WO2014017507A1 - Solid pharmaceutical preparation - Google Patents

Solid pharmaceutical preparation Download PDF

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Publication number
WO2014017507A1
WO2014017507A1 PCT/JP2013/069979 JP2013069979W WO2014017507A1 WO 2014017507 A1 WO2014017507 A1 WO 2014017507A1 JP 2013069979 W JP2013069979 W JP 2013069979W WO 2014017507 A1 WO2014017507 A1 WO 2014017507A1
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WO
WIPO (PCT)
Prior art keywords
ibuprofen
preparation
particles
polyvinyl alcohol
preparation particles
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PCT/JP2013/069979
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French (fr)
Japanese (ja)
Inventor
哲央 小野
和寛 石井
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大正製薬株式会社
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Priority to JP2014526952A priority Critical patent/JP6361925B2/en
Publication of WO2014017507A1 publication Critical patent/WO2014017507A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/609—Amides, e.g. salicylamide
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

  • the present invention relates to the field of solid preparations, and more particularly to a solid preparation containing ibuprofen and etenzamide as active ingredients.
  • Ibuprofen which is widely used as an active ingredient in headache and general cold medicines, is a low-melting drug with a melting point of 75-77 ° C. It was known (see Non-Patent Document 1).
  • the melting point drop of ibuprofen which has a large content among the active ingredients, makes handling of the powder extremely difficult, causing adhesion and aggregation, and may cause problems such as discoloration after commercialization.
  • Non-Patent Document 2 In a solid preparation containing ibuprofen and etenzamide as active ingredients, if they are mixed in different granules, etc., and provided as a double tablet or multilayer tablet, even if ibuprofen and etenzamide are combined in the same preparation, It was possible to avoid the direct contact and prevent the melting point drop of ibuprofen (see Non-Patent Document 2).
  • the object of the present invention is to combine the active ingredients ibuprofen and etenzamide into separate granules, etc., and to select and preserve the most effective film base to suppress the melting point drop when coating ibuprofen-containing granules etc. It is to provide a solid preparation containing ibuprofen and etezamide such as powders and granules excellent in stability and administration.
  • the embodiments of the present invention obtained from such findings are as follows.
  • Ibuprofen and etenzaamide are blended in different preparation particles, and the preparation particles containing ibuprofen are coated with a film layer containing polyvinyl alcohol or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.
  • the content of polyvinyl alcohol or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in the film layer is 0.04 to 0.4 parts by mass with respect to 1 part by mass of ibuprofen.
  • solid preparations such as powders and granules containing ibuprofen and etenzamide as active ingredients. Further, by coating ibuprofen-containing granules and the like with PVA or PVA copolymer, sublimation and bitterness of ibuprofen are suppressed, and it has become possible to provide a solid preparation excellent in storage stability and ingestion.
  • the ibuprofen and etenzamide-containing solid preparation of the present invention is a film layer in which ibuprofen and etezamide are blended in different preparation particles, and the preparation particles containing ibuprofen contain polyvinyl alcohol or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. It is characterized by being covered with.
  • the active ingredients ibuprofen and etenzamide are mixed, the melting point is lowered. Therefore, in the present invention, these active ingredients are blended in separate preparation particles.
  • Formulation particles means, for example, a dry granulation, spray-drying granulation, kneading granulation, extrusion granulation, stirring granulation after mixing powders containing additives described below in addition to active ingredients Solid particles having a geometric average particle diameter of 80 to 400 ⁇ m prepared by wet granulation such as fluidized bed granulation, stirred fluidized bed granulation, rolling fluidized bed granulation, and rolling granulation.
  • ibuprofen-containing preparation particles examples include, for example, Forms, binders, disintegrants and other medicinal ingredients can be mentioned.
  • the excipient may be any component that gives a certain bulk in a solid preparation, such as light anhydrous silicic acid, crystalline cellulose, candy powder, talc, magnesium stearate, lactose, sucrose, D-mannitol, potato starch, Corn starch can be mentioned.
  • the binder may be any component that provides a binding force between particles in a solid preparation.
  • crystalline cellulose sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose
  • examples include gelatin, methylcellulose, and sodium carboxymethylcellulose.
  • the disintegrating agent may be any component that promotes the disintegration and dispersion of solid preparations.
  • the disintegrating agent may be any component that promotes the disintegration and dispersion of solid preparations.
  • Other medicinal ingredients are not particularly limited, and examples thereof include vitamins (such as riboflavin) and anhydrous caffeine that assists the analgesic effect of ibuprofen and ethenamide caffeine.
  • the preferred content (blending) amount of ibuprofen in the ibuprofen-containing preparation particles according to the present invention is 30 to 60% by mass
  • the preferred content (blending) amount of ethenamide in the ethenamide-containing preparation particles according to the present invention is: It is 10 to 35% by mass in the ethenzamide-containing preparation particles.
  • the ibuprofen-containing preparation particles are always subjected to film coating, they are preferably hard particles having a particle strength of 7% by mass or less in the following friability test.
  • the friability is such that 5 g of particles of 850 ⁇ m or less and two metal spheres having a diameter of 20 mm and a mass of 28 g are filled into a cylindrical metal container (for example, a ball mill grinder) having a diameter of 32 mm and a height of 88 mm, and an amplitude of 15 mm.
  • the sample is classified with a 850 ⁇ m sieve, the residue of the sieve is removed, the sample that has passed through the 850 ⁇ m sieve is mixed, and the ratio (%) of the fine powder of 75 ⁇ m is measured.
  • the ethenamide-containing preparation particles do not necessarily need to be film-coated, but if the film coating is applied, it should have a particle strength comparable to that of the ibuprofen-containing preparation particles.
  • ibuprofen-containing preparation particles need to be coated with a film layer containing PVA or a PVA copolymer, but ethenamide-containing preparation particles do not necessarily have to be coated. This is because the drug particles containing ibuprofen having a low melting point are more effective in suppressing the melting point drop.
  • ibuprofen since ibuprofen has a large content (formulation), it is easy to sublimate and has a bitter taste with a specific irritation, so that it has a large merit for coating ibuprofen-containing preparation particles from the viewpoint of sublimation prevention and bitterness masking. Because.
  • Polyvinyl alcohol (PVA) is a polymer obtained by saponifying polyvinyl acetate, and is a white or slightly yellowish white powder.
  • the type of PVA used in the present invention is not particularly limited, but it is preferable to use a partially saponified product in consideration of adhesion and solubility, and a preferable saponification degree is 85 to 90 mol%. It is a product.
  • Suitable commercial products of the PVA of the present invention include Gohsenol (registered trademark) EG-05P (manufactured by Nippon Synthetic Chemical Co., Ltd., degree of saponification: 86.5 to 89.0 mol%, viscosity: 4.8 to 5.8 mPas). S (measured by a Heppler viscometer for a 4% aqueous solution at 20 ° C.)).
  • Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (PVA copolymer) is a polymer obtained by copolymerizing partially saponified polyvinyl alcohol with acrylic acid and methyl methacrylate. It is.
  • the preferred average degree of polymerization of the “PVA copolymer” according to the present invention is 450 to 550.
  • the preferred weight average molecular weight of the “PVA copolymer” according to the present invention is about 40,000.
  • PVACOAT registered trademark
  • F manufactured by Daido Kasei Kogyo, weight average molecular weight: about 40,000, average degree of polymerization: 450 to 550, polymerization ratio: 80% by mass of partially saponified polyvinyl alcohol, 17.5% by mass of acrylic acid, and 2.5% by mass of methyl methacrylate).
  • the content (formulation) of the PVA or PVA copolymer is 0.04 mass relative to 1 mass part of ibuprofen from the viewpoint of sufficiently suppressing the melting point drop of ibuprofen in consideration of the specific surface area of the ibuprofen-containing preparation particles. Part or more is preferable, and unnecessary coating is not preferable from the viewpoint of economy and the like, so 0.4 mass part is the upper limit.
  • the coating of the ibuprofen-containing preparation particles with the film layer containing PVA or PVA copolymer can be performed by a technique generally used in the field of solid preparations.
  • the technique include a method in which the preparation particles are charged in a fluidized bed granulation dryer (fluidized bed coating machine) and dried while spraying a film coating solution containing PVA or PVA copolymer.
  • the film coating solution in addition to PVA or PVA copolymer, other coating agents, plasticizers, suspending agents, fluidizing agents, coloring agents and the like may be dissolved and suspended in purified water or the like.
  • Examples of other coating agents include hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, carmellose sodium, carmellose potassium, cellulose acetate, cellulose acetate, cellulose acetate phthalate and the like, polyvinyl acetal Polymeric materials such as diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, natural such as carnauba wax, gelatin, succinylated gelatin, gum arabic, shellac And polysaccharides such as pulling polymers, pullulan and chitosan.
  • polyvinyl acetal Polymeric materials such as diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoal
  • plasticizer examples include sucrose fatty acid ester, paraffin, dioctyl adipate, triethyl citrate, triacetin, glycerin, concentrated glycerin, and propylene glycol.
  • suspending agent examples include sucrose fatty acid ester, polysorbate (polysorbate-80, etc.), polyglycerin fatty acid ester, lecithin, polyoxyethylene hydrogenated castor oil, and polyoxyethylene / polyoxypropylene copolymer.
  • Examples of the fluidizing agent include talc, magnesium aluminate metasilicate, hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide, magnesium stearate, and calcium stearate.
  • colorant examples include titanium oxide, zinc oxide, talc, turmeric extract, caramel, carotene solution, ⁇ -carotene, copper chlorophyll, copper chlorophyllin sodium, riboflavin, carbon black, medicinal charcoal, edible yellow No. 4, edible yellow Tar-type pigments such as No. 5, Edible Red No. 2, Edible Red No. 102, Edible Blue No. 1, Edible Blue No. 2, Edible Yellow No. 4 Aluminum Lake, and the like.
  • the solid preparation of the present invention contains, as necessary, preparation particles containing ibuprofen or etezamide and a contraindicated active ingredient, a medicinal ingredient that assists the analgesic effect of ibuprofen or ethenamide.
  • Preparation particles containing, for example, bromovaleryl urea, fluidizing agents, and the like may be added and mixed to provide powders, granules, fine granules, capsules, and the like.
  • the fluidizing agent to be added to and mixed with ibuprofen-containing preparation particles and ethenamide-containing preparation particles may be any component that improves the fluidity of the preparation particles, and examples thereof include magnesium aluminate metasilicate described above. .
  • the production of the solid preparation containing ibuprofen and ethenzamide of the present invention can be performed, for example, by the following method. First, they are blended into separate powders so that ibuprofen and etenzamide do not come into contact. That is, ibuprofen is mixed with the above-mentioned additive, and after rolling and fluidized bed granulation, it is dried to obtain ibuprofen-containing preparation particles. The obtained particles are charged into a Wurster column type fluidized bed coating machine, and PVA or PVA copolymer, the aforementioned plasticizer, suspending agent, coloring agent, etc. are dissolved and suspended in purified water, and the solid content concentration is about 15%.
  • ibuprofen-containing preparation particles coated with a film layer containing PVA or PVA copolymer Is sprayed at 0.75 to 3.7 parts by mass with respect to 1 part by mass of the ibuprofen-containing preparation particles to obtain ibuprofen-containing preparation particles coated with a film layer containing PVA or PVA copolymer.
  • ethenzamide is mixed with the above-mentioned additives, and is dried after rolling-fluidized bed granulation to obtain ethenzamide-containing preparation particles.
  • the ibuprofen-containing preparation particles coated with the film layer and the ethenamide-containing preparation particles are mixed together with the fluidizing agent and the like to obtain the intended solid preparation containing ibuprofen and etenzamid.
  • the solid preparation thus obtained is filled in a packaging container or a sachet according to the size of the particle and provided as a powder, granule, etc. It can also be provided as an agent.
  • the resulting granulated product is dried using a fluidized bed dryer (Freund), and after drying, it is classified with a 30M (500 ⁇ m) sieve, and the sieve residue is crushed and ethenzamide-containing preparation particles having an average particle size of 164 ⁇ m.
  • Example 1 570 g of the preparation particles obtained in Production Example 1 were charged into a fluidized bed granulator / dryer equipped with a draft tube (GPCG (trade name): manufactured by POWREC), 36 g of hypromellose, PVA (GOHSENOL EG-05P (trade name): Nippon Synthetic Co., Ltd.) Chemical Co., Ltd.) 36 g, paraffin 9.6 g, carnauba wax 9.6 g, sucrose fatty acid ester 2.4 g, polysorbate-80 2.4 g and titanium oxide 24 g dissolved and dispersed in purified water 720 g using a coating solution According to the method, 630 g of formulation particles coated with a film layer (covering amount: 10% of formulation particles) was produced.
  • GPCG trade name: manufactured by POWREC
  • PVA GOHSENOL EG-05P (trade name): Nippon Synthetic Co., Ltd.) Chemical Co., Ltd.
  • 36 g paraffin 9.6 g,
  • Example 2 Coating in which 570 g of the preparation particles obtained in Production Example 1 were dissolved and dispersed in 96 g of PVA copolymer (POVACOAT type F (trade name): manufactured by Daido Kasei Kogyo), 9.6 g of talc and 14.4 g of titanium oxide in 586 g of purified water. Using the solution, 630 g of formulation particles coated with a film layer (coating amount: 10% of formulation particles) was produced in the same manner as in Example 1.
  • PVACOAT type F trade name
  • Comparative Example 1 630 g of formulation particles coated with a film layer in the same manner as in Example 1 using a coating solution obtained by dissolving and dispersing 570 g of the formulation particles obtained in Production Example 1 in 68 g of hypromellose and 46 g of talc in 1150 g of purified water Amount: 10% of formulation particles).
  • the powder was filled into a packaging material to obtain a solid preparation containing ibuprofen and ethenzamide.
  • Test Example 1 (Test Example 1) [Evaluation methods] The test preparation was stored for 3 months under conditions of 40 ° C. and 75% RH, and then sieved based on the Japanese Pharmacopoeia General Test Method Particle Size Test Method, and the state of solidification / aggregation of the preparation particles was observed.
  • solid preparations composed of preparation particles that were not subjected to film coating produced a large amount of coarse particles due to aggregation of the preparation particles, whereas film coating was performed to form a film layer.
  • the generation of coarse particles is suppressed, and in particular, a film containing PVA (Example 1) and PVA copolymer (Example 2)
  • a film containing PVA (Example 1) and PVA copolymer Example 2

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Abstract

A solid pharmaceutical preparation comprising ibuprofen and ethenzamide is characterized in that ibuprofen and ethenzamide are added to different pharmaceutical preparation particles and the pharmaceutical preparation particles containing ibuprofen are coated by a film layer comprising polyvinyl alcohol or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

Description

固形製剤Solid preparation
　本発明は、固形製剤の分野に関し、詳しくは、有効成分としてイブプロフェン及びエテンザミドを含有する固形製剤に関する。 The present invention relates to the field of solid preparations, and more particularly to a solid preparation containing ibuprofen and etenzamide as active ingredients.
　頭痛薬や総合感冒薬の有効成分として汎用されているイブプロフェンは融点７５～７７℃の低融点薬物であるが、同じく頭痛薬や総合感冒薬の有効成分として知られるエテンザミドと混在すると融点降下を引き起こすことが知られていた（非特許文献１参照）。有効成分の中でも含有量が多いイブプロフェンの融点降下は、粉体のハンドリングを著しく困難にし、付着や凝集を引き起こす他、製品化後に変色等の問題を招来することがあった。 Ibuprofen, which is widely used as an active ingredient in headache and general cold medicines, is a low-melting drug with a melting point of 75-77 ° C. It was known (see Non-Patent Document 1). The melting point drop of ibuprofen, which has a large content among the active ingredients, makes handling of the powder extremely difficult, causing adhesion and aggregation, and may cause problems such as discoloration after commercialization.
　そのため、有効成分としてイブプロフェンとエテンザミドを配合した固形製剤では、これらを異なる顆粒等に配合し、二重錠や多層錠として提供すれば、イブプロフェンとエテンザミドが同一の製剤中に配合されていても、直接の接触を回避してイブプロフェンの融点降下を防止することが可能であった（非特許文献２参照）。 Therefore, in a solid preparation containing ibuprofen and etenzamide as active ingredients, if they are mixed in different granules, etc., and provided as a double tablet or multilayer tablet, even if ibuprofen and etenzamide are combined in the same preparation, It was possible to avoid the direct contact and prevent the melting point drop of ibuprofen (see Non-Patent Document 2).
　しかしながら、イブプロフェンとエテンザミドを配合した散剤、顆粒剤等を提供する場合には、単にこれらの成分を異なる顆粒等に配合しただけでは充分に接触を回避できず、イブプロフェンの融点降下を充分に抑制することができなかった。 However, when providing powders, granules, etc. containing ibuprofen and etenzamide, contact with these ingredients alone is not enough to avoid contact and sufficiently suppress the melting point drop of ibuprofen. I couldn't.
特開平７－２７７９６２号公報JP-A-7-277962 特許第４８５３８１８号公報Japanese Patent No. 4835818
　そこで、常套手段としてはイブプロフェンとエテンザミドを異なる顆粒等に配合した後、少なくともその何れかをフィルムコーティングすることが考えられるが（特許文献１及び２参照）、フィルム基剤として最もポピュラーなヒプロメロース（ヒドロキシプロピルメチルセルロース）を主基剤とするフィルム層でイブプロフェン含有顆粒を被覆し、エテンザミド含有顆粒と混合したところ、イブプロフェンの融点降下を充分に抑制することはできなかった（後述の比較例１参照）。 Thus, as a conventional means, it is conceivable to mix ibuprofen and etenzamide into different granules and then coat at least one of them (see Patent Documents 1 and 2), but the most popular hypromellose (hydroxyl) as a film base. When the ibuprofen-containing granule was coated with a film layer mainly composed of propylmethylcellulose and mixed with the ethenamide-containing granule, the melting point drop of ibuprofen could not be sufficiently suppressed (see Comparative Example 1 described later).
　本発明の課題は、有効成分であるイブプロフェンとエテンザミドを別々の顆粒等に配合し、イブプロフェン含有顆粒等を被覆するにあたって、その融点降下を抑制するのに最も有効なフィルム基剤を選定し、保存安定性や服用性に優れた散剤、顆粒剤等のイブプロフェン及びエテンザミド含有固形製剤を提供することである。 The object of the present invention is to combine the active ingredients ibuprofen and etenzamide into separate granules, etc., and to select and preserve the most effective film base to suppress the melting point drop when coating ibuprofen-containing granules etc. It is to provide a solid preparation containing ibuprofen and etezamide such as powders and granules excellent in stability and administration.
　本発明者らは、上記課題を解決すべく鋭意検討した結果、フィルム基剤としてポリビニルアルコール（以下、適宜に「ＰＶＡ」と略記する。）若しく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（以下、適宜に「ＰＶＡコポリマー」と略記する。）を採択した場合にのみエテンザミド含有顆粒との混在によるイブプロフェンの融点降下を効果的に抑制しうることを見出した。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that polyvinyl alcohol (hereinafter, abbreviated as “PVA” as appropriate) or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer ( In the following, it has been found that the drop in melting point of ibuprofen due to the mixture with the ethenamide-containing granule can be effectively suppressed only when it is appropriately abbreviated as “PVA copolymer”.
　かかる知見により得られた本発明の態様は次のとおりである。
（１）イブプロフェンとエテンザミドが異なる製剤粒子中に配合され、イブプロフェンを含有する製剤粒子がポリビニルアルコール又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含有するフィルム層で被覆されていることを特徴とするイブプロフェン及びエテンザミド含有固形製剤。
（２）フィルム層中のポリビニルアルコール又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の含有量が、イブプロフェンの１質量部に対して０．０４～０．４質量部である前記（１）に記載のイブプロフェン及びエテンザミド含有固形製剤。
（３）固形製剤が散剤、顆粒剤、微粒剤又はカプセル剤である前記（１）又は（２）に記載のイブプロフェン及びエテンザミド含有固形製剤。 The embodiments of the present invention obtained from such findings are as follows.
(1) Ibuprofen and etenzaamide are blended in different preparation particles, and the preparation particles containing ibuprofen are coated with a film layer containing polyvinyl alcohol or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. A solid preparation containing ibuprofen and etezamide.
(2) The content of polyvinyl alcohol or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in the film layer is 0.04 to 0.4 parts by mass with respect to 1 part by mass of ibuprofen. A solid preparation containing ibuprofen and etezamide as described in 1. above.
(3) The ibuprofen and ethenzamide-containing solid preparation according to (1) or (2) above, wherein the solid preparation is a powder, granule, fine granule or capsule.
　本発明により、有効成分としてイブプロフェンとエテンザミドを配合した散剤、顆粒剤等の固形製剤を提供することが可能となった。また、イブプロフェン含有顆粒等をＰＶＡ又はＰＶＡコポリマーで被覆することによりイブプロフェンの昇華や苦味も抑制され、保存安定性及び服用性に優れた固形製剤として提供することが可能となった。 According to the present invention, it has become possible to provide solid preparations such as powders and granules containing ibuprofen and etenzamide as active ingredients. Further, by coating ibuprofen-containing granules and the like with PVA or PVA copolymer, sublimation and bitterness of ibuprofen are suppressed, and it has become possible to provide a solid preparation excellent in storage stability and ingestion.
　本発明のイブプロフェン及びエテンザミド含有固形製剤は、イブプロフェンとエテンザミドが異なる製剤粒子中に配合され、イブプロフェンを含有する製剤粒子がポリビニルアルコール又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含有するフィルム層で被覆されていることを特徴とするものである。 The ibuprofen and etenzamide-containing solid preparation of the present invention is a film layer in which ibuprofen and etezamide are blended in different preparation particles, and the preparation particles containing ibuprofen contain polyvinyl alcohol or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. It is characterized by being covered with.
　有効成分であるイブプロフェン及びエテンザミドは混在すると融点降下を引き起こすため、本発明では、これら有効成分を別々の製剤粒子中に配合する。 When the active ingredients ibuprofen and etenzamide are mixed, the melting point is lowered. Therefore, in the present invention, these active ingredients are blended in separate preparation particles.
　「製剤粒子」とは、有効成分の他に後述の添加剤を配合した粉体を混合等した後、乾式造粒、噴霧乾燥造粒、又は、練合造粒、押し出し造粒、撹拌造粒、流動層造粒、撹拌流動層造粒、転動流動層造粒、転動造粒等の湿式造粒を経て調製された幾何平均粒子径８０～４００μｍの固形の粒子である。 “Formulation particles” means, for example, a dry granulation, spray-drying granulation, kneading granulation, extrusion granulation, stirring granulation after mixing powders containing additives described below in addition to active ingredients Solid particles having a geometric average particle diameter of 80 to 400 μm prepared by wet granulation such as fluidized bed granulation, stirred fluidized bed granulation, rolling fluidized bed granulation, and rolling granulation.
　本発明にかかる、イブプロフェンを含有する製剤粒子及びエテンザミドを含有する製剤粒子（以下、「イブプロフェン含有製剤粒子」及び「エテンザミド含有製剤粒子」とも各々称する。）に配合する添加剤としては、例えば、賦形剤、結合剤、崩壊剤、他の薬効成分が挙げられる。 Examples of the additive to be blended with the preparation particles containing ibuprofen and the preparation particles containing ethenamide (hereinafter also referred to as “ibuprofen-containing preparation particles” and “ethenzamid-containing preparation particles”) according to the present invention include, for example, Forms, binders, disintegrants and other medicinal ingredients can be mentioned.
　賦形剤としては、固形製剤において一定のかさを与える成分であればよく、例えば、軽質無水ケイ酸、結晶セルロース、アメ粉、タルク、ステアリン酸マグネシウム、乳糖、白糖、Ｄ－マンニトール、バレイショデンプン、コーンスターチが挙げられる。 The excipient may be any component that gives a certain bulk in a solid preparation, such as light anhydrous silicic acid, crystalline cellulose, candy powder, talc, magnesium stearate, lactose, sucrose, D-mannitol, potato starch, Corn starch can be mentioned.
　結合剤としては、固形製剤において粒子間に結合力を与える成分であればよく、例えば、結晶セルロース、白糖、Ｄ－マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、デンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウムが挙げられる。 The binder may be any component that provides a binding force between particles in a solid preparation. For example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, Examples include gelatin, methylcellulose, and sodium carboxymethylcellulose.
　崩壊剤としては、固形製剤の崩壊や分散を促進する成分であればよく、例えば、低置換度ヒドロキシプロピルセルロース、クロスポビドン、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、カルメロースカルシウム、バレイショデンプン、コーンスターチが挙げられる。 The disintegrating agent may be any component that promotes the disintegration and dispersion of solid preparations. For example, low-substituted hydroxypropylcellulose, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, carmellose calcium, potato starch, corn starch Is mentioned.
　他の薬効成分としては特に制限はなく、例えば、ビタミン類（リボフラビン等）や、イブプロフェン及びエテンザミドカフェインによる鎮痛効果を補助する無水カフェイン等が挙げられる。 Other medicinal ingredients are not particularly limited, and examples thereof include vitamins (such as riboflavin) and anhydrous caffeine that assists the analgesic effect of ibuprofen and ethenamide caffeine.
　また、本発明にかかるイブプロフェン含有製剤粒子におけるイブプロフェンの好適な含有（配合）量は、３０～６０質量％であり、本発明にかかるエテンザミド含有製剤粒子におけるエテンザミドの好適な含有（配合）量は、エテンザミド含有製剤粒子中１０～３５質量％である。 Further, the preferred content (blending) amount of ibuprofen in the ibuprofen-containing preparation particles according to the present invention is 30 to 60% by mass, and the preferred content (blending) amount of ethenamide in the ethenamide-containing preparation particles according to the present invention is: It is 10 to 35% by mass in the ethenzamide-containing preparation particles.
　イブプロフェン含有製剤粒子については必ずフィルムコーティングを施すので、通常下記の摩損度試験で摩損度７質量％以下の粒子強度を有する硬い粒子であることが好ましい。 Since the ibuprofen-containing preparation particles are always subjected to film coating, they are preferably hard particles having a particle strength of 7% by mass or less in the following friability test.
　なお、摩損度は、８５０μｍ以下の粒子５ｇと直径２０ｍｍ、質量２８ｇの金属球２個を直径３２ｍｍ、高さ８８ｍｍの円柱状の金属製の容器（例えば、ボールミル粉砕機）に充填し、振幅１５ｍｍ、振動数１５００回／分で１分間振動させたときに発生する７５μｍ以下の微粉の割合（％）の増加量である。具体的には、サンプルを８５０μｍの篩で分級し、篩残を除去し、８５０μｍの篩を通過したサンプルを混合して、７５μｍの微粉の割合（％）を測定しておく。次に８５０μｍの篩を通過したサンプルの５ｇを直径２０ｍｍ、質量２８ｇのステンレス球２個と共に直径３２ｍｍ、高さ８８ｍｍの円筒状のステンレス製容器（ベータミル（商品名）：三菱化学エンジニアリング製）に充填する。容器を振幅１５ｍｍ、振動数１５００回／分で１分間振動させた後、７５μｍ以下の微粉の割合（％）を測定する。「摩損度」は、測定前後の７５μｍ以下の微粉の割合（％）の増加量として求められる。 The friability is such that 5 g of particles of 850 μm or less and two metal spheres having a diameter of 20 mm and a mass of 28 g are filled into a cylindrical metal container (for example, a ball mill grinder) having a diameter of 32 mm and a height of 88 mm, and an amplitude of 15 mm. The increase in the proportion (%) of fine powder of 75 μm or less generated when vibrating for 1 minute at a frequency of 1500 times / minute. Specifically, the sample is classified with a 850 μm sieve, the residue of the sieve is removed, the sample that has passed through the 850 μm sieve is mixed, and the ratio (%) of the fine powder of 75 μm is measured. Next, 5 g of the sample that passed through the 850 μm sieve was filled into a cylindrical stainless steel container (beta mill (trade name): manufactured by Mitsubishi Chemical Engineering Co., Ltd.) having a diameter of 32 mm and a height of 88 mm together with two stainless balls having a diameter of 20 mm and a mass of 28 g. To do. The container is vibrated for 1 minute at an amplitude of 15 mm and a frequency of 1500 times / minute, and then the ratio (%) of fine powder of 75 μm or less is measured. The “friability” is determined as an increase in the ratio (%) of fine powder of 75 μm or less before and after measurement.
　本発明においてエテンザミド含有製剤粒子には必ずしもフィルムコーティングを施す必要はないが、フィルムコーティングを施すならイブプロフェン含有製剤粒子と同程度の粒子強度があった方がよい。 In the present invention, the ethenamide-containing preparation particles do not necessarily need to be film-coated, but if the film coating is applied, it should have a particle strength comparable to that of the ibuprofen-containing preparation particles.
　本発明では、イブプロフェン含有製剤粒子はＰＶＡ又はＰＶＡコポリマーを含有するフィルム層で被覆される必要があるが、エテンザミド含有製剤粒子の方は必ずしも被覆されている必要はない。これは、低融点のイブプロフェンを含有する製剤粒子の方を被覆した方が融点降下の抑制効果が大きいからである。また、イブプロフェンは含有（配合）量も多い上、昇華し易く、特有の刺激のある苦味を有するため、昇華防止や苦味のマスキングという点からも、イブプロフェン含有製剤粒子の方を被覆するメリットが大きいからである。 In the present invention, ibuprofen-containing preparation particles need to be coated with a film layer containing PVA or a PVA copolymer, but ethenamide-containing preparation particles do not necessarily have to be coated. This is because the drug particles containing ibuprofen having a low melting point are more effective in suppressing the melting point drop. In addition, since ibuprofen has a large content (formulation), it is easy to sublimate and has a bitter taste with a specific irritation, so that it has a large merit for coating ibuprofen-containing preparation particles from the viewpoint of sublimation prevention and bitterness masking. Because.
　「ポリビニルアルコール（ＰＶＡ）」とは、ポリ酢酸ビニルをけん化して得た重合物で、白色若しくは微黄白色の粉末である。ここで本発明において使用するＰＶＡは、その種類が特に制限されるものではないが、付着力と溶解性を考慮すれば部分けん化物を使用することが好ましく、好ましいけん化度は８５～９０モル％品である。 “Polyvinyl alcohol (PVA)” is a polymer obtained by saponifying polyvinyl acetate, and is a white or slightly yellowish white powder. Here, the type of PVA used in the present invention is not particularly limited, but it is preferable to use a partially saponified product in consideration of adhesion and solubility, and a preferable saponification degree is 85 to 90 mol%. It is a product.
　本発明のＰＶＡの好適な市販品の例としては、ゴーセノール（登録商標）ＥＧ－０５Ｐ（日本合成化学社製、けん化度：８６．５～８９．０ｍｏｌ％、粘度：４．８～５．８ｍＰａ・ｓ（２０℃における４％水溶液についてのヘプラー粘度計による測定値））が挙げられる。 Examples of suitable commercial products of the PVA of the present invention include Gohsenol (registered trademark) EG-05P (manufactured by Nippon Synthetic Chemical Co., Ltd., degree of saponification: 86.5 to 89.0 mol%, viscosity: 4.8 to 5.8 mPas). S (measured by a Heppler viscometer for a 4% aqueous solution at 20 ° C.)).
　「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（ＰＶＡコポリマー）」とは、部分けん化ポリビニルアルコールにアクリル酸とメタクリル酸メチルを共重合した高分子であり，白色～帯黄白色の塊又は粉末である。 “Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (PVA copolymer)” is a polymer obtained by copolymerizing partially saponified polyvinyl alcohol with acrylic acid and methyl methacrylate. It is.
　本発明にかかる「ＰＶＡコポリマー」における好適な平均重合度は、４５０～５５０である。本発明にかかる「ＰＶＡコポリマー」の好適な重量平均分子量は、約４０，０００である。 The preferred average degree of polymerization of the “PVA copolymer” according to the present invention is 450 to 550. The preferred weight average molecular weight of the “PVA copolymer” according to the present invention is about 40,000.
　本発明にかかるＰＶＡコポリマーの好適な市販品の例としては、ＰＯＶＡＣＯＡＴ（登録商標）Ｔｙｐｅ：Ｆ（大同化成工業製、重量平均分子量：約４０，０００、平均重合度：４５０～５５０、重合割合：部分けん化ポリビニルアルコールが８０質量％、アクリル酸が１７．５質量％、及びメタクリル酸メチルが２．５質量％）が挙げられる。 Examples of suitable commercially available PVA copolymers according to the present invention include POVACOAT (registered trademark) Type: F (manufactured by Daido Kasei Kogyo, weight average molecular weight: about 40,000, average degree of polymerization: 450 to 550, polymerization ratio: 80% by mass of partially saponified polyvinyl alcohol, 17.5% by mass of acrylic acid, and 2.5% by mass of methyl methacrylate).
　ＰＶＡ又はＰＶＡコポリマーの含有（配合）量は、イブプロフェン含有製剤粒子の比表面積等を勘案し、イブプロフェンの融点降下を充分に抑制するという観点から、イブプロフェンの１質量部に対して、０．０４質量部以上が好ましく、必要以上のコーティングは経済性等の観点から好ましくないので、０．４質量部が上限となる。 The content (formulation) of the PVA or PVA copolymer is 0.04 mass relative to 1 mass part of ibuprofen from the viewpoint of sufficiently suppressing the melting point drop of ibuprofen in consideration of the specific surface area of the ibuprofen-containing preparation particles. Part or more is preferable, and unnecessary coating is not preferable from the viewpoint of economy and the like, so 0.4 mass part is the upper limit.
　ＰＶＡ又はＰＶＡコポリマーを含有するフィルム層による、イブプロフェン含有製剤粒子の被覆は、固形製剤の分野で一般的に用いられている手法により行うことができる。手法としては、例えば、流動層造粒乾燥機（流動層コーティング機）に製剤粒子を仕込んで、ＰＶＡ又はＰＶＡコポリマーを含有するフィルムコーティング液をスプレーしながら乾燥させる方法が挙げられる。 The coating of the ibuprofen-containing preparation particles with the film layer containing PVA or PVA copolymer can be performed by a technique generally used in the field of solid preparations. Examples of the technique include a method in which the preparation particles are charged in a fluidized bed granulation dryer (fluidized bed coating machine) and dried while spraying a film coating solution containing PVA or PVA copolymer.
　フィルムコーティング液には、ＰＶＡ又はＰＶＡコポリマー以外に、他のコーティング剤、可塑剤、懸濁剤、流動化剤、着色剤等が精製水等に溶解・懸濁され含有されていてもよい。 In the film coating solution, in addition to PVA or PVA copolymer, other coating agents, plasticizers, suspending agents, fluidizing agents, coloring agents and the like may be dissolved and suspended in purified water or the like.
　他のコーティング剤としては、例えば、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、エチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、カルメロースナトリウム、カルメロースカリウム、酢酸セルロース、酢酸フタル酸セルロース等のセルロース誘導体、ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタクリレートコポリマーＥ、アミノアルキルメタクリレートコポリマーＲＳ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＳ等の高分子物質、カルナウバロウ、ゼラチン、コハク化ゼラチン、アラビアゴム、セラック等の天然系高分子物質、プルラン、キトサン等の多糖類が挙げられる。 Examples of other coating agents include hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, carmellose sodium, carmellose potassium, cellulose acetate, cellulose acetate, cellulose acetate phthalate and the like, polyvinyl acetal Polymeric materials such as diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, natural such as carnauba wax, gelatin, succinylated gelatin, gum arabic, shellac And polysaccharides such as pulling polymers, pullulan and chitosan.
　可塑剤としては、例えば、ショ糖脂肪酸エステル、パラフィン、アジピン酸ジオクチル、クエン酸トリエチル、トリアセチン、グリセリン、濃グリセリン、プロピレングリコールが挙げられる。 Examples of the plasticizer include sucrose fatty acid ester, paraffin, dioctyl adipate, triethyl citrate, triacetin, glycerin, concentrated glycerin, and propylene glycol.
　懸濁剤としては、例えば、ショ糖脂肪酸エステル、ポリソルベート（ポリソルベート－８０等）、ポリグリセリン脂肪酸エステル、レシチン、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレン・ポリオキシプロピレン共重合物が挙げられる。 Examples of the suspending agent include sucrose fatty acid ester, polysorbate (polysorbate-80, etc.), polyglycerin fatty acid ester, lecithin, polyoxyethylene hydrogenated castor oil, and polyoxyethylene / polyoxypropylene copolymer.
　流動化剤として、例えば、タルク、メタケイ酸アルミン酸マグネシウム、含水二酸化ケイ素、軽質無水ケイ酸、酸化チタン、ステアリン酸マグネシウム、ステアリン酸カルシウムが挙げられる。 Examples of the fluidizing agent include talc, magnesium aluminate metasilicate, hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide, magnesium stearate, and calcium stearate.
　着色剤としては、例えば、酸化チタン、酸化亜鉛、タルク、ウコン抽出液、カラメル、カロチン液、β－カロテン、銅クロロフィル、銅クロロフィリンナトリウム、リボフラビン、カーボンブラック、薬用炭、食用黄色４号、食用黄色５号、食用赤色２号、食用赤色１０２号、食用青色１号、食用青色２号、食用黄色４号アルミニウムレーキ等のタール系色素が挙げられる。 Examples of the colorant include titanium oxide, zinc oxide, talc, turmeric extract, caramel, carotene solution, β-carotene, copper chlorophyll, copper chlorophyllin sodium, riboflavin, carbon black, medicinal charcoal, edible yellow No. 4, edible yellow Tar-type pigments such as No. 5, Edible Red No. 2, Edible Red No. 102, Edible Blue No. 1, Edible Blue No. 2, Edible Yellow No. 4 Aluminum Lake, and the like.
　本発明の固形製剤は、イブプロフェン含有製剤粒子及びエテンザミド含有製剤粒子の他、必要に応じて、イブプロフェンやエテンザミドと配合禁忌の有効成分を含有する製剤粒子、イブプロフェンやエテンザミドの鎮痛効果を補助する薬効成分（例えば、ブロモバレリル尿素）を含有する製剤粒子、流動化剤等を添加・混合し、散剤、顆粒剤、微粒剤、カプセル剤等として提供することもできる。なお、イブプロフェン含有製剤粒子及びエテンザミド含有製剤粒子等に添加・混合する流動化剤としては、製剤粒子の流動性を向上させる成分であればよく、例えば、前述のメタケイ酸アルミン酸マグネシウム等が挙げられる。 In addition to ibuprofen-containing preparation particles and etenzamide-containing preparation particles, the solid preparation of the present invention contains, as necessary, preparation particles containing ibuprofen or etezamide and a contraindicated active ingredient, a medicinal ingredient that assists the analgesic effect of ibuprofen or ethenamide. Preparation particles containing, for example, bromovaleryl urea, fluidizing agents, and the like may be added and mixed to provide powders, granules, fine granules, capsules, and the like. The fluidizing agent to be added to and mixed with ibuprofen-containing preparation particles and ethenamide-containing preparation particles may be any component that improves the fluidity of the preparation particles, and examples thereof include magnesium aluminate metasilicate described above. .
　本発明のイブプロフェン及びエテンザミド含有固形製剤の製造は、例えば、以下の方法にて行うことができる。先ずイブプロフェンとエテンザミドが接触しないようにそれらを別々の粉体に配合する。すなわち、イブプロフェンを前述の添加剤とともに混合し、転動流動層造粒後乾燥し、イブプロフェン含有製剤粒子を得る。得られた粒子をワースターコラム型の流動層コーティング機に仕込み、ＰＶＡ又はＰＶＡコポリマーや前述の可塑剤、懸濁剤、着色剤等を精製水に溶解・懸濁させた固形分濃度約１５％のコーティング液をイブプロフェン含有製剤粒子の１質量部に対して０．７５～３．７質量部でスプレーし、ＰＶＡ又はＰＶＡコポリマー含有のフィルム層で被覆されたイブプロフェン含有製剤粒子を得る。次いで、エテンザミドを前述の添加剤とともに混合し、転動流動層造粒後乾燥し、エテンザミド含有製剤粒子を得る。フィルム層で被覆されたイブプロフェン含有製剤粒子とエテンザミド含有製剤粒子を前記流動化剤等とともに混合し、目的とするイブプロフェン及びエテンザミド含有固形製剤が得られる。 The production of the solid preparation containing ibuprofen and ethenzamide of the present invention can be performed, for example, by the following method. First, they are blended into separate powders so that ibuprofen and etenzamide do not come into contact. That is, ibuprofen is mixed with the above-mentioned additive, and after rolling and fluidized bed granulation, it is dried to obtain ibuprofen-containing preparation particles. The obtained particles are charged into a Wurster column type fluidized bed coating machine, and PVA or PVA copolymer, the aforementioned plasticizer, suspending agent, coloring agent, etc. are dissolved and suspended in purified water, and the solid content concentration is about 15%. Is sprayed at 0.75 to 3.7 parts by mass with respect to 1 part by mass of the ibuprofen-containing preparation particles to obtain ibuprofen-containing preparation particles coated with a film layer containing PVA or PVA copolymer. Next, ethenzamide is mixed with the above-mentioned additives, and is dried after rolling-fluidized bed granulation to obtain ethenzamide-containing preparation particles. The ibuprofen-containing preparation particles coated with the film layer and the ethenamide-containing preparation particles are mixed together with the fluidizing agent and the like to obtain the intended solid preparation containing ibuprofen and etenzamid.
　また、このようにして得られた固形製剤は、粒子の大きさ等に応じ包装容器や分包に充填されて、散剤、顆粒剤等として提供される他、ゼラチン製のカプセルに充填してカプセル剤としても提供されうる。 The solid preparation thus obtained is filled in a packaging container or a sachet according to the size of the particle and provided as a powder, granule, etc. It can also be provided as an agent.
　以下に、製造例、実施例、比較例及び試験例を挙げ、本説明をさらに詳細に説明する。 Hereinafter, this description will be described in more detail with reference to production examples, examples, comparative examples, and test examples.
　製造例１　イブプロフェン含有製剤粒子の調製
　イブプロフェン２７,０００ｇ、リボフラビン２４０ｇ、軽質無水ケイ酸３,０００ｇ、結晶セルロース１２,０００ｇ、アメ粉２１,０００ｇを秤量、混合した粉体を、ヒドロキシプロピルセルロース（ＨＰＣ－Ｌ）５,４００ｇを精製水５４,６００ｇに溶解した溶液を結合液として、転動流動層造粒機（マルチプレックス（商品名）：パウレック社製）を用いて造粒し、平均粒子径２２２μｍのイブプロフェン含有製剤粒子を製造した。 Production Example 1 Preparation of ibuprofen-containing preparation particles 27,000 g of ibuprofen, 240 g of riboflavin, 3,000 g of light anhydrous silicic acid, 12,000 g of crystalline cellulose, and 21,000 g of candy powder were weighed and mixed with hydroxypropyl cellulose (HPC). -L) Using a solution obtained by dissolving 5,400 g in purified water 54,600 g as a binding liquid, granulation using a tumbling fluidized bed granulator (Multiplex (trade name): manufactured by POWREC), the average particle size 222 μm ibuprofen-containing formulation particles were produced.
　製造例２　エテンザミド含有製剤粒子の調製
　エテンザミド１２６ｇ、無水カフェイン７５ｇ、結晶セルロース６０ｇ、Ｄ－マンニトール３００ｇ、ヒドロキシプロピルセルロース（ＨＰＣ－Ｌ微粉）３０ｇ、軽質無水ケイ酸６ｇを秤量、混合した粉体を精製水を造粒溶媒とし、攪拌造粒機（バーチカルグラニュレータ（商品名）：パウレック社製）を用いて造粒した。得られた造粒物を流動層乾燥機（フロイント社製）を用いて乾燥し、乾燥後３０Ｍ（５００μｍ）の篩で分級し、篩残は粗砕して平均粒子径１６４μｍのエテンザミド含有製剤粒子を得た。 Production Example 2 Preparation of ethenamide-containing preparation particles 126 g of ethenamide, 75 g of anhydrous caffeine, 60 g of crystalline cellulose, 300 g of D-mannitol, 30 g of hydroxypropylcellulose (HPC-L fine powder) and 6 g of light anhydrous silicic acid were weighed and mixed. Using purified water as a granulating solvent, granulation was carried out using a stirring granulator (vertical granulator (trade name): manufactured by POWREC). The resulting granulated product is dried using a fluidized bed dryer (Freund), and after drying, it is classified with a 30M (500 μm) sieve, and the sieve residue is crushed and ethenzamide-containing preparation particles having an average particle size of 164 μm. Got.
　製造例３　その他の製剤粒子
　ブロモバレリル尿素３００ｇ、結晶セルロース６０ｇ、Ｄ－マンニトール２０４ｇ、ヒドロキシプロピルセルロース（ＨＰＣ－Ｌ微粉）３０ｇ、軽質無水ケイ酸６ｇを製造例２と同様の手法により造粒し平均粒子径１２７μｍの製剤粒子を得た。 Production Example 3 Other Preparation Particles 300 g of bromovaleryl urea, 60 g of crystalline cellulose, 204 g of D-mannitol, 30 g of hydroxypropylcellulose (HPC-L fine powder), and 6 g of light anhydrous silicic acid were granulated by the same method as in Production Example 2 and averaged particles Preparation particles having a diameter of 127 μm were obtained.
　（実施例１）
　製造例１で得られた製剤粒子５７０ｇをドラフトチューブ付き流動層造粒乾燥機（ＧＰＣＧ（商品名）：パウレック社製）に仕込み、ヒプロメロース３６ｇ、ＰＶＡ（ゴーセノールＥＧ－０５Ｐ（商品名）：日本合成化学社製）３６ｇ、パラフィン９．６ｇ、カルナウバロウ９．６ｇ、ショ糖脂肪酸エステル２．４ｇ、ポリソルベート－８０　２．４ｇ及び酸化チタン２４ｇを精製水７２０ｇに溶解・分散させたコーティング液を用いてスプレー法によりフィルム層で被覆された製剤粒子６３０ｇ（被覆量：対製剤粒子１０％）を製造した。得られたフィルム層で被覆された製剤粒子０．４２ｇに製造例２で得られた製剤粒子０．３９７ｇ、製造例３で得られた製剤粒子０．３９９ｇ，メタケイ酸アルミン酸マグネシウム０．０１２ｇ，甘味料及び香料を加え混合した粉体を包材に充填し、目的とするイブプロフェン及びエテンザミド含有固形製剤を得た。 (Example 1)
570 g of the preparation particles obtained in Production Example 1 were charged into a fluidized bed granulator / dryer equipped with a draft tube (GPCG (trade name): manufactured by POWREC), 36 g of hypromellose, PVA (GOHSENOL EG-05P (trade name): Nippon Synthetic Co., Ltd.) Chemical Co., Ltd.) 36 g, paraffin 9.6 g, carnauba wax 9.6 g, sucrose fatty acid ester 2.4 g, polysorbate-80 2.4 g and titanium oxide 24 g dissolved and dispersed in purified water 720 g using a coating solution According to the method, 630 g of formulation particles coated with a film layer (covering amount: 10% of formulation particles) was produced. 0.42 g of the preparation particles coated with the obtained film layer, 0.397 g of the preparation particles obtained in Production Example 2, 0.399 g of the preparation particles obtained in Production Example 3, 0.012 g of magnesium aluminate metasilicate, The powder obtained by adding the sweetener and the fragrance and mixing the mixture was filled in the packaging material to obtain the intended solid preparation containing ibuprofen and ethenzamide.
　（実施例２）
　製造例１で得られた製剤粒子５７０ｇをＰＶＡコポリマー（ＰＯＶＡＣＯＡＴタイプＦ（商品名）：大同化成工業製）９６ｇ、タルク９．６ｇ及び酸化チタン１４．４ｇを精製水５８６ｇに溶解・分散させたコーティング液を用いて実施例１と同様の手法によりフィルム層で被覆された製剤粒子６３０ｇ（被覆量：対製剤粒子１０％）を製造した。得られたフィルム層で被覆された製剤粒子０．４２ｇに製造例２で得られた製剤粒子０．３９７ｇ、製造例３で得られた製剤粒子０．３９９ｇ、メタケイ酸アルミン酸マグネシウム０．０１２ｇ、甘味料及び香料を加え混合した粉体を包材に充填し、目的とするイブプロフェン及びエテンザミド含有固形製剤を得た。 (Example 2)
Coating in which 570 g of the preparation particles obtained in Production Example 1 were dissolved and dispersed in 96 g of PVA copolymer (POVACOAT type F (trade name): manufactured by Daido Kasei Kogyo), 9.6 g of talc and 14.4 g of titanium oxide in 586 g of purified water. Using the solution, 630 g of formulation particles coated with a film layer (coating amount: 10% of formulation particles) was produced in the same manner as in Example 1. 0.42 g of the preparation particles coated with the obtained film layer, 0.397 g of the preparation particles obtained in Production Example 2, 0.399 g of the preparation particles obtained in Production Example 3, 0.012 g of magnesium aluminate metasilicate, The powder obtained by adding the sweetener and the fragrance and mixing the mixture was filled in the packaging material to obtain the intended solid preparation containing ibuprofen and ethenzamide.
　（比較例１）
　製造例１で得られた製剤粒子５７０ｇをヒプロメロース６８ｇ及びタルク４６ｇを精製水１１５０ｇに溶解・分散させたコーティング液を用いて実施例１と同様の手法によりフィルム層で被覆された製剤粒子６３０ｇ（被覆量：対製剤粒子１０％）を製造した。得られた製剤粒子０．４２ｇに製造例２で得られた顆粒０．３９７ｇ、製造例３で得られた製剤粒子０．３９９ｇ、メタケイ酸アルミン酸マグネシウム０．０１２ｇ、甘味料及び香料を加え混合した粉体を包材に充填し、イブプロフェン及びエテンザミド含有固形製剤を得た。 (Comparative Example 1)
630 g of formulation particles coated with a film layer in the same manner as in Example 1 using a coating solution obtained by dissolving and dispersing 570 g of the formulation particles obtained in Production Example 1 in 68 g of hypromellose and 46 g of talc in 1150 g of purified water Amount: 10% of formulation particles). Add 0.397 g of the granules obtained in Preparation Example 2, 0.399 g of the preparation particles obtained in Preparation Example 3, 0.012 g of magnesium aluminate metasilicate, sweeteners and flavors to 0.42 g of the resulting preparation particles and mix. The powder was filled into a packaging material to obtain a solid preparation containing ibuprofen and ethenzamide.
　（比較例２）
　製造例１で得られた製剤粒子０．３８ｇ、製造例２で得られた製剤粒子０．３９７ｇ、製造例３で得られた製剤粒子０．３９９ｇ、メタケイ酸アルミン酸マグネシウム０．０３６ｇ，甘味料及び香料を混合した粉体を包材に充填し、イブプロフェン及びエテンザミド含有固形製剤を得た。 (Comparative Example 2)
0.38 g of preparation particles obtained in Production Example 1, 0.397 g of preparation particles obtained in Production Example 2, 0.399 g of preparation particles obtained in Production Example 3, 0.036 g of magnesium aluminate metasilicate, sweetener The powder mixed with the fragrance was filled in the packaging material to obtain a solid preparation containing ibuprofen and ethenzamide.
　（比較例３）
　製造例１で得られた製剤粒子０．３８ｇ、製造例２で得られた製剤粒子０．３９７ｇ、製造例３で得られた製剤粒子０．３９９ｇ、軽質無水ケイ酸０．０３６ｇ、甘味料及び香料を混合した粉体を包材に充填し、イブプロフェン及びエテンザミド含有固形製剤を得た。 (Comparative Example 3)
0.38 g of the preparation particles obtained in Production Example 1, 0.397 g of the preparation particles obtained in Production Example 2, 0.399 g of the preparation particles obtained in Production Example 3, 0.036 g of light anhydrous silicic acid, The powder mixed with the fragrance was filled in the packaging material to obtain a solid preparation containing ibuprofen and ethenzamide.
　（試験例１）
［評価方法］
　被験製剤を４０℃７５％ＲＨの条件下に３カ月間保存した後、日本薬局方一般試験法粒度試験法に基づき篩分けし、製剤粒子の固結・凝集の状態を観察した。 (Test Example 1)
[Evaluation methods]
The test preparation was stored for 3 months under conditions of 40 ° C. and 75% RH, and then sieved based on the Japanese Pharmacopoeia General Test Method Particle Size Test Method, and the state of solidification / aggregation of the preparation particles was observed.
［結果］
　結果を表１に示す。 [result]
The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１から明らかな通り、フィルムコーティングを行わなかった製剤粒子からなる固形製剤（比較例２及び３）では製剤粒子の凝集による粗大粒子が多量に発生したのに対し、フィルムコーティングを行い、フィルム層で被覆されたイブプロフェン含有製剤粒子を含む固形製剤（実施例１、２及び比較例１）では粗大粒子の発生が抑制され、中でもＰＶＡ（実施例１）及びＰＶＡコポリマー（実施例２）を含むフィルム層で被覆されたイブプロフェン含有製剤粒子を含む固形製剤では凝集の発生がほとんど認められなかった。 As apparent from Table 1, solid preparations (Comparative Examples 2 and 3) composed of preparation particles that were not subjected to film coating produced a large amount of coarse particles due to aggregation of the preparation particles, whereas film coating was performed to form a film layer. In the solid preparations containing ibuprofen-containing preparation particles coated with (Examples 1 and 2 and Comparative Example 1), the generation of coarse particles is suppressed, and in particular, a film containing PVA (Example 1) and PVA copolymer (Example 2) In the solid preparation containing ibuprofen-containing preparation particles coated with a layer, almost no aggregation was observed.
　本発明により、イブプロフェン及びエテンザミドを配合した固形製剤を散剤や顆粒剤等としても提供することが可能となったので、従来の二重錠や多層錠に加えてバリエーションが広がり、消費者（患者）のニーズにより的確に対応できるようになった。 According to the present invention, it has become possible to provide a solid preparation containing ibuprofen and etenzamide as a powder or granule, so that in addition to conventional double tablets and multilayer tablets, variations have been widened, and consumers (patients) Can now respond more accurately to the needs of

Claims (3)

  1. 　イブプロフェンとエテンザミドが異なる製剤粒子中に配合され、イブプロフェンを含有する製剤粒子がポリビニルアルコール又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含有するフィルム層で被覆されていることを特徴とするイブプロフェン及びエテンザミド含有固形製剤。 Ibuprofen and etenzamide are blended in different pharmaceutical particles, and the pharmaceutical particles containing ibuprofen are coated with a film layer containing polyvinyl alcohol or a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. And ethenamide-containing solid preparations.
  2. 　フィルム層中のポリビニルアルコール又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の含有量が、イブプロフェンの１質量部に対して０．０４～０．４質量部である請求項１に記載のイブプロフェン及びエテンザミド含有固形製剤。 The ibuprofen according to claim 1, wherein the content of polyvinyl alcohol or polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in the film layer is 0.04 to 0.4 parts by mass with respect to 1 part by mass of ibuprofen. And ethenamide-containing solid preparations.
  3. 　固形製剤が散剤、顆粒剤、微粒剤又はカプセル剤である請求項１又は２に記載のイブプロフェン及びエテンザミド含有固形製剤。 The solid preparation containing ibuprofen and ethenzamide according to claim 1 or 2, wherein the solid preparation is a powder, granule, fine granule or capsule.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017066134A (en) * 2015-09-29 2017-04-06 大正製薬株式会社 Solid preparation
JP2018538374A (en) * 2015-10-02 2018-12-27 ディーエスエム アイピー アセッツ ビー．ブイ．Ｄｓｍ Ｉｐ Ａｓｓｅｔｓ Ｂ．Ｖ． New coating system
JP2019178173A (en) * 2014-11-05 2019-10-17 日本酢ビ・ポバール株式会社 Film coating composition, oral solid preparation and method for producing the same

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61134315A (en) * 1984-12-05 1986-06-21 Taisho Pharmaceut Co Ltd Antipyretic and analgesic agent
JPH06329556A (en) * 1993-05-20 1994-11-29 Japan Tobacco Inc Method for preventing blending incompatibility in powder and solid agent
JP2002316928A (en) * 2001-04-17 2002-10-31 Lion Corp Coated tablet and method for preventing peeling of coated tablet
JP2004231546A (en) * 2003-01-29 2004-08-19 Taisho Pharmaceut Co Ltd Antipyretic analgesic composition
JP2009007295A (en) * 2007-06-28 2009-01-15 Kowa Co Solid preparation suppressing ibuprofen sublimation
JP2009269874A (en) * 2008-05-09 2009-11-19 Daido Kasei Kogyo Kk Aqueous liquid preparation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61134315A (en) * 1984-12-05 1986-06-21 Taisho Pharmaceut Co Ltd Antipyretic and analgesic agent
JPH06329556A (en) * 1993-05-20 1994-11-29 Japan Tobacco Inc Method for preventing blending incompatibility in powder and solid agent
JP2002316928A (en) * 2001-04-17 2002-10-31 Lion Corp Coated tablet and method for preventing peeling of coated tablet
JP2004231546A (en) * 2003-01-29 2004-08-19 Taisho Pharmaceut Co Ltd Antipyretic analgesic composition
JP2009007295A (en) * 2007-06-28 2009-01-15 Kowa Co Solid preparation suppressing ibuprofen sublimation
JP2009269874A (en) * 2008-05-09 2009-11-19 Daido Kasei Kogyo Kk Aqueous liquid preparation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019178173A (en) * 2014-11-05 2019-10-17 日本酢ビ・ポバール株式会社 Film coating composition, oral solid preparation and method for producing the same
US11020353B2 (en) 2014-11-05 2021-06-01 Japan Vam & Poval Co., Ltd. Film coating composition, solid oral formulation, and method for producing the same
JP2022048272A (en) * 2014-11-05 2022-03-25 日本酢ビ・ポバール株式会社 Film coating composition, oral solid preparation and method for producing the same
JP7062618B2 (en) 2014-11-05 2022-05-06 日本酢ビ・ポバール株式会社 Film coating composition and oral solid preparation and method for producing the same
JP2017066134A (en) * 2015-09-29 2017-04-06 大正製薬株式会社 Solid preparation
JP2018538374A (en) * 2015-10-02 2018-12-27 ディーエスエム アイピー アセッツ ビー．ブイ．Ｄｓｍ Ｉｐ Ａｓｓｅｔｓ Ｂ．Ｖ． New coating system
US10982113B2 (en) 2015-10-02 2021-04-20 Dsm Ip Assets B.V. Coating system

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