WO2020071231A1 - Solifenacin-containing coated preparation - Google Patents

Solifenacin-containing coated preparation

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Publication number
WO2020071231A1
WO2020071231A1 PCT/JP2019/037834 JP2019037834W WO2020071231A1 WO 2020071231 A1 WO2020071231 A1 WO 2020071231A1 JP 2019037834 W JP2019037834 W JP 2019037834W WO 2020071231 A1 WO2020071231 A1 WO 2020071231A1
Authority
WO
WIPO (PCT)
Prior art keywords
solifenacin
core
coated preparation
amorphous
mass
Prior art date
Application number
PCT/JP2019/037834
Other languages
French (fr)
Japanese (ja)
Inventor
慎 井實
浩二 堀
Original Assignee
ニプロ株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ニプロ株式会社 filed Critical ニプロ株式会社
Priority to JP2020550351A priority Critical patent/JPWO2020071231A1/en
Publication of WO2020071231A1 publication Critical patent/WO2020071231A1/en

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • the present invention relates to a coated preparation containing amorphous solifenacin, a pharmacologically acceptable salt thereof, or a solvate thereof.
  • Solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof (hereinafter, solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof may be referred to as “solifenacin”). Crystalline bodies are very unstable and are known to degrade during storage.
  • Patent Document 1 discloses that an amorphous product of solifenacin succinate generates a decomposed product of solifenacin succinate in a short period of time after the start of storage, and has a higher storage stability than a crystalline product. It was stated that it was inferior. Therefore, in Patent Document 1, solifenacin succinate and the amount of water in a granulated product containing a substance having an ethylene oxide chain as an amorphization inhibitor were adjusted, and a tablet obtained from the granulated product was used. Coated tablets coated with a liquid containing hydroxypropyl methylcellulose, macrogol 6000, talc, titanium oxide, red iron sesquioxide are described. In Patent Document 1, when the water content in the granulated product is low, the amorphous content of solifenacin at the start of storage is low, and the proportion of the amount of the main degradation product after storage for 6 months is suppressed. It is described.
  • Patent Literature 1 only describes that solifenacin is suppressed from becoming amorphous by suppressing the amorphization of solifenacin. No consideration is given to suppressing decomposition.
  • an object of the present invention is to provide a coated preparation containing stabilized solifenacin in an amorphous form, and a method for stabilizing solifenacin in an amorphous form.
  • the present inventors have conducted intensive studies and as a result, by maintaining the solifenacin-containing coated preparation of the present invention as follows, the amorphous form of solifenacin was maintained, and the solifenacin in the amorphous form was stabilized. Found that it can be
  • the solifenacin-containing coated preparation according to the present invention comprises a core containing amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof, and a polyvinyl alcohol copolymer coating the core. And a coating layer containing the coalescence.
  • the amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof is preferably solifenacin succinate.
  • the polyvinyl alcohol copolymer is preferably a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.
  • the coating layer preferably contains a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in an amount of 10% by mass or more of the coating layer.
  • the mass of the coating layer is preferably 1% or more and 20% or less of the mass of the core.
  • the core is preferably an uncoated tablet or an uncoated granule.
  • the nucleus preferably contains amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof in an amount of 0.1% by mass to 20% by mass of the core.
  • the nucleus preferably contains propyl gallate.
  • the nucleus preferably contains propyl gallate in an amount of 0.001% by mass or more and 10% by mass or less of the nucleus.
  • the nucleus preferably contains at least a solid dispersion of amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof and propyl gallate.
  • the solifenacin-containing coated preparation is preferably a film-coated tablet.
  • the method for stabilizing amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof according to the present invention comprises the amorphous solifenacin or a pharmacologically acceptable salt thereof. Covering the core containing the salt or solvate thereof with a coating layer containing a polyvinyl alcohol copolymer.
  • the present invention it is possible to provide a coated preparation containing stabilized amorphous solifenacin and a method for stabilizing amorphous solifenacin.
  • the solifenacin-containing coated preparation according to the present invention comprises a core containing amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof, and a core coated with a polyvinyl alcohol copolymer. Containing coating layer.
  • the salt of solifenacin is not particularly limited as long as it is a pharmacologically acceptable salt, for example, hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate Salts with inorganic acids such as salts, salts with organic acids such as succinate, citrate, oxalate, acetate, malate, tartrate, maleate, fumarate, benzenesulfonate, etc.
  • Salts with alkaline earth metals such as calcium, magnesium and magnesium salts, salts with alkali metals such as lithium salts, potassium salts and sodium salts, and organic bases such as ethylenediamine salts, diethanolamine salts and N-methylglucamine salts. And the like. These may be used alone or in combination of two or more.
  • the pharmacologically acceptable salt is preferably a salt with an organic acid, and among the salts with an organic acid, succinic acid is more preferably used.
  • Solifenacin or a salt thereof may be an anhydride thereof or a solvate such as a hydrate.
  • solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof in the present invention is an “amorphous form” can be evaluated by X-ray diffraction. In the case where a solifenacin-specific peak is confirmed, it can be evaluated that the crystal has partially changed to a crystalline form, and in the case of the halo peak, it can be evaluated that the amorphous state is maintained.
  • the nucleus contains at least amorphous solifenacin, a pharmacologically acceptable salt thereof, or a solvate thereof.
  • the nucleus preferably contains amorphous solifenacin, a pharmacologically acceptable salt thereof, or a solvate thereof in an amount of 0.1% by mass to 20% by mass of the core.
  • the nucleus is amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof in addition to a crystalline amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof. May be included, but it is preferable that the amount of the crystalline substance is small and the amount of the amorphous substance is large.
  • amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof and crystalline solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof
  • the total content of solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof in an amorphous form is preferably more than 77% by mass, and is 80% by mass or more. Is more preferably 85% by mass or more, still more preferably 90% by mass or more, still more preferably 95% by mass or more, and particularly preferably 99% by mass or more. , 99.5% by mass or more.
  • amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof and a crystalline solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof are used.
  • the ratio is measured by an X-ray diffraction method.
  • the nucleus may contain an inert component, and solifenacin is present, for example, in a dispersed state in a matrix of the inert component, i.e., solifenacin and the inert component constitute a solid dispersion. May be.
  • the core contains an inert component
  • the inert component is more preferably lactose hydrate or crystalline cellulose.
  • the nucleus preferably contains propyl gallate in an amount of 0.001% by mass or more and 10% by mass or less of the nucleus, and at least amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof. It preferably comprises a solid dispersion formed from and propyl gallate.
  • the method for producing a core include: (1) a method in which particles of a pharmaceutical composition are directly mixed with a sugar or a sugar alcohol or a selected disintegrant and compressed under pressure to produce a tablet; ) The particles of the pharmaceutical composition are mixed with sugar or sugar alcohols or a selected disintegrant and granulated with a binder solution, and the appropriate other tablet additives are mixed with the particles and compressed. (3) mixing a saccharide with low moldability with the particles of the pharmaceutical composition, spraying the mixture with a saccharide having high moldability as a binder, and coating and / or granulating the mixture at a low pressure.
  • production methods such as a method of producing a tablet by compressing, humidifying and drying.
  • the production method should not be limited to the method described here, and any method may be employed for tableting, such as a mold method and a wet molding drying method.
  • the core is preferably an uncoated tablet or an uncoated granule.
  • the nucleus is coated with a coating layer, and is produced, for example, as a film coating agent.
  • the coating layer preferably contains a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer as the polyvinyl alcohol copolymer.
  • the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer is not limited and is contained at 10% by mass or more of the coating layer, preferably at 25% by mass or more, more preferably at least 50% by mass.
  • components used as a conventional tablet coating agent can be used in combination, for example, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, titanium oxide, talc, lactose And the like, but are not limited thereto.
  • the mass of the coating layer is preferably 1% or more and 20% or less of the mass of the core.
  • the solifenacin-containing coated preparation of the present invention may further include an outer layer that covers the outside of the coating layer.
  • the solifenacin-containing coated preparation of the present invention can be produced using various pharmaceutical additives used as commonly used additives.
  • the pharmaceutical additive include a flavoring agent, a sweetening agent, a flavor, a coloring agent, a stabilizing (stabilizing) agent, an antioxidant, a pH adjusting agent, a solubilizing agent, a solubilizing agent, a fluidizing agent, and a buffering agent.
  • Additives are typically binders incorporated to enhance the binding of drug particles, and may optionally contain dissolution rate improvers such as saccharides and disintegrants. is there.
  • the excipient is not particularly limited, and for example, crystalline cellulose, calcium hydrogen phosphate hydrate, lactose, sucrose, glucose, mannitol, silicon dioxide and the like can be used.
  • the binder is not particularly limited, and examples thereof include ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone.
  • the disintegrant is not particularly limited, and examples thereof include carmellose sodium, carmellose calcium, croscarmellose sodium, sodium carboxymethyl starch, and sodium starch glycolate.
  • the lubricant is not particularly limited, and includes, for example, magnesium stearate, talc, silica and the like.
  • the coloring agent is not particularly limited, and examples thereof include yellow iron sesquioxide and red iron sesquioxide.
  • the antioxidant is not particularly limited, and includes, for example, tocopherol acetate, sodium sulfite, sodium bisulfite, ascorbic acid, and the like.
  • the acidulant is not particularly limited, and examples include malic acid.
  • the flavor is not particularly limited, and examples thereof include menthol and lemon.
  • the artificial sweetener is not particularly limited, and includes, for example, aspartame, stevia and the like.
  • the surfactant is not particularly limited, and includes, for example, sodium lauryl sulfate, polyoxyethylene sorbitan aliphatic ester, and the like.
  • the core of the solifenacin-containing coated preparation of the present invention is, as an example, amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof, for example, propyl gallate or lactose hydrate or a crystal.
  • An inactive component such as cellulose is mixed, pulverized, and granulated. Magnesium stearate or the like is added to the granulated product, and the mixture is tabletted.
  • the nucleus can be added to solifenacin or a pharmacologically acceptable salt thereof by adding, for example, a suitable additive particle (eg, crystalline cellulose (particles), purified sucrose spherical particles, mannitol spherical particles, etc.) using a fluidized bed coating device or the like.
  • a suitable additive particle eg, crystalline cellulose (particles), purified sucrose spherical particles, mannitol spherical particles, etc.
  • a suitable additive particle eg, crystalline cellulose (particles), purified sucrose spherical particles, mannitol spherical particles, etc.
  • a suitable additive particle eg, crystalline cellulose (particles), purified sucrose spherical particles, mannitol spherical particles, etc.
  • it may be prepared by spraying a solution in which a solvate thereof and a binder or the like are dissolved or disper
  • the thus obtained core is film-coated with a coating material of a solution or suspension containing a polyvinyl alcohol copolymer and polyethylene glycol, talc, titanium oxide, etc., to obtain a solifenacin-containing coated preparation.
  • a method of coating with a machine widely used for coating a particulate pharmaceutical composition such as a fluidized bed coating device, a rolling coating device, and a centrifugal rolling coating device, is employed. Is preferred.
  • a method of coating with a machine widely used for coating a particulate composition such as a fluidized bed coating device, a rolling coating device, and a centrifugal rolling coating device.
  • a machine widely used for coating a particulate composition such as a fluidized bed coating device, a rolling coating device, and a centrifugal rolling coating device.
  • a required amount of the liquid containing the components of the outer layer may be sprayed with a spray gun while the particles on which the coating layer is formed are fluidized.
  • the liquid containing the outer layer component is prepared by dissolving or dispersing essential components and the like in a solvent such as water, ethanol, and methanol.These solvents can be used by appropriately mixing, for example, as a solvent. Only water may be used. Needless to say, the method of coating these layers is not limited to the wet method.
  • Example 1 10 g of solifenacin succinate and 10 g of hydroxypropylmethylcellulose were dissolved in 240 g of water to prepare a drug substance solution. Next, 7 g of hydroxypropylcellulose was dissolved in 200 g of ethanol to prepare a coating solution.
  • a fluidized bed granulator (manufactured by Powrex Co., Ltd .: MP-01 type) was charged with 240 g of lactose hydrate, 20 g of corn starch, and 15 g of low-substituted hydroxypropylcellulose, and spray-granulated and coated with the liquid prepared while flowing. After drying, a granulated product was prepared.
  • the measurement conditions of the X-ray diffraction profile were as follows. X-ray output: 40 kV, 40 mA, goniometer: SmartLab, attachment: ASC6-reflection, filter: Cu_K-beta, CBO selection slit: BB, detector: D / tex Ultra, scan mode: CONTINUOUS, scan speed 10 deg / min, Step width: 0.02 deg, scan axis: 2 ⁇ / ⁇ , scan range: 5-40 deg, entrance slit 1/2 deg, longitudinal limit slit: 10 mm, light receiving slit 1: 8 mm, light receiving slit 2: 13 mm
  • Example 2 A film-coated tablet was obtained in the same manner as in Example 1, except that 1 g of propyl gallate was added to the coating solution during granulation of Example 1. When the granules were prepared, it was confirmed by measuring the X-ray diffraction pattern that solifenacin in the granules was amorphous.
  • Example 1 A film-coated tablet was obtained in the same manner as in Example 1, except that 4 g of hydroxypropylmethylcellulose was used in place of the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in the coating liquid of Example 1. When the granules were prepared, it was confirmed by measuring the X-ray diffraction pattern that solifenacin in the granules was amorphous.
  • a coated preparation containing stabilized amorphous solifenacin and a method for stabilizing amorphous solifenacin can be provided.

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  • Oil, Petroleum & Natural Gas (AREA)
  • Urology & Nephrology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

[Problem] To provide a coated preparation containing stabilized amorphous solifenacin, and a method for stabilizing amorphous solifenacin. [Solution] This solifenacin-containing coated preparation includes: a core containing amorphous solifenacin, a pharmacologically acceptable salt thereof, or a solvate of these; and a coating layer containing a polyvinyl copolymer, the coating layer coating the core. This method for stabilizing amorphous solifenacin includes coating a core that contains amorphous solifenacin using a coating layer that contains a polyvinyl alcohol copolymer.

Description

ソリフェナシン含有被覆製剤Solifenacin-containing coated preparation
　本発明は、非晶質のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を含有する被覆製剤に関する。 (4) The present invention relates to a coated preparation containing amorphous solifenacin, a pharmacologically acceptable salt thereof, or a solvate thereof.
　ソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物（以下、ソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を「ソリフェナシン」と呼ぶ場合もある。）の非晶質体は非常に不安定であり、保存中に分解することが知られている。 Solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof (hereinafter, solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof may be referred to as “solifenacin”). Crystalline bodies are very unstable and are known to degrade during storage.
　そのため、従来、ソリフェナシンの経時的な分解を抑制することを目的とした、ソリフェナシンまたはその塩の固形製剤が提案されている。 Therefore, a solid preparation of solifenacin or a salt thereof for the purpose of suppressing the degradation of solifenacin over time has been proposed.
　例えば、特開２０１０－１６３４４２号公報（特許文献１）には、コハク酸ソリフェナシンの非晶質品は、保存開始後短期間でコハク酸ソリフェナシンの分解物が生じ、結晶品よりも保存安定性が劣っていたことが記載されている。そこで、特許文献１では、コハク酸ソリフェナシンと、酸化エチレン鎖を有する物質を非晶質化抑制剤として含有する造粒物中の水分量を調節し、この造粒物から得られた錠剤を、ヒドロキシプロピルメチルセルロース、マクロゴール６０００、タルク、酸化チタン、赤色三二酸化鉄を含む液でコーティングしたコーティング錠が記載されている。特許文献１には、造粒物中の水分量が低い場合、保存開始時のソリフェナシンの非晶質含有量が低く、６ヶ月間の保存後の主分解物の生成量の割合が抑えられたことが記載されている。 For example, Japanese Patent Application Laid-Open No. 2010-163442 (Patent Document 1) discloses that an amorphous product of solifenacin succinate generates a decomposed product of solifenacin succinate in a short period of time after the start of storage, and has a higher storage stability than a crystalline product. It was stated that it was inferior. Therefore, in Patent Document 1, solifenacin succinate and the amount of water in a granulated product containing a substance having an ethylene oxide chain as an amorphization inhibitor were adjusted, and a tablet obtained from the granulated product was used. Coated tablets coated with a liquid containing hydroxypropyl methylcellulose, macrogol 6000, talc, titanium oxide, red iron sesquioxide are described. In Patent Document 1, when the water content in the granulated product is low, the amorphous content of solifenacin at the start of storage is low, and the proportion of the amount of the main degradation product after storage for 6 months is suppressed. It is described.
特開２０１０－１６３４４２号公報JP 2010-163442 A
　しかしながら、特許文献１には、ソリフェナシンの非晶質化を抑制することによってソリフェナシンの経時的な分解を抑制することしか記載されておらず、ソリフェナシンを非晶質体のままで、ソリフェナシンの経時的分解を抑制することについては考えられていない。 However, Patent Literature 1 only describes that solifenacin is suppressed from becoming amorphous by suppressing the amorphization of solifenacin. No consideration is given to suppressing decomposition.
　そこで、本発明の目的は、安定化された非晶質体のソリフェナシンを含有する被覆製剤と、非晶質体のソリフェナシンの安定化方法を提供することである。 Accordingly, an object of the present invention is to provide a coated preparation containing stabilized solifenacin in an amorphous form, and a method for stabilizing solifenacin in an amorphous form.
　本発明者らは、鋭意検討を重ねた結果、本発明のソリフェナシン含有被覆製剤を次のように構成することによって、ソリフェナシンの非晶質体を維持し、かつ、非晶質体のソリフェナシンを安定化することができることを見出した。 The present inventors have conducted intensive studies and as a result, by maintaining the solifenacin-containing coated preparation of the present invention as follows, the amorphous form of solifenacin was maintained, and the solifenacin in the amorphous form was stabilized. Found that it can be
　すなわち、本発明に従ったソリフェナシン含有被覆製剤は、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を含有する核と、核を被覆する、ポリビニルアルコール共重合体を含有する被覆層とを含む。 That is, the solifenacin-containing coated preparation according to the present invention comprises a core containing amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof, and a polyvinyl alcohol copolymer coating the core. And a coating layer containing the coalescence.
　非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物は、コハク酸ソリフェナシンであることが好ましい。 The amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof is preferably solifenacin succinate.
　ポリビニルアルコール共重合体は、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体であることが好ましい。 The polyvinyl alcohol copolymer is preferably a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.
　被覆層は、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を被覆層の１０質量％以上含むことが好ましい。 The coating layer preferably contains a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in an amount of 10% by mass or more of the coating layer.
　被覆層の質量は、核の質量の１％以上２０％以下であることが好ましい。 質量 The mass of the coating layer is preferably 1% or more and 20% or less of the mass of the core.
　核は、素錠または素顆粒であることが好ましい。 The core is preferably an uncoated tablet or an uncoated granule.
　核は、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を核の０．１質量％以上２０質量％以下含有することが好ましい。 The nucleus preferably contains amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof in an amount of 0.1% by mass to 20% by mass of the core.
　核は、没食子酸プロピルを含有することが好ましい。 The nucleus preferably contains propyl gallate.
　核は、没食子酸プロピルを核の０．００１質量％以上１０質量％以下含有することが好ましい。 The nucleus preferably contains propyl gallate in an amount of 0.001% by mass or more and 10% by mass or less of the nucleus.
　核は、少なくとも非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物と没食子酸プロピルとから形成された固体分散体を含むことが好ましい。 The nucleus preferably contains at least a solid dispersion of amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof and propyl gallate.
　ソリフェナシン含有被覆製剤は、フィルムコーティング錠であることが好ましい。 The solifenacin-containing coated preparation is preferably a film-coated tablet.
　また、本発明に従った非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物の安定化方法は、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を含有する核を、ポリビニルアルコール共重合体を含有する被覆層によって被覆することを含む。 The method for stabilizing amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof according to the present invention comprises the amorphous solifenacin or a pharmacologically acceptable salt thereof. Covering the core containing the salt or solvate thereof with a coating layer containing a polyvinyl alcohol copolymer.
　本発明に従えば、安定化された非晶質体のソリフェナシンを含有する被覆製剤と、非晶質体のソリフェナシンの安定化方法を提供することができる。 According to the present invention, it is possible to provide a coated preparation containing stabilized amorphous solifenacin and a method for stabilizing amorphous solifenacin.
　以下、本発明の実施形態を説明する。 Hereinafter, embodiments of the present invention will be described.
　本発明に従ったソリフェナシン含有被覆製剤は、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を含有する核と、核を被覆する、ポリビニルアルコール共重合体を含有する被覆層とを含む。 The solifenacin-containing coated preparation according to the present invention comprises a core containing amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof, and a core coated with a polyvinyl alcohol copolymer. Containing coating layer.
　本発明のソリフェナシン含有被覆製剤において、ソリフェナシンの塩は、薬理学的に許容される塩であれば特に限定されず、例えば、塩酸塩、ヨウ化水素酸塩、臭化水素酸塩、硝酸塩、硫酸塩等の無機酸との塩、コハク酸塩、クエン酸塩、シュウ酸塩、酢酸塩、リンゴ酸塩、酒石酸塩、マレイン酸塩、フマル酸塩、ベンゼンスルホン酸塩等の有機酸との塩、カルシウム塩、マグネシウム塩等のアルカリ土類金属との塩、リチウム塩、カリウム塩、ナトリウム塩等のアルカリ金属との塩、エチレンジアミン塩、ジエタノールアミン塩、Ｎ－メチルグルカミン塩等の有機塩基との塩等が挙げられる。これらは単独で用いてもよく、２種以上を併用してもよい。薬理学的に許容される塩は、有機酸との塩であることが好ましく、有機酸との塩のうち、コハク酸を用いることがより好ましい。また、ソリフェナシン又はその塩は、これらの無水物であってもよく、水和物等の溶媒和物であってもよい。 In the solifenacin-containing coated preparation of the present invention, the salt of solifenacin is not particularly limited as long as it is a pharmacologically acceptable salt, for example, hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate Salts with inorganic acids such as salts, salts with organic acids such as succinate, citrate, oxalate, acetate, malate, tartrate, maleate, fumarate, benzenesulfonate, etc. Salts with alkaline earth metals such as calcium, magnesium and magnesium salts, salts with alkali metals such as lithium salts, potassium salts and sodium salts, and organic bases such as ethylenediamine salts, diethanolamine salts and N-methylglucamine salts. And the like. These may be used alone or in combination of two or more. The pharmacologically acceptable salt is preferably a salt with an organic acid, and among the salts with an organic acid, succinic acid is more preferably used. Solifenacin or a salt thereof may be an anhydride thereof or a solvate such as a hydrate.
　本発明におけるソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物が「非晶質体」であるかどうかは、Ｘ線回折により評価できる。ソリフェナシンに特異的なピークが確認された場合を、一部結晶体に変化したものと評価し、ハローピークの場合、非晶質状態を維持したものと評価することができる。 ソ Whether solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof in the present invention is an “amorphous form” can be evaluated by X-ray diffraction. In the case where a solifenacin-specific peak is confirmed, it can be evaluated that the crystal has partially changed to a crystalline form, and in the case of the halo peak, it can be evaluated that the amorphous state is maintained.
　本発明のソリフェナシン含有被覆製剤において、核は、少なくとも非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を含有する。核は、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を核の０．１質量％以上２０質量％以下含有することが好ましい。 核 In the solifenacin-containing coated preparation of the present invention, the nucleus contains at least amorphous solifenacin, a pharmacologically acceptable salt thereof, or a solvate thereof. The nucleus preferably contains amorphous solifenacin, a pharmacologically acceptable salt thereof, or a solvate thereof in an amount of 0.1% by mass to 20% by mass of the core.
　核は、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物の他に、結晶体の非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を含んでいてもよいが、結晶体の量が少なく、非晶質体の量が多い方が好ましい。より具体的には、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物と、結晶体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物との合計含有量に対する、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物の含有量が、７７質量％超であることが好ましく、８０質量％以上であることがより好ましく、８５質量％以上であることがさらに好ましく、９０質量％以上であることがより一層好ましく、９５質量％以上であることがさらに一層好ましく、９９質量％以上であることが特に好ましく、９９．５質量％以上であることが最も好ましい。本発明において、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物と、結晶体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物との割合は、Ｘ線回折法により測定する。 The nucleus is amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof in addition to a crystalline amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof. May be included, but it is preferable that the amount of the crystalline substance is small and the amount of the amorphous substance is large. More specifically, amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof, and crystalline solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof With respect to the total content of solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof in an amorphous form is preferably more than 77% by mass, and is 80% by mass or more. Is more preferably 85% by mass or more, still more preferably 90% by mass or more, still more preferably 95% by mass or more, and particularly preferably 99% by mass or more. , 99.5% by mass or more. In the present invention, amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof, and a crystalline solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof are used. The ratio is measured by an X-ray diffraction method.
　核は、不活性な成分を含んでもよく、ソリフェナシンが、例えば、不活性な成分のマトリクス中に分散された状態で存在するもの、すなわち、ソリフェナシンと不活性な成分とが固体分散体を構成していてもよい。核が不活性な成分を含む場合には、該不活性な成分は、乳糖水和物または結晶セルロースであることがより好ましい。また、核は、没食子酸プロピルを核の０．００１質量％以上１０質量％以下含有することが好ましく、少なくとも非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物と没食子酸プロピルとから形成された固体分散体を含むことが好ましい。 The nucleus may contain an inert component, and solifenacin is present, for example, in a dispersed state in a matrix of the inert component, i.e., solifenacin and the inert component constitute a solid dispersion. May be. When the core contains an inert component, the inert component is more preferably lactose hydrate or crystalline cellulose. The nucleus preferably contains propyl gallate in an amount of 0.001% by mass or more and 10% by mass or less of the nucleus, and at least amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof. It preferably comprises a solid dispersion formed from and propyl gallate.
　具体的に核の製法を例示すれば、（１）医薬組成物の粒子をそのまま糖又は糖アルコール類や選択された崩壊剤とともに混合して加圧圧縮することにより錠剤に製する方法、（２）医薬組成物の粒子を糖又は糖アルコール類や選抜した崩壊剤などと混合し結合剤溶液で造粒して製した粒子に、適切なその他の錠剤用添加剤を混合して加圧圧縮することにより錠剤に製する方法、（３）医薬組成物の粒子に成形性の低い糖類を混合し、かかる混合物を成形性の高い糖類を結合剤として噴霧し被覆及び／または造粒したものを低圧圧縮成形した後、加湿、乾燥して錠剤に製する方法など、様々な製法がある。なお、製造方法については、ここで述べた方法に限定するべきではなく、鋳型法、湿式成形乾燥法など、錠剤化に際していかなる方法が採用されても差し支えはない。 Specific examples of the method for producing a core include: (1) a method in which particles of a pharmaceutical composition are directly mixed with a sugar or a sugar alcohol or a selected disintegrant and compressed under pressure to produce a tablet; ) The particles of the pharmaceutical composition are mixed with sugar or sugar alcohols or a selected disintegrant and granulated with a binder solution, and the appropriate other tablet additives are mixed with the particles and compressed. (3) mixing a saccharide with low moldability with the particles of the pharmaceutical composition, spraying the mixture with a saccharide having high moldability as a binder, and coating and / or granulating the mixture at a low pressure. There are various production methods such as a method of producing a tablet by compressing, humidifying and drying. In addition, the production method should not be limited to the method described here, and any method may be employed for tableting, such as a mold method and a wet molding drying method.
　核は、素錠または素顆粒であることが好ましい。本発明のソリフェナシン含有被覆製剤においては、核が被覆層によって被覆され、例えばフィルムコーティング剤として製造される。 The core is preferably an uncoated tablet or an uncoated granule. In the solifenacin-containing coated preparation of the present invention, the nucleus is coated with a coating layer, and is produced, for example, as a film coating agent.
　本発明のソリフェナシン含有被覆製剤において、被覆層は、ポリビニルアルコール共重合体として、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含むことが好ましい。ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体は、限定ではなく、被覆層の１０質量％以上含まれ、好ましくは２５質量％以上、より好ましくは５０質量％以上含まれる。 に お い て In the solifenacin-containing coated preparation of the present invention, the coating layer preferably contains a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer as the polyvinyl alcohol copolymer. The polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer is not limited and is contained at 10% by mass or more of the coating layer, preferably at 25% by mass or more, more preferably at least 50% by mass.
　被覆層には、必要に応じて、従来の錠剤のコーティング剤として用いられる成分を併用することができ、例えば、ヒドロキシプロピルメチルセルロース、メチルセルロース、エチルセルロース、カルボキシメチルセルロース、セルロースアセテートフタレート、酸化チタン、タルク、乳糖等が挙げられるが、これらに限定されない。 In the coating layer, if necessary, components used as a conventional tablet coating agent can be used in combination, for example, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, titanium oxide, talc, lactose And the like, but are not limited thereto.
　被覆層の質量は、核の質量の１％以上２０％以下であることが好ましい。 質量 The mass of the coating layer is preferably 1% or more and 20% or less of the mass of the core.
　本発明のソリフェナシン含有被覆製剤は、被覆層の外側を被覆する外層をさらに備えてもよい。 ソ The solifenacin-containing coated preparation of the present invention may further include an outer layer that covers the outside of the coating layer.
　本発明のソリフェナシン含有被覆製剤は、慣用される添加物として使用される各種医薬添加剤を使用して製造することができることは言うまでもない。医薬添加剤としては、例えば、矯味剤、甘味剤、香料、着色剤、安定（化）剤、抗酸化剤、ｐＨ調節剤、可溶化剤、溶解補助剤、流動化剤、緩衝剤などが挙げられるが、これらに限定されるものではない。添加剤は、典型的には、薬物の粒子の結合性を高めるために配合される結合剤であり、必要に応じて、糖類や崩壊剤等の溶解速度改善剤等を含有させることは自由である。賦形剤としては、特に限定されず、例えば、結晶セルロース、リン酸水素カルシウム水和物、乳糖、白糖、ブドウ糖、マンニトール、二酸化ケイ素等を用いることができる。結合剤は、特に限定されず、例えば、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ポリエチレングリコール、ポリビニルアルコール、ポリビニルピロリドン等が挙げられる。崩壊剤は、特に限定されず、例えば、カルメロースナトリウム、カルメロースカルシウム、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、デンプングリコール酸ナトリウム等が挙げられる。滑沢剤は、特に限定されず、例えば、ステアリン酸マグネシウム、タルク、シリカ等が挙げられる。着色剤としては、特に限定されず、例えば、黄色三二酸化鉄、赤色三二酸化鉄等が挙げられる。抗酸化剤としては、特に限定されず、例えば、酢酸トコフェロール、亜硫酸ナトリウム、亜硫酸水素ナトリウム、アスコルビン酸等が挙げられる。酸味料は、特に限定されず、例えば、リンゴ酸等が挙げられる。香料は、特に限定されず、例えば、メントール、レモン等が挙げられる。人工甘味料としては、特に限定されず、例えば、アスパルテーム、ステビア等が挙げられる。界面活性剤としては、特に限定されず、例えば、ラウリル硫酸ナトリウム、ポリオキシエチレンソルビタン脂肪族エステル等が挙げられる。 ソ Needless to say, the solifenacin-containing coated preparation of the present invention can be produced using various pharmaceutical additives used as commonly used additives. Examples of the pharmaceutical additive include a flavoring agent, a sweetening agent, a flavor, a coloring agent, a stabilizing (stabilizing) agent, an antioxidant, a pH adjusting agent, a solubilizing agent, a solubilizing agent, a fluidizing agent, and a buffering agent. However, the present invention is not limited to these. Additives are typically binders incorporated to enhance the binding of drug particles, and may optionally contain dissolution rate improvers such as saccharides and disintegrants. is there. The excipient is not particularly limited, and for example, crystalline cellulose, calcium hydrogen phosphate hydrate, lactose, sucrose, glucose, mannitol, silicon dioxide and the like can be used. The binder is not particularly limited, and examples thereof include ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone. The disintegrant is not particularly limited, and examples thereof include carmellose sodium, carmellose calcium, croscarmellose sodium, sodium carboxymethyl starch, and sodium starch glycolate. The lubricant is not particularly limited, and includes, for example, magnesium stearate, talc, silica and the like. The coloring agent is not particularly limited, and examples thereof include yellow iron sesquioxide and red iron sesquioxide. The antioxidant is not particularly limited, and includes, for example, tocopherol acetate, sodium sulfite, sodium bisulfite, ascorbic acid, and the like. The acidulant is not particularly limited, and examples include malic acid. The flavor is not particularly limited, and examples thereof include menthol and lemon. The artificial sweetener is not particularly limited, and includes, for example, aspartame, stevia and the like. The surfactant is not particularly limited, and includes, for example, sodium lauryl sulfate, polyoxyethylene sorbitan aliphatic ester, and the like.
　次に、本発明のソリフェナシン含有被覆製剤の製造方法を説明する。 Next, a method for producing the solifenacin-containing coated preparation of the present invention will be described.
　本発明のソリフェナシン含有被覆製剤の核は、一例として、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物と、例えば、没食子酸プロピルや乳糖水和物または結晶セルロースのような不活性成分とが混合され、粉砕され、造粒されて得られた造粒物に、ステアリン酸マグネシウム等を加え、打錠して得られる。 The core of the solifenacin-containing coated preparation of the present invention is, as an example, amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof, for example, propyl gallate or lactose hydrate or a crystal. An inactive component such as cellulose is mixed, pulverized, and granulated. Magnesium stearate or the like is added to the granulated product, and the mixture is tabletted.
　この他、核は、例えば流動層コーティング装置などにより、適当な添加物粒子（例えば結晶セルロース（粒）、精製白糖球状粒子、マンニトール球状粒子等）に、ソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物と、結合剤などを溶解又は分散した液を噴霧して調製されてもよい。 In addition, the nucleus can be added to solifenacin or a pharmacologically acceptable salt thereof by adding, for example, a suitable additive particle (eg, crystalline cellulose (particles), purified sucrose spherical particles, mannitol spherical particles, etc.) using a fluidized bed coating device or the like. Alternatively, it may be prepared by spraying a solution in which a solvate thereof and a binder or the like are dissolved or dispersed.
　このようにして得られた核に、ポリビニルアルコール共重合体と、ポリエチレングリコール、タルク、酸化チタン等を含有する溶液または懸濁液の被覆材がフィルムコーティングされて、ソリフェナシン含有被覆製剤が得られる。 核 The thus obtained core is film-coated with a coating material of a solution or suspension containing a polyvinyl alcohol copolymer and polyethylene glycol, talc, titanium oxide, etc., to obtain a solifenacin-containing coated preparation.
　核上に被覆層を形成する方法としては、流動層コーティング装置、転動コーティング装置、遠心転動コーティング装置など、粒子状医薬組成物の被覆操作に汎用されている機械によって被覆する方法を採用することが好ましい。 As a method of forming the coating layer on the core, a method of coating with a machine widely used for coating a particulate pharmaceutical composition, such as a fluidized bed coating device, a rolling coating device, and a centrifugal rolling coating device, is employed. Is preferred.
　被覆層上にさらに外層を被覆する方法としては、流動層コーティング装置、転動コーティング装置、遠心転動コーティング装置など、粒子状組成物の被覆操作に汎用されている機械によって被覆する方法を採用することが好ましい。例えば、転動流動層コーティング装置中で、被覆層が形成された粒子を流動させながら、スプレーガンにて外層の成分を含有する液を必要量噴霧すればよい。この外層成分を含有する液は、必須成分などを水、エタノール、メタノール等の溶媒に溶解又は分散して調製されるが、これらの溶媒は適宜混合して用いることも可能であり、例えば溶媒として水のみを用いてもかまわない。なお、これらの層の被覆方法については、湿式法に限定されるものではないことは言うまでもない。 As a method of further coating the outer layer on the coating layer, a method of coating with a machine widely used for coating a particulate composition, such as a fluidized bed coating device, a rolling coating device, and a centrifugal rolling coating device, is employed. Is preferred. For example, in a tumbling fluidized bed coating apparatus, a required amount of the liquid containing the components of the outer layer may be sprayed with a spray gun while the particles on which the coating layer is formed are fluidized. The liquid containing the outer layer component is prepared by dissolving or dispersing essential components and the like in a solvent such as water, ethanol, and methanol.These solvents can be used by appropriately mixing, for example, as a solvent. Only water may be used. Needless to say, the method of coating these layers is not limited to the wet method.
　以下、実施例により本発明をより具体的に説明するが、本発明はこれらの実施例により限定されるものではない。 Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
　＜実施例１＞
　水２４０ｇに、ソリフェナシンコハク酸塩１０ｇ、ヒドロキシプロピルメチルセルロース１０ｇを溶解し、原薬溶解液を調製した。次に、エタノール２００ｇに、ヒドロキシプロピルセルロース７ｇを溶解し、コーティング液を調製した。流動層造粒機（株式会社パウレック製：ＭＰ－０１型）に乳糖水和物２４０ｇ、トウモロコシデンプン２０ｇ、低置換度ヒドロキシプロピルセルロース１５ｇを投入し、流動させながら調製した液を噴霧造粒・コーティングし乾燥して、造粒物を調製した。 <Example 1>
10 g of solifenacin succinate and 10 g of hydroxypropylmethylcellulose were dissolved in 240 g of water to prepare a drug substance solution. Next, 7 g of hydroxypropylcellulose was dissolved in 200 g of ethanol to prepare a coating solution. A fluidized bed granulator (manufactured by Powrex Co., Ltd .: MP-01 type) was charged with 240 g of lactose hydrate, 20 g of corn starch, and 15 g of low-substituted hydroxypropylcellulose, and spray-granulated and coated with the liquid prepared while flowing. After drying, a granulated product was prepared.
　造粒物中のソリフェナシンが非晶質体であることをＸ線回折パターンを測定して確認した。 (4) It was confirmed by measuring an X-ray diffraction pattern that solifenacin in the granulated product was amorphous.
　Ｘ線回折プロファイルの測定条件は次の通りであった。
　Ｘ線出力：４０ｋＶ,４０ｍＡ、ゴニオメーター：ＳｍａｒｔＬａｂ、アタッチメント：ＡＳＣ６-反射、フィルター：Ｃｕ＿Ｋ－ｂｅｔａ、ＣＢＯ選択スリット：ＢＢ、検出器：Ｄ／ｔｅＸ　Ｕｌｔｒａ、スキャンモード：ＣＯＮＴＩＮＵＯＵＳ、スキャンスピード１０ｄｅｇ／ｍｉｎ、ステップ幅：０．０２ｄｅｇ、スキャン軸：２θ／θ、スキャン範囲：５―４０ｄｅｇ、入射スリット１／２ｄｅｇ、長手制限スリット：１０ｍｍ、受光スリット１：８ｍｍ、受光スリット２:１３ｍｍ The measurement conditions of the X-ray diffraction profile were as follows.
X-ray output: 40 kV, 40 mA, goniometer: SmartLab, attachment: ASC6-reflection, filter: Cu_K-beta, CBO selection slit: BB, detector: D / tex Ultra, scan mode: CONTINUOUS, scan speed 10 deg / min, Step width: 0.02 deg, scan axis: 2θ / θ, scan range: 5-40 deg, entrance slit 1/2 deg, longitudinal limit slit: 10 mm, light receiving slit 1: 8 mm, light receiving slit 2: 13 mm
　実施例１の造粒物では、結晶構造を有する結晶性ソリフェナシン特有のピークが観察されず、ハローパターンが観察された。このことは、実施例１で用いられる造粒物中のソリフェナシンコハク酸塩が非晶質体であることを意味する。 で は In the granulated product of Example 1, a halo pattern was observed without a peak specific to crystalline solifenacin having a crystal structure. This means that solifenacin succinate in the granulated product used in Example 1 is an amorphous material.
　次に、造粒物１４８.５ｇにステアリン酸マグネシウム１．５ｇを添加して打錠し、錠剤を得た。 (5) Next, 1.5 g of magnesium stearate was added to 148.5 g of the granulated product, and the mixture was tableted to obtain a tablet.
　次に、水５０ｇ、エタノール６ｇの混液に、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体（大同化成工業株式会社製　ＰＯＶＡＣＯＡＴ（登録商標））４ｇを溶解し、タルク２．４ｇ、酸化チタン１．６ｇ、黄色二三酸化鉄０．０１ｇを分散してコーティング液を得た。このコーティング液を核である錠剤に対してフィルムコーティングして、１００錠質量が０．４ｇ増加した時点を終点とし、被覆層によって被覆されたソリフェナシン含有被覆製剤としてフィルムコーティング錠を得た。 Next, in a mixed solution of 50 g of water and 6 g of ethanol, 4 g of a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT (registered trademark) manufactured by Daido Kasei Kogyo Co., Ltd.) was dissolved, and 2.4 g of talc and 1 g of titanium oxide were dissolved. 0.6 g and 0.01 g of yellow ferric oxide were dispersed to obtain a coating liquid. The coating liquid was coated on the core tablet by film coating, and the time when the mass of 100 tablets increased by 0.4 g was taken as the end point to obtain a film-coated tablet as a solifenacin-containing coated preparation coated with a coating layer.
　＜実施例２＞
　実施例１の造粒時のコーティング液に、没食子酸プロピル１ｇを加えた他は、実施例１と同様にしてフィルムコーティング錠を得た。造粒物を調製した時点で、造粒物中のソリフェナシンが非晶質体であることをＸ線回折パターンを測定して確認した。 <Example 2>
A film-coated tablet was obtained in the same manner as in Example 1, except that 1 g of propyl gallate was added to the coating solution during granulation of Example 1. When the granules were prepared, it was confirmed by measuring the X-ray diffraction pattern that solifenacin in the granules was amorphous.
　＜比較例１＞
　実施例１のコーティング液において、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体の代わりにヒドロキシプロピルメチルセルロース４ｇを用いた他は、実施例１と同様にしてフィルムコーティング錠を得た。造粒物を調製した時点で、造粒物中のソリフェナシンが非晶質体であることをＸ線回折パターンを測定して確認した。 <Comparative Example 1>
A film-coated tablet was obtained in the same manner as in Example 1, except that 4 g of hydroxypropylmethylcellulose was used in place of the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in the coating liquid of Example 1. When the granules were prepared, it was confirmed by measuring the X-ray diffraction pattern that solifenacin in the granules was amorphous.
　＜比較例２＞
　実施例２のコーティング液において、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体の代わりにヒドロキシプロピルメチルセルロース４ｇを用いた他は、実施例２と同様にしてフィルムコーティング錠を得た。造粒物を調製した時点で、造粒物中のソリフェナシンが非晶質体であることをＸ線回折パターンを測定して確認した。 <Comparative Example 2>
Film-coated tablets were obtained in the same manner as in Example 2, except that 4 g of hydroxypropylmethylcellulose was used instead of the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in the coating liquid of Example 2. When the granules were prepared, it was confirmed by measuring the X-ray diffraction pattern that solifenacin in the granules was amorphous.
　＜安定性試験＞
　得られた実施例１～２、比較例１～２のフィルムコーティング錠を６０℃７５％ＲＨ、無包装で７日間又は１４日間保存後の類縁物質量を高速液体クロマトグラフィによって測定した。類縁物質量は、ソリフェナシンコハク酸塩と分解物の総量に対する類縁物質の割合（％）を示す。結果を表１～３に示す。 <Stability test>
The amounts of related substances of the obtained film-coated tablets of Examples 1 and 2 and Comparative Examples 1 and 2 after storage for 7 days or 14 days without packaging at 60 ° C. and 75% RH were measured by high performance liquid chromatography. The amount of the related substance indicates the ratio (%) of the related substance to the total amount of solifenacin succinate and the decomposition product. The results are shown in Tables 1 to 3.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　表１，２に示すように、実施例１，２のフィルムコーティング錠では、主類縁物質量も総類縁物質も、７日後にも１４日後にもそれぞれ比較例１，２よりも抑えられた。 As shown in Tables 1 and 2, in the film-coated tablets of Examples 1 and 2, the amounts of the main analogous substances and the total analogous substances were suppressed as compared with Comparative Examples 1 and 2 after 7 days and 14 days, respectively.
　さらに、表３に示すように、核中においてソリフェナシンコハク酸塩と没食子酸プロピルを固体分散体にすることによって、主類縁物質量も総類縁物質もさらに抑えられた。 Furthermore, as shown in Table 3, by making solifenacin succinate and propyl gallate into a solid dispersion in the nucleus, the amount of the main related substances and the total related substances were further suppressed.
　また、各保存後のフィルムコーティング錠に含まれるソリフェナシンコハク酸塩が非晶質体であるかどうかをＸ線回折パターンを測定して確認した。実施例１，２では、１４日保管後にもソリフェナシンが非晶質体であることが確認された。 Further, it was confirmed by measuring the X-ray diffraction pattern whether or not the solifenacin succinate contained in each of the film-coated tablets after storage was amorphous. In Examples 1 and 2, it was confirmed that solifenacin was an amorphous body even after storage for 14 days.
　以上のように、本発明に従えば、安定化された非晶質体のソリフェナシンを含有する被覆製剤と、非晶質体のソリフェナシンの安定化方法を提供することができる。 As described above, according to the present invention, a coated preparation containing stabilized amorphous solifenacin and a method for stabilizing amorphous solifenacin can be provided.
　以上に開示された実施の形態と実施例はすべての点で例示であって制限的なものではないと考慮されるべきである。本発明の範囲は、以上の説明ではなく、請求の範囲によって示され、請求の範囲と均等の意味および範囲内でのすべての変形を含むものである。

  The embodiments and examples disclosed above are to be considered in all respects as illustrative and not restrictive. The scope of the present invention is defined by the terms of the claims, rather than the description above, and includes any modifications within the scope and meaning equivalent to the terms of the claims.

Claims (12)

  1. 　非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を含有する核と、
    　前記核を被覆する、ポリビニルアルコール共重合体を含有する被覆層とを含む、ソリフェナシン含有被覆製剤。     A core containing amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof;
    And a coating layer containing a polyvinyl alcohol copolymer, which coats the core.
  2. 　前記非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物は、コハク酸ソリフェナシンである、請求項１に記載のソリフェナシン含有被覆製剤。 The solifenacin-containing coated preparation according to claim 1, wherein the amorphous solifenacin or a pharmaceutically acceptable salt thereof or a solvate thereof is solifenacin succinate.
  3. 　前記ポリビニルアルコール共重合体は、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体である、請求項１または請求項２に記載のソリフェナシン含有被覆製剤。 The solifenacin-containing coated preparation according to claim 1 or 2, wherein the polyvinyl alcohol copolymer is a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.
  4. 　前記被覆層は、前記ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を前記被覆層の１０質量％以上含む、請求項３に記載のソリフェナシン含有被覆製剤。 ソ The solifenacin-containing coated preparation according to claim 3, wherein the coating layer contains the polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in an amount of 10% by mass or more of the coating layer.
  5. 　前記被覆層の質量は、前記核の質量の１％以上２０％以下である、請求項１から請求項４までのいずれか１項に記載のソリフェナシン含有被覆製剤。 ソ The solifenacin-containing coated preparation according to any one of claims 1 to 4, wherein the mass of the coating layer is 1% or more and 20% or less of the mass of the core.
  6. 　前記核は、素錠または素顆粒である、請求項１から請求項５までのいずれか１項に記載のソリフェナシン含有被覆製剤。 ソ The solifenacin-containing coated preparation according to any one of claims 1 to 5, wherein the core is an uncoated tablet or an elementary granule.
  7. 　前記核は、前記非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を前記核の０．１質量％以上２０質量％以下含有する、請求項１から請求項６までのいずれか１項に記載のソリフェナシン含有被覆製剤。 The said core contains 0.1 mass% or more and 20 mass% or less of said amorphous solifenacin, its pharmacologically acceptable salt, or those solvates thereof in the said core. 6. The solifenacin-containing coated preparation according to any one of 6 to 6.
  8. 　前記核は、没食子酸プロピルを含有する、請求項１から請求項７までのいずれか１項に記載のソリフェナシン含有被覆製剤。 ソ The solifenacin-containing coated preparation according to any one of claims 1 to 7, wherein the nucleus contains propyl gallate.
  9. 　前記核は、前記没食子酸プロピルを前記核の０．００１質量％以上１０質量％以下含有する、請求項８に記載のソリフェナシン含有被覆製剤。 The solifenacin-containing coated preparation according to claim 8, wherein the core contains the propyl gallate in an amount of 0.001% by mass or more and 10% by mass or less of the core.
  10. 　前記核は、少なくとも非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物と没食子酸プロピルとから形成された固体分散体を含む、請求項８または請求項９に記載のソリフェナシン含有被覆製剤。 10. The method according to claim 8, wherein the nucleus comprises at least a solid dispersion of amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof and propyl gallate. The coated preparation containing solifenacin according to the above.
  11. 　フィルムコーティング錠である、請求項１から請求項１０までのいずれか１項に記載のソリフェナシン含有被覆製剤。 The solifenacin-containing coated preparation according to any one of claims 1 to 10, which is a film-coated tablet.
  12. 　非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物を含有する核を、ポリビニルアルコール共重合体を含有する被覆層によって被覆することを含む、非晶質体のソリフェナシン又はその薬理学的に許容される塩又はそれらの溶媒和物の安定化方法。 Covering a core containing amorphous solifenacin or a pharmacologically acceptable salt thereof or a solvate thereof with a coating layer containing a polyvinyl alcohol copolymer, A method for stabilizing solifenacin, a pharmacologically acceptable salt thereof, or a solvate thereof.
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