WO2013018766A1 - Composition pharmaceutique stable - Google Patents

Composition pharmaceutique stable Download PDF

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Publication number
WO2013018766A1
WO2013018766A1 PCT/JP2012/069354 JP2012069354W WO2013018766A1 WO 2013018766 A1 WO2013018766 A1 WO 2013018766A1 JP 2012069354 W JP2012069354 W JP 2012069354W WO 2013018766 A1 WO2013018766 A1 WO 2013018766A1
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WIPO (PCT)
Prior art keywords
parts
mass
loxoprofen
salt
butyl scopolamine
Prior art date
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PCT/JP2012/069354
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English (en)
Japanese (ja)
Inventor
俊樹 薄井
Original Assignee
興和株式会社
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Application filed by 興和株式会社 filed Critical 興和株式会社
Priority to JP2013526914A priority Critical patent/JP6010538B2/ja
Publication of WO2013018766A1 publication Critical patent/WO2013018766A1/fr

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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
    • A61K31/33—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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a stable pharmaceutical composition. More specifically, it relates to a stable pharmaceutical composition containing loxoprofen or a salt thereof and butyl scopolamine bromide.
  • Loxoprofen is a type of non-steroidal anti-inflammatory analgesic (NSAID), including rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, cervical-shoulder arm syndrome, toothache, acute upper respiratory inflammation, post-surgical / post-traumatic It is known as effective for anti-inflammatory, analgesic and antipyretic after tooth extraction (Non-patent Document 1).
  • NSAID non-steroidal anti-inflammatory analgesic
  • Loxoprofen is a compound that has recently been converted to so-called switch OTC, and is expected as an active ingredient in OTC pharmaceuticals.
  • loxoprofen is also a kind of NSAID, and as a side effect, there is a possibility that disorders due to increased gastrointestinal motility may occur. Therefore, it has been proposed to take butyl scopolamine bromide with analgesic / antispasmodic action together with loxoprofen from the viewpoint of taking side-effect reduction measures while obtaining sufficient antipyretic analgesic effect, and contains loxoprofen sodium and butyl scopolamine bromide As a preparation, a capsule containing these two components is known (Patent Document 1).
  • Patent Document 1 there is no mention of how loxoprofen sodium and butyl scopolamine bromide are blended in the capsule, and there is no study on the stability of such a capsule. It has not been. Thus, at present, the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide has not been studied so far.
  • an object of the present invention is to provide a stable pharmaceutical composition containing loxoprofen or a salt thereof and butyl scopolamine bromide.
  • the present inventor has eagerly studied the storage stability of a pharmaceutical composition containing loxoprofen or a salt thereof and butyl scopolamine bromide in order to solve the above-mentioned problems. It was clarified that the interaction caused by this was the cause of the storage stability problem. Then, this inventor discovered that the said interaction could be suppressed by making a pharmaceutical composition contain so that a loxoprofen or its salt, and butyl scopolamine bromide may not contact substantially.
  • the present invention provides a pharmaceutical composition containing loxoprofen or a salt thereof and butyl scopolamine bromide so as not to substantially contact each other.
  • the present invention also provides a pharmaceutical composition comprising a granule containing loxoprofen or a salt thereof and butyl scopolamine bromide, wherein loxoprofen or a salt thereof and butyl scopolamine bromide are contained so as not to substantially contact each other. It is to provide.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a granular material containing butyl scopolamine bromide and loxoprofen or a salt thereof, wherein loxoprofen or a salt thereof and butyl scopolamine bromide are contained so as not to substantially contact each other. It is to provide.
  • the present invention includes a granule containing loxoprofen or a salt thereof and a granule containing butyl scopolamine bromide, wherein loxoprofen or a salt thereof and butyl scopolamine bromide are contained so as not to substantially contact each other.
  • a pharmaceutical composition is provided.
  • a pharmaceutical composition that not only reduces or suppresses damage caused by increased gastrointestinal motility, which is a side effect of loxoprofen, but also has excellent storage stability.
  • the pharmaceutical composition of the present invention contains loxoprofen or a salt thereof and butyl scopolamine bromide. First, these components will be described.
  • Loxoprofen or a salt thereof used in the pharmaceutical composition of the present invention includes loxoprofen itself, a pharmaceutically acceptable salt of loxoprofen, and further a solvation of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol or the like. Things are also included. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).
  • the content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriately examining the dose per day according to the sex, age, symptoms, etc. of the user.
  • the amount that can be taken 10 to 300 mg of loxoprofen or a salt thereof is preferable, more preferably 30 to 240 mg, more preferably 60 to 180 mg per day.
  • the daily dose may be divided into 1 to 4 doses, and preferably 3 divided doses.
  • 60 mg of loxoprofen sodium anhydride is preferable.
  • the content of loxoprofen or a salt thereof is preferably 0.4 to 90% by mass, and 1.2 to 75% by mass in terms of anhydrous loxoprofen sodium, based on the total mass of the pharmaceutical composition. Is more preferably 3 to 50% by mass, still more preferably 5 to 47% by mass.
  • the butyl scopolamine bromide used in the pharmaceutical composition of the present invention is a known compound, and can be produced by a known method or commercially available.
  • the content of butyl scopolamine bromide in the pharmaceutical composition of the present invention may be determined by appropriately examining the daily dose according to the sex, age, symptoms, etc. of the user.
  • the amount of scopolamine bromide is preferably 3 to 1000 mg, more preferably 5 to 500 mg, and even more preferably 30 to 100 mg per day.
  • the daily dose may be divided into 1 to 5 doses, and preferably 3 divided doses.
  • the dose per dose is preferably 10 to 20 mg at a time, more preferably 10 mg and 20 mg as butyl scopolamine bromide.
  • the content ratio of loxoprofen or a salt thereof and butyl scopolamine bromide contained in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the daily dose of each component described above.
  • Those containing 05 to 10 parts by mass are more preferred, those containing 0.05 to 1 part by mass are more preferred, and those containing 0.1 to 0.5 parts by mass are particularly preferred.
  • the content of butyl scopolamine bromide is preferably 1 to 10% by mass, more preferably 2 to 9% by mass, and more preferably 3 to 8% by mass with respect to the total mass of the pharmaceutical composition. Is more preferable.
  • the present invention it has been found for the first time that an interaction is caused by contact of loxoprofen or a salt thereof and butylscopolamine bromide in a pharmaceutical composition. Based on this finding, the interaction between the two components is improved by containing loxoprofen or a salt thereof and butyl scopolamine bromide so as not to substantially contact in the pharmaceutical composition. That is, the pharmaceutical composition of the present invention contains loxoprofen or a salt thereof and butyl scopolamine bromide so that the loxoprofen or a salt thereof and butyl scopolamine bromide do not substantially contact each other in the pharmaceutical composition.
  • the phrase “containing so as not to substantially contact each other” means containing in a pharmaceutical composition such that loxoprofen or a salt thereof and butyl scopolamine bromide do not come into contact with each other to the extent that they do not exhibit an interaction.
  • the pharmaceutical composition of the present invention can be formulated into various dosage forms by using known formulation additives according to known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
  • the dosage form according to the pharmaceutical composition of the present invention is not particularly limited, but a solid preparation containing loxoprofen or a salt thereof and butyl scopolamine bromide is preferable from the viewpoint of ease of administration, management of drug dosage, and the like.
  • solid preparations include, for example, tablets (orally disintegrating tablets, chewable tablets, dispersible tablets, dissolving tablets; including oral tablets such as lozenges, sublingual tablets, buccal tablets, adhesive tablets, and gums)
  • oral preparations such as capsules, pills, granules, fine granules, powders, dry syrups, oral jelly preparations, and the like which are orally administered are preferable.
  • the pharmaceutical composition of the present invention may be coated with a sugar coating, a film coating or the like by a known method.
  • the embodiment of the pharmaceutical composition of the present invention will be described in more detail by taking a solid preparation as an example.
  • the solid preparation of the present invention includes (A) loxoprofen or a salt thereof, or a solid composition containing loxoprofen or a salt thereof, and (B) a solid composition containing butyl scopolamine bromide itself or butyl scopolamine bromide.
  • a solid composition containing butyl scopolamine bromide itself or butyl scopolamine bromide is mentioned.
  • These solid compositions are in the form of powder, granules, tablets, and the like.
  • loxoprofen or a salt thereof and butyl scopolamine bromide is granulated by an appropriate method to form a granular material, and the other loxoprofen or a salt thereof or butyl scopolamine bromide is blended without granulation.
  • Loxoprofen or a salt thereof and butyl scopolamine bromide are separately granulated by an appropriate method to form a granular material, and a powder or granule prepared by blending these, and the granular material by an appropriate method. Coated formulation.
  • the xanthine derivative etc. which are mentioned later may be contained in either one of the granular materials or in both granular materials, or may be formulated separately from these granular materials.
  • the multi-layer tablet is preferably one in which loxoprofen or a salt thereof and butyl scopolamine bromide are located in different layers, and the multi-layer tablet having three or more layers includes a layer containing loxoprofen or a salt thereof and a layer containing butyl scopolamine bromide. Those positioned so as not to contact each other are more preferable.
  • the granular material manufactured by said (I) and (II) can be used as a loxoprofen or its salt, and a butyl scopolamine bromide.
  • the xanthine derivative and the like described later may be located in either the layer containing loxoprofen or a salt thereof, the layer containing butyl scopolamine bromide, or in both layers.
  • a preparation prepared such that loxoprofen or a salt thereof and butyl scopolamine bromide do not substantially contact each other when the dosage form is a tablet, it is called a sugar-coated tablet or a film-coated tablet).
  • Granules in the above (I) and (II) are known granulations such as extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, crushed granulation, melt granulation, etc. Depending on the method, it may be prepared using appropriate formulation additives.
  • any of the granular material containing loxoprofen or a salt thereof and the granular material containing butyl scopolamine bromide may be produced by the same granulation method or by different granulation methods. It may be.
  • the granule containing loxoprofen or a salt thereof can be produced by granulating by an appropriate method based on a known method.
  • Ponaperto (registered trademark) 10% fine granules, 10% Lingelies (Registered Trademark) manufactured by Yoshindo Co., Ltd., 10% Loxonin (Registered Trademark) manufactured by Daiichi Sankyo Co., Ltd., Lolfenamin (Registered Trademark) manufactured by Nichi-Iko Co., Ltd. Commercially available products such as 10% can be used.
  • xanthine derivatives tranexamic acid or a salt thereof, a silicate compound, a carbonic acid
  • xanthine derivatives tranexamic acid or a salt thereof
  • silicate compound a silicate compound
  • carbonic acid One or more selected from the group consisting of compounds, phosphate compounds, hydroxides, metal oxides, cellulose derivatives or salts thereof and oils and fats (in the present specification, these are collectively referred to as xanthine derivatives, etc.) Can also be suppressed.
  • the pharmaceutical composition containing these xanthine derivatives etc. is also mentioned as an aspect of this invention.
  • Loxoprofen or a salt thereof, butyl scopolamine bromide, xanthine derivative, etc., and either loxoprofen or a salt thereof and butyl scopolamine bromide are granulated by an appropriate method to form a granular material, and the other loxoprofen or Powders and granules prepared by blending the salt or butyl scopolamine bromide without granulation, and preparations in which the granules are further coated by an appropriate method.
  • the xanthine derivative or the like may be contained in the granular material, or may be contained separately from the granular material.
  • V A multi-layer tablet produced using loxoprofen or a salt thereof, butyl scopolamine bromide and xanthine derivatives, etc. so that loxoprofen or a salt thereof and butyl scopolamine bromide are not substantially in contact with each other, and the multi-layer tablet by an appropriate method. Coated formulation.
  • the multi-layer tablet is preferably one in which loxoprofen or a salt thereof and butyl scopolamine bromide are located in different layers, and the multi-layer tablet having three or more layers includes a layer containing loxoprofen or a salt thereof and a layer containing butyl scopolamine bromide. Those positioned so as not to contact each other are more preferable.
  • the granular material manufactured by said (i) and (ii) can be used as a loxoprofen or its salt, and a butyl scopolamine bromide.
  • the xanthine derivative or the like may be located in either the layer containing loxoprofen or a salt thereof, the layer containing butyl scopolamine bromide, or may be located in both layers. Moreover, you may locate in the intermediate
  • Loxoprofen or a salt thereof, butyl scopolamine bromide and xanthine derivatives, etc., and either loxoprofen or a salt thereof and butyl scopolamine bromide are arranged in a core tablet (also referred to as a core tablet or a central tablet), and loxoprofen or a salt thereof And a nucleated tablet produced so that butylscopolamine bromide does not substantially contact each other, and a preparation in which the nucleated tablet is further coated by an appropriate method.
  • the granular material manufactured by said (i) and (ii) can be used as a loxoprofen or its salt, and a butyl scopolamine bromide.
  • the xanthine derivative or the like may be positioned in the core tablet, may be positioned in the outer shell, or may be separately positioned in either the core tablet or the outer shell.
  • Loxoprofen or a salt thereof, butyl scopolamine bromide and xanthine derivative, etc. are used, and instead of the granular material of (i) or (ii) above, either or both of loxoprofen or a salt thereof and butyl scopolamine bromide is ⁇ -
  • a preparation using an inclusion compound which is included by cyclodextrins such as cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin.
  • the xanthine derivative or the like may be located in the vicinity of either one of the clathrate compounds, or may be located in the vicinity of both clathrate compounds.
  • the xanthine derivative or the like may be located in a preparation prepared by a usual method, may be located in a sugar coating layer or a film coating layer, and separately located in either a sugar coating layer or a film coating layer. Further, it may be located in any of the sugar coating layer and the film coating layer in the preparation.
  • xanthine derivatives and the like that is, “consisting of“ xanthine derivative, tranexamic acid or its salt, silicic acid compound, carbonic acid compound, phosphoric acid compound, hydroxide, metal oxide, cellulose derivative or its salt and fats and oils ”
  • xanthine derivative tranexamic acid or its salt, silicic acid compound, carbonic acid compound, phosphoric acid compound, hydroxide, metal oxide, cellulose derivative or its salt and fats and oils
  • xanthine derivative used in the pharmaceutical composition of the present invention a compound represented by the following general formula (I) is preferable.
  • R 1 and R 2 each independently represent a hydrogen atom or a methyl group.
  • R 3 represents a hydrogen atom, a methyl group, a monohydroxypropyl group or a dihydroxypropyl group.
  • the monohydroxypropyl group is preferably a 2-hydroxypropyl group.
  • the dihydroxypropyl group is preferably a 2,3-dihydroxypropyl group.
  • R 1 is a methyl group, R 2 is a methyl group, and R 3 is a methyl group means caffeine.
  • R 1 is a methyl group, R 2 is a methyl group, and R 3 is a hydrogen atom means theophylline.
  • R 1 is a hydrogen atom, R 2 is a methyl group, and R 3 is a methyl group means theobromine.
  • R 1 is a methyl group, R 2 is a hydrogen atom, and R 3 is a methyl group means paraxanthine.
  • a compound in which R 1 is a methyl group, R 2 is a methyl group, and R 3 is a 2-hydroxypropyl group means proxyphylline.
  • R 1 is a methyl group, R 2 is a methyl group, and R 3 is a 2,3-dihydroxypropyl group means a diprofylline.
  • the compounds of the general formula (I), especially the above-mentioned compounds are known, and in the present invention, commercially available products can be used in addition to those produced by known methods.
  • the caffeine and theophylline those in which a double salt is formed (sodium benzoate caffeine (double salt of sodium benzoate and caffeine), aminophylline (double salt of theophylline and ethylenediamine)) or the like may be used. it can.
  • the xanthine derivative used in the pharmaceutical composition of the present invention caffeine is preferable from the viewpoint of using the pharmaceutical composition of the present invention as an antipyretic analgesic or a general cold medicine.
  • Specific examples of the caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine and caffeine citrate. Among these, caffeine hydrate, anhydrous caffeine, and sodium benzoate caffeine are more preferable.
  • the content of the xanthine derivative is appropriately determined based on the interaction inhibitory effect of loxoprofen or a salt thereof and butyl scopolamine bromide and the daily dose according to the sex, age, symptom, etc. of the user.
  • the amount that can be taken 10 to 1000 mg per day is preferred, the amount that can be taken 20 to 800 mg is more preferred, and the amount that can be taken 40 to 600 mg is even more preferred.
  • the content of the xanthine derivative is preferably 2 to 90% by mass, more preferably 10 to 85% by mass, further preferably 20 to 80% by mass, and further preferably 20 to 50% by mass with respect to the total mass of the pharmaceutical composition.
  • the content ratio of loxoprofen or a salt thereof and a xanthine derivative may be determined by appropriate examination according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen sodium)
  • the amount of xanthine derivative is preferably 0.03 to 100 parts by mass, more preferably 0.08 to 27 parts by mass, and 0.2 to 10 parts by mass of xanthine derivatives. More preferred are those containing 0.2 to 5 parts by mass.
  • Tranexamic acid or a salt thereof used in the pharmaceutical composition of the present invention includes tranexamic acid itself, a pharmaceutically acceptable salt of tranexamic acid, and further, tranexamic acid or a pharmaceutically acceptable salt thereof, water, alcohol, etc. And solvates thereof. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • tranexamic acid or a salt thereof tranexamic acid is preferable from the viewpoint of using the pharmaceutical composition of the present invention as an antipyretic analgesic, a general cold medicine, or the like, and Japanese Pharmacopoeia tranexamic acid is preferable.
  • the content of tranexamic acid or a salt thereof is one day according to the inhibitory effect on the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide, the sex, age, and symptoms of the user.
  • the dose may be determined by appropriate examination according to the dose per dose, but it is preferably an amount that can be taken from 50 to 2000 mg in terms of free form of tranexamic acid, more preferably an amount that can be taken from 70 to 750 mg, and an amount that can be taken from 400 to 750 mg. Is more preferable.
  • the content of tranexamic acid or a salt thereof is preferably 10 to 95% by mass, more preferably 30 to 85% by mass, further preferably 40 to 80% by mass, and more preferably 40 to 70% by mass with respect to the total mass of the pharmaceutical composition. % Is particularly preferred. Further, the content ratio of loxoprofen or a salt thereof and tranexamic acid or a salt thereof may be appropriately determined and determined according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof.
  • tranexamic acid or a salt thereof is preferably contained in an amount of 0.1 to 200 parts by mass in terms of a free form of tranexamic acid, more preferably 0.2 to 25 parts by mass.
  • the content is preferably 2 to 12.5 parts by mass, more preferably 2 to 5 parts by mass.
  • silicate compound used in the pharmaceutical composition of the present invention examples include silicate compounds and salts of silicate compounds.
  • a salt of such a silicic acid compound an inorganic salt is preferable.
  • the inorganic salt include metal salts, and examples of the metal constituting such metal ions include alkaline earth metals such as magnesium and calcium; alkali metals such as sodium; and group 13 metals such as aluminum.
  • Specific examples of the silicate compound as described above include synthetic aluminum silicate, hydrous magnesium silicate, hydrous magnesium silicate (natural), synthetic sodium magnesium silicate, hydrous silicon dioxide, magnesium aluminate silicate, calcium silicate.
  • hydrous silicic acid compounds such as hydrous silicon dioxide, hydrous magnesium silicate, hydrous magnesium silicate (natural) or salts thereof; light anhydrous silicic acid such as light anhydrous silicic acid or salts thereof; Silicic acid such as silicon dioxide, calcium silicate, magnesium aluminate silicate and magnesium aluminate metasilicate or a salt thereof is preferred.
  • a salt of a hydrous silicate compound, light anhydrous silicic acid, and a silicate are more preferable.
  • the content of the silicate compound is determined based on the inhibitory effect of the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide, and the daily dose according to the sex, age, and symptoms of the user. Depending on the situation, it may be determined by appropriate examination. For example, the amount of the silicic acid compound that can be taken from 1 to 1500 mg per day is preferred, the amount that can be taken from 5 to 1000 mg is more preferred, and the amount that can be taken from 10 to 500 mg is even more preferred.
  • the content of the silicate compound is preferably 0.05 to 80% by mass, more preferably 0.1 to 60% by mass, and still more preferably 0.2 to 55% by mass with respect to the total mass of the pharmaceutical composition. 0.2 to 35% by mass is more preferable, and 0.2 to 5% by mass is particularly preferable.
  • the content ratio of loxoprofen or a salt thereof and a silicate compound may be determined by appropriate examination according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen) Those containing 0.003 to 150 parts by mass of a silicic acid compound, more preferably 0.02 to 35 parts by mass, and 0.04 to 10 parts by mass in terms of sodium anhydride) Are more preferable, and those containing 0.04 to 1 part by mass are more preferable.
  • the carbonate compound used in the pharmaceutical composition of the present invention includes potassium carbonate, magnesium carbonate, aluminum hydroxide / magnesium carbonate mixed dried gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, calcium carbonate, precipitated carbonate Calcium, sodium hydrogen carbonate, sodium hydrogen carbonate hydrate, potassium hydrogen carbonate, aluminum hydroxide / sodium hydrogen carbonate coprecipitation products, etc., including carbonate compounds, using bandit bones, stone decision, oysters, etc. Also good. These are known compounds and the like, and can be produced by known methods or commercially available products.
  • salts composed of metal ions such as alkali metals (sodium, potassium, etc.) and alkaline earth metals (magnesium, calcium, etc.) and carbonate ions or hydrogen carbonate ions, and hydrates of such salts
  • metal ions such as alkali metals (sodium, potassium, etc.) and alkaline earth metals (magnesium, calcium, etc.) and carbonate ions or hydrogen carbonate ions
  • hydrates of such salts A coprecipitation product is preferable, and a salt composed of alkaline earth metal ions and carbonate ions or a coprecipitation product thereof is more preferable.
  • the content of the carbonic acid compound is not particularly limited, and the effect of suppressing the interaction between loxoprofen or a salt thereof and butylscopolamine bromide and the sex, age, and symptoms of the user per day It may be determined by appropriate examination according to the dose.
  • the amount that can be taken 1 to 1500 mg of carbonic acid compound per day is preferable, the amount that can be taken 5 to 1000 mg is more preferable, and the amount that can be taken 10 to 500 mg is more preferable.
  • the content of the carbonic acid compound is preferably 0.05 to 80% by mass, more preferably 0.1 to 60% by mass, and still more preferably 0.2 to 55% by mass with respect to the total mass of the pharmaceutical composition.
  • the content ratio of loxoprofen or a salt thereof and a carbonic acid compound may be appropriately determined and determined according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen sodium)
  • the amount of carbonic acid compound is preferably 0.003 to 150 parts by weight, more preferably 0.02 to 35 parts by weight, and more preferably 0.05 to 10 parts by weight. preferable.
  • Examples of the phosphoric acid compound used in the pharmaceutical composition of the present invention include metal ions such as alkali metals (sodium, potassium, etc.) and alkaline earth metals (magnesium, calcium, etc.), phosphate ions, phosphoric acid (one). Examples thereof include salts composed of hydrogen ions, dihydrogen phosphate ions, glycerophosphate ions or pyrophosphate ions, and hydrates of such salts.
  • Such phosphoric acid compounds include calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, tetrasodium pyrophosphate, trisodium phosphate, sodium hydrogen phosphate hydrate, anhydrous sodium pyrophosphate, anhydrous phosphoric acid Examples thereof include sodium hydrogen and calcium glycerophosphate, and bandit bones and oysters containing a phosphate compound may be used. These are known compounds and the like, and can be produced by known methods or commercially available products.
  • a salt composed of alkaline earth metal ions and hydrogen phosphate ions is preferable.
  • the content of the phosphoric acid compound is determined by the daily dose according to the inhibitory effect on the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide, the sex, age, and symptoms of the user. Depending on the situation, it may be determined by appropriate examination.
  • the amount that can be taken 1 to 1500 mg of carbonic acid compound per day is preferable, the amount that can be taken 5 to 1000 mg is more preferable, and the amount that can be taken 10 to 500 mg is more preferable.
  • the content of the phosphoric acid compound is preferably 0.05 to 80% by mass, more preferably 0.1 to 60% by mass, further preferably 0.2 to 55% by mass, based on the total mass of the pharmaceutical composition.
  • the content ratio of loxoprofen or a salt thereof and a phosphoric acid compound may be appropriately determined and determined according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen) Those containing 0.003 to 150 parts by mass of a phosphoric acid compound, more preferably 0.02 to 35 parts by mass, and 0.05 to 10 parts by mass with respect to sodium anhydride Are more preferable, and those containing 0.1 to 1 part by mass are particularly preferable.
  • hydroxide used in the pharmaceutical composition of the present invention examples include dihydroxyaluminum aminoacetate (aluminum glycinate), magnesium magnesium hydroxide, aluminum hydroxide, aluminum hydroxide gel, sodium hydroxide, magnesium hydroxide, dried Aluminum hydroxide, dry aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium hydroxide / Examples include a coprecipitation product of potassium aluminum sulfate. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • a salt composed of a metal ion and a hydroxide ion, a coprecipitation product of such a salt, and a (dry) gel are preferable.
  • the metal include alkali metals (sodium, potassium, etc.); alkaline earth metals (magnesium, calcium, etc.); Group 13 metals (aluminum, etc.), and alkaline earth metals are preferred.
  • the content of hydroxide depends on the daily dose according to the inhibitory effect of the interaction between loxoprofen or its salt and butyl scopolamine bromide and the sex, age, symptoms, etc. of the user. Therefore, it may be determined after appropriate consideration.
  • the amount that can be taken 1 to 1500 mg of hydroxide per day is preferable, the amount that can be taken 5 to 1000 mg is more preferable, and the amount that can be taken 10 to 500 mg is more preferable.
  • the content of the hydroxide is preferably 0.05 to 80% by mass, more preferably 0.1 to 60% by mass, and further preferably 0.2 to 55% by mass with respect to the total mass of the pharmaceutical composition.
  • the content ratio of loxoprofen or a salt thereof and a hydroxide may be determined by appropriate examination according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen) Those containing 0.003 to 150 parts by weight of hydroxide, more preferably 0.02 to 35 parts by weight, more preferably 0.05 to 10 parts by weight based on sodium anhydride Is more preferable.
  • the metal in the metal oxide used in the pharmaceutical composition of the present invention is preferably an alkaline earth metal (magnesium, calcium, etc.), a transition metal (titanium, iron, etc.), a group 13 metal (aluminum, etc.), and the like.
  • alkaline earth metal magnesium, calcium, etc.
  • transition metal titanium, iron, etc.
  • group 13 metal aluminum, etc.
  • the metal oxide composed of the above metals include aluminum oxide, magnesium oxide, titanium oxide, yellow iron sesquioxide, brown iron oxide, black iron oxide, iron sesquioxide, and synthetic hydrotalcite. These are known compounds and can be produced by a known method or commercially available.
  • the content of the metal oxide depends on the daily dose according to the inhibitory effect of the interaction between loxoprofen or its salt and butyl scopolamine bromide and the sex, age, and symptoms of the user. Therefore, it may be determined after appropriate consideration.
  • the amount that can be taken 0.01 to 800 mg of metal oxide per day is preferred, the amount that can be taken 0.1 to 600 mg is more preferred, and the amount that can be taken 1 to 400 mg is more preferred.
  • the content of the metal oxide is preferably 0.0002 to 80% by mass, more preferably 0.002 to 60% by mass, and further preferably 0.02 to 55% by mass with respect to the total mass of the pharmaceutical composition.
  • the content ratio of loxoprofen or a salt thereof and a metal oxide may be determined by appropriate examination according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen)
  • the amount of the metal oxide is preferably 0.00003 to 80 parts by mass, more preferably 0.0004 to 20 parts by mass, and 0.005 to 7 parts by mass in terms of sodium anhydride Is more preferable.
  • Cellulose derivatives or salts thereof used in the pharmaceutical composition of the present invention include cellulose itself, etherified hydroxy groups in cellulose, etherified cellulose esters, cross-linked polymers thereof and salts thereof, etc. Is mentioned.
  • Examples of such salts include metal salts such as alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, etc.).
  • cellulose such as crystalline cellulose and powdered cellulose
  • carboxyalkyl cellulose such as carmellose, carmellose potassium, carmellose calcium, and carmellose sodium or a salt thereof
  • a carboxyalkyl cellulose derivative such as croscarmellose sodium or a salt thereof
  • Hydroxyalkyl celluloses such as hydroxyethyl cellulose, low substituted hydroxypropyl cellulose, (not low substituted) hydroxypropyl cellulose; hydroxyalkylalkyl celluloses such as hypromellose (hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, etc.); Hydroxypropyl methylcellulose acetate succinate, etc.
  • the carbon number of the alkyl group in the carboxyalkyl cellulose, carboxyalkyl cellulose derivative, hydroxyalkyl cellulose, hydroxyalkylalkyl cellulose, and hydroxyalkylalkylcellulose derivative is preferably 1 to 4. These are known compounds and can be produced by a known method or commercially available.
  • cellulose, carboxyalkyl cellulose or salt thereof, carboxyalkyl cellulose derivative or salt thereof, hydroxyalkyl cellulose, hydroxyalkylalkyl cellulose are preferred, hydroxyalkyl cellulose, hydroxyalkylalkyl cellulose are more preferred, Low-substituted hydroxypropylcellulose and hypromellose are more preferable.
  • the official documents include Japanese Pharmacopoeia, US Pharmacopoeia, British Pharmacopoeia, European Pharmacopoeia, Chinese Pharmacopoeia and so on. In Japan, Japanese pharmacopoeia, low-substituted hydroxypropyl cellulose, and Japanese pharmacopoeia hypromellose are particularly preferred.
  • the degree of substitution of the hydroxypropoxy group of the low-substituted hydroxypropylcellulose is preferably 3 to 35%, more preferably 5 to 16%. Further, the substitution degree of the methoxy group in the hypromellose is preferably 15 to 35%, more preferably 16.5 to 30%. On the other hand, the substitution degree of the hydroxypropoxy group is preferably 3 to 35%, more preferably 4 to 32%.
  • the content of the cellulose derivative or a salt thereof is determined based on the interaction inhibitory effect of loxoprofen or a salt thereof and butyl scopolamine bromide, the sex, age, symptoms, etc. of the user. It may be determined by appropriate examination according to the dose.
  • the amount that can be taken 1 to 1500 mg of cellulose derivative or a salt per day is preferred, the amount that can be taken 5 to 1000 mg is more preferred, and the amount that can be taken 10 to 500 mg is more preferred.
  • the content of the cellulose derivative or a salt thereof is preferably 0.05 to 90% by mass, more preferably 0.1 to 80% by mass, and further preferably 0.2 to 60% by mass with respect to the total mass of the pharmaceutical composition. 5 to 55% by mass is preferable. Further, the content ratio of loxoprofen or a salt thereof and a cellulose derivative or a salt thereof may be determined by appropriate examination according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof.
  • the amount of cellulose derivative or salt thereof is preferably 0.003 to 150 parts by weight, more preferably 0.02 to 35 parts by weight, more preferably 0.05 to 10 parts by weight (in terms of loxoprofen sodium anhydrate). Those containing parts are more preferred.
  • Examples of the fats and oils used in the pharmaceutical composition of the present invention include waxes, hardened oil, hardened soybean oil and the like.
  • waxes include plant-derived waxes such as carnauba wax, wood wax (goose wax, urushi wax), and castor wax; animal-derived waxes such as beeswax, white beeswax, whale wax, and purified lanolin; and petroleum-derived waxes such as paraffin and microcrystalline wax. Natural waxes such as montanic acid ester wax and purified montan wax, synthetic waxes, and the like. Fats and oils are known compounds, and can be produced by known methods, and commercially available products can be used. Among the oils and fats as described above, carnauba wax, castor wax, beeswax, beeswax wax, paraffin, synthetic wax, hardened oil, and hardened soybean oil are preferable.
  • the content of fats and oils depends on the daily dose according to the inhibitory effect of the interaction between loxoprofen or a salt thereof and butylscopolamine bromide, the sex, age, symptoms, etc. of the user, What is necessary is just to consider and decide suitably.
  • the amount that can be taken 0.1 to 1000 mg of fats and oils per day is preferred, the amount that can be taken 0.5 to 600 mg is more preferred, and the amount that can be taken 1 to 300 mg is more preferred.
  • the content of the fats and oils is preferably 0.001 to 70% by mass, more preferably 0.01 to 60% by mass, and still more preferably 0.1 to 55% by mass with respect to the total mass of the pharmaceutical composition.
  • the content ratio of loxoprofen or a salt thereof and fats and oils may be appropriately determined and determined according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen sodium) (In terms of non-hydrate) the fats and oils are preferably contained in an amount of 0.0003 to 100 parts by weight, more preferably 0.002 to 20 parts by weight, and further preferably 0.005 to 5 parts by weight. preferable.
  • those other than capsules containing 60 mg of loxoprofen sodium, 10 mg of butyl scopolamine bromide, appropriate amount of crystalline cellulose, 10 mg of calcium carboxymethylcellulose and 1 mg of magnesium stearate and having a total mass of 150 mg are preferable.
  • the pharmaceutical composition of the present invention includes drugs other than loxoprofen or a salt thereof and butylscopolamine bromide, such as antipyretic analgesics, antihistamines, antitussives, noscapine, bronchodilators, expectorants, hypnotic sedatives, vitamins, antiseptics It may contain one or more selected from the group consisting of inflammatory agents, gastric mucosal protective agents, anticholinergic agents, herbal medicines, Kampo prescriptions and the like.
  • antipyretic analgesics examples include aspirin, aspirin aluminum, ibuprofen, isopropylantipyrine, ethenzamide, sazapyrine, salicylamide, sodium salicylate, thiaramide hydrochloride, lactylphenetidine and the like.
  • Antihistamines include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, clemastine fumarate.
  • Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, codeine phosphate, dihydrocodeine phosphate, dibutarate sodium, dimemorphan Examples thereof include phosphate, dextromethorphan hydrobromide, dextromethorphan / phenol phthaline salt, tipepidine citrate, and tipepidine hibenzate.
  • noscapine examples include noscapine hydrochloride and noscapine.
  • bronchodilators examples include trimethquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, dl -Methylephedrine saccharin salt, methoxyphenamine hydrochloride and the like.
  • ambroxol hydrochloride ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, methylcysteine hydrochloride,
  • examples thereof include l-menthol and lysozyme hydrochloride.
  • the hypnotic sedative include allyl isopropyl acetyl urea and bromvalerylurea.
  • vitamins examples include vitamin B 1 , vitamin B 2 , vitamin B 5 , vitamin B 6 , vitamin B 12 , vitamin C, hesperidin and derivatives thereof and salts thereof (for example, thiamine, thiamine chloride hydrochloride, thiamine).
  • Nitrates dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisbutiamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate Esters, riboflavin butyrate, sodium riboflavin phosphate, panthenol, panthetin, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobara Min, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).
  • anti-inflammatory agent examples include glycyrrhizic acid and derivatives thereof and salts thereof (for example, dipotassium glycyrrhizinate and monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, proctase, pronase, bromelain and the like.
  • gastric mucosa protective agent examples include aminoacetic acid, aldioxa, gefarnate, sucralfate, cetraxate hydrochloride, sofalcone, teprenone, copper chlorophyllin potassium, copper chlorophyllin sodium, methylmethionine sulfonium chloride and the like.
  • anticholinergic agent examples include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipedium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl- l-hyostiamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodide isopropamide, diphenylpiperidinomethyldioxolane iodide, funnel extract, funnel root, funnel root total alkaloid Examples include acid salts.
  • Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyoukaku (horny lamb), fennel (yuka), turmeric (depressed gold), engosaku (yenkogyo), enmaiso (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Oubak (yellow twilight), Spruce (cherry skin), Auren (yellow ream), Onji (distant), Gajutsu (we), Ganoderma (deer herb), Chamomile, Caronin (Karojin), Licorice (licorice), Kyo-kyo (kikyo), Kyo-nin (Kyojin), Kukoshi (coconut), Kuko-yo (Kashiwa), Keihi (Kinko), Ketsumeishi (Katsumeko), Gentiana, Gennoshouko (current evidence), Koubushi (Katsuk
  • Kampo prescriptions include, for example, Kakkon-yu, Katsue-yu, Koso-san, Saiko-Kei-do, Sho-saiko-to, Shosei-ryu, Mumon-tou-yu, Hanka-kopaku-to, Mao-to, and the like.
  • the pharmaceutical composition of the present invention contains loxoprofen or a salt thereof and butyl scopolamine bromide, from the viewpoint of being used as an antipyretic analgesic or the like, as a drug other than loxoprofen or a salt thereof and butyl scopolamine bromide, isopropyl Drugs such as antipyretic analgesics such as antipyrine and etenzamid, and gastric mucosa protective agents such as methylmethioninesulfonium chloride are preferred.
  • the pharmaceutical composition of the present invention is preferably used as an antipyretic analgesic or the like.
  • the pharmaceutical composition of the present invention is in a packaging form that prevents intrusion of liquid or solid foreign matters in a normal handling or storage state.
  • the packaging form include bottle packaging, SP packaging (Stripe Package) packaging, PTP (Press Through Package) packaging, and stick packaging.
  • Test Example 1 Examination of interaction (1) Loxoprofen sodium hydrate 204.3 parts by mass and butyl scopolamine bromide 30 parts by mass were mixed, put in a glass bottle and stored at 60 ° C. (Reference Example A). As comparative controls, loxoprofen sodium hydrate alone (Control Example 1) and butyl scopolamine bromide alone (Control Example 2) were similarly placed in glass bottles and stored at 60 ° C. About these reference examples A and control examples 1 and 2, the state in the glass bottle immediately after the start of storage, one day later, two days later and one week later was evaluated. The results are shown in Table 1.
  • Reference Example B Loxoprofen sodium hydrate 204.3 parts by mass and butyl scopolamine bromide 30 parts by mass were mixed to obtain a composition.
  • Reference Example 1 204.3 parts by mass of loxoprofen sodium hydrate, 30 parts by mass of butyl scopolamine bromide and 250 parts by mass of anhydrous caffeine were mixed to obtain a composition.
  • Reference Example 2 A composition was obtained in the same manner as in Reference Example 1 except that caffeine anhydride was changed to 750 parts by mass of tranexamic acid.
  • Reference Example 3 A composition was obtained in the same manner as in Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of magnesium aluminate silicate.
  • Reference Example 4 A composition was obtained in the same manner as in Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of magnesium aluminate metasilicate.
  • Reference Example 5 A composition was obtained in the same manner as Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of calcium silicate.
  • Reference Example 6 A composition was obtained in the same manner as in Reference Example 1 except that the anhydrous caffeine was replaced with 234.3 parts by weight of light anhydrous silicic acid.
  • Reference Example 7 A composition was obtained in the same manner as in Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of hydrous magnesium silicate (natural).
  • Reference Example 8 A composition was obtained in the same manner as Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of precipitated calcium carbonate.
  • Reference Example 9 A composition was obtained in the same manner as in Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of anhydrous calcium hydrogen phosphate.
  • Reference Example 10 A composition was obtained in the same manner as Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of magnesium hydroxide.
  • Reference Example 11 A composition was obtained in the same manner as in Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of magnesium oxide.
  • Reference Example 12 A composition was obtained in the same manner as in Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of titanium oxide.
  • Reference Example 13 A composition was obtained in the same manner as in Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of low-substituted hydroxypropylcellulose.
  • Reference Example 14 A composition was obtained in the same manner as in Reference Example 1, except that anhydrous caffeine was replaced with 234.3 parts by mass of hypromellose (hydroxypropylmethylcellulose 2910).
  • Reference Example 15 A composition was obtained in the same manner as in Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by weight of Carnauba wax.
  • Reference Example 16 A composition was obtained in the same manner as in Reference Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of hydrogenated oil.
  • the compositions of Reference Example B and Reference Examples 1 to 16 the conditions in the glass bottles immediately after the start of storage, 1 day, 2 days, and 1 week were evaluated. The results are shown in Table 2.
  • the interaction that occurs between loxoprofen or a salt thereof and butyl scopolamine bromide can be converted into a xanthine derivative, tranexamic acid or a salt thereof, a silicic acid compound, a carbonic acid compound, a phosphoric acid compound, a hydroxide, a metal oxide, a cellulose derivative or a salt thereof. And oils and fats were found to be suppressed.
  • Comparative Example 1 Loxoprofen sodium hydrate 68.1 parts by mass, 29.2 parts by mass of macrogol 6000, corn starch 24.3 parts by mass and butyl scopolamine bromide 10 parts by mass were mixed.
  • Example 1 68.1 parts by weight of loxoprofen sodium hydrate, 29.2 parts by weight of macrogol 6000 and 24.3 parts by weight of corn starch were stirred in a glass beaker on a 65 ° C water bath and then cooled. Thereafter, the mixture was sieved with a No. 18 sieve to obtain a granulated product.
  • the granulated product thus obtained was mixed with 10 parts by weight of butyl scopolamine bromide to obtain a granular preparation. And about the composition of the said Example 1 and the comparative example 1, the state in the glass bottle immediately after a storage start, 1 day, 2 days later, and 1 week after was evaluated, respectively. The results are shown in Table 3.
  • granulation was performed to obtain a granulated product. 32.4 parts by mass of talc was added to and mixed with the two types of granules obtained to obtain granules for tableting. The obtained granules for tableting were tableted to obtain tablets capable of taking 204.3 mg of loxoprofen sodium hydrate and 30 mg of butyl scopolamine bromide per day.
  • the mixture was kneaded and granulated, and then granulated to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
  • the obtained granules for tableting were tableted to obtain tablets capable of taking 204.3 mg of loxoprofen sodium hydrate and 30 mg of butyl scopolamine bromide per day.
  • butyl scopolamine bromide 180 parts by mass of allyl isopropyl acetyl urea, 100 parts by mass of magnesium aluminate metasilicate, 16.2 parts by mass of hydroxypropyl cellulose, 24.3 parts by mass of low-substituted hydroxypropyl cellulose and 95 of crystalline cellulose .2 parts by mass was mixed, kneaded with ethanol, granulated, and then granulated to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting. The obtained granules for tableting were tableted to obtain tablets capable of taking 204.3 mg of loxoprofen sodium hydrate and 30 mg of butyl scopolamine bromide per day.
  • Production Example 12 23.1 parts by mass of hypromellose and 0.9 part by mass of macrogol 6000 are dissolved in 240 parts by mass of purified water, and 0.3 parts by mass of titanium oxide and 5.7 parts by mass of talc are dispersed therein to form a film coating solution.
  • a film coating solution was prepared.
  • the above-mentioned film coating solution was sprayed and coated to have a film layer of 10 mg per tablet (plain tablet) obtained in Production Examples 1 to 11.
  • glazing was applied with carnauba wax (trace amount), and film-coated tablets were obtained for each of the tablets obtained in Production Examples 1 to 11.
  • Production Example 18 10 parts by weight of butyl scopolamine bromide, 24.3 parts by weight of hydroxypropyl cellulose, 81 parts by weight of carmellose calcium and 618.5 parts by weight of crystalline cellulose are mixed, kneaded with purified water, granulated, and then granulated. To obtain a granulated product. After mixing 733.8 parts by mass of the obtained granulated product, 68.1 parts by mass of loxoprofen sodium hydrate and 8.1 parts by mass of magnesium stearate, the mixture was tableted to give 204. loxoprofen sodium hydrate per day. The tablet which can take 3 mg and 30 mg of butyl scopolamine bromide was obtained.
  • Production Example 19 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hydroxypropylcellulose, 40.5 parts by mass of carmellose calcium and 280.2 parts by mass of crystalline cellulose, they were kneaded with purified water, After granulation, the granules were sized to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hydroxypropyl cellulose, 40.5 parts by mass of carmellose calcium and 338.3 parts by mass of crystalline cellulose were mixed, kneaded using purified water, and granulated. Thereafter, the mixture was sized to obtain a granulated product.
  • Production Example 37 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 180.2 parts by mass of lactose hydrate and 100 parts by mass of crystalline cellulose, purified water is used. After kneading and granulating, granulation was performed to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 238.3 parts by mass of lactose hydrate, and 100 parts by mass of crystalline cellulose were mixed and then purified using purified water.
  • Production Example 38 Purification after mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of low-substituted hydroxypropylcellulose, 180.2 parts by mass of lactose hydrate and 100 parts by mass of crystalline cellulose After kneading with water and granulating, granulation was performed to obtain a granulated product. Also, after mixing 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of low-substituted hydroxypropylcellulose, 238.3 parts by mass of lactose hydrate and 100 parts by mass of crystalline cellulose, purified water is added.
  • the mixture was kneaded and granulated, and then granulated to obtain a granulated product.
  • tableting was performed, and 204.3 mg of loxoprofen sodium hydrate per day, and butyl scopolamine bromide were added.
  • dosed 30 mg was obtained.
  • Production Example 39 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of crospovidone, 180.2 parts by mass of lactose hydrate and 100 parts by mass of crystalline cellulose, purified water is used. After kneading and granulating, granulation was performed to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of crospovidone, 238.3 parts by mass of lactose hydrate and 100 parts by mass of crystalline cellulose were mixed and then kneaded using purified water.
  • Production Example 40 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium and 280.2 parts by mass of anhydrous calcium hydrogen phosphate, kneading with purified water, After granulation, the granules were sized to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium and 338.3 parts by mass of anhydrous calcium hydrogen phosphate were mixed and then kneaded using purified water, and granulated. And then granulated to obtain a granulated product.
  • the mixture was kneaded with purified water, granulated, and then granulated to obtain a granulated product.
  • tableting was performed, and 204.3 mg of loxoprofen sodium hydrate per day, and butyl scopolamine bromide were added.
  • dosed 30 mg was obtained.
  • Production Example 42 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of magnesium silicate, 150.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose. The mixture was kneaded with purified water, granulated, and then granulated to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of magnesium silicate, 208.3 parts by mass of corn starch and 100 parts by mass of crystalline cellulose were purified.
  • the granules were sized to obtain a granulated product.
  • tableting was performed, and 204.3 mg of loxoprofen sodium hydrate per day, and butyl scopolamine bromide were added. The tablet which can be taken
  • Production Example 43 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of magnesium oxide, 150.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose, After kneading and granulating with purified water, granulation was performed to obtain a granulated product.
  • Production Example 44 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of magnesium hydroxide, 150.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose. The mixture was kneaded with purified water, granulated, and then granulated to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of magnesium hydroxide, 208.3 parts by mass of corn starch and 100 parts by mass of crystalline cellulose were purified.
  • Production Example 45 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of precipitated calcium carbonate, 150.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose. The mixture was kneaded with purified water, granulated, and then granulated to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of precipitated calcium carbonate, 208.3 parts by mass of corn starch and 100 parts by mass of crystalline cellulose were purified.
  • the mixture was kneaded with purified water, granulated, and then granulated to obtain a granulated product.
  • tableting was performed, and 204.3 mg of loxoprofen sodium hydrate per day, and butyl scopolamine bromide were added.
  • dosed 30 mg was obtained.
  • Production Example 47 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of hydrous silicon dioxide, 150.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose. The mixture was kneaded with purified water, granulated, and then granulated to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of hydrous silicon dioxide, 208.3 parts by mass of corn starch and 100 parts by mass of crystalline cellulose were purified.
  • Production Example 48 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of calcium silicate, 150.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose. The mixture was kneaded with purified water, granulated, and then granulated to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 30 parts by mass of calcium silicate, 208.3 parts by mass of corn starch and 100 parts by mass of crystalline cellulose were purified.
  • Production Example 50 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 10 parts by mass of hardened oil, 170.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose, After kneading and granulating with purified water, granulation was performed to obtain a granulated product.
  • Production Example 51 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 10 parts by mass of titanium oxide, 170.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose, After kneading and granulating with purified water, granulation was performed to obtain a granulated product.
  • Production Example 52 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 180.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose, the mixture is purified using purified water. After granulation, granulation was performed to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 238.3 parts by mass of corn starch and 100 parts by mass of crystalline cellulose were mixed and then kneaded using purified water.
  • the granules were sized to obtain a granulated product. 400.9 parts by mass and 8.2 parts by mass of talc were mixed with each of the obtained two types of granulated products, and then tableted. 204.3 mg of loxoprofen sodium hydrate and 30 mg of butyl scopolamine bromide were taken per day. Tablets that can be obtained.
  • Production Example 53 After mixing 68.1 parts by mass of loxoprofen sodium hydrate, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 180.2 parts by mass of corn starch and 100 parts by mass of crystalline cellulose, the mixture is purified using purified water. After granulation, granulation was performed to obtain a granulated product. Further, 10 parts by mass of butyl scopolamine bromide, 12.1 parts by mass of hypromellose, 40.5 parts by mass of carmellose calcium, 238.3 parts by mass of corn starch and 100 parts by mass of crystalline cellulose were mixed and then kneaded using purified water.
  • the granules were sized to obtain a granulated product. After mixing 400.9 parts by mass, 5.2 parts by mass of magnesium stearate and 3 parts by mass of carnauba wax, the obtained two types of granulated products were tableted, and 204.3 mg of loxoprofen sodium hydrate per day was mixed. The tablet which can take 30 mg of butyl scopolamine bromide was obtained.
  • Production Example 54 A film coating solution is prepared by dissolving 23.1 parts by mass of hypromellose and 0.9 part by mass of macrogol 6000 in 240 parts by mass of purified water, and dispersing 0.3 parts by mass of titanium oxide and 5.7 parts by mass of talc. Was prepared. Using the coating apparatus, the above-mentioned film coating solution was sprayed and coated to have a film layer of 10 mg per tablet (plain tablet) obtained in Production Examples 13 to 53. Subsequently, glazing was applied with carnauba wax (trace amount), and film-coated tablets were obtained for each of the tablets obtained in Production Examples 13 to 53.
  • a pharmaceutical composition comprising loxoprofen or a salt thereof and butyl scopolamine bromide having excellent storage stability can be provided.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • Pain & Pain Management (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique stable contenant du loxoprofène ou un sel de celui-ci et du bromure de butylscopolamine. Le loxoprofrène ou un sel de celui-ci et le bromure de butylscopolamine qui sont contenus dans la composition pharmaceutique n'entrent substantiellement pas en contact l'un avec l'autre.
PCT/JP2012/069354 2011-07-29 2012-07-30 Composition pharmaceutique stable WO2013018766A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014058491A (ja) * 2012-09-19 2014-04-03 Fuji Capsule Kk 医薬品組成物
EP2939666A1 (fr) * 2014-04-29 2015-11-04 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations pharmaceutiques de loxoprophène

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62242616A (ja) * 1986-04-14 1987-10-23 Sankyo Co Ltd ロキソプロフエン・ナトリウム含有製剤
JP2004002454A (ja) * 1998-05-06 2004-01-08 Kowa Co 消化管運動抑制剤
JP4787912B2 (ja) * 2010-01-29 2011-10-05 興和株式会社 ロキソプロフェン含有医薬組成物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000026313A (ja) * 1998-05-06 2000-01-25 Hokuriku Seiyaku Co Ltd 消化管運動抑制剤
JP2011116750A (ja) * 2009-10-30 2011-06-16 Kowa Co ロキソプロフェン含有医薬組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62242616A (ja) * 1986-04-14 1987-10-23 Sankyo Co Ltd ロキソプロフエン・ナトリウム含有製剤
JP2004002454A (ja) * 1998-05-06 2004-01-08 Kowa Co 消化管運動抑制剤
JP4787912B2 (ja) * 2010-01-29 2011-10-05 興和株式会社 ロキソプロフェン含有医薬組成物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014058491A (ja) * 2012-09-19 2014-04-03 Fuji Capsule Kk 医薬品組成物
EP2939666A1 (fr) * 2014-04-29 2015-11-04 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations pharmaceutiques de loxoprophène
WO2015165847A1 (fr) * 2014-04-29 2015-11-05 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulations pharmaceutiques du loxoprofène

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