WO2019172420A1 - Pharmaceutical composition - Google Patents

Pharmaceutical composition 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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WIPO (PCT)
Prior art keywords
pharmaceutical composition
salt
soluble
granulated product
mass
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PCT/JP2019/009317
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French (fr)
Japanese (ja)
Inventor
宮本　祐司
崇郁 佐藤
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協和発酵キリン株式会社
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Publication of WO2019172420A1 publication Critical patent/WO2019172420A1/en

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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

Abstract

The present invention provides a pharmaceutical composition containing dry granules in an amount of 30 to 90% by mass, wherein each of the dry granules comprises a solid dispersion containing a poorly water-soluble drug and a gel-formable water-soluble polymer and a salt, wherein the content of the salt in the dry granules is 1 to 20% by mass relative to the whole amount of the pharmaceutical composition.

Description

医薬組成物Pharmaceutical composition
　本発明は、医薬組成物に関する。本発明は、より詳細には、即放性医薬組成物に関する。 The present invention relates to a pharmaceutical composition. The present invention relates more particularly to immediate release pharmaceutical compositions.
　難水溶性薬物を水溶性高分子に担持させた固体分散体を製剤中に含有し、速やかな崩壊性を得るための製剤化方法として、以下の方法が知られている。
　特許文献１および非特許文献１には、難水溶性薬物がゲル化形成水溶性高分子に担持された固体分散体を含有し、アルカリと弱酸または強酸との塩物質を含ませた、医薬組成物が開示されている。当該医薬組成物は、速やかな崩壊性および溶解性を示すとされている。
　特許文献２には、薬物のゲル化による薬物の放出遅延を抑制するために塩析剤を含有する方法が開示されている。当該方法は、速やかに薬物を溶出させるとされている。 The following method is known as a formulation method for obtaining a rapid disintegration by containing a solid dispersion in which a poorly water-soluble drug is supported on a water-soluble polymer in the formulation.
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.
　特許文献３には、薬物、水溶性高分子を含有する造粒粒子および中性から酸性の水溶性塩を存在させた製剤が開示されている。当該製剤は、ゲル化による崩壊遅延を抑制するとされている。 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.
特許第３９８８１９３号Patent No. 3988193 特開２０１５－１１０６４６号公報JP 2015-110646 A 特開２０１３－２４５１７３号公報JP 2013-245173 A
　しかしながら、特許文献１には、医薬組成物に乾式造粒物を含有させることは記載されていない。さらに特許文献１～３および非特許文献１に開示された製剤では、難水溶性薬物を水溶性高分子に担持させた固体分散体を製剤中に高含量で含有する場合、医薬組成物が崩壊せずに体内で有効成分を放出させることができない。 However, 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.
　本発明が解決しようとする課題は、速やかな崩壊性および溶出性を示す、難水溶性薬物を含有する医薬組成物を提供することである。 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.
　本発明者らは、上記課題を解決するために鋭意検討を行った結果、特定の構成を有する乾式造粒物を含む医薬組成物は、速やかに崩壊し、目的とする有効成分を放出させることができることを見いだし、本発明を完成させるに至った。 As a result of intensive studies to solve the above problems, 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.
　すなわち、本発明は、以下のとおりである。
［１］
　乾式造粒物を３０～９０質量％含有する、医薬組成物であって、
　前記乾式造粒物が、難水溶性薬物とゲル化形成水溶性高分子とを含む固体分散体と、塩と、を含有し、
　前記塩の含有量が、前記医薬組成物全量に対し１～２０質量％である、医薬組成物。
［２］
　ゲル化形成水溶性高分子が、ヒドロキシプロピルセルロース、ポリビニルピロリドン、およびヒプロメロースからなる群より選択される少なくとも１種を含む、［１］に記載の医薬組成物。換言すると、ゲル化形成水溶性高分子が、ヒドロキシプロピルセルロース、ポリビニルピロリドン、またはヒプロメロースを含む１種以上のゲル化形成水溶性高分子である、［１］に記載の医薬組成物。
［３］
　塩が、塩化ナトリウム、グルタミン酸ナトリウム、およびクエン酸ナトリウムからなる群より選択される少なくとも１種を含む、［１］または［２］に記載の医薬組成物。換言すると、塩が、塩化ナトリウム、グルタミン酸ナトリウム、またはクエン酸ナトリウムを含む１種以上の塩である、［１］または［２］に記載の医薬組成物。
［４］
　難水溶性薬物を含む医薬組成物の製造方法であって、
i）難水溶性薬物とゲル化形成水溶性高分子とを混合し、固体分散体を調製する工程と、
ii）前記固体分散体と塩とを混合し、乾式造粒を行い、乾式造粒物を得る工程と、
iii）前記乾式造粒物と薬学的に許容される添加剤とを混合し、医薬組成物を得る工程と、
を含む、製造方法。
［５］
　医薬組成物中の乾式造粒物の含有量が、３０～９０質量％である、［４］に記載の製造方法。
［６］
　医薬組成物中の塩の含有量が、前記医薬組成物全量に対し１～２０質量％である、［４］または［５］に記載の製造方法。
［７］
　ゲル化形成水溶性高分子が、ヒドロキシプロピルセルロース、ポリビニルピロリドン、およびヒプロメロースからなる群より選択される少なくとも１種を含む、［４］～［６］のいずれかに記載の製造方法。換言すると、ゲル化形成水溶性高分子が、ヒドロキシプロピルセルロース、ポリビニルピロリドン、またはヒプロメロースを含む１種以上のゲル化形成水溶性高分子である、［４］～［６］のいずれかに記載の製造方法。
［８］
　塩が、塩化ナトリウム、グルタミン酸ナトリウム、およびクエン酸ナトリウムからなる群より選択される少なくとも１種を含む、［４］～［７］のいずれかに記載の製造方法。換言すると、塩が、塩化ナトリウム、グルタミン酸ナトリウム、またはクエン酸ナトリウムを含む１種以上の塩である、［４］～［７］のいずれかに記載の製造方法。 That is, the present invention is as follows.
[1]
A pharmaceutical composition containing 30 to 90% by mass of a dry granulated product,
The 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.
[2]
The pharmaceutical composition according to [1], wherein the gel-forming water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone, and hypromellose. In other words, 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.
[3]
The pharmaceutical composition according to [1] or [2], wherein the salt comprises at least one selected from the group consisting of sodium chloride, sodium glutamate, and sodium citrate. In other words, the pharmaceutical composition according to [1] or [2], wherein the salt is one or more salts containing sodium chloride, sodium glutamate, or sodium citrate.
[4]
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.
[6]
The production method according to [4] or [5], wherein 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. In other words, 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. In other words, the production method according to any one of [4] to [7], wherein the salt is one or more salts containing sodium chloride, sodium glutamate, or sodium citrate.
　本発明によれば、速やかな崩壊性および溶出性を示す、難水溶性薬物を含有する医薬組成物を提供することができる。 According to the present invention, it is possible to provide a pharmaceutical composition containing a poorly water-soluble drug that exhibits rapid disintegration and dissolution.
実施例および比較例で得られた医薬組成物の、溶出率（％）と時間（分）との関係を表すグラフを示す図である。It is a figure which shows the graph showing the relationship between elution rate (%) and time (minute) of the pharmaceutical composition obtained by the Example and the comparative example.
　以下に本発明を実施するための形態について詳細に説明するが、本発明はこれに限定されるものではなく、その要旨を逸脱しない範囲で様々な変形が可能である。なお、本明細書において、「～」を用いてその前後に数値または物性値を挟んで表現する場合、その前後の値を含むものとして用いる。例えば「１～１００」との数値範囲の表記は、その上限値「１００」および下限値「１」の双方を包含するものとする。言い換えれば、例えば「１～１００」との数値範囲の表記は、１以上１００以下の数値範囲として理解される。また、他の数値範囲の表記も同様である。 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Modes for carrying out the present invention will be described in detail below, but the present invention is not limited to these, and various modifications can be made without departing from the scope of the present invention. In the present specification, when “˜” is used to express a value or a physical property value before and after that, it is used as including the value before and after that. For example, the description of a numerical range of “1 to 100” includes both the upper limit value “100” and the lower limit value “1”. In other words, for example, the description of a numerical range of “1 to 100” is understood as a numerical range of 1 or more and 100 or less. This also applies to other numerical range notations.
＜医薬組成物＞
　本発明の医薬組成物は、乾式造粒物を３０～９０質量％含有する、医薬組成物である。本発明における乾式造粒物は、難水溶性薬物とゲル化形成水溶性高分子とを含む固体分散体と、塩と、を含有する。また、上記乾式造粒物中の塩の含有量は、上記医薬組成物全量に対し１～２０質量％である。 <Pharmaceutical composition>
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.
（固体分散体）
　固体分散体は、難水溶性薬物とゲル化形成水溶性高分子とを含む。本発明における固体分散体とは、難水溶性薬物がゲル化形成水溶性高分子中に分散している組成物である。固体分散体においては、難水溶性薬物がゲル化形成水溶性高分子中に微粒子または分子状態で分散されていてもよい。
　また、固体分散体は、難水溶性薬物の非晶質体ということもできる。そして、本発明の医薬組成物が難水溶性薬物の非晶質体を含むこと（すなわち固体分散体を含むこと）は、例えば、Ｘ線粉末回折装置によって得られる本発明の医薬組成物のスペクトルデータと、Ｘ線粉末回折装置によって得られる難水溶性薬物単体のスペクトルデータ（結晶回折パターン）とを比較し、本発明の医薬組成物のスペクトルデータにおいて難水溶性薬物の固有の結晶回折パターンが見られないことにより確認することができる。 (Solid dispersion)
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. In the solid dispersion, 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 fact that the pharmaceutical composition of the present invention contains an amorphous form of a poorly water-soluble drug (that is, contains a solid dispersion) means that, for example, the spectrum of the pharmaceutical composition of the present invention obtained by an X-ray powder diffractometer Data and the spectrum data (crystal diffraction pattern) of the poorly water-soluble drug obtained by the X-ray powder diffractometer, and the inherent crystal diffraction pattern of the poorly water-soluble drug in the spectrum data of the pharmaceutical composition of the present invention It can be confirmed by not being seen.
　本発明における難水溶性薬物とは、第１７改正日本薬局方における溶解性を示す用語において、極めて溶けやすい、溶けやすい、やや溶けやすい、やや溶けにくい、溶けにくい、極めて溶けにくい、ほとんど溶けないとされているもののうち、やや溶けやすい、やや溶けにくい、溶けにくい、極めて溶けにくい、またはほとんど溶けないに分類される薬物を意味する。
　難水溶性薬物としては、特に限定されるものではないが、例えば、インドメタシン、カルバマゼピン、トルブタミド、ジピリダモール、イトラコナゾール、オキサプロジン、ナプロキセン、プランルカスト水和物、ハロペリドール、ベンズブロマロン等が挙げられる。難水溶性薬物は、１種単独で配合されてもよく、２種以上が配合されてもよい。 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 | blended individually by 1 type, and 2 or more types may be mix | blended.
　固体分散体における難水溶性薬物とゲル化形成水溶性高分子との配合比は、特に制限されず、難水溶性薬物とゲル化形成水溶性高分子との合計質量を１００質量％としたとき、難水溶性薬物の含有量が、好ましくは１～６０質量％であり、より好ましくは５～５０質量％であり、さらに好ましくは１０～４０質量％であり、よりさらに好ましくは２０～３０質量％である。
　固体分散体には、必要に応じて界面活性剤等の添加剤が含まれていてもよいが、本発明における固体分散体は、難水溶性薬物およびゲル化形成水溶性高分子を主成分とすることが好ましく、難水溶性薬物およびゲル化形成水溶性高分子からなることがより好ましい。
　なお、「主成分とする」とは、固体分散体における、難水溶性薬物およびゲル化形成水溶性高分子が占める割合が、通常７０質量％以上、好ましくは８０質量％以上、より好ましくは９０質量％以上であることを指す。固体分散体における、難水溶性薬物およびゲル化形成水溶性高分子が占める割合の上限は、１００質量％である。 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. However, 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.
　固体分散体は、難水溶性薬物とゲル化形成水溶性高分子とを、スプレードライ法やホットメルトエクストルージョン（ＨＭＥ）法等の公知の方法により製造することにより得られる。固体分散体を製造する方法としては、常温での製造が可能であることから、スプレードライ法が好ましい。混合する方法としては、通常薬学的に各成分を均一に混合できる方法であれば、特に制限されない。 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. As a method for producing a solid dispersion, 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.
　混合する方法としては、均一な固体分散体とする観点から、難水溶性薬物とゲル化形成水溶性高分子とを溶媒に溶解して得られる溶液を、乾燥させ、固体分散体を得る方法が好ましく、上記溶液を、スプレードライにより乾燥させ、固体分散体を得る方法がより好ましい。 As 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. Preferably, a method of obtaining a solid dispersion by drying the solution by spray drying is more preferable.
　難水溶性薬物とゲル化形成水溶性高分子とを溶媒に溶解するときに使用される溶媒としては、難水溶性薬物およびゲル化形成水溶性高分子を溶解でき、薬学的に許容される溶媒であれば特に制限されないが、例えば、水、エタノール、アセトン等が挙げられる。これらは、１種単独で用いても、２種以上を組み合わせて用いてもよい。 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 | limit in particular, For example, water, ethanol, acetone, etc. are mentioned. These may be used alone or in combination of two or more.
　スプレードライ等により固体分散体を得る場合、固体分散体は、粒子として得られる。粒子のサイズは、通常１μｍ以上５００μｍ以下であり、好ましくは２μｍ以上３００μｍ以下であり、より好ましくは３μｍ以上２００μｍ以下である。 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 μm or more and 500 μm or less, preferably 2 μm or more and 300 μm or less, more preferably 3 μm or more and 200 μm or less.
　固体分散体をスプレードライにより得る場合、噴霧乾燥の条件、すなわち、温度、難水溶性薬物とゲル化形成水溶性高分子とを含む溶液のフィード流量、噴霧圧は、通常の噴霧乾燥を行う条件であればよい。
　また、噴霧乾燥により得られた固体分散体は、さらに乾燥を行ってもよく、かかる乾燥の条件、すなわち、温度および時間は、難水溶性薬物の種類により適宜調節すればよい。 When the solid dispersion is obtained by spray drying, 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.
　本発明におけるゲル化形成水溶性高分子とは、水溶性を有し、ゲル化能を有する高分子であれば特に制限されない。
　本発明において、「水溶性を有する」とは、第１７改正日本薬局方における溶解性を示す用語において、極めて溶けやすい、溶けやすい、やや溶けやすい、やや溶けにくい、溶けにくい、極めて溶けにくい、ほとんど溶けないとされているもののうち、極めて溶けやすい、やや溶けやすい、やや溶けにくい、溶けにくい、極めて溶けにくいに分類されることを意味する。
　また、本発明において、「ゲル化能を有する」とは、水溶性高分子が部分的溶解することでゲル状になる能力を有することを意味する。 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.
In the present invention, “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.
Further, in the present invention, “having gelling ability” means having the ability to form a gel by partially dissolving the water-soluble polymer.
　一般的に、ゲル化形成水溶性高分子は、難水溶性薬物を当該ゲル化形成水溶性高分子に分散させ、難水溶性薬物の運動を分子状態で抑制する。通常、このゲル化形成水溶性高分子を含む製剤は、水に接触および溶解した際に、ゲル化し、製剤の崩壊を妨げると考えられる。一方、本発明の医薬組成物は、当該組成物中のゲル化形成水溶性高分子が水に接触および溶解したとしても、製剤が速やかに崩壊し、難水溶性薬物が製剤より溶出できる。 Generally, 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. In general, 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. On the other hand, in 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.
　ゲル化形成水溶性高分子としては、例えば、メチルセルロース、カルメロース、カルボキシプロピルセルロース、ヒドロキシプロピルセルロース、ヒプロメロース（ヒドロキシプロピルメチルセルロースともいう）等のセルロース誘導体；α化デンプン等のデンプン；ポリビニルアルコール；ポリビニルピロリドン；プルラン等が挙げられる。これらは、１種単独で用いても、２種以上を組み合わせて用いてもよい。
　ゲル化形成水溶性高分子としては、ヒドロキシプロピルセルロース、ポリビニルピロリドン、およびヒプロメロースが好ましい。すなわち、本発明におけるゲル化形成水溶性高分子は、ヒドロキシプロピルセルロース、ポリビニルピロリドン、またはヒプロメロースを含む１種以上のゲル化形成水溶性高分子であることが好ましい。 Examples of the gel-forming water-soluble polymer 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.
As the gel-forming water-soluble polymer, hydroxypropylcellulose, polyvinylpyrrolidone, and hypromellose are preferable. That is, the gel-forming water-soluble polymer in the present invention is preferably at least one gel-forming water-soluble polymer containing hydroxypropyl cellulose, polyvinyl pyrrolidone, or hypromellose.
（塩）
　本発明における塩は、酸に由来する陰イオンと塩基に由来する陽イオンとがイオン結合した化合物である。本発明における塩は、生体内での安全性や、組成物中の成分の分解や変性を抑制する観点から、中性、弱酸性、弱塩基性を示すことが好ましい。 (salt)
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.
　本発明における塩は、好ましくは、無機塩、アミノ酸塩、および生体に存在するカルボン酸の塩である。また、本発明の塩は、より好ましくは、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩である。 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.
　無機塩としては、例えば、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素カルシウム、炭酸水素マグネシウム、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸マグネシウム、リン酸ナトリウム、リン酸カリウム、リン酸カルシウム、リン酸マグネシウム等が挙げられる。 Examples of 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.
　アミノ酸塩としては、例えば、グルタミン酸ナトリウム、グルタミン酸カリウム、グルタミン酸カルシウム、グルタミン酸マグネシウム、アスパラギン酸ナトリウム、アスパラギン酸カリウム、アスパラギン酸カルシウム、アスパラギン酸マグネシウム等が挙げられる。 Examples of amino acid salts include sodium glutamate, potassium glutamate, calcium glutamate, magnesium glutamate, sodium aspartate, potassium aspartate, calcium aspartate, and magnesium aspartate.
　生体に存在するカルボン酸の塩としては、例えば、クエン酸ナトリウム、クエン酸カリウム、クエン酸カルシウム、クエン酸マグネシウム、アスコルビン酸ナトリウム、アスコルビン酸カリウム、アスコルビン酸カルシウム、アスコルビン酸マグネシウム、コハク酸ナトリウム、コハク酸カリウム、コハク酸カルシウム、コハク酸マグネシウム、フマル酸ナトリウム、フマル酸カリウム、フマル酸カルシウム、フマル酸マグネシウム、リンゴ酸ナトリウム、リンゴ酸カリウム、リンゴ酸カルシウム、リンゴ酸マグネシウム等が挙げられる。 Examples of 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.
　本発明における塩は、１種単独で用いても、２種以上を組み合わせて用いてもよい。 The salts in the present invention may be used singly or in combination of two or more.
　上記の塩の中でも、好ましくは、塩化ナトリウム、グルタミン酸ナトリウムおよびクエン酸ナトリウムである。すなわち、本発明における塩は、塩化ナトリウム、グルタミン酸ナトリウム、またはクエン酸ナトリウムを含む１種以上の塩であることが好ましい。 Among the above-mentioned salts, sodium chloride, sodium glutamate and sodium citrate are preferable. That is, the salt in the present invention is preferably one or more salts containing sodium chloride, sodium glutamate, or sodium citrate.
（乾式造粒物）
　本発明における乾式造粒物は、固体分散体と、塩と、を含有する。
　乾式造粒物とは、造粒時に水を用いず、乾燥状態を維持して形成された粒子を指す。
　乾式造粒物は、公知の乾式造粒機を使用することにより製造することができ、具体的には、固体分散体と、塩と、を混合して得られた混合物を、乾式造粒機に供し製造される。 (Dry granulated product)
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.
　乾式造粒物における固体分散体の配合比は、特に制限されず、乾式造粒物を１００質量％としたとき、固体分散体の含有量が、好ましくは４０～９０質量％であり、より好ましくは５０～８５質量％であり、さらに好ましくは６０～８０質量％である。 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%.
　乾式造粒物における塩の配合比は、乾式造粒物を１００質量％としたとき、好ましくは１～３０質量％であり、より好ましくは３～２８質量％であり、さらに好ましくは、５～２０質量％である。 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.
　乾式造粒物には、固体分散体および塩以外に、安定剤、潤沢剤、基剤、吸着剤、結合剤、懸濁剤、光沢化剤、コーティング剤、湿潤剤、湿潤調整剤、帯電防止剤、充填剤、着色剤、粘着増強剤、粘稠剤、賦形剤、離型剤、分散剤、崩壊剤、崩壊助剤、防湿剤、流動化剤等の薬学的に許容される添加剤を含んでいてもよい。薬学的に許容される添加剤は、１種単独で用いても、２種以上を組み合わせて用いてもよい。これらの添加剤の中でも、本発明における乾式造粒物は、流動化剤を含むことが好ましい。
　添加剤としては、具体的には、軽質無水ケイ酸、メタケイ酸アルミン酸マグネシウム、ケイ酸カルシウム、ステアリン酸マグネシウム等の流動化剤が好適に挙げられる。
　乾式造粒物における添加剤の配合比は、特に限定されず、乾式造粒物を１００質量％としたとき、好ましくは１～６０質量％であり、より好ましくは５～４０質量％であり、さらに好ましくは、５～２０質量％である。
　本発明における乾式造粒物は、固体分散体と、塩と、上記薬学的に許容される添加剤とからなることが好ましい。 For dry granulated products, in addition to solid dispersions and salts, stabilizers, lubricants, bases, adsorbents, binders, suspending agents, brighteners, coating agents, wetting agents, wetting regulators, antistatic agents Pharmaceutically acceptable additives such as agents, fillers, colorants, adhesion enhancers, thickeners, excipients, mold release agents, dispersants, disintegrants, disintegration aids, dampproofing agents, fluidizing agents, etc. May be included. Pharmaceutically acceptable additives may be used singly or in combination of two or more. Among these additives, the dry granulated product in the present invention preferably contains a fluidizing agent.
Specific examples of 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.
　本発明における乾式造粒物は、乾式造粒機により製造された造粒品を、さらに公知の整粒機によって整粒した整粒品であってもよい。
　整粒するときのスクリーンサイズは、好ましくは４～５０メッシュであり、より好ましくは６．５～４２メッシュであり、さらに好ましくは１２～３０メッシュである。
　本発明における乾式造粒物の平均粒子径は、好ましくは１０～１０００μｍであり、より好ましくは５０～５００μｍであり、さらに好ましくは１００～４００μｍである。上記平均粒子径は、乾式造粒機により造粒する際に、造粒の圧力、撹拌速度、整粒におけるスクリーンサイズ等を調整することによって、制御することができる。 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 μm, more preferably 50 to 500 μm, and further preferably 100 to 400 μm. 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.
　乾式造粒機により乾式造粒物を製造するとき、造粒の圧力、撹拌速度は、通常の乾式造粒を行う範囲であればよい。 When producing a dry granulated product with a dry granulator, the pressure and stirring speed of the granulation may be within the range in which normal dry granulation is performed.
（医薬組成物）
　本発明の医薬組成物は、固体分散体と、塩と、を含有する乾式造粒物を、３０～９０質量％含有する。乾式造粒物の含有量は、好ましくは４０～８５質量％であり、より好ましくは５０～８０質量％である。本発明の医薬組成物中の乾式造粒物の量を３０質量％以上９０質量％以下とすることにより、医薬組成物が速やかに崩壊し、難水溶性薬物が溶出しやすくなる。
　本発明の医薬組成物中の乾式造粒物に含まれる塩の量は、医薬組成物全量に対し１～２０質量％であり、好ましくは３～１８質量％であり、より好ましくは５～１５質量％である。乾式造粒物に含まれる塩の量を１質量％以上とすることにより、医薬組成物が速やかに崩壊し、難水溶性薬物が溶出しやすくなる。乾式造粒物に含まれる塩の量を２０質量％以下とすることにより、固体分散体と塩とを含む混合物を造粒する際の形成性に優れる。 (Pharmaceutical composition)
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. When 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. 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.
　本発明の医薬組成物は、乾式造粒物以外に、薬学的に許容される添加剤を含むことが好ましい。
　薬学的に許容される添加剤としては、特に制限されず、例えば、安定剤、潤沢剤、基剤、吸着剤、結合剤、懸濁剤、光沢化剤、コーティング剤、湿潤剤、湿潤調整剤、帯電防止剤、充填剤、着色剤、粘着増強剤、粘稠剤、賦形剤、離型剤、分散剤、崩壊剤、崩壊助剤、防湿剤、流動化剤等が挙げられる。これらは、１種単独で用いても、２種以上を組み合わせて用いてもよい。
　これらの添加剤の中でも好ましくは、賦形剤、結合剤、崩壊剤、滑沢剤、流動化剤を使用することが好ましい。 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. , Antistatic agents, fillers, colorants, adhesion enhancers, thickeners, excipients, mold release agents, dispersants, disintegrating agents, disintegrating aids, moisture-proofing agents, fluidizing agents, and the like. These may be used alone or in combination of two or more.
Among these additives, it is preferable to use an excipient, a binder, a disintegrant, a lubricant, and a fluidizing agent.
　賦形剤としては、例えば、乳糖、白糖、デンプン、結晶セルロース、Ｄ－マンニトール、Ｄ－ソルビトール、デンプン誘導体（コーンスターチ等）、セルロース誘導体、炭酸塩、リン酸塩、および硫酸塩等が挙げられる。
　結合剤としては、例えば、ポビドン、ポリビニルアルコール、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロース等が挙げられる。
　崩壊剤としては、例えば、クロスポビドン、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、および低置換度ヒドロキシプロピルセルロース等が挙げられる。
　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、タルク、およびモノステアリン酸グリセリン等が挙げられる。
　流動化剤としては、例えば、軽質無水ケイ酸、メタケイ酸アルミン酸マグネシウム、ケイ酸カルシウム、ステアリン酸マグネシウム等が挙げられる。
　添加剤として、さらに、例えば、香料等を任意に加えてもよい。 Examples of the excipient include lactose, sucrose, starch, crystalline cellulose, D-mannitol, D-sorbitol, starch derivatives (such as corn starch), cellulose derivatives, carbonates, phosphates, sulfates and the like.
Examples of the binder include povidone, polyvinyl alcohol, hydroxypropylmethylcellulose, and hydroxypropylcellulose.
Examples of the disintegrant include crospovidone, croscarmellose sodium, carboxymethyl starch sodium, and low-substituted hydroxypropylcellulose.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, and glyceryl monostearate.
Examples of the fluidizing agent include light anhydrous silicic acid, magnesium aluminate metasilicate, calcium silicate, magnesium stearate and the like.
As an additive, for example, a fragrance may be optionally added.
　添加剤としては、具体的には、軽質無水ケイ酸、ステアリン酸マグネシウム、結晶セルロース、クロスカルメロースナトリウム、ヒドロキシプロピルセルロース等が好適に挙げられる。 Specific examples of suitable additives include light anhydrous silicic acid, magnesium stearate, crystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and the like.
　本発明の医薬組成物における、薬学的に許容される添加剤の含有量は、通常１０～７０質量％であり、好ましくは１５～６０質量％であり、より好ましくは２０～５０質量％である。
　本発明の医薬組成物は、固体分散体と塩とを含有する乾式造粒物と、薬学的に許容される添加剤との合計が１００質量％となることが好ましい。 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. .
In the pharmaceutical composition of the present invention, the total of the dry granulated product containing the solid dispersion and the salt and the pharmaceutically acceptable additive is preferably 100% by mass.
　本発明の医薬組成物は、経口用医薬組成物として用いることもできる。
　経口医薬組成物としては、経口投与できる製剤であれば、特に限定されるものではないが、中でも、散剤、細粒剤、顆粒剤、錠剤、またはカプセル剤の形状であってよい。これらの中でも、好ましくは錠剤である。錠剤の形状としては、特に制限されず、例えば、円形、楕円形、多角形等の形状が挙げられる。また、錠剤の長径（円形であれば直径）は、通常３ｍｍ以上２５ｍｍ以下であり、好ましくは５ｍｍ以上２０ｍｍ以下であり、より好ましくは５ｍｍ以上１１０ｍｍ以下である。 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.
＜医薬組成物の製造方法＞
　また、本発明は、
i）難水溶性薬物とゲル化形成水溶性高分子とを混合し、固体分散体を調製する工程と、
ii）前記固体分散体と塩とを混合し、乾式造粒を行い、乾式造粒物を得る工程と、
iii）前記乾式造粒物と薬学的に許容される添加剤とを混合し、医薬組成物を得る工程と、を含む、医薬組成物の製造方法に関する。 <Method for producing pharmaceutical composition>
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.
　本発明の製造方法において、医薬組成物は、例えば、乾式造粒物と薬学的に許容される添加剤とを混合し混合物を得て、かかる混合物を公知の錠剤成形機等を用いて打錠して錠剤として得ることができる。
　錠剤成形機としては、例えば、圧縮成型機等が好適である。圧縮するときの打錠圧力は、通常０ｋＮ超過３００ｋＮ以下であり、好ましくは１ｋＮ以上２０ｋＮ以下であり、より好ましくは３ｋＮ以上１５ｋＮ以下である。
　錠剤の形状としては、特に制限されず、例えば、円形、楕円形、多角形等の形状が挙げられる。また、錠剤の長径（円形であれば直径）は、通常３ｍｍ以上２５ｍｍ以下であり、好ましくは５ｍｍ以上２０ｍｍ以下であり、より好ましくは５ｍｍ以上１１０ｍｍ以下である。 In the production method of the present invention, 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.
As the 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.
　本発明の製造方法における、難水溶性薬物、ゲル化形成水溶性高分子、固体分散体、塩、乾式造粒物、および薬学的に許容される添加剤の種類、並びにそれらの配合比、具体的な調製方法等の態様は、前記＜医薬組成物＞における説明と同様の態様を挙げることができ、また、同様の好ましい態様を挙げることができる。
　また、本発明の製造方法に用いられる難水溶性薬物または本発明の医薬組成物に配合される難水溶性薬物は、結晶の形態であってもよく、アモルファスの形態であってもよく、上記結晶の形態を公知の方法により易溶化させた形態あってもよい。 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, Examples of typical preparation methods and the like can include the same aspects as described in the above <Pharmaceutical composition>, and the same preferable aspects.
Further, 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.
［製造例１］
　インドメタシン２５０ｇをアセトン１５．５ｋｇおよび精製水１ｋｇに溶解させた。その後、ヒプロメロース（ＨＰＭＣ ＴＣ－５Ｅ、信越化学工業）７５０ｇを加え完全溶解させ、溶液を得た。その溶液をスプレードライヤー（ＣＬ－８、大川原製作所）にて以下の条件で噴霧乾燥を行い、スプレードライ品を得た。
　得られたスプレードライ品を真空乾燥機（ＶＯ－４００）にてさらに二次乾燥を行い、固体分散体（以下、「ＳＤ品」と記載する）を得た。 [Production Example 1]
250 g of indomethacin was dissolved in 15.5 kg of acetone and 1 kg of purified water. Thereafter, 750 g of hypromellose (HPMC TC-5E, Shin-Etsu Chemical Co., Ltd.) was added and completely dissolved to obtain a solution. The solution was spray-dried under the following conditions with a spray dryer (CL-8, Okawara Seisakusho) to obtain a spray-dried product.
The obtained spray-dried product was further subjected to secondary drying with a vacuum dryer (VO-400) to obtain a solid dispersion (hereinafter referred to as “SD product”).
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
［実施例１］
　製造例１で得られたＳＤ品２０ｇ、軽質無水ケイ酸４ｇ（アドソリダー（登録商標）１０１、フロイント産業）、クエン酸ナトリウム４ｇ（メルク）およびステアリン酸マグネシウム０．１４ｇ（ＰＡＲＴＥＣＫ（登録商標） ＬＵＢ ＭＳＴ、Ｍｅｒｃｋ ＫＧａＡ）を加え、２Ｌポリ袋にて１００回混合して、混合品を得た。
　得られた混合品は、乾式造粒機（ＴＦ－Ｌａｂｏ、フロイント産業）を用いて以下の条件で乾式造粒を行い、乾式造粒物を得た。
　得られた乾式造粒物は、乾式造粒機用オシレータ整粒機（ＴＦ－Ｌａｂｏ、フロイント産業）を用いてスクリーンサイズ２２メッシュにて整粒を行い、乾式造粒整粒物を得た。 [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.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　得られた乾式造粒整粒物２．８ｇ、結晶セルロース０．２２ｇ（セオラス（登録商標）ＵＦ－７０２、旭化成ケミカルズ）、クロスカルメロースナトリウム０．８ｇ（Ａｃ－Ｄｉ－Ｓｏｌ（登録商標）、ＦＭＣ Ｈｅａｌｔｈ ａｎｄ Ｎｕｔｒｉｔｉｏｎ）、ヒドロキシプロピルセルロース０．１２ｇ（ＨＰＣ－ＳＳＬ、日本曹達）、軽質無水ケイ酸０．０４ｇ（アドソリダー（登録商標）１０１、フロイント産業）を秤量し、ガラス瓶内で１００回混合した。その後、ステアリン酸マグネシウム０．０２ｇ（ＰＡＲＴＥＣＫ（登録商標） ＬＵＢ ＭＳＴ、Ｍｅｒｃｋ ＫＧａＡ）を加え、更に１００回混合して、混合物を得た。
　得られた混合物２００ｍｇを秤量し、φ８ｍｍ隅角平の臼杵を用い簡易圧縮成型機（ＨＡＮＤＴＡＢ（登録商標）２００、市橋精機）にて打錠圧力８ｋＮにて打錠して錠剤を得た。 2.8 g of the obtained dry granulated sized product, 0.22 g of crystalline cellulose (Theolas (registered trademark) UF-702, Asahi Kasei Chemicals), 0.8 g of croscarmellose sodium (Ac-Di-Sol (registered trademark)), FMC Health and Nutrition), 0.12 g of hydroxypropyl cellulose (HPC-SSL, Nippon Soda), 0.04 g of light anhydrous silicic acid (ADSOLIDER (registered trademark) 101, Freund Industries) and weighed 100 times in a glass bottle. . Then, 0.02 g of 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 φ8 mm corner flat mortar.
［実施例２］
　製造例１で得られたＳＤ品２０ｇ、軽質無水ケイ酸４ｇ（アドソリダー（登録商標）１０１、フロイント産業）、グルタミン酸ナトリウム４ｇ（和光純薬）およびステアリン酸マグネシウム０．１４ｇ（ＰＡＲＴＥＣＫ（登録商標） ＬＵＢ ＭＳＴ、Ｍｅｒｃｋ ＫＧａＡ）を加え、２Ｌポリ袋にて１００回混合して、混合品を得た。
　得られた混合品を、乾式造粒機（ＴＦ－Ｌａｂｏ、フロイント産業）を用いて以下の条件で乾式造粒を行い、乾式造粒物を得た。
　得られた乾式造粒物は、乾式造粒機用オシレータ整粒機（ＴＦ－Ｌａｂｏ、フロイント産業）を用いてスクリーンサイズ２２メッシュにて整粒を行い、乾式造粒整粒物を得た。 [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.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　得られた乾式造粒整粒物２．８ｇ、結晶セルロース０．２２ｇ（セオラス（登録商標）ＵＦ－７０２、旭化成ケミカルズ）、クロスカルメロースナトリウム０．８ｇ（Ａｃ－Ｄｉ－Ｓｏｌ（登録商標）、ＦＭＣ Ｈｅａｌｔｈ ａｎｄ Ｎｕｔｒｉｔｉｏｎ）、ヒドロキシプロピルセルロース０．１２ｇ（ＨＰＣ－ＳＳＬ、日本曹達）、軽質無水ケイ酸０．０４ｇ（アドソリダー（登録商標）１０１、フロイント産業）を秤量し、ガラス瓶内で１００回混合した。その後、ステアリン酸マグネシウム０．０２ｇ（ＰＡＲＴＥＣＫ（登録商標） ＬＵＢ ＭＳＴ、Ｍｅｒｃｋ ＫＧａＡ）を加え、更に１００回混合して、混合物を得た。
　得られた混合物２００ｍｇを秤量し、φ８ｍｍ隅角平の臼杵を用い簡易圧縮成型機（ＨＡＮＤＴＡＢ２００、市橋精機）にて打錠圧力８ｋＮにて打錠して錠剤を得た。 2.8 g of the obtained dry granulated sized product, 0.22 g of crystalline cellulose (Theolas (registered trademark) UF-702, Asahi Kasei Chemicals), 0.8 g of croscarmellose sodium (Ac-Di-Sol (registered trademark)), FMC Health and Nutrition), 0.12 g of hydroxypropyl cellulose (HPC-SSL, Nippon Soda), 0.04 g of light anhydrous silicic acid (ADSOLIDER (registered trademark) 101, Freund Industries) and weighed 100 times in a glass bottle. . Then, 0.02 g of 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 (HANDTAB200, Ichihashi Seiki) at a tableting pressure of 8 kN using a φ8 mm corner flat mortar.
［実施例３］
　製造例１で得られたＳＤ品２０ｇ、軽質無水ケイ酸４ｇ（アドソリダー（登録商標）１０１、フロイント産業）、塩化ナトリウム４ｇ（富田製薬）およびステアリン酸マグネシウム０．１４ｇ（ＰＡＲＴＥＣＫ（登録商標） ＬＵＢ ＭＳＴ、Ｍｅｒｃｋ ＫＧａＡ）を加え、２Ｌポリ袋にて１００回混合して、混合品を得た。
　得られた混合品を、乾式造粒機（ＴＦ－Ｌａｂｏ、フロイント産業）を用いて以下の条件で乾式造粒を行い、乾式造粒物を得た。
　得られた乾式造粒物は、乾式造粒機用オシレータ整粒機（ＴＦ－Ｌａｂｏ、フロイント産業）を用いてスクリーンサイズ２２メッシュにて整粒を行い、乾式造粒整粒物を得た。 [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.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　得られた乾式造粒整粒物２．８ｇ、結晶セルロース０．２２ｇ（セオラス（登録商標）ＵＦ－７０２、旭化成ケミカルズ）、クロスカルメロースナトリウム０．８ｇ（Ａｃ－Ｄｉ－Ｓｏｌ（登録商標）、ＦＭＣ Ｈｅａｌｔｈ ａｎｄ Ｎｕｔｒｉｔｉｏｎ）、ヒドロキシプロピルセルロース０．１２ｇ（ＨＰＣ－ＳＳＬ、日本曹達）、軽質無水ケイ酸０．０４ｇ（アドソリダー（登録商標）１０１、フロイント産業）を秤量し、ガラス瓶内で１００回混合した。その後、ステアリン酸マグネシウム０．０２ｇ（ＰＡＲＴＥＣＫ（登録商標） ＬＵＢ ＭＳＴ、Ｍｅｒｃｋ ＫＧａＡ）を加え、更に１００回混合して、混合物を得た。
　得られた混合物２００ｍｇを秤量し、φ８ｍｍ隅角平の臼杵を用い簡易圧縮成型機（ＨＡＮＤＴＡＢ（登録商標）２００、市橋精機）にて打錠圧力８ｋＮにて打錠して錠剤を得た。 2.8 g of the obtained dry granulated sized product, 0.22 g of crystalline cellulose (Theolas (registered trademark) UF-702, Asahi Kasei Chemicals), 0.8 g of croscarmellose sodium (Ac-Di-Sol (registered trademark)), FMC Health and Nutrition), 0.12 g of hydroxypropyl cellulose (HPC-SSL, Nippon Soda), 0.04 g of light anhydrous silicic acid (ADSOLIDER (registered trademark) 101, Freund Industries) and weighed 100 times in a glass bottle. . Then, 0.02 g of 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 φ8 mm corner flat mortar.
［比較例１］
　製造例１で得られたＳＤ品２ｇ、結晶セルロース１．０２ｇ（セオラス（登録商標）ＵＦ－７０２、旭化成ケミカルズ）、クロスカルメロースナトリウム０．８ｇ（Ａｃ－Ｄｉ－Ｓｏｌ（登録商標）、ＦＭＣ Ｈｅａｌｔｈ ａｎｄ Ｎｕｔｒｉｔｉｏｎ）、ヒドロキシプロピルセルロース０．１２ｇ（ＨＰＣ－ＳＳＬ、日本曹達）、軽質無水ケイ酸０．０４ｇ（アドソリダー（登録商標）１０１、フロイント産業）を秤量し、ガラス瓶内で１００回混合した。その後、ステアリン酸マグネシウム０．０２ｇ（ＰＡＲＴＥＣＫ（登録商標） ＬＵＢ ＭＳＴ、Ｍｅｒｃｋ ＫＧａＡ）を加え、更に１００回混合して、混合物を得た。
　得られた混合物２００ｍｇを秤量し、φ８ｍｍ隅角平の臼杵を用い簡易圧縮成型機（ＨＡＮＤＴＡＢ（登録商標）２００、市橋精機）にて打錠圧力８ｋＮにて打錠して錠剤を得た。 [Comparative Example 1]
2 g of SD product obtained in Production Example 1, 1.02 g of crystalline cellulose (Theolas (registered trademark) UF-702, Asahi Kasei Chemicals), 0.8 g of croscarmellose sodium (Ac-Di-Sol (registered trademark), FMC Health) and Nutrition), 0.12 g of hydroxypropylcellulose (HPC-SSL, Nippon Soda) and 0.04 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Sangyo) were weighed and mixed 100 times in a glass bottle. Then, 0.02 g of 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 φ8 mm corner flat mortar.
［比較例２］
　製造例１で得られたＳＤ品７０ｇ、軽質無水ケイ酸１４ｇ（アドソリダー（登録商標）１０１、フロイント産業）およびステアリン酸マグネシウム０．４２ｇ（ＰＡＲＴＥＣＫ（登録商標） ＬＵＢ ＭＳＴ、Ｍｅｒｃｋ ＫＧａＡ）を加え、２Ｌポリ袋にて１００回混合して、混合品を得た。
　得られた混合品は、乾式造粒機（ＴＦ－Ｌａｂｏ、フロイント産業）を用いて以下の条件で乾式造粒を行い、乾式造粒物を得た。
　得られた乾式造粒物は、乾式造粒機用オシレータ整粒機（ＴＦ－Ｌａｂｏ、フロイント産業）を用いてスクリーンサイズ２２メッシュにて整粒を行い、乾式造粒整粒品を得た。 [Comparative Example 2]
70 g of SD product obtained in Production Example 1, 14 g of light anhydrous silicic acid (ADSOLIDER (registered trademark) 101, Freund Sangyo) and 0.42 g of magnesium stearate (PARTECK (registered trademark) LUB MST, Merck KGaA) were added. The mixture was obtained by mixing 100 times in a plastic bag.
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 sized with a screen size of 22 mesh using an oscillator granulator for dry granulator (TF-Labo, Freund Industries) to obtain a dry granulated sized product.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　得られた乾式造粒整粒品２．４ｇ、結晶セルロース０．６２ｇ（セオラス（登録商標）ＵＦ－７０２、旭化成ケミカルズ）、クロスカルメロースナトリウム０．８ｇ（Ａｃ－Ｄｉ－Ｓｏｌ（登録商標）、ＦＭＣ Ｈｅａｌｔｈ ａｎｄ Ｎｕｔｒｉｔｉｏｎ）、ヒドロキシプロピルセルロース０．１２ｇ（ＨＰＣ－ＳＳＬ、日本曹達）、軽質無水ケイ酸０．０４ｇ（アドソリダー（登録商標）１０１、フロイント産業）を秤量し、ガラス瓶内で１００回混合した。その後、ステアリン酸マグネシウム０．０２ｇ（Ｐａｒｔｅｃｋ（登録商標） ＬＵＢ ＭＳＴ、Ｍｅｒｃｋ ＫＧａＡ）を加え、更に１００回混合して、混合物を得た。
　得られた混合物２００ｍｇを秤量し、φ８ｍｍ隅角平の臼杵を用い簡易圧縮成型機（ＨＡＮＤＴＡＢ（登録商標）２００、市橋精機）にて打錠圧力８ｋＮにて打錠して錠剤を得た。 2.4 g of the obtained dry granulated sized product, 0.62 g of crystalline cellulose (Theolas (registered trademark) UF-702, Asahi Kasei Chemicals), 0.8 g of croscarmellose sodium (Ac-Di-Sol (registered trademark)), FMC Health and Nutrition), 0.12 g of hydroxypropyl cellulose (HPC-SSL, Nippon Soda), 0.04 g of light anhydrous silicic acid (ADSOLIDER (registered trademark) 101, Freund Industries) and weighed 100 times in a glass bottle. . Thereafter, 0.02 g of 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 φ8 mm corner flat mortar.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
＜崩壊性および溶解性の評価＞
（崩壊時間）
　実施例および比較例により得られた錠剤を、第１７改正日本薬局方の崩壊試験に準じて崩壊時間を測定した。試験液は精製水を使用し、３７℃とした。また、試験例数はｎ＝６とした。
（溶解性）
　実施例および比較例により得られた錠剤の溶解性を評価した。錠剤を、試験液に第１７改正日本薬局方第２液９００ｍＬを用い、パドル法により、毎分５０回転で試験を行った。なお、６０分から９０分は１５０回転で試験を行った。溶出試験開始５、１０、１５、３０、４５、６０および９０分後、溶出液５ｍＬをそれぞれとり、孔径０．４５μｍ以下のＰＴＦＥ製のメンブランフィルターでろ過した。初めのろ液５ｍＬを除き、次のろ液を試料溶液とした。溶出液を採取した後、別に新たな試験液１０ｍＬをとり、容器内の試験液に加えた。
　別途、定量用の主薬約２８ｍｇを精密に量り、メタノールに溶かし、５分間の超音波照射を行ったのち、正確に１００ｍＬとした。この液５ｍＬを正確に量り、第１７改正日本薬局方第２液を加えて正確に５０ｍＬとし、標準溶液とした。
　試料溶液および標準溶液１０μＬずつを正確にとり、液体クロマトグラフィーにより試験を行い、それぞれの液の難水溶性薬物のピーク面積から溶出濃度を測定した。試験例数ｎは、ｎ＝３とした。結果を図１に示す。 <Evaluation of disintegration and solubility>
(Collapse time)
The disintegration time of the tablets obtained in Examples and Comparative Examples was measured according to the disintegration test of the 17th revised Japanese Pharmacopoeia. The test solution used purified water and was 37 degreeC. The number of test examples was n = 6.
(Solubility)
The solubility of the tablets obtained by Examples and Comparative Examples was evaluated. The tablets were tested at 50 rotations per minute by the paddle method using 900 mL of the 17th revised Japanese Pharmacopoeia second liquid as the test liquid. The test was performed at 150 revolutions from 60 minutes to 90 minutes. 5, 10, 15, 30, 45, 60 and 90 minutes after the start of the dissolution test, 5 mL of the eluate was taken and filtered through a PTFE membrane filter having a pore size of 0.45 μm or less. Except for 5 mL of the first filtrate, the next filtrate was used as a sample solution. After collecting the eluate, another 10 mL of a new test solution was taken and added to the test solution in the container.
Separately, about 28 mg of the main drug for quantification was accurately weighed, dissolved in methanol, and subjected to ultrasonic irradiation for 5 minutes, and then accurately adjusted to 100 mL. 5 mL of this solution was accurately weighed, and the 17th revised Japanese Pharmacopoeia second solution was added to make exactly 50 mL to obtain a standard solution.
10 μL each of the sample solution and the standard solution were accurately taken and tested by liquid chromatography, and the elution concentration was measured from the peak area of the poorly water-soluble drug in each solution. The number n of test examples was n = 3. The results are shown in FIG.
Figure JPOXMLDOC01-appb-T000007
  
Figure JPOXMLDOC01-appb-T000007
  

Claims (8)

  1. 　乾式造粒物を３０～９０質量％含有する、医薬組成物であって、
    　前記乾式造粒物が、難水溶性薬物とゲル化形成水溶性高分子とを含む固体分散体と、塩と、を含有し、
    　前記塩の含有量が、前記医薬組成物全量に対し１～２０質量％である、医薬組成物。     A pharmaceutical composition containing 30 to 90% by mass of a dry granulated product,
    The 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.
  2. 　ゲル化形成水溶性高分子が、ヒドロキシプロピルセルロース、ポリビニルピロリドン、およびヒプロメロースからなる群より選択される少なくとも１種を含む、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the gel-forming water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone, and hypromellose.
  3. 　塩が、塩化ナトリウム、グルタミン酸ナトリウム、およびクエン酸ナトリウムからなる群より選択される少なくとも１種を含む、請求項１または２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the salt comprises at least one selected from the group consisting of sodium chloride, sodium glutamate, and sodium citrate.
  4. 　難水溶性薬物を含む医薬組成物の製造方法であって、
    i）難水溶性薬物とゲル化形成水溶性高分子とを混合し、固体分散体を調製する工程と、
    ii）前記固体分散体と塩とを混合し、乾式造粒を行い、乾式造粒物を得る工程と、
    iii）前記乾式造粒物と薬学的に許容される添加剤とを混合し、医薬組成物を得る工程と、
    を含む、製造方法。     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. 　医薬組成物中の乾式造粒物の含有量が、３０～９０質量％である、請求項４に記載の製造方法。 The production method according to claim 4, wherein the content of the dry granulated product in the pharmaceutical composition is 30 to 90% by mass.
  6. 　塩の含有量が、前記医薬組成物全量に対し１～２０質量％である、請求項４または５に記載の製造方法。 The production method according to claim 4 or 5, wherein the salt content is 1 to 20% by mass relative to the total amount of the pharmaceutical composition.
  7. 　ゲル化形成水溶性高分子が、ヒドロキシプロピルセルロース、ポリビニルピロリドン、およびヒプロメロースからなる群より選択される少なくとも１種を含む、請求項４～６のいずれか一項に記載の製造方法。 The production method according to any one of claims 4 to 6, wherein the gel-forming water-soluble polymer contains at least one selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone, and hypromellose.
  8. 　塩が、塩化ナトリウム、グルタミン酸ナトリウム、およびクエン酸ナトリウムからなる群より選択される少なくとも１種を含む、請求項４～７のいずれか一項に記載の製造方法。
          The production method according to any one of claims 4 to 7, wherein the salt comprises at least one selected from the group consisting of sodium chloride, sodium glutamate, and sodium citrate.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997006781A1 (en) * 1995-08-11 1997-02-27 Nissan Chemical Industries, Ltd. Methods for making hardly soluble medicine amorphous
JPH09104620A (en) * 1994-12-27 1997-04-22 Kanebo Ltd Long active preparation
WO1998029137A1 (en) * 1996-12-25 1998-07-09 Yamanouchi Pharmaceutical Co., Ltd. Immediately disintegrable medicinal compositions
CN104473897A (en) * 2014-11-27 2015-04-01 天津坤健生物制药有限公司 Preparation method of ethionamide tablet
WO2016175230A1 (en) * 2015-04-28 2016-11-03 アステラス製薬株式会社 Pharmaceutical composition for oral administration
CN106580895A (en) * 2016-12-07 2017-04-26 万全万特制药（厦门）有限公司 Orally disintegrating tablet containing vilazodone hydrochloride solid dispersions and preparation method thereof
WO2017095697A1 (en) * 2015-11-30 2017-06-08 Ironwood Pharmaceuticals, Inc. Solid dispersions comprising a sgc stimulator

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09104620A (en) * 1994-12-27 1997-04-22 Kanebo Ltd Long active preparation
WO1997006781A1 (en) * 1995-08-11 1997-02-27 Nissan Chemical Industries, Ltd. Methods for making hardly soluble medicine amorphous
WO1998029137A1 (en) * 1996-12-25 1998-07-09 Yamanouchi Pharmaceutical Co., Ltd. Immediately disintegrable medicinal compositions
CN104473897A (en) * 2014-11-27 2015-04-01 天津坤健生物制药有限公司 Preparation method of ethionamide tablet
WO2016175230A1 (en) * 2015-04-28 2016-11-03 アステラス製薬株式会社 Pharmaceutical composition for oral administration
WO2017095697A1 (en) * 2015-11-30 2017-06-08 Ironwood Pharmaceuticals, Inc. Solid dispersions comprising a sgc stimulator
CN106580895A (en) * 2016-12-07 2017-04-26 万全万特制药（厦门）有限公司 Orally disintegrating tablet containing vilazodone hydrochloride solid dispersions and preparation method thereof

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