succinate, and succinate.
  • Examples include potassium acid, calcium succinate, magnesium succinate, sodium fumarate, potassium fumarate, calcium fumarate, magnesium fumarate, sodium malate, potassium malate, calcium malate, and magnesium malate.
  • the salts in the present invention may be used singly or in combination of two or more.
  • the salt in the present invention is preferably one or more salts containing sodium chloride, sodium glutamate, or sodium citrate.
  • the dry granulated product in the present invention contains a solid dispersion and a salt.
  • the dry granulated product refers to particles formed while maintaining a dry state without using water during granulation.
  • the dry granulated product can be produced by using a known dry granulator. Specifically, a dry granulator is prepared by mixing a mixture obtained by mixing a solid dispersion and a salt. Manufactured for use.
  • the mixing ratio of the solid dispersion in the dry granulated product is not particularly limited, and when the dry granulated product is 100% by mass, the content of the solid dispersion is preferably 40 to 90% by mass, and more preferably. Is 50 to 85 mass%, more preferably 60 to 80 mass%.
  • the compounding ratio of the salt in the dry granulated product is preferably 1 to 30% by mass, more preferably 3 to 28% by mass, and further preferably 5 to 5%, based on 100% by mass of the dry granulated product. 20% by mass.
  • the dry granulated product in the present invention preferably contains a fluidizing agent.
  • additives include fluidizing agents such as light anhydrous silicic acid, magnesium aluminate metasilicate, calcium silicate, and magnesium stearate.
  • the mixing ratio of the additive in the dry granulated product is not particularly limited, and is preferably 1 to 60% by mass, more preferably 5 to 40% by mass when the dry granulated product is 100% by mass, More preferably, it is 5 to 20% by mass.
  • the dry granulated product in the present invention preferably comprises a solid dispersion, a salt, and the above pharmaceutically acceptable additive.
  • the dry granulated product in the present invention may be a granulated product obtained by further granulating a granulated product produced by a dry granulator using a known granulator.
  • the screen size when sizing is preferably 4 to 50 mesh, more preferably 6.5 to 42 mesh, and still more preferably 12 to 30 mesh.
  • the average particle size of the dry granulated product in the present invention is preferably 10 to 1000 ⁇ m, more preferably 50 to 500 ⁇ m, and further preferably 100 to 400 ⁇ m.
  • the above average particle diameter can be controlled by adjusting the granulation pressure, stirring speed, screen size in sizing, etc. when granulating with a dry granulator.
  • the pressure and stirring speed of the granulation may be within the range in which normal dry granulation is performed.
  • the pharmaceutical composition of the present invention contains 30 to 90% by mass of a dry granulated product containing a solid dispersion and a salt.
  • the content of the dry granulated product is preferably 40 to 85% by mass, more preferably 50 to 80% by mass.
  • the amount of the dry granulated product in the pharmaceutical composition of the present invention is 30% by mass or more and 90% by mass or less, the pharmaceutical composition is rapidly disintegrated and the poorly water-soluble drug is easily eluted.
  • the amount of the salt contained in the dry granulated product in the pharmaceutical composition of the present invention is 1 to 20% by mass, preferably 3 to 18% by mass, more preferably 5 to 15%, based on the total amount of the pharmaceutical composition. % By mass.
  • the pharmaceutical composition By making the amount of the salt contained in the dry granulated product 1% by mass or more, the pharmaceutical composition is rapidly disintegrated and the poorly water-soluble drug is easily eluted. By making the amount of the salt contained in the dry granulated product 20% by mass or less, the formability when granulating the mixture containing the solid dispersion and the salt is excellent.
  • the pharmaceutical composition of the present invention preferably contains a pharmaceutically acceptable additive in addition to the dry granulated product.
  • the pharmaceutically acceptable additive is not particularly limited, and for example, a stabilizer, a lubricant, a base, an adsorbent, a binder, a suspending agent, a brightening agent, a coating agent, a wetting agent, a wetting adjuster.
  • excipient examples include lactose, sucrose, starch, crystalline cellulose, D-mannitol, D-sorbitol, starch derivatives (such as corn starch), cellulose derivatives, carbonates, phosphates, sulfates and the like.
  • binder examples include povidone, polyvinyl alcohol, hydroxypropylmethylcellulose, and hydroxypropylcellulose.
  • disintegrant examples include crospovidone, croscarmellose sodium, carboxymethyl starch sodium, and low-substituted hydroxypropylcellulose.
  • the lubricant examples include magnesium stearate, calcium stearate, talc, and glyceryl monostearate.
  • the fluidizing agent examples include light anhydrous silicic acid, magnesium aluminate metasilicate, calcium silicate, magnesium stearate and the like.
  • a fragrance may be optionally added.
  • suitable additives include light anhydrous silicic acid, magnesium stearate, crystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and the like.
  • the content of the pharmaceutically acceptable additive in the pharmaceutical composition of the present invention is usually 10 to 70% by mass, preferably 15 to 60% by mass, more preferably 20 to 50% by mass. .
  • the total of the dry granulated product containing the solid dispersion and the salt and the pharmaceutically acceptable additive is preferably 100% by mass.
  • the pharmaceutical composition of the present invention can also be used as an oral pharmaceutical composition.
  • the oral pharmaceutical composition is not particularly limited as long as it is a preparation that can be administered orally, but in particular, it may be in the form of a powder, fine granules, granules, tablets, or capsules. Among these, tablets are preferable.
  • the shape of the tablet is not particularly limited, and examples thereof include a circular shape, an elliptical shape, and a polygonal shape.
  • the major axis of the tablet (in the case of a circle, the diameter) is usually 3 mm or more and 25 mm or less, preferably 5 mm or more and 20 mm or less, more preferably 5 mm or more and 110 mm or less.
  • the present invention also provides: i) a step of mixing a poorly water-soluble drug and a gel-forming water-soluble polymer to prepare a solid dispersion; ii) mixing the solid dispersion and salt, performing dry granulation to obtain a dry granulated product, and iii) mixing the dry granulated product and a pharmaceutically acceptable additive to obtain a pharmaceutical composition, and a method for producing a pharmaceutical composition.
  • the pharmaceutical composition is prepared by, for example, mixing a dry granulated product and a pharmaceutically acceptable additive to obtain a mixture, and then compressing the mixture using a known tableting machine or the like. And can be obtained as a tablet.
  • a tablet molding machine for example, a compression molding machine or the like is suitable.
  • the tableting pressure when compressing is usually 0 kN over 300 kN, preferably 1 kN or more and 20 kN or less, more preferably 3 kN or more and 15 kN or less.
  • the shape of the tablet is not particularly limited, and examples thereof include a circular shape, an elliptical shape, and a polygonal shape.
  • the major axis of the tablet (in the case of a circle, the diameter) is usually 3 mm or more and 25 mm or less, preferably 5 mm or more and 20 mm or less, more preferably 5 mm or more and 110 mm or less.
  • Types of poorly water-soluble drugs, gelation-forming water-soluble polymers, solid dispersions, salts, dry granulated products, and pharmaceutically acceptable additives, and their blending ratios in the production method of the present invention can include the same aspects as described in the above ⁇ Pharmaceutical composition>, and the same preferable aspects.
  • the poorly water-soluble drug used in the production method of the present invention or the poorly water-soluble drug compounded in the pharmaceutical composition of the present invention may be in a crystalline form or an amorphous form. The crystal may be easily dissolved by a known method.
  • Example 1 20 g of SD product obtained in Production Example 1, 4 g of light anhydrous silicic acid (ADSOLIDER (registered trademark) 101, Freund Corporation), 4 g of sodium citrate (Merck) and 0.14 g of magnesium stearate (PARTECK (registered trademark) LUB MST) , Merck KGaA) was added and mixed 100 times in a 2 L plastic bag to obtain a mixture.
  • the obtained mixed product was subjected to dry granulation using a dry granulator (TF-Labo, Freund Industries) under the following conditions to obtain a dry granulated product.
  • the obtained dry granulated product was granulated with a screen size of 22 mesh using an oscillator granulator for dry granulator (TF-Labo, Freund Industries) to obtain a dry granulated granulated product.
  • Example 2 20 g of SD product obtained in Production Example 1, 4 g of light anhydrous silicic acid (ADSOLIDER (registered trademark) 101, Freund Industries), 4 g of sodium glutamate (Wako Pure Chemical Industries) and 0.14 g of magnesium stearate (PARTECK (registered trademark) LUB) MST, Merck KGaA) was added and mixed 100 times in a 2 L plastic bag to obtain a mixture.
  • the obtained mixture was dry granulated using a dry granulator (TF-Labo, Freund Industries) under the following conditions to obtain a dry granulated product.
  • the obtained dry granulated product was granulated with a screen size of 22 mesh using an oscillator granulator for dry granulator (TF-Labo, Freund Industries) to obtain a dry granulated granulated product.
  • Example 3 20 g of SD product obtained in Production Example 1, 4 g of light anhydrous silicic acid (ADSOLIDER (registered trademark) 101, Freund Sangyo), 4 g of sodium chloride (Tonda Pharmaceutical) and 0.14 g of magnesium stearate (PARTECK (registered trademark) LUB MST) , Merck KGaA) was added and mixed 100 times in a 2 L plastic bag to obtain a mixture.
  • the obtained mixture was dry granulated using a dry granulator (TF-Labo, Freund Industries) under the following conditions to obtain a dry granulated product.
  • the obtained dry granulated product was granulated with a screen size of 22 mesh using an oscillator granulator for dry granulator (TF-Labo, Freund Industries) to obtain a dry granulated granulated product.
  • magnesium stearate (Parteck (registered trademark) LUB MST, Merck KGaA) was added and further mixed 100 times to obtain a mixture. 200 mg of the obtained mixture was weighed and tableted with a simple compression molding machine (HANDTAB (registered trademark) 200, Ichihashi Seiki) at a tableting pressure of 8 kN using a ⁇ 8 mm corner flat mortar.
  • HANDTAB registered trademark 200, Ichihashi Seiki

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Abstract

La présente invention concerne une composition pharmaceutique contenant des granules secs en une quantité de 30 à 90 % en masse, chacun des granules secs comprenant une dispersion solide contenant un médicament faiblement soluble dans l'eau et un polymère soluble dans l'eau formable en gel et un sel, la teneur du sel dans les granules secs étant de 1 à 20 % en masse par rapport à la quantité totale de la composition pharmaceutique.
PCT/JP2019/009317 2018-03-09 2019-03-08 Composition pharmaceutique WO2019172420A1 (fr)

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JP2018-043456 2018-03-09

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