WO2013018765A1 - Pharmaceutical composition containing loxoprofen - Google Patents

Pharmaceutical composition containing loxoprofen Download PDF

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Publication number
WO2013018765A1
WO2013018765A1 PCT/JP2012/069353 JP2012069353W WO2013018765A1 WO 2013018765 A1 WO2013018765 A1 WO 2013018765A1 JP 2012069353 W JP2012069353 W JP 2012069353W WO 2013018765 A1 WO2013018765 A1 WO 2013018765A1
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salt
trade name
manufactured
magnesium
group
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PCT/JP2012/069353
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French (fr)
Japanese (ja)
Inventor
俊樹 薄井
政明 春原
雅哉 高宮
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興和株式会社
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Priority to JP2013526913A priority Critical patent/JP6008857B2/en
Publication of WO2013018765A1 publication Critical patent/WO2013018765A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K9/1611—Inorganic compounds
    • 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
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01017—Lysozyme (3.2.1.17)

Definitions

  • the present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof.
  • 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), and its excellent antipyretic analgesic action is expected to be incorporated into a general cold medicine, antipyretic analgesic, and the like.
  • NSAID non-steroidal anti-inflammatory analgesic
  • antipyretic analgesics in addition to antipyretic analgesic components, antihistamine component, expectorant component, anti-inflammatory enzyme component, antitussive component, central nervous excitable component, hypnotic sedative component, antiacetylcholine component, anti Various combinations of ingredients such as plasmin ingredients and herbal medicine ingredients are blended.
  • chlorpheniramine or a salt thereof; clemastine or a salt thereof; carbinoxamine or a salt thereof; diphenylpyraline or a salt thereof, etc. It is used in various pharmaceuticals such as pharmaceuticals (Non-Patent Documents 2 to 5). Of the above, chlorpheniramine has the following formula:
  • clemastine has the following formula:
  • Carbinoxamine has the following formula:
  • diphenylpyraline has the following formula:
  • the expectorant component examples include bromhexine or a salt thereof; ambroxol or a salt thereof; phenol derivative such as guaiacol sulfonic acid or a salt thereof, guaifenesin, cresolsulfonic acid or a salt thereof, or the like.
  • bromhexine has the following formula:
  • Non-patent Document 6 It has the expectorant action based on the viscosity adjustment action to dilute mucus by promoting secretion of the respiratory tract mucosa, and is approved as a switch OTC drug, used for general cold medicine, and for medical use It is used for expectoration such as acute and chronic bronchitis and pneumoconiosis (Non-patent Document 6).
  • Ambroxol has the following formula:
  • Non-patent Document 7 Is known as an active metabolite of the above bromhexine, which is an expectorant component, and is also called a mucosal lubricating component. In addition to being approved as a switch OTC drug and used for general cold medicine, it is used for expectoration of acute and chronic bronchitis, pneumoconiosis, etc. for medical use (Non-patent Document 7).
  • phenol derivatives or salts thereof such as guaiacol sulfonic acid or its salt, guaifenesin, cresol sulfonic acid or its salt are components having airway secretion promoting action and the like (Non-patent Document 8).
  • anti-inflammatory enzyme component examples include lysozyme or a salt thereof. These have mucopolysaccharide decomposing action, anti-inflammatory action, etc. In addition to comprehensive cold medicine, antitussive expectorant and rhinitis oral medicine, in anticipation of mucopolysaccharide decomposing action to decompose sputum and nasal pus mucus and anti-inflammatory action (Non-patent document 9).
  • the antitussive component examples include codeines; ephedrines; dextromethorphan or a salt thereof.
  • codeines are known to be narcotic antitussive components having an antitussive action by suppressing the function of the cough center. And based on this effect
  • ephedrines are known to have an antitussive effect by bronchodilating action based on sympathomimetic action.
  • Non-patent Documents 11 and 12 dextromethorphan or a salt thereof is a central non-narcotic antitussive component, and is known to exhibit an antitussive action by acting directly on the cough center and suppressing the cough reflex. And based on this effect
  • central nervous excitatory components include xanthine derivatives such as caffeine.
  • Caffeine exhibits central excitatory action, cardiotonic / diuretic action, gastric acid secretion enhancing action, smooth muscle relaxing action, etc., and is a drug used for antipyretic analgesics, antitussive expectorants, etc. in addition to general cold medicine (Non-patent Document 13) ).
  • other xanthine derivatives such as theophylline, paraxanthine, theobromine, aminophylline, diprofylline, and proxyphylline having a structure similar to caffeine have pharmacological effects similar to caffeine.
  • Theophylline exhibits central excitatory action, cardiotonic / diuretic action, smooth muscle relaxing action, etc., and is a drug used for antitussive expectorant, antipruritics and the like.
  • Aminophylline is a double salt of theophylline and ethylenediamine, and exhibits the same action as theophylline, and diprofylline also exhibits the same action as theophylline (Non-patent Document 14).
  • Proxyphyrin also shows the same action as theophylline (Non-patent Document 15), and paraxanthine and theobromine show the same action.
  • hypnotic sedative component examples include isovaleryl urea derivatives such as bromovalerylurea and allylisopropylacetylurea.
  • bromvalerylurea has the following formula:
  • Allyl isopropyl acetyl urea is represented by the following formula:
  • Non-patent Document 16 It is a compound represented by these. All of these isovaleryl urea derivatives have a sedative effect and are drugs that are blended in antipyretic analgesics and the like.
  • anti-acetylcholine component examples include drip extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, funnel extract, methyl scopolamine or a salt thereof, tropane alkaloids such as butyl scopolamine or a salt thereof, ), As well as general cold medicine for the purpose of analgesia and antispasmodic action.
  • Patent Document 1 includes (1) one or more selected from clemastines, phenylamines, carbinoxamine maleate, ephedrines, codeines, phenylpropanolamine hydrochloride, serrapeptase, lysozyme chloride, and bromhexine hydrochloride.
  • a pharmaceutical composition and (2) a pharmaceutical composition containing loxoprofen as an active ingredient is described, and this document enhances analgesic action by combining with carbinoxamine maleate, chlorpheniramine maleate or phenylpropanolamine hydrochloride Action; potentiation of anti-inflammatory action by combining with dihydrocodeine phosphate, carbinoxamine maleate or bromohexine hydrochloride; enhancement of antipyretic action by combining with carbinoxamine maleate or lysozyme chloride Use; and potentiation of anti-histamine action it has been disclosed by be combined with clemastine fumarate or d- chlorpheniramine maleate.
  • Patent Document 2 describes a composition for cold and rhinitis comprising at least one selected from the group consisting of (a) loxoprofen and (b) an antiallergic agent and an antihistamine, An effect of improving nasal congestion by combining with carbinoxamine maleate or chlorpheniramine maleate is disclosed.
  • Patent Document 3 describes a composition for colds containing an expectorant and loxoprofen or a salt thereof, and enhances the effect on cough symptoms by combining with bromhexine hydrochloride or ambroxol. The effect is disclosed.
  • Patent Document 4 describes a pharmaceutical composition containing loxoprofen and ambroxol or bromhexine to suppress expectoration or airway goblet cell hyperplasia, which is combined with ambroxol hydrochloride or bromhexine hydrochloride. It is disclosed that a goblet cell hyperplasia inhibitory action is expressed.
  • Patent Document 5 describes a pharmaceutical composition for antitussive or expectorant containing loxoprofen, and one or more selected from caffeine, ephedrine and codeine, and contains codeine phosphate or anhydrous Expression of goblet cell hyperplasia inhibitory action by combining with caffeine is disclosed.
  • Patent Document 6 describes an inhibitor against gastrointestinal motility-promoting action caused by a nonsteroidal anti-inflammatory agent, which contains a quaternary ammonium anticholinergic agent as an active ingredient.
  • Loxoprofen and butylscopolamine Capsules containing bromide are disclosed.
  • Patent Document 7 describes a pharmaceutical composition containing at least one selected from the group consisting of belladonna alkaloids, belladonna total alkaloids and belladonna extracts and loxoprofen or a salt thereof, and in combination with belladonna alkaloids, etc. It is disclosed that gastrointestinal disorders caused by loxoprofen or a salt thereof are reduced / suppressed.
  • X represents a single bond or an oxygen atom
  • Y represents a methine group or a nitrogen atom
  • R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group
  • R 2 has a substituent.
  • R 3 represents a hydrogen atom or a halogen atom.
  • a salt thereof 2 represented by the following general formula (2), including bromhexine or a salt thereof, ambroxol or a salt thereof
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom or a hydroxyl group.
  • a salt thereof 3 including guaiacolsulfonic acid or a salt thereof, guaifenesin, cresolsulfonic acid or a salt thereof, and the like.
  • R 6 represents an alkyl group or an alkoxy group which may have a substituent
  • R 7 represents a hydrogen atom or a sulfo group.
  • the phenolic hydroxyl group in Formula (3) may be etherified.
  • a salt thereof 4 lysozyme or a salt thereof 5 codeine 6 ephedrine 7 dextromethorphan or a salt 8 xanthine derivative 9 isovaleryl urea derivative 10 tropane alkaloids (in the present specification, from 1 to 10 above) (One or more selected components may be referred to as “interactive components”.)
  • an object of the present invention is to provide a pharmaceutical composition in which the interaction between loxoprofen or a salt thereof and the interactive component is suppressed.
  • the present inventors further studied to solve this problem, and as a result, the interaction was suppressed by allowing loxoprofen or a salt thereof and the interactive component to coexist with a basic compound having acid neutralizing ability. As a result, the present invention was completed.
  • the present invention includes the following components (A), (B) and (C): (A) Loxoprofen or a salt thereof (B) One or more selected from the group consisting of the following components (B-1) to (B-10) (B-1)
  • X represents a single bond or an oxygen atom
  • Y represents a methine group or a nitrogen atom
  • R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group
  • R 2 has a substituent.
  • R 3 represents a hydrogen atom or a halogen atom.
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom or a hydroxyl group.
  • R 6 represents an alkyl group or an alkoxy group which may have a substituent
  • R 7 represents a hydrogen atom or a sulfo group.
  • the phenolic hydroxyl group in Formula (3) may be etherified.
  • B-4) Lysozyme or its salt B-5) Codeine (B-6) Ephedrine (B-7) Dextromethorphan or its salt (B-8)
  • Xanthine derivative B-9) Isovaleryl urea derivative (B-10)
  • a tropane alkaloid (C) A pharmaceutical composition containing a basic compound having an acid neutralizing ability is provided.
  • the interaction between loxoprofen or a salt thereof and an interactive component can be suppressed. Therefore, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and an interactive component having excellent storage stability. In addition, a pharmaceutical composition containing loxoprofen or a salt thereof and an interactive component, in which interaction is suppressed, can be provided easily and inexpensively without going through complicated steps.
  • Component (A) of the present invention is loxoprofen or a salt thereof.
  • “loxoprofen or a salt thereof” includes not only loxoprofen itself but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol or the like. It is. 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 is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, 10 to 300 mg, more preferably 30 to 240 mg, particularly preferably 60 to 180 mg in terms of loxoprofen sodium anhydride can be contained per day.
  • loxoprofen or a salt thereof is preferably contained in an amount of 0.4 to 50% by mass in terms of anhydrous loxoprofen sodium, more preferably 1.2 to 30% by mass, based on the total mass of the pharmaceutical composition.
  • the content is 1.2 to 25% by mass.
  • the content is preferably 1.2 to 20% by mass, more preferably 2.4 to 15% by mass, and particularly preferably 2.4 to 12% by mass.
  • X represents a single bond or an oxygen atom
  • Y represents a methine group or a nitrogen atom
  • R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group
  • R 2 has a substituent.
  • R 3 represents a hydrogen atom or a halogen atom.
  • a pharmaceutically acceptable salt of the compound represented by the general formula (1) is also included.
  • the compound represented by the general formula (1) or a salt thereof include, for example, a compound represented by the general formula (1), an inorganic acid salt or an organic acid salt of the compound represented by the general formula (1) (for example, hydrochloride, maleate, fumarate, diphenyl disulfonate, theocrate, salicylate, tannate, besylate, phosphate, etc.).
  • a compound represented by the general formula (1) for example, hydrochloride, maleate, fumarate, diphenyl disulfonate, theocrate, salicylate, tannate, besylate, phosphate, etc.
  • an asymmetric carbon when an asymmetric carbon exists, it has various optical isomers. Or a mixture of various optical isomers.
  • the compound represented by the general formula (1) or a salt thereof may be in the form of a solvate, and a solvate of the compound represented by the general formula (1) or a salt thereof with water, alcohol or the like. Are also included in the “compound represented by the general formula (1) or a salt thereof”.
  • the alkyl group is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, and a methyl group is preferable. Further, as the R 1, a hydrogen atom, preferably an alkyl group, a hydrogen atom, more preferably a methyl group.
  • the “cyclic amino group” in the cyclic amino group which may have a substituent is a 5- to 7-membered member having at least one, preferably 1 or 2, nitrogen atoms as ring-constituting atoms.
  • An alicyclic group is meant.
  • Specific examples of such cyclic amino groups include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, and homopiperazinyl groups.
  • a piperidinyl group, a piperazinyl group, and a homopiperazinyl group are preferable, and a piperidinyl group and a piperazinyl group are more preferable.
  • Examples of the “substituent” in the cyclic amino group which may have a substituent include, for example, an alkylbenzoyl group, a 1,3-dihydro-2H-benzimidazol-2-one-1-yl group, and a carboxyalkoxy group.
  • Examples thereof include an alkyl group which may be substituted with one or more groups selected from a group, a carboxyl group, a carboxyalkylphenyl group and a hydroxyl group.
  • an alkyl group, a carboxyalkoxyalkyl group, and a carboxyalkylphenyl (hydroxy) alkyl group are preferable.
  • substituted examples include, for example, methyl group, 3- (4-tert-butylbenzoyl) propyl group, 3- (1,3-dihydro-2H-benzimidazol-2-one-1-yl ) Propyl group, 2- (carboxymethoxy) ethyl group, 4- [4- (2-carboxypropan-2-yl) phenyl] -4-hydroxybutyl group, 3-carboxypropyl group and the like.
  • the “optionally substituted cyclic amino group” includes a 1-methylpiperidin-4-yl group, a 4-methylhomopiperazin-1-yl group, 1- [3- (4 -Tert-butylbenzoyl) propyl] piperidin-4-yl group, 4- [3- (1,3-dihydro-2H-benzoimidazol-2-one-1-yl) propyl] piperazin-1-yl group, 4 -[2- (carboxymethoxy) ethyl] piperazin-1-yl group, 1- ⁇ 4- [4- (2-carboxypropan-2-yl) phenyl] -4-hydroxybutyl ⁇ piperidin-4-yl group, The 1- (3-carboxypropyl) piperidin-4-yl group is preferred.
  • the “aminoalkyl group” in the aminoalkyl group which may have a substituent is an amino group, a monoalkylamino group, a dialkylamino group or a cyclic amino group (the “cyclic amino group” is the above The same as the “cyclic amino group” in the “cyclic amino group which may have a substituent”.
  • an alkyl group substituted with a dialkylamino group or a cyclic amino group is preferable.
  • the cyclic amino group is preferably a pyrrolidinyl group.
  • aminoalkyl groups include 2- (dimethylamino) ethyl group, 2- (pyrrolidin-2-yl) ethyl group, 2-[(isopropyl) (methyl) amino] ethyl group, and the like. Is mentioned.
  • substituent examples include a hydroxyl group, a phenyl group, and an alkyl group.
  • the “optionally substituted aminoalkyl group” includes 2- (dimethylamino) ethyl group, 2- (1-methylpyrrolidin-2-yl) ethyl group, 2-[( A methyl) (1-phenyl-1-hydroxypropan-2-yl) amino] ethyl group is preferred.
  • alkyl group moiety in the “alkyl group” “alkylbenzoyl group”, “carboxyalkylphenyl group”, “aminoalkyl group”, “monoalkylamino group”, “dialkylamino group”,
  • alkyl group having 1 to 6 carbon atoms is preferable, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
  • the alkoxy group moiety in the “carboxyalkoxy group” is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, and a propoxy group. , Butoxy group, pentyloxy group, hexyloxy group and the like.
  • examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the present invention, a chlorine atom is preferable.
  • the substitution position on the phenyl group of R 3 is not particularly limited, but substitution at the 4-position is preferable.
  • X is a single bond
  • Y is a nitrogen atom
  • R 1 is a hydrogen atom
  • R 2 is an aminoalkyl group which may have a substituent
  • R 3 is a halogen atom.
  • X is an oxygen atom
  • Y is a methine group
  • R 1 is an alkyl group
  • R 2 is an aminoalkyl group which may have a substituent
  • R 3 is a halogen atom
  • X is an oxygen atom
  • Y is a nitrogen atom
  • R 1 is a hydrogen atom
  • R 2 is an aminoalkyl group which may have a substituent
  • R 3 is a halogen atom
  • Iv X is an oxygen atom
  • Y is a methine group
  • R 1 is a hydrogen atom
  • R 2 is an optionally substituted cyclic amino group
  • R 3 is hydrogen
  • a compound having a diarylmethyl structure as a common skeleton thereof specifically, for example, ebastine or a salt thereof; oxatomide or a salt thereof; Carbinoxamine such as diphenyldisulfonate and carbinoxamine maleate or a salt thereof; clemastine or a salt thereof such as clemastine fumarate; chlorpheny such as d-chlorpheniramine maleate and dl-chlorpheniramine maleate Lamin or a salt thereof; Dipheterol or a salt thereof such as dipheterol hydrochloride or dipheterol phosphate; Diphenylpyrine or a salt thereof such as diphenylpyraline hydrochloride or diphenylpyraline theocrate; Diphenhydramine hydrochloride, diphenhydramine salicylate, diph Diphenhydramine or its salt such as hydramine tannate
  • the content of the compound represented by the general formula (1) or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. .
  • it contains 0.01 to 400 mg, more preferably 0.03 to 300 mg, particularly preferably 0.1 to 200 mg of a compound represented by the general formula (1) or a salt thereof per day. It can be shown.
  • suitable content in the case of using a specific component as a compound represented by General formula (1) or its salt is illustrated below, this invention is not limited to this at all.
  • the content when ebastine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.1 to 50 mg per day, The amount that can be taken from 0.5 to 30 mg is more preferred, and the amount that can be taken from 1 to 20 mg is even more preferred.
  • the content when oxatomide or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.3 to 200 mg per day, The amount that can be taken 1 to 100 mg is more preferred, and the amount that can be taken 6 to 60 mg is more preferred.
  • the content thereof is preferably an amount that can be taken from 0.1 to 60 mg per day, The amount that can be taken from 0.5 to 30 mg is more preferred, and the amount that can be taken from 1 to 16 mg is even more preferred.
  • clemastine or a salt thereof when clemastine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content thereof is 0.01 to The amount that can be taken 5 mg is preferred, the amount that can be taken 0.05 to 3 mg is more preferred, and the amount that can be taken 0.1 to 2 mg is more preferred. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine. In the pharmaceutical composition of the present invention, when chlorpheniramine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is 0.1 to 20 mg per day. The amount that can be taken 0.6 to 12 mg is more preferable.
  • d-chlorpheniramine maleate when d-chlorpheniramine maleate is used as chlorpheniramine or a salt thereof, an amount that can be taken 0.1 to 15 mg per day is preferable, and an amount that can be taken 0.6 to 6 mg is more preferable. An amount that can be taken up to 5 mg is more preferred.
  • the amount that can be taken from 0.5 to 20 mg per day is preferred, the amount that can be taken from 1 to 12 mg is more preferred, and the amount that can be taken from 2 to 10 mg is even more preferred.
  • the content is preferably an amount that can be taken in an amount of 1 to 300 mg per day.
  • the amount that can be taken 150 mg is more preferred, and the amount that can be taken 10 to 100 mg is more preferred.
  • the content is an amount that can be taken from 0.1 to 13.5 mg per day.
  • the amount that can be taken 1 to 4.5 mg is more preferable.
  • diphenylpyraline hydrochloride is used as diphenylpyraline or a salt thereof, the amount that can be taken 0.1 to 12 mg per day is preferable, and the amount that can be taken 1 to 4 mg is more preferable.
  • diphenylpyraline theocuroate the amount that can be taken 0.1 to 13.5 mg per day is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred.
  • the content when diphenhydramine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken from 1 to 300 mg per day. An amount that can be taken at 200 mg is more preferred, and an amount that can be taken at 15 to 150 mg is even more preferred.
  • the content when cetirizine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.1 to 50 mg per day, The amount that can be taken 0.3 to 30 mg is more preferred, and the amount that can be taken 1 to 20 mg is more preferred.
  • the content thereof can be taken in an amount of 0.3 to 200 mg per day.
  • the amount that can be taken 1 to 100 mg is more preferable, and the amount that can be taken 6 to 60 mg is more preferable.
  • the content is preferably an amount that can be taken 0.1 to 40 mg per day, The amount that can be taken from 0.5 to 30 mg is more preferred, and the amount that can be taken from 2 to 20 mg is even more preferred.
  • the content is an amount that can be taken 0.3 to 180 mg per day.
  • the amount that can be taken 1 to 90 mg is more preferred, the amount that can be taken 3 to 60 mg is more preferred.
  • chlorpheniramine or a salt thereof clemastine or a salt thereof
  • carbbinoxamine or a salt thereof or “diphenylpyrine or a salt thereof”
  • chlorpheniramine or a salt thereof includes not only chlorpheniramine itself but also a pharmaceutically acceptable salt of chlorpheniramine. Since chlorpheniramine has an asymmetric carbon, it has optical isomers. However, in the present invention, any optical isomer may be included, which may be a single optical isomer or a mixture of various optical isomers. . Of these, d-form and dl-form are preferred in the present invention. Specific examples of the chlorpheniramine or a salt thereof include chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate and the like.
  • d-chlorpheniramine maleate and dl-chlorpheniramine maleate are preferable, and d-chlorpheniramine maleate is particularly preferable.
  • d-chlorpheniramine maleate and dl-chlorpheniramine maleate are preferable, and d-chlorpheniramine maleate is particularly preferable.
  • These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • the content of chlorpheniramine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose.
  • the content is preferably 0.004 to 1.5% by mass with respect to the total mass of the pharmaceutical composition. Of these, 0.02 to 1% by mass is preferably contained, and 0.04 to 0.9% by mass is more preferred.
  • loxoprofen or a salt thereof and chlorpheniramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the daily dose of each component described above.
  • loxoprofen or a salt thereof contains 0.0001 to 1.5 parts by mass of chlorpheniramine or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 0.7 Those containing parts by mass are more preferred, and those containing 0.001 to 0.5 parts by mass are particularly preferred.
  • clemastine or a salt thereof includes not only clemastine itself but also a pharmaceutically acceptable salt of clemastine.
  • Specific examples of clemastine or a salt thereof include, for example, clemastine, a mineral salt of clemastine (hydrochloride, nitrate, sulfate, etc.), an organic acid salt of clemastine (fumarate, methanesulfonate, etc.), etc.
  • clemastine fumarate is preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • the content of clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose, but clemastine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.008 to 0.4% by mass in terms of free mass of clemastine relative to the mass. Of these, 0.01 to 0.3% by mass is preferable, and 0.015 to 0.25% by mass is more preferable. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
  • the content ratio of loxoprofen or a salt thereof and clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the daily dose of each component described above. Alternatively, it is preferable to contain 0.0006 to 0.5 parts by mass of clemastine or a salt thereof in terms of free form of clemastine with respect to 1 part by mass of loxoprofen sodium anhydride in terms of its salt. More preferred are those containing 0.002 to 0.1 parts by mass.
  • carbinoxamine or a salt thereof includes not only carbinoxamine itself but also a pharmaceutically acceptable salt of carbinoxamine.
  • Specific examples of carbinoxamine or a salt thereof include carbinoxamine, carbinoxamine maleate, carbinoxamine diphenyl disulfonate, and the like, and carbinoxamine maleate is more preferable in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • the content of carbinoxamine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose.
  • Carbinoxamine or a salt thereof may be added to the entire pharmaceutical composition.
  • the content is preferably 0.004 to 4% by mass, more preferably 0.02 to 2% by mass, and still more preferably 0.04 to 1.8% by mass.
  • the content ratio of loxoprofen or a salt thereof and carbinoxamine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof is contained in an amount of 0.0003 to 6 parts by mass, more preferably 0.002 to 1 part by mass with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. More preferably, 0.005 to 0.3 parts by mass is contained.
  • diphenylpyrine or a salt thereof includes not only diphenylpyraline itself but also a pharmaceutically acceptable salt of diphenylpyraline.
  • diphenylpyraline or a salt thereof include, for example, diphenylpyraline, diphenylpyraline hydrochloride, diphenylpyraline theocuroate and the like.
  • diphenylpyraline hydrochloride and diphenylpyraline theocuroate are preferable, Diphenylpyraline hydrochloride is particularly preferred.
  • the content of diphenylpyralin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the above-mentioned daily dose.
  • the content is preferably 0.004 to 1% by mass, more preferably 0.004 to 1% by mass, still more preferably 0.04 to 1% by mass, more preferably 0.06% by mass based on the total mass of the product. It is particularly preferable to contain 1 to 1% by mass.
  • loxoprofen or a salt thereof and diphenylpyraline or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above.
  • loxoprofen or a salt thereof contains 0.0001 to 3 parts by mass of diphenylpyraline or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 2.5 parts by mass. More preferred are those containing 0.001 to 1 part by mass, and particularly preferred are those containing 0.001 to 0.5 part by mass.
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom or a hydroxyl group.
  • a pharmaceutically acceptable salt of the compound represented by the general formula (2) is also included in the compound represented by general formula (2).
  • Specific examples of the compound represented by the general formula (2) or a salt thereof include, for example, an inorganic acid salt such as a compound represented by the general formula (2), a hydrochloride of the compound represented by the general formula (2), and the like.
  • Organic acid salt is mentioned, The hydrochloride of the compound represented by General formula (2) is more preferable.
  • R 5 when R 5 is a hydroxyl group, the ⁇ carbon of the substituent is an asymmetric center, and there are isomers selected from the S and R isomers. In the present invention, Any of them may be sufficient, and a mixture thereof may be sufficient. In addition, these compounds may be used independently and may mix and use 2 or more types. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • the content of the compound represented by the general formula (2) or the salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. .
  • the compound represented by the general formula (2) or a salt thereof is bromohexine or a salt thereof, 0.1 to 50 mg, more preferably 0, of bromhexine or a salt thereof converted into bromohexine hydrochloride per day. It can be contained in an amount of 5 to 25 mg, particularly preferably 1 to 15 mg.
  • the compound represented by the general formula (2) or a salt thereof is ambroxol or a salt thereof
  • 0.1 to 150 mg of ambroxol or a salt thereof is converted into ambroxol hydrochloride per day. More preferably, it can be contained in an amount of 0.5 to 100 mg, particularly preferably 1 to 50 mg.
  • the compound represented by the general formula (2) or a salt thereof is preferably contained in an amount of 0.001 to 20% by mass with respect to the total mass of the pharmaceutical composition.
  • the compound represented by the general formula (2) or a salt thereof is bromohexine or a salt thereof, it is preferably contained in an amount of 0.004 to 5% by mass in terms of bromohexine hydrochloride with respect to the total mass of the pharmaceutical composition. 0.02 to 4% by mass is more preferable, and 0.04 to 3% by mass is particularly preferable.
  • the compound represented by the general formula (2) or a salt thereof is ambroxol or a salt thereof
  • 0.004 to 20% by mass in terms of ambroxol hydrochloride is contained with respect to the total mass of the pharmaceutical composition.
  • the content is preferably 0.02 to 15% by mass, more preferably 0.04 to 10% by mass.
  • the content ratio of loxoprofen or a salt thereof and the compound represented by the general formula (2) or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and depends on the daily dose of each component described above.
  • loxoprofen or a salt thereof is added to 1 part by mass in terms of anhydrous loxoprofen sodium
  • those containing 0.0001 to 10 parts by mass of bromhexine or a salt thereof in terms of bromohexine hydrochloride are preferred, those containing 0.0005 to 2 parts by mass are more preferred, and those containing 0.001 to 1 part by mass. Particularly preferred.
  • loxoprofen or a salt thereof is added to 1 part by mass in terms of loxoprofen sodium anhydride with respect to an ambroxol or a salt thereof.
  • Those containing 0.0001 to 10 parts by mass in terms of ambroxol hydrochloride are preferred, those containing 0.0005 to 5 parts by mass are more preferred, and those containing 0.001 to 3 parts by mass are particularly preferred.
  • R 6 represents an alkyl group or an alkoxy group which may have a substituent
  • R 7 represents a hydrogen atom or a sulfo group.
  • the phenolic hydroxyl group in the formula may be etherified.
  • a pharmaceutically acceptable salt of the compound represented by the general formula (3) is also included in the compound represented by general formula (3).
  • Specific examples of the compound represented by the general formula (3) or a salt thereof include, for example, an alkali metal salt such as a compound represented by the general formula (3) and a potassium salt of the compound represented by the general formula (3).
  • the potassium salt of the compound represented by the general formula (3) is more preferable.
  • the alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Etc. In the present invention, a methyl group is preferred.
  • the alkoxy group is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, and the like. Is mentioned.
  • a methoxy group is preferred.
  • the group that can be substituted with the alkoxy group include a hydroxyl group; a halogen atom such as a bromine atom, a chlorine atom, a fluorine atom, and an iodine atom, and may have one or more of these.
  • examples of the case where the phenolic hydroxyl group is etherified include, for example, those in which the phenolic hydroxyl group is etherified with a linear or branched monohydric alcohol having 1 to 3 carbon atoms. Examples thereof include those in which a phenolic hydroxyl group is etherified with a chain or branched polyhydric alcohol having 1 to 3 carbon atoms. Examples of the monohydric alcohol include methanol, ethanol, and propanol. Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, and glycerin.
  • linear or branched polyhydric alcohols having 1 to 3 carbon atoms particularly those obtained by etherifying a phenolic hydroxyl group with glycerin are preferred.
  • the etherification reaction is not particularly limited.
  • (v) to (vii) are preferable as the combination of the phenolic hydroxyl group, R 6 and R 7 in the formula (3).
  • (vii) Combination of phenolic hydroxyl group not etherified, R 6 is an alkyl group, and R 7 is a sulfo group
  • Preferred examples of the compound represented by the general formula (3) of the present invention or a salt thereof include 2-methoxyphenol derivatives (guaiacol derivatives) or salts thereof, 2-methylphenol derivatives (cresol derivatives) or salts thereof.
  • Examples of guaiacol derivatives or salts thereof include guaifenesin (guaiacol glycerol ether; (2RS) -3- (2-methoxyphenoxy) propane-1,2-diol) or salts thereof; guaiacol sulfones such as guaiacol sulfonic acid and potassium guaiacol sulfonate.
  • An acid or a salt thereof is preferred.
  • the cresol derivative or a salt thereof is preferably a cresol sulfonic acid such as cresol sulfonic acid (2-methylphenol sulfonic acid) or potassium cresol sulfonate or a salt thereof.
  • the compound represented by the general formula (3) or a salt thereof is preferably a guaiacol derivative or a salt thereof, more preferably guaiacol sulfonic acid or a salt thereof, or guaifenesin, and particularly preferably potassium guaiacol sulfonate or guaifenesin.
  • the content of the compound represented by the general formula (3) or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. .
  • the compound represented by the general formula (3) or a salt thereof can be contained in an amount that can be taken from 5 to 600 mg, more preferably from 10 to 450 mg, particularly preferably from 25 to 300 mg per day.
  • the guaiacol derivative or a salt thereof is preferably 10 to 600 mg, more preferably 20 to 450 mg, particularly preferably per day.
  • the cresol derivative or a salt thereof is preferably 5 to 550 mg, more preferably 10 to 400 mg, particularly preferably per day. It is preferable to contain an amount that can be taken from 25 to 270 mg.
  • the compound represented by the general formula (3) or a salt thereof is preferably contained in an amount of 0.2 to 40% by mass based on the total mass of the pharmaceutical composition.
  • the compound represented by the general formula (3) or a salt thereof is a guaiacol derivative or a salt thereof, it is preferably contained in an amount of 0.4 to 40% by mass relative to the total mass of the pharmaceutical composition, 0.8 to The content is more preferably 35% by mass, and even more preferably 1.2 to 30% by mass.
  • the compound represented by the general formula (3) or a salt thereof is a cresol derivative or a salt thereof, it is preferably contained in an amount of 0.2 to 35% by mass relative to the total mass of the pharmaceutical composition, 0.4 to The content is more preferably 25% by mass, and particularly preferably 1 to 20% by mass.
  • the content ratio of loxoprofen or a salt thereof and the compound represented by the general formula (3) or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and depends on the daily dose of each component described above.
  • the amount of loxoprofen or a salt thereof contained in 0.015 to 60 parts by mass of the compound represented by the general formula (3) or a salt thereof is 1 part by mass in terms of loxoprofen sodium anhydride. Those containing 0.04 to 15 parts by mass are more preferred, and those containing 0.13 to 5 parts by mass are more preferred.
  • lysozyme or a salt thereof includes not only lysozyme itself but also a pharmaceutically acceptable salt of lysozyme.
  • Specific examples of the lysozyme or a salt thereof include lysozyme and lysozyme hydrochloride, and lysozyme hydrochloride is preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • the content of lysozyme or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, per day, lysozyme or a salt thereof is converted to a lysozyme hydrochloride titer of 5 to 450 mg (titer), more preferably 10 to 360 mg (titer), particularly preferably 15 to 270 mg (titer). ) Can be taken in an amount that can be taken.
  • lysozyme hydrochloride When lysozyme hydrochloride is used as lysozyme or a salt thereof, lysozyme hydrochloride is 5 to 450 mg (titer), more preferably 10 to 360 mg (titer), particularly preferably 15 to 270 mg per day. (Titer) It is preferable to include an amount that can be taken.
  • lysozyme or a salt thereof is preferably contained in an amount of 0.2 to 30% by mass (titer) in terms of titer of lysozyme hydrochloride with respect to the total mass of the pharmaceutical composition, and 0.4 to 25% by mass. % (Titer) is more preferable, and 0.6 to 20% by mass (titer) is particularly preferable.
  • loxoprofen or a salt thereof and lysozyme or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above.
  • loxoprofen or a salt thereof contains 0.01 to 45 parts by mass (titer) of lysozyme or a salt thereof in terms of titer of lysozyme hydrochloride with respect to 1 part by mass of loxoprofen sodium anhydride.
  • Those containing 0.03 to 30 parts by mass (titer) are more preferable, those containing 0.04 to 12 parts by mass (titer) are more preferable, and those containing 0.08 to 5 parts by mass (titer) Is particularly preferred.
  • codeines means one or more selected from the group consisting of codeine, dihydrocodeine, salts thereof, and solvates thereof. This group includes codeine and dihydrocodeine itself, as well as pharmaceutically acceptable salts of codeine and dihydrocodeine and solvates thereof. Specific examples of codeines include, for example, codeine, dihydrocodeine, codeine phosphate hydrate, dihydrocodeine phosphate and the like. From the viewpoint of using the pharmaceutical composition of the present invention as a general cold medicine, codeine phosphate water More preferred are Japanese and dihydrocodeine phosphate, and more preferred is dihydrocodeine phosphate. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • the content of codeine in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user.
  • 2-60 mg of codeine can be contained per day, more preferably 4-48 mg, particularly preferably 6-36 mg.
  • codeine phosphate hydrate is used as codeine
  • 4-60 mg, more preferably 8-48 mg, particularly preferably 12-36 mg of codeine phosphate hydrate is contained per day.
  • dihydrocodeine phosphate it is preferable to contain 2 to 30 mg, more preferably 4 to 24 mg, particularly preferably 6 to 24 mg of dihydrocodeine phosphate per day.
  • the codeine is preferably contained in an amount of 0.08 to 8% by mass, more preferably 0.08 to 7% by mass, based on the total mass of the pharmaceutical composition.
  • codeine is codeine phosphate hydrate
  • it is preferably contained in an amount of 0.15 to 4% by mass, more preferably 0.3 to 3% by mass, based on the total mass of the pharmaceutical composition. It is particularly preferable to contain 5 to 2.5% by mass.
  • the codeine is dihydrocodeine phosphate, it is preferably contained in an amount of 0.08 to 6.5% by mass, more preferably 0.16 to 6% by mass, based on the total mass of the pharmaceutical composition, More preferably, the content is 0.24 to 5.5% by mass.
  • the content ratio of loxoprofen or a salt thereof and codeines contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the daily dose of each component described above.
  • Loxoprofen or a salt thereof is preferably 0.005 to 4 parts by mass of codeine, more preferably 0.01 to 2 parts by mass with respect to 1 part by mass of loxoprofen sodium anhydride. Those containing 0.02 to 1 part by mass are particularly preferred.
  • ephedrines mean one or more selected from the group consisting of ephedrine, ephedrine derivatives, and salts thereof.
  • examples of derivatives of ephedrine include norephedrine (phenylpropanolamine) and methylephedrine.
  • examples of the salt include salts of pharmaceutically acceptable inorganic acids and organic acids, and preferred specific examples include hydrochloride, sulfate, and saccharin salt.
  • any optical isomer may be included, and a single optical isomer may be used. A mixture of In the present invention, l-form and dl-form are preferable.
  • ephedrines include, for example, 1-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, 1-methylephedrine saccharin salt, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, pseudoephedrine sulfate and the like. These may be used alone or in combination of two or more. Ephedrine and pseudoephedrine are in an enantiomeric relationship with each other. Of these, dl-methylephedrine hydrochloride is preferred in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • ephedrines can also be used mah (mao) containing these as ingredients.
  • Maou is a member of Ephedra sinica Stapf, Ephdra intermedia Schrenk et C.
  • A. Means the ground stem of Meyer or Ephedra equisetina Bunge (Ephedlacea).
  • Maow can be adjusted in shape as needed, and can be cut or crushed into small pieces, lumps, or ground into powder. For example, Maow powder is called “Maow powder”.
  • Maou is a liquid obtained by adding an appropriate leaching agent after concentrating to an appropriate size based on a known method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations, etc. It may be “extract” or “tinced”.
  • Leaching agents include lower monohydric alcohols such as methanol, ethanol and n-butanol; lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol and glycerine; ethers such as diethyl ether; acetone and ethyl Ketones such as methyl ketone; esters such as ethyl acetate; halogenoalkanes such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene and toluene; and water. These may be used alone or in combination of two or more. Furthermore, the extract can be dried.
  • lower monohydric alcohols such as methanol, ethanol and n-butanol
  • lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol and glycerine
  • ethers such as diethyl ether
  • acetone and ethyl Ketones such
  • maou when maou is used as the ephedrine, maou powder, maou stream extract, maou soft extract, mao dry extract, mao extract and the like are preferable, and these can be used alone or in combination of two or more.
  • Chinese herbal prescriptions including maou, kaachi (Kakdar), shosei ryoutou (Sho Seiryuto), maoutou (maoyuto), etc. can also be used. These may be produced by known methods, or commercially available products may be used.
  • the content of ephedrines in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, an amount of ephedrines that can be taken in an amount of 5 to 500 mg, more preferably 10 to 360 mg, and particularly preferably 20 to 240 mg per day can be included. In addition, a part or all of ephedrines can be substituted for the above-mentioned maou.
  • ephedrine when using ephedrine as ephedrines, for example, 0.1 to 25 g (powder equivalent) of maow per day, more preferably 0.25 to 10 g (powder equivalent), particularly preferably 0 4 to 4 g (concentration in bulk drug substance) can be included.
  • the ephedrine is preferably contained in an amount of 0.1 to 40% by weight, more preferably 0.5 to 20% by weight, and more preferably 1 to 10% by weight based on the total weight of the pharmaceutical composition. More preferably, the content is 2 to 10% by mass.
  • maou when using maou as the ephedrine, it is preferable to contain 1 to 98% by mass, more preferably 2 to 50% by mass, and more preferably 4 to 20% by mass with respect to the total mass of the pharmaceutical composition. It is particularly preferable to do this.
  • the content ratio of loxoprofen or a salt thereof and ephedrine contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the daily dose of each component described above.
  • Loxoprofen or a salt thereof is preferably 0.001 to 50 parts by mass, more preferably 0.005 to 50 parts by mass of ephedrine, relative to 1 part by mass of loxoprofen sodium anhydride.
  • Those containing 0.015 to 50 parts by mass are more preferable. Of these, those containing 0.05 to 12 parts by mass are more preferred, and those containing 0.1 to 4 parts by mass are particularly preferred.
  • the term “dextromethorphan or a salt thereof” includes dextromethorphan itself, pharmaceutically acceptable salts of dextromethorphan, and pharmaceutically acceptable salts of dextromethorphan and dextromethorphan. Solvates with water or alcohol are also included. Specific examples of dextromethorphan or a salt thereof include, for example, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenol phthaline salt, etc., and dextromethorphan hydrobromide hydrate. Dextromethorphan phenol phthaline salt is preferred, and dextromethorphan hydrobromide hydrate is particularly preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • the content of dextromethorphan or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, 0.1 to 270 mg, more preferably 0.5 to 180 mg, and particularly preferably 1 to 90 mg of dextromethorphan or a salt thereof can be contained per day.
  • dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate, 6 to 60 mg, more preferably 15 to 60 mg of dextromethorphan hydrobromide hydrate per day, It is particularly preferable to add an amount that can be taken from 20 to 60 mg.
  • dextromethorphan or a salt thereof when dextromethorphan or a salt thereof is dextromethorphan phenol phthalin salt, 9 to 90 mg, more preferably 22 to 90 mg, particularly preferably 30 to 90 mg of dextromethorphan phenol phthalin salt per day. It is preferable to contain an amount that can be taken by 90 mg.
  • dextromethorphan or a salt thereof is preferably contained in an amount of 0.004 to 20% by mass, more preferably 0.02 to 15% by mass, more preferably 0.04%, based on the total mass of the pharmaceutical composition. The content is particularly preferably 10 to 10% by mass.
  • the content ratio of loxoprofen or a salt thereof and dextromethorphan or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and is determined by appropriate examination according to the daily dose of each component described above. It is preferable that loxoprofen or a salt thereof contains 0.0001 to 20 parts by mass of dextromethorphan or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 10 masses. More preferred are those containing 0.001 to 5 parts by mass.
  • the “xanthine derivative” is preferably a compound represented by the following general formula (4).
  • R 8 and R 9 each independently represent a hydrogen atom or a methyl group
  • R 10 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 8 is a methyl group, R 9 is a methyl group, and R 10 is a methyl group means caffeine.
  • R 8 is a methyl group, R 9 is a methyl group, and R 10 is a hydrogen atom means theophylline.
  • R 8 is a hydrogen atom, R 9 is a methyl group, and R 10 is a methyl group means theobromine.
  • R 8 is a methyl group, R 9 is a hydrogen atom and R 10 is a methyl group is intended to mean a paraxanthine.
  • a compound in which R 8 is a methyl group, R 9 is a methyl group, and R 10 is a 2-hydroxypropyl group means proxyphylline.
  • the case where R 8 is a methyl group, R 9 is a methyl group, and R 10 is a 2,3-dihydroxypropyl group means diprofylline.
  • the compounds of the general formula (4) are known.
  • commercially available products can be used in addition to those produced by known methods.
  • a pharmaceutically acceptable salt thereof for example, a double salt formed (sodium benzoate caffeine (sodium benzoate and caffeine)). Indium), aminophylline (theophylline and ethylenediamine double salt))), compounds represented by the general formula (4) or a solvate of the salt thereof with water or alcohol, etc.
  • xanthine derivative are also included in the “xanthine derivative”, and the above-mentioned compounds (caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprofylline) also include the compound, a salt thereof, and a solvate thereof. In the present invention, one or more of these xanthine derivatives can be used.
  • the xanthine derivative is preferably one or more selected from the group consisting of caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprofylline.
  • the pharmaceutical composition of the present invention is used as an antipyretic analgesic or a general cold medicine.
  • Caffeine is preferred from the standpoint of use as a etc.
  • Specific examples of the caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. Among these, caffeine hydrate, caffeine anhydride, benzoic acid are preferable. Sodium caffeine is particularly preferred.
  • the content of the xanthine derivative in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, 10 to 1000 mg, more preferably 20 to 800 mg, particularly preferably 30 to 600 mg of xanthine derivative can be contained per day.
  • the xanthine derivative is preferably contained in an amount of 0.4 to 65% by mass relative to the total mass of the pharmaceutical composition, more preferably 0.8 to 50% by mass, and 1.6 to 40% by mass. It is particularly preferable to contain it.
  • the blending ratio of loxoprofen or a salt thereof and xanthine derivative 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.
  • the salt thereof preferably contains 0.03 to 100 parts by mass, more preferably 0.08 to 27 parts by mass of xanthine derivative with respect to 1 part by mass of loxoprofen sodium anhydride. Those containing 2 to 10 parts by mass are more preferable.
  • the “isovaleryl urea derivative” means one or more selected from the group consisting of bromovalerylurea, allylisopropylacetylurea and salts thereof. Of these, bromovalerylurea is preferred. Since the isovaleryl urea derivative has an asymmetric carbon, there are various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used. A mixture of
  • the content of the isovaleryl urea derivative in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user.
  • the isovaleryl urea derivative is bromvaleryl urea or a salt thereof, it contains 10 to 1000 mg, more preferably 30 to 800 mg, particularly preferably 60 to 600 mg of bromvalerylurea per day in terms of free form. It can be shown.
  • the isovaleryl urea derivative is allyl isopropyl acetyl urea or a salt thereof
  • 1 to 500 mg, more preferably 10 to 300 mg, particularly preferably 20 to 180 mg of allyl isopropyl acetyl urea per day is converted in free form.
  • An amount that can be contained can be included.
  • the isovaleryl urea derivative it is preferable to contain 0.1 to 95% by mass of the isovaleryl urea derivative with respect to the total mass of the pharmaceutical composition.
  • the isovaleryl urea derivative is bromvaleryl urea or a salt thereof
  • the isovaleryl urea derivative is allyl isopropyl acetyl urea or a salt thereof
  • the content ratio of loxoprofen or a salt thereof and isovaleryl urea derivative contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above.
  • the isovaleryl urea derivative is bromvaleryl urea or a salt thereof
  • 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium is contained in an amount of 0.03 to 100 parts by mass of bromvaleryl urea or a salt thereof in terms of free form
  • Those containing 0.05 to 50 parts by mass are more preferred, those containing 0.1 to 30 parts by mass are more preferred, and those containing 0.3 to 10 parts by mass are particularly preferred.
  • 1 part by mass of loxoprofen or a salt thereof in terms of loxoprofen sodium anhydride is 0.003 to Those containing 50 parts by mass are preferred, those containing 0.04 to 10 parts by mass are more preferred, and those containing 0.1 to 3 parts by mass are particularly preferred.
  • tropane alkaloids mean alkaloids having a tropane skeleton or derivatives thereof. Specifically, tropane alkaloids (atropine, scopolamine, hyoscyamine, etc.) and derivatives thereof (for example, methylatropine, methylscopolamine, And quaternary ammonium derivatives such as butyl scopolamine) and components containing these alkaloids (datsura extract, belladonna alkaloid, belladonna total alkaloid, belladonnacon, belladonna extract, rotocon total alkaloid, rotocon, funnel extract). These may be in the form of a pharmaceutically acceptable salt or solvate.
  • suitable specific examples of the salt include bromide salts (for example, butyl scopolamine bromide), hydrobromides (for example, scopolamine hydrobromide hydrate), citrates (for example, Rotcon total alkaloid citrate, etc.).
  • bromide salts for example, butyl scopolamine bromide
  • hydrobromides for example, scopolamine hydrobromide hydrate
  • citrates for example, Rotcon total alkaloid citrate, etc.
  • solvates include hydrates.
  • the tropane alkaloid is preferably one or more selected from the group consisting of datsura extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, rotcon total alkaloid citrate, funnel extract and butyl scopolamine bromide, and butyl scopolamine bromide. Particularly preferred.
  • datsura extract belladonna alkaloid, belladonna total alkaloid, belladonna extract, rotcon total alkaloid citrate, funnel extract and butyl scopolamine bromide, and butyl scopolamine bromide.
  • rotcon total alkaloid citrate rotcon total alkaloid citrate
  • funnel extract and butyl scopolamine bromide, and butyl scopolamine bromide.
  • butyl scopolamine bromide Particularly preferred.
  • These are known components, which can be produced by a known method or commercially available.
  • the content of tropane alkaloids in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user.
  • the amount of tropane alkaloids that can be taken per day is 0.05 to 1000 mg, more preferably 0.1 to 500 mg, and particularly preferably 0.12 to 100 mg per day.
  • butyl scopolamine bromide is used as the tropane alkaloids, it can be contained in an amount of 3 to 1000 mg, more preferably 5 to 500 mg, particularly preferably 30 to 100 mg per day.
  • belladonna alkaloids belladonna total alkaloids, rotcon total alkaloids as tropane alkaloids, 0.05 to 2 mg per day, more preferably 0.1 to 1 mg, particularly preferably 0.12 to 0.00.
  • the amount that can be taken 8 mg can be included.
  • datsura extract, belladonna extract, or funnel extract is used as the tropane alkaloids, it can contain 1 to 200 mg, more preferably 5 to 100 mg, and particularly preferably 10 to 80 mg per day.
  • the tropane alkaloids are preferably contained in a total amount of 0.005 to 60% by mass, more preferably 0.01 to 50% by mass, more preferably 0.02 to What contains 40 mass% is preferable.
  • butyl scopolamine bromide when used as the tropane alkaloids, it preferably contains 1 to 10% by mass of butyl scopolamine bromide with respect to the total mass of the pharmaceutical composition, and more preferably contains 2 to 8% by mass. Those containing 3 to 7% by mass are particularly preferred.
  • the content ratio of loxoprofen or a salt thereof and tropane alkaloids contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. , Preferably containing 0.0001 to 1000 parts by mass of tropane alkaloids, more preferably 0.0005 to 500 parts by mass with respect to 1 part by mass of loxoprofen sodium salt in terms of loxoprofen sodium anhydride. Those containing 0.001 to 300 parts by mass are particularly preferable.
  • loxoprofen or a salt thereof contains 0.01 to 100 parts by mass of butyl scopolamine bromide with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. Those containing 0.02 to 20 parts by mass are particularly preferable.
  • Component (C) is a basic compound having acid neutralizing ability.
  • the “basic compound having acid neutralizing ability” means a basic compound having acid neutralizing ability.
  • the “acid neutralizing ability” can be determined by conducting a test according to the antacid test method described in the Fifteenth Amendment Japanese Pharmacopoeia General Test Method.
  • examples of the basic compound having an acid neutralizing ability include alkaline earth metals such as magnesium, aluminum and calcium and / or alkaline metal basic inorganic compounds such as magnesium and aluminum, and alkali metal basics such as sodium and potassium.
  • Basic inorganic compounds such as inorganic compounds and amine basic inorganic compounds; alkaline earth metals such as magnesium, aluminum and calcium and / or earth metal basic organic compounds, alkali metal basic organic such as sodium and potassium Examples thereof include basic organic compounds such as compounds and amine basic organic compounds.
  • examples of the alkaline earth metal and / or earth metal-based basic inorganic compound include magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, and water.
  • alkali metal basic inorganic compound examples include dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, tetrasodium pyrophosphate, trisodium phosphate, sodium hydrogen phosphate hydrate, Examples thereof include inorganic salts of metals selected from sodium and potassium, such as anhydrous sodium pyrophosphate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, and potassium carbonate.
  • the basic inorganic compound having acid neutralizing ability includes magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide / potassium aluminum sulfate , Magnesium carbonate, Synthetic hydrotalcite, Magnesium aluminate metasilicate, Dry aluminum hydroxide gel, Synthetic aluminum silicate, Synthetic aluminum silicate, Hydroxypropyl starch, Crystalline cellulose, Magnesium aluminate hydroxide, Aluminum hydroxide gel, Water Aluminum oxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, bentonite, silica Calcium, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, calcium hydrogen phosphate anhydrous, sodium bicarbonate is preferred.
  • examples of the alkaline earth metal and / or earth metal-based basic organic compound include aldioxa, dihydroxyaluminum aminoacetate, sucralfate hydrate, calcium pantothenate, and the like.
  • examples of the alkali metal basic organic compound include sodium citrate hydrate, disodium succinate hexahydrate, DL-sodium tartrate, sodium L-tartrate, copper chlorophyllin sodium, sodium polyacrylate, 5 '-Ribonucleotide disodium, copper chlorophyllin potassium and the like.
  • examples of the amine basic organic compound include aminoacetic acid, L-arginine, meglumine and the like.
  • aldioxa dihydroxyaluminum aminoacetate and sucralfate hydrate are preferable.
  • a crude drug containing a basic compound such as bandit bone, stone decision, or oyster may be used as the basic compound.
  • the basic compound having acid neutralizing ability include magnesium aluminate silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, precipitated carbonic acid.
  • 1 or more types selected from the group consisting of calcium, anhydrous calcium hydrogen phosphate and magnesium aluminate metasilicate are mentioned, and particularly preferred are magnesium aluminate silicate, magnesium silicate, and calcium silicate in terms of inhibition of interaction.
  • the said basic compound may be individual, and may combine 2 or more types. These are known compounds, and can be produced by known methods, or commercially available products can be used.
  • basic compound having acid neutralizing ability those which can be used as an antacid are mentioned as preferred specific examples.
  • Specific examples of basic compounds having acid neutralizing ability that can be used as antacids include aminoacetic acid, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, and magnesium oxide.
  • Antacids are broadly classified into absorbent antacids and local antacids due to their properties. In the present invention, local antacids are preferred from the viewpoint of preventing alkalosis.
  • the content of the basic compound having acid neutralization ability in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the inhibitory effect of the interaction between loxoprofen and the interactive component. .
  • the amount taken from 1 to 20000 mg per day is preferred, the amount taken from 10 to 10000 mg is more preferred, and the amount taken from 20 to 5000 mg is particularly preferred.
  • the basic compound having acid neutralizing ability is preferably contained in an amount of 0.04 to 99.9% by mass, and preferably 0.4 to 99.9% by mass, based on the total mass of the pharmaceutical composition. Is more preferable, 0.8 to 99.9% by mass is more preferable, and 25 to 75% by mass is particularly preferable.
  • aldioxa When aldioxa is used as the basic compound having acid neutralizing ability, the amount taken from 10 to 800 mg per day is preferred, and the amount taken from 30 to 400 mg is more preferred. In the case of using the bandage bone, the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred. When using dry aluminum hydroxide gel, the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred. When using magnesium aluminate silicate, the amount taken from 10 to 8000 mg per day is preferred, and the amount taken from 30 to 4000 mg per day is more preferred.
  • the dose taken from 1 to 600 mg per day is preferred, and the dose taken from 30 to 300 mg is more preferred.
  • magnesium silicate the amount taken from 10 to 12000 mg per day is preferred, and the amount taken from 30 to 6000 mg is more preferred.
  • magnesium aluminum silicate the amount taken from 1 to 500 mg per day is preferred, and the amount taken from 20 to 225 mg is more preferred.
  • synthetic aluminum silicate the amount taken from 10 to 20000 mg per day is preferred, and the amount taken from 30 to 10,000 mg is more preferred.
  • synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose the amount taken from 10 to 3500 mg per day is preferred, and the amount taken from 30 to 1800 mg is more preferred.
  • the amount taken from 10 to 8000 mg per day is preferred, and the amount taken from 30 to 4000 mg is more preferred.
  • magnesium oxide the amount taken from 10 to 2000 mg per day is preferred, and the amount taken from 30 to 1000 mg is more preferred.
  • dihydroxyaluminum aminoacetate is used, the dose taken from 10 to 6000 mg per day is preferred, and the dose taken from 30 to 3000 mg is more preferred.
  • alumina magnesium hydroxide the amount taken from 10 to 8000 mg per day is preferred, and the amount taken from 30 to 4000 mg is more preferred.
  • the amount taken from 10 to 6000 mg per day in terms of dry aluminum hydroxide gel is preferred, and the amount taken from 30 to 3000 mg is more preferred.
  • the dose taken is preferably 10 to 4000 mg per day, more preferably 30 to 2000 mg.
  • the dose taken is preferably 10 to 6000 mg per day, more preferably 30 to 3000 mg.
  • the amount taken is preferably 10 to 8000 mg per day, and more preferably 30 to 4000 mg.
  • the amount taken from 10 to 5000 mg per day is preferred, and the amount taken from 30 to 2400 mg is more preferred.
  • the amount taken is preferably 10 to 4000 mg per day, more preferably 30 to 2000 mg.
  • sucralfate hydrate When using sucralfate hydrate, the amount taken from 10 to 6500 mg per day is preferred, and the amount taken from 30 to 3250 mg is more preferred. When using stone decision, the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred. In the case of using sodium bicarbonate, the amount taken from 10 to 10,000 mg per day is preferred, and the amount taken from 30 to 5000 mg is more preferred. When calcium carbonate is used, the amount taken is preferably 10 to 1500 mg per day, and more preferably 30 to 700 mg. When using magnesium carbonate, the dose taken from 10 to 4000 mg per day is preferred, and the dose taken from 30 to 2000 mg is more preferred.
  • the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred.
  • the amount taken is preferably 1 to 200 mg per day, and more preferably 10 to 100 mg.
  • the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred.
  • the amount taken is preferably 10 to 5000 mg per day, and more preferably 30 to 2400 mg.
  • magnesium aluminate metasilicate an amount taken from 10 to 8000 mg per day is preferred, and an amount taken from 30 to 4000 mg per day is more preferred.
  • calcium hydrogen phosphate the amount taken from 10 to 9000 mg per day is preferred, and the amount taken from 30 to 4500 mg is more preferred.
  • loxoprofen or a salt thereof and a basic compound having acid neutralizing ability contained in the pharmaceutical composition of the present invention is not particularly limited, and is appropriately examined according to the inhibitory effect of the interaction between loxoprofen and the interactive component.
  • loxoprofen or a salt thereof contains 0.003 to 2000 parts by mass of a basic compound having an acid neutralizing ability with respect to 1 part by mass in terms of anhydrous loxoprofen sodium.
  • Those containing 0.01 to 100 parts by mass are more preferred, those containing 0.02 to 30 parts by mass are more preferred, and those containing 0.04 to 10 parts by mass are particularly preferred.
  • the pharmaceutical composition of the present invention includes the following components (A), (B) and (C): (A) Loxoprofen or a salt thereof; (B) one or more selected from the group consisting of the following components (B-1-1) to (B-10-1); (B-1-1) Chlorpheniramine or a salt thereof, (B-1-2) Clemastine or a salt thereof, (B-1-3) Carbinoxamine or a salt thereof, (B-1-4) Diphenylpyramine or a salt thereof (B-2-1) bromohexine or a salt thereof, (B-2-2) ambroxol or a salt thereof, (B-3-1) a guaiacol derivative or a salt thereof, (B-3-2) a cresol derivative or a salt thereof One or more selected from the group consisting of a salt thereof, (B-4) lysozyme or a salt thereof, (B-5-1) codeine, dihydrocodeine and a salt thereof, and a solvate thereof,
  • the pharmaceutical composition of the present invention can be produced by, for example, a known method described in the 15th revision Japanese Pharmacopoeia, General Rules for Preparations.
  • the dosage form is not particularly limited, and may be any of solid, semi-solid, and liquid shapes, and may be a shape usually used in pharmaceuticals depending on the purpose of use and the like. it can.
  • the dosage form include tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets), troches, drops, hard capsules, soft capsules, granules, fine granules, Solid preparations such as powders, pills, dry syrups, suppositories, poultices, plasters; licks, chewing gums, jellies, jelly drops, whippings, ointments, creams, foams, inhalers 15th revision Japanese Pharmacy, including liquid preparations such as syrups, drinks, suspensions, spirits, liquids, eye drops, aerosols, sprays, sprays, etc.
  • the dosage forms described in the General Rules for Preparations are listed.
  • solid preparations are preferable, solid preparations selected from the group consisting of tablets, capsules, pills, granules, powders, and fine granules are more preferable, tablets or capsules are more preferable, and tablets are particularly preferable.
  • solid preparations are generally advantageous not only in terms of ease of administration and management of drug doses, but also as specifically described in Test Example 15 below, the pharmaceutical composition of the present invention.
  • Test Example 15 the pharmaceutical composition of the present invention.
  • the product was a solid preparation, it was revealed that the swelling over time was suppressed. Therefore, according to the present invention, it is possible to provide a solid preparation with excellent stability, which is less likely to cause cracking or chipping of the coating, sugar coating or capsule when the coating or sugar coating is applied or when the capsule is filled. .
  • the pharmaceutical composition of the present invention is a solid preparation
  • loxoprofen or a salt thereof and the interactive component in the solid preparation are contained so as not to come into contact with each other. More preferably.
  • the preparations prepared so as to be substantially in contact with each other can be easily understood by general pharmaceutical technology researchers, using appropriate formulation additives based on known methods. Can be manufactured and formulated. Specifically, as the form of the solid preparation, the following (I)-(VI) can be exemplified, and these can be produced and formulated by known methods.
  • Loxoprofen or a salt thereof, and any one of the interactive components are granulated by an appropriate method to form a granular material, and the other is not granulated, and the powder or granule produced by containing the other,
  • a preparation in which the granular material is further coated by an appropriate method may be contained in a granular material, and may be contained separately from a granular material.
  • Loxoprofen or a salt thereof and an interactive component are separately granulated by an appropriate method to form granules, and powders and granules produced by containing these, and the granules are further suitable.
  • the basic compound having acid neutralizing ability used in the present invention may be contained in any one of the granular materials, or may be contained in both granular materials, or these granular materials. You may make it contain separately.
  • the multi-layer tablet is preferably one in which loxoprofen or a salt thereof and an interactive component are located in different layers, and as a multi-layer tablet having three or more layers, a layer containing loxoprofen or a salt thereof and an interactive component are included. More preferably, the layers included are positioned so as not to contact each other.
  • the granular material manufactured by said (I) and (II) can be used as a loxoprofen or its salt, and an interactive component.
  • the basic compound having acid neutralizing ability may be located in either the layer containing loxoprofen or a salt thereof or the layer containing an interactive component, or separately in both layers. May be.
  • the granular material manufactured by said (I) and (II) can be used as a loxoprofen or its salt, and an interactive component.
  • the basic compound having acid neutralizing ability may be located in the nuclear tablet, may be located in the outer shell, or separately, located in either the nuclear tablet or the outer shell. Also good.
  • the above-mentioned solid preparation may be coated with sugar coating, film coating or the like by a known method.
  • Examples of the route of administration of the pharmaceutical composition of the present invention include oral and parenteral such as rectal and vaginal, and in the present invention, oral preparations are preferred.
  • the pharmaceutical composition of the present invention can be taken 1 to 4 times per day before meals, between meals, after meals, before going to bed.
  • the pharmaceutical composition of the present invention includes, as a pharmaceutical component, a drug other than loxoprofen or a salt thereof, an interactive component, and a basic compound having acid neutralizing ability, such as antipyretic analgesics, antihistamines, antitussives, noscapines, It may contain one or more selected from the group consisting of bronchodilators, expectorants, vitamins, anti-inflammatory agents, gastric mucosal protective agents, anticholinergic agents, herbal medicines, Kampo prescriptions and the like. These components are preferably blended in the solid preparation.
  • antipyretic analgesics examples include aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, 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, ketotifen fumarate, triprolidine hydrochloride, tripelenamine hydrochloride, tondylamine hydrochloride Phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, mequitazine, methodirazine hydrochloride, mebhydroline napadisilate and the like.
  • Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, dibutate sodium, dimemorphan phosphate, tipepidine citrate, And tipepidine hibenzate.
  • noscapine examples include noscapine hydrochloride and noscapine.
  • bronchodilator examples include trimethquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and the like.
  • expectorants include ammonia and fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, methylcysteine hydrochloride, l-menthol and the like.
  • vitamins 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 nitrification) , Dicetiamine hydrochloride, cetothiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisivethiamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate , Riboflavin butyrate, sodium riboflavin phosphate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate , Hesperidin, etc.).
  • salts thereof for example,
  • anti-inflammatory agents examples include glycyrrhizic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate and monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, bromelain and the like. .
  • gastric mucosa protective agents examples include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride, and the like.
  • anticholinergic agents examples include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, tipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, etc. .
  • Herbal medicines include Akamegashiwa (red buds), Asenyaku (Asenyaku), Yinakukaku (Ryokan), Fennel (Yongxiang), Engosaku (Yancho), Ogon (Yellow), Ousei (Yellow), Oubak (Yellow), Spruce (Cherry bark), auren (yellow ream), onji (distant), gadgets (weather), valerian (deer grass), chamomile, caronin (karojin), kyokyo (kikyo), kyonin (kyojin), kokushi ( ⁇ ) Child), cucumber yoi, kei gai, keihi cinnamon, katsumeishi (decided child), gentiana, gennoshouko (current evidence), kobushi (kosuke), goo (oxen yellow), trash (tasty), saishin ( Spicy), Salamander, Zion (Zhi), Ziqoppi (Skin
  • Herbal formulas include Keishito (Keishaeyu), Kousosan (Kousosan), Psychokeito (Shibako Keiedo), Shosai Koto (Koshisaifuto), Bakumondou (Bakumon Fuyuto), Hangekou Bokuto (Hankatsu Koboku-yu).
  • composition of the present invention those other than the following (a) to (l) are preferable.
  • pseudoephedrine hydrochloride 180 mg, loxoprofen sodium 90 mg, ibuprofen 225 mg, magnesium oxide 350 mg, magnesium metasilicate aluminate 140 mg, crystalline cellulose 120 mg, corn starch 140 mg, hydroxypropylcellulose 60 mg, croscarmellose sodium 15 mg , 25 mg of magnesium stearate, 6 mg of triacetin and a suitable amount of lactose.
  • (K) Capsules containing loxoprofen sodium dihydrate 60 mg, magnesium oxide 240 mg, caffeine or theophylline 30 mg, hydroxypropylcellulose 50 mg, magnesium stearate 10 mg, polysorbate 80 15 mg and corn starch in 1 to 2 capsules .
  • (L) Loxoprofen sodium dihydrate 60 mg, magnesium oxide 240 mg, caffeine or theophylline 30 mg, hydroxypropylcellulose 50 mg, sodium benzoate 140 mg, citric acid 80 mg, concentrated glycerin 530 mg, polyvinyl alcohol 100 mg, ethanol (95 %) A syrup containing 220 mg and the balance of purified water.
  • the pharmaceutical composition of the present invention may be further stored in the presence of a desiccant from the viewpoint of inhibition of interaction.
  • a desiccant from the viewpoint of inhibition of interaction.
  • pharmaceutical formulation what contains the pharmaceutical composition and desiccant of this invention in a container.
  • the desiccant is not particularly limited.
  • the shape is not limited, for example, a plate-shaped or bag-shaped sheet type, a cylindrical shape (tablet type), etc., and a cylindrical shape with paper wrapping or film coating. But you can.
  • the desiccant include silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride, magnesium oxide. Etc., and a mixture of these and activated carbon may be used.
  • silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve), and calcium chloride is more preferable.
  • desiccant Commercially available products can be used as the desiccant. Examples of commercially available products include Siblet, MS-Tablet, MS-Serum W, Tokai Gel, Decite Kite 25, Alp Sheet, Yamanin Pharmaceutical Co., Ltd. manufactured by Tokai Chemical Industry Co., Ltd. Dryan (registered trademark) packaged product, Dryan (registered trademark) tablet, Dryan (registered trademark) sheet, Sekawa, Allosheet, Zeosheet manufactured by Shinagawa Kasei Co., Ltd., OZO manufactured by OZO Chemical Engineering Co., Ltd. An ID sheet made by the company ID, an ID packing desiccant, etc.
  • the content of the desiccant may be appropriately determined and determined, but is preferably 0.05 to 35 parts by weight, and 0.15 to 17 parts by weight with respect to 1 part by weight of loxoprofen or a salt thereof. Part is more preferred. In addition, 0.001 to 1 part by mass is preferable, and 0.004 to 0.4 part by mass is more preferable with respect to 1 part by mass of the pharmaceutical composition of the present invention.
  • the container used for the pharmaceutical preparation of the present invention is not particularly limited as long as it can be used as a container for foods, supplements, pharmaceuticals, health foods, and the like, but any of a fixed container and an amorphous container can be used and sealed. What is possible is preferred.
  • Examples of the fixed container include bottles, cans, and boxes.
  • Examples of the amorphous container include bags (pillow packaging, stick packaging, PTP packaging, SP packaging, etc.) and the like. Of these containers, specifically, bottles and bags are preferable.
  • the forming member of the container is not particularly limited, and examples thereof include paper, glass, resin or resin film, or metal or metal film, and a composite structure or multilayer structure in which these members are appropriately combined. It may be a thing. Moreover, it is preferable that moisture permeation prevention processing is performed about the member which has moisture permeability, such as paper.
  • the container may be transparent, translucent, or opaque.
  • the method for storing the pharmaceutical composition of the present invention and the desiccant in a container is not particularly limited, and both can be achieved by arranging them by appropriate means such as charging into the container.
  • the desiccant preferably, a columnar shape (tablet shape)
  • the bottle is placed in the bottle, or stored in the back side (inner cap) of the bottle lid, and stored in the container.
  • the pharmaceutical composition of the present invention is preferably a solid preparation.
  • the container when the container is a bag, it can be achieved by storing the desiccant (preferably, a plate-like or bag-like sheet type) and the pharmaceutical composition of the present invention in the bag.
  • the pharmaceutical composition of the present invention is preferably a solid preparation.
  • the pharmaceutical composition of the present invention may be once packaged by SP packaging, PTP packaging or a bag, and then the packaged pharmaceutical composition and desiccant may be enclosed in a bag. More specifically, the form which carries out pillow packaging, combining the pharmaceutical composition which carried out SP packaging or PTP packaging, and a plate-shaped or bag-shaped sheet type desiccant etc. is mentioned. Further, the pillow packaging form may be stored in a box or the like.
  • the pharmaceutical composition of the present invention is preferably a solid preparation.
  • the pharmaceutical composition of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain ⁇ Bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain), pain relief, chills, antipyretic fever, cold symptoms (throat pain, chills, fever, headache, joint pain, muscles It is useful as a general cold medicine (cold medicine) or antipyretic analgesic.
  • [Mixture 1-C] A mixture 1-C was obtained in the same manner as the mixture 1-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
  • [Mixture 1-D] A mixture 1-D was obtained in the same manner as the mixture 1-B, except that 500 mg of anhydrous calcium hydrogen phosphate (trade name: anhydrous calcium hydrogen phosphate GS-H) was used instead of magnesium hydroxide. It was.
  • [Mixture 1-E] A mixture 1-E was obtained in the same manner as the mixture 1-B, except that 500 mg of magnesium oxide (trade name, heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
  • [Mixture 2-D] A mixture 2-D was obtained in the same manner as the mixture 2-B, except that 500 mg of magnesium oxide (trade name, heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
  • [Mixture 2-E] A mixture 2-E was obtained in the same manner as the mixture 2-B, except that 500 mg of magnesium aluminate metasilicate (trade name: Neusilin UFL2) was used instead of magnesium hydroxide.
  • [Mixture 2-F] A mixture 2-F was obtained in the same manner as the mixture 2-B, except that 500 mg of precipitated calcium carbonate (trade name: precipitated carbon dioxide CA, manufactured by Sankyo Seimitsu) was used instead of magnesium hydroxide.
  • [Mixture 3-C] A mixture 3-C was obtained in the same manner as the mixture 3-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
  • [Mixture 3-D] A mixture 3-D was obtained in the same manner as the mixture 3-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
  • [Mixture 3-E] A mixture 3-E was obtained in the same manner as the mixture 3-B, except that 500 mg of magnesium aluminate metasilicate (trade name: Neusilin UFL2) was used instead of magnesium hydroxide.
  • [Mixture 4-C] A mixture 4-C was obtained in the same manner as the mixture 4-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
  • [Mixture 4-D] A mixture 4-D was obtained in the same manner as the mixture 4-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
  • [Mixture 4-E] A mixture 4-E was obtained in the same manner as the mixture 4-B, except that 500 mg of precipitated calcium carbonate (manufactured by Sankyo Seimitsu Co., Ltd .: trade name precipitated carbonated CA) was used instead of magnesium hydroxide.
  • the basic compound having acid neutralizing ability used in 4-B to 4-E is represented by the general formula (1) including loxoprofen or a salt thereof and diphenylpyraline or a salt thereof. It became clear that it has the effect
  • the basic compound having acid neutralizing ability used in 5-B to 5-D is a compound represented by the general formula (2) including loxoprofen or a salt thereof and bromhexine or a salt thereof. Or it became clear that it has the effect
  • the basic compound having acid neutralizing ability used in 7-B to 7-E is represented by the general formula (3) including loxoprofen or a salt thereof and guaiacol sulfonic acid or a salt thereof. It became clear that it has the effect
  • [Mixture 8-D] A mixture 8-D was obtained in the same manner as the mixture 8-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
  • [Mixture 8-E] A mixture 8-E was obtained in the same manner as the mixture 8-B, except that 500 mg of precipitated calcium carbonate (manufactured by Sankyo Seimitsu Co., Ltd., trade name: precipitated carbonated CA) was used instead of magnesium hydroxide.
  • [Mixture 8-F] A mixture 8-F was obtained in the same manner as the mixture 8-B, except that 500 mg of magnesium silicate (trade name: magnesium silicate (light)) was used instead of magnesium hydroxide.
  • [Mixture 10-F] A mixture 10-F was obtained in the same manner as the mixture 10-B, except that 500 mg of precipitated calcium carbonate (manufactured by Sankyo Seimitsu Co., Ltd .: trade name precipitated carbonated CA) was used instead of magnesium hydroxide.
  • [Mixture 10-G] A mixture 10-G was obtained in the same manner as the mixture 10-B, except that 500 mg of magnesium aluminate metasilicate (product name: Neusilin UFL2) was used instead of magnesium hydroxide.
  • [Mixture 12-D] A mixture 12-D was obtained in the same manner as the mixture 12-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
  • [Mixture 12-E] A mixture 12-E was obtained in the same manner as the mixture 12-B, except that 500 mg of magnesium aluminate metasilicate (product name: Neusilin UFL2) was used instead of magnesium hydroxide.
  • [Mixture 12-F] A mixture 12-F was obtained in the same manner as the mixture 12-B, except that 500 mg of precipitated calcium carbonate (trade name: precipitated carbon dioxide CA manufactured by Sankyo Seimitsu) was used instead of magnesium hydroxide.
  • [Mixture 14-G] A mixture 14-G was obtained in the same manner as the mixture 14-B, except that 234.3 parts by mass of magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd., trade name: Kyowasui Mug) was used instead of magnesium aluminate silicate.
  • [Mixture 14-H] A mixture 14-H was obtained in the same manner as the mixture 14-B, except that 234.3 parts by mass of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium aluminate silicate.
  • Test Example 15 Examination of swelling of tablets containing loxoprofen sodium hydrate and an interactive component Interaction between loxoprofen or a salt thereof confirmed in Test Examples 1 to 14 and an interactive component (solidification, In order to confirm the influence of a change in state such as wetting) on the solid preparation, a tablet containing loxoprofen sodium hydrate and an interactive component was produced, and the presence or absence of swelling over time was confirmed. Specifically, after preparing tablets 15-A to 15-C shown below, each tablet was stored at 60 ° C. for 1 month, the thickness of the tablet immediately after preparation and after storage for 1 month was measured, and further expanded according to the following formula The rate (%) was calculated. The results (average value of the expansion rate of 3 tablets per various tablets) are shown in Table 15.
  • Expansion rate (%) ⁇ (tablet thickness after 1 month storage) ⁇ (thickness of tablet immediately after preparation) ⁇ / (thickness of tablet immediately after preparation) ⁇ 100
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 340.5 g, d-chlorpheniramine maleate (manufactured by Kongo Chemicals: trade name D-chlorpheniramine maleate) 5 .8 g, dl-methylephedrine hydrochloride (Alps Yakuhin Kogyo Co., Ltd .: trade name: Japanese Pharmacopoeia dl-Methylephedrine hydrochloride powder) 100.0 g, Guayphenesine (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia Guayphenesine) 416.7 g, anhydrous Caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 66.7 g, hydroxypropylcellulose (manufactured by Nippo
  • This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type).
  • a granulator Okada Seiko Co., Ltd .: ND-10 type.
  • 3.87.5 g of this sized product and 182.5 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a blender (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 5 mm punch, and tablets with a weight of 270 mg were obtained.
  • a tableting machine manufactured by Hata Iron Works: Model HT-AP18SS
  • Tablet 15-B was obtained in the same manner as Tablet 15-A, except that anhydrous calcium hydrogen phosphate, which is a basic compound having acid neutralizing ability, was used instead of crystalline cellulose.
  • anhydrous calcium hydrogen phosphate which is a basic compound having acid neutralizing ability
  • loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate
  • d-chlorpheniramine maleate manufactured by Kongo Chemical Co., Ltd .: trade name D-maleic acid) Chlorpheniramine
  • 5.8 g dl-methylephedrine hydrochloride (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia dl-methyl ephedrine hydrochloride powder) 100.0 g, guaifenesin (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia Guayphenesin) 416.7
  • This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type).
  • a granulator Okada Seiko Co., Ltd .: ND-10 type.
  • 3.87.5 g of this sized product and 182.5 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a blender (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 5 mm punch, and tablets with a weight of 270 mg were obtained.
  • a tableting machine manufactured by Hata Iron Works: Model HT-AP18SS
  • Tablet 15-C is obtained in the same manner as Tablet 15-A except that a combination of anhydrous calcium hydrogen phosphate and magnesium aluminate metasilicate, which is a basic compound having acid neutralizing ability, is used instead of crystalline cellulose. It was.
  • loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 340.5 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-maleic acid) Chlorpheniramine) 5.8 g, dl-methylephedrine hydrochloride (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia dl-methyl ephedrine hydrochloride powder) 100.0 g, guaifenesin (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia Guayphenesin) 416.7 g, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 66.7 g, hydroxypropylcellulose (manufactured by Nippon So,
  • This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type).
  • a granulator Okada Seiko Co., Ltd .: ND-10 type.
  • 3.87.5 g of this sized product and 182.5 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a blender (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 5 mm punch, and tablets with a weight of 270 mg were obtained.
  • a tableting machine manufactured by Hata Iron Works: Model HT-AP18SS
  • Example 1 Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical: trade name: D-chlorpheniramine maleate) 7 g , 400 g of magnesium hydroxide (Kyowa Chemical Industry, trade name: Kyowasui Mug), 145.8 g of hydroxypropyl cellulose (trade name: HPC-L, manufactured by Nippon Soda), 486 g of carmellose calcium (trade name: ECG505), and Crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd .: trade name: Theolas PH-101) was charged into a high-speed stirring granulator (manufactured by Paulek: model VG-25) and mixed, and then 1972.6 g of
  • a granulated product was obtained.
  • This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type).
  • 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.
  • a tableting machine manufactured by Hata Iron Works: Model HT-AP18SS
  • Example 2 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 3.5 mg
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1682mg
  • Example 3 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • 204.3mg d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 3.5 mg
  • Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1682mg
  • Example 4 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • 204.3mg d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate)
  • Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Lactose hydrate 1682mg
  • Example 5 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 1.34 mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1684.16mg Magnesium stearate 24.3mg
  • Example 6 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1678mg Magnesium stearate 24.3mg
  • Example 7 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Carbinoxamine maleate manufactured by Kongo Chemicals: trade name carbinoxamine maleate
  • Precipitated calcium carbonate Sankyo Seiyaku: Product name Precipitated Carbonate CA
  • Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1678mg
  • Example 8 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 4.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Carbinoxamine maleate manufactured by Kongo Chemicals: trade name carbinoxamine maleate
  • Magnesium oxide trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical
  • Example 9 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Diphenylpyraline hydrochloride product of Kongo Chemicals: trade name diphenylpyraline hydrochloride
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1681.5mg Magnesium stearate 24.3mg
  • Example 10 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Diphenylpyraline hydrochloride (product of Kongo Chemicals: trade name diphenylpyraline hydrochloride) 4mg
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1681.5mg Magnesium stearate 24.3mg
  • Example 11 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Bromhexine hydrochloride (trade name: Bromhexine hydrochloride, manufactured by Sanyo Chemical) 12 mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1673.5mg Magnesium stearate 24.3mg
  • Example 12 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 12mg
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1673.5mg
  • Example 13 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 12mg
  • Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1673.5mg
  • Example 14 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Ambroxol hydrochloride product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1640.5mg Magnesium stearate 24.3mg
  • Example 15 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Ambroxol hydrochloride product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2
  • Example 16 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Ambroxol hydrochloride product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry
  • Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1640.5mg
  • Example 17 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Guaifenesin product name: Guaifenesin
  • Magnesium hydroxide manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug
  • Example 18 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Guaifenesin product name: Guaifenesin
  • Magnesium aluminate silicate Tonda Pharmaceutical: Brand name Magnesium aluminate) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1435.5mg
  • Example 19 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Guaifenesin (product name: Guaifenesin) 250 mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1435.5mg Magnesium stearate 24.3mg
  • Example 20 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Guaifenesin product name: Guaifenesin
  • Magnesium oxide trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical
  • Example 21 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Guaifenesin product name: Guaifenesin
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2
  • Example 22 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • 204.3mg Guaifenesin (product name: Guaifenesin) 250 mg
  • Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1435.5mg
  • Example 23 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Potassium guaiacol sulfonate (trade name: Potassium guaiacol sulfonate manufactured by Yonezawa Hamari Chemical Co., Ltd.) 250mg
  • Magnesium hydroxide manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1435.5mg
  • Example 24 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate) 250mg
  • Magnesium aluminate silicate Tonda Pharmaceutical: Brand name Magnesium aluminate) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1435.5mg Magnesium stearate 24.3mg
  • Example 25 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate)
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1435.5mg Magnesium stearate 24.3mg
  • Example 26 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate) 250mg
  • Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1435.5mg Magnesium stearate 24.3mg
  • Example 27 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate)
  • Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1435.5mg
  • Example 28 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate)
  • Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1435.5mg
  • Example 29 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
  • Magnesium hydroxide manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1661.5mg Magnesium stearate 24.3mg
  • Example 30 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1661.5mg Magnesium stearate 24.3mg
  • Example 31 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”) 24mg
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1661.5mg Magnesium stearate 24.3mg
  • Example 32 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”) 24mg
  • Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1661.5mg
  • Example 33 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 4.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”
  • Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Lactose hydrate 1661.5mg
  • Example 34 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
  • Magnesium hydroxide manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug
  • Example 35 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1625.5mg Magnesium stearate 24.3mg
  • Example 36 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
  • Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1625.5mg Magnesium stearate 24.3mg
  • Example 37 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
  • Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1625.5mg Magnesium stearate 24.3mg
  • Example 38 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 4.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
  • Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Lactose hydrate 1625.5mg Magnesium stearate 24.3mg
  • Example 39 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Anhydrous caffeine product name: anhydrous caffeine, manufactured by Shizuoka Caffeine Industry
  • Magnesium hydroxide manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug
  • Example 40 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Anhydrous caffeine product name: anhydrous caffeine, manufactured by Shizuoka Caffeine Industry
  • Magnesium aluminate silicate Tonda Pharmaceutical: Brand name Magnesium aluminate
  • Example 41 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Anhydrous caffeine product name: anhydrous caffeine, manufactured by Shizuoka Caffeine Industry
  • Anhydrous calcium hydrogen phosphate manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H
  • Example 42 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Anhydrous caffeine manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine
  • Magnesium oxide trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical
  • Example 43 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1535.5mg Magnesium stearate 24.3mg
  • Example 44 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg
  • Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1535.5mg Magnesium stearate 24.3mg
  • Example 45 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg Dry aluminum hydroxide gel (Kyowa Chemical Industry: trade name Dry aluminum hydroxide gel) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1535.5mg Magnesium stearate 24.3mg
  • Example 46 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Anhydrous caffeine manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine
  • Synthetic hydrotalcite trade name: Synthetic hydrotalcite, manufactured by Tomita Pharmaceutical
  • Example 47 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Bromvalerylurea product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P
  • Magnesium oxide trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical
  • Example 48 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Bromvalerylurea (product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P) 600mg
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1085.5mg Magnesium stearate 24.3mg
  • Example 49 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Bromvalerylurea product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P
  • 600mg Dry aluminum hydroxide gel (Kyowa Chemical Industry: trade name Dry aluminum hydroxide gel) 200mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1085.5mg
  • Example 50 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Bromvalerylurea product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P
  • Synthetic hydrotalcite trade name: Synthetic hydrotalcite, manufactured by Tomita Pharmaceutical
  • Example 51 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Allyl isopropyl acetyl urea product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”
  • Magnesium oxide trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical
  • Example 52 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Allyl isopropyl acetyl urea (product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”) 180 mg
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2
  • Hydroxypropylcellulose 72.9mg
  • Example 53 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Allyl isopropyl acetyl urea product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”
  • Dry aluminum hydroxide gel Karl-alcoholic Chemical Industry: trade name Dry aluminum hydroxide gel
  • Carmellose calcium 243mg Crystalline cellulose 1505.5mg
  • Example 54 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Allyl isopropyl acetyl urea product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”
  • Synthetic hydrotalcite trade name: Synthetic hydrotalcite, manufactured by Tomita Pharmaceutical
  • Example 55 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Clemastine fumarate manufactured by Daito: trade name clemastine fumarate
  • Lysozyme hydrochloride product of Eisai: trade name lysozyme chloride
  • 90mg Belladonna Total Alkaloid 0.3mg Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”
  • Noscapine 48mg dl-Methylephedrine hydrochloride manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia
  • Example 56 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Ambroxol hydrochloride product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry
  • Dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”
  • 24 mg dl-Methylephedrine hydrochloride manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder
  • 60mg dl-chlorpheniramine maleate manufactured by Kongo Chemicals: trade name
  • Example 57 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Ethenzamid 252mg Bromvalerylurea (product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P) 600mg
  • Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 883.5mg Magnesium stearate 24.3mg
  • Example 58 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Allyl isopropyl acetyl urea (product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”) 180 mg
  • Anhydrous caffeine manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine
  • Magnesium oxide (trade name: Heavy magnesium oxide, manufactured by Tomita Pharmaceutical) 300 mg Hydroxypropylcellulose 72.9mg Carmellose calcium 243mg Crystalline cellulose 1165.5mg Magnesium stearate 24.3mg
  • Example 59 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Allyl isopropyl acetyl urea (product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”) 180 mg Butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Butyl scopolamine bromide) 30mg Calcium silicate (product of Tokuyama: trade name FLORITE RE) 8.1mg Tranexamic acid 420mg Crystalline cellulose 25.2mg Lactose hydrate 25.2mg Hydroxypropylcellulose 32.4mg Carmellose calcium 24.3mg Crospovidone 24.3mg Magnesium
  • Example 60 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Butyl scopolamine bromide) 30mg
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2
  • 100mg Crystalline cellulose 194.7mg Lactose hydrate 200mg Hydroxypropylcellulose 32.4mg Croscarmellose sodium 24.3mg Hydrous silicon dioxide 8.1mg Magnesium stearate 16.2mg
  • Example 61 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Butyl scopolamine bromide) 30mg Calcium silicate (product of Tokuyama: trade name FLORITE RE) 8.1mg Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 100 mg Crystalline cellulose 170.4mg Lactose hydrate 200mg Hydroxypropylcellulose 32.4mg Low substituted hydroxypropylcellulose 24.3mg Crospovidone 24.3mg Magnesium stearate 16.2mg
  • Example 62 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Belladonna extract (trade name: Japanese Pharmacopoeia Belladonna Extract) 30mg Calcium silicate (product of Tokuyama: trade name FLORITE RE) 8.1mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 100 mg Crystalline cellulose 170.4mg Lactose hydrate 200mg Hydroxypropylcellulose 32.4mg Low substituted hydroxypropylcellulose 24.3mg Crospovidone 24.3mg Magnesium stearate 16.2mg
  • Example 63 Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Rohto extract Alphas Yakuhin Kogyo: trade name: Japanese Pharmacopoeia Roto Extract
  • Magnesium aluminate metasilicate (Fuji Kagaku Kogyo: trade name Neusilin UFL2) 100 mg Crystalline cellulose 194.7mg Lactose hydrate 200mg Hydroxypropylcellulose 32.4mg Croscarmellose sodium 24.3mg Hydrous silicon dioxide 8.1mg Magnesium stearate 16.2mg
  • Example 64 Thirty tablets obtained in Example 1 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 65 Thirty tablets obtained in Example 2 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 66 Thirty tablets obtained in Example 3 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 67 Thirty tablets obtained in Example 4 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 68 Thirty tablets obtained in Example 5 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 69 Thirty tablets obtained in Example 6 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 70 Thirty tablets obtained in Example 7 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 71 Thirty tablets obtained in Example 8 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 72 Thirty tablets obtained in Example 9 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 73 Thirty tablets obtained in Example 10 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 74 Thirty tablets obtained in Example 11 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 75 Thirty tablets obtained in Example 12 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 76 Thirty tablets obtained in Example 13 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 77 Thirty tablets obtained in Example 14 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 78 Thirty tablets obtained in Example 15 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 79 Thirty tablets obtained in Example 16 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 80 Thirty tablets obtained in Example 17 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 81 Thirty tablets obtained in Example 18 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 82 Thirty tablets obtained in Example 19 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 83 Thirty tablets obtained in Example 20 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 84 Thirty tablets obtained in Example 21 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 85 Thirty tablets obtained in Example 22 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 86 Thirty tablets obtained in Example 23 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 87 Thirty tablets obtained in Example 24 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 88 Thirty tablets obtained in Example 25 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 89 Thirty tablets obtained in Example 26 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 90 Thirty tablets obtained in Example 27 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 91 Thirty tablets obtained in Example 28 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 92 Thirty tablets obtained in Example 29 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 93 Thirty tablets obtained in Example 30 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 94 Thirty tablets obtained in Example 31 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 95 30 tablets obtained in Example 32 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • synthetic zeolite manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506
  • Example 96 Thirty tablets obtained in Example 33 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 97 Thirty tablets obtained in Example 34 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 98 Thirty tablets obtained in Example 35 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 99 Thirty tablets obtained in Example 36 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • synthetic zeolite manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506
  • Example 100 Thirty tablets obtained in Example 37 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 101 Thirty tablets obtained in Example 38 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 102 Thirty tablets obtained in Example 39 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 103 Thirty tablets obtained in Example 40 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 104 Thirty tablets obtained in Example 41 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 105 Thirty tablets obtained in Example 42 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 106 Thirty tablets obtained in Example 43 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 107 Thirty tablets obtained in Example 44 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 108 Thirty tablets obtained in Example 45 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 109 Thirty tablets obtained in Example 46 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 110 Thirty tablets obtained in Example 47 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 111 30 tablets obtained in Example 48 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • synthetic zeolite manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506
  • Example 112 Thirty tablets obtained in Example 49 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 113 Thirty tablets obtained in Example 50 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 114 Thirty tablets obtained in Example 51 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 115 Thirty tablets obtained in Example 52 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 116 Thirty tablets obtained in Example 53 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 117 Thirty tablets obtained in Example 54 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 118 Thirty tablets obtained in Example 55 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 119 Thirty tablets obtained in Example 56 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 120 Thirty tablets obtained in Example 57 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 121 Thirty tablets obtained in Example 58 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 122 Thirty tablets obtained in Example 59 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 123 Thirty tablets obtained in Example 60 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 124 Thirty tablets obtained in Example 61 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 125 Thirty tablets obtained in Example 62 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 126 Thirty tablets obtained in Example 63 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
  • Example 127 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact with each other Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29 Stir 2 g of macrogol 6000 (manufactured by NOF Corporation: trade name Macrogol 6000P) and 24.3 g of corn starch (manufactured by Nissho Chemical Co., Ltd .: trade name corn starch ST-C) in a glass beaker on a 65 ° C. water bath. Then, after cooling, it was sieved with No.
  • dihydrocodeine phosphate 8 g (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”)
  • carmellose calcium 81 g (manufactured by Gotoku Pharmaceutical: trade name ECG505)
  • lactose hydrate 524.6 g Made by DMV: Trade name Lactose 200M
  • Magnesium hydroxide 66.7 g Kyowasui Mug
  • Magnesium stearate 8.1 g (Taihei Chemical Industry: trade name Magnesium stearate (vegetable))
  • tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a punch with a diameter of 8.5 mm to obtain a tablet having a mass of 270 mg.
  • Example 128 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact Tablets having the following ingredients and amounts in 9 tablets were produced in the same manner as in Example 117.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1573.9mg
  • Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Magnesium stearate 24.3mg
  • Example 129 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate do not substantially contact each other 9 tablets in 9 tablets were produced in the same manner as in Example 117.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg Hardened oil (manufactured by Kawaken Fine Chemicals: Trade name K-3 Wax-200) 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1573.9mg Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Magnesium stearate 2
  • Example 130 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”
  • Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1573.9mg
  • Precipitated calcium carbonate Surankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Magnesium stearate 24.3mg
  • Example 131 Preparation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”
  • Hardened oil 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1573.9mg
  • Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg Magnesium stearate 24.3mg
  • Example 132 Preparation in which loxoprofen sodium hydrate and dihydrocodeine phosphate do not substantially come into contact Tablets having the following components and amounts in 9 tablets were produced in the same manner as in Example 117.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1573.9mg
  • Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg Magnesium stearate 24.3mg
  • Example 133 Formulation in which loxoprofen sodium hydrate and d-chlorpheniramine maleate are not substantially in contact with each other
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 3.5 mg Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1594.4mg
  • Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Magnesium stearate 24.3mg
  • Example 134 Formulation in which loxoprofen sodium hydrate and d-chlorpheniramine maleate are not substantially in contact with each other
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • 204.3mg d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 3.5 mg
  • Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg Magnesium stearate 24.3mg
  • Example 135 Preparation in which loxoprofen sodium hydrate and clemastine fumarate are not substantially in contact
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Clemastine fumarate manufactured by Daito: trade name clemastine fumarate
  • Hardened oil 87.6mg
  • Corn starch 72.9mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Magnesium stearate 24.3mg
  • Example 136 Preparation in which loxoprofen sodium hydrate and carbinoxamine maleate are not substantially in contact with each other
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1590.4mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Magnesium stearate 24.3mg
  • Example 137 Formulation in which loxoprofen sodium hydrate and carbinoxamine maleate are not substantially in contact 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured by.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Carbinoxamine maleate manufactured by Kongo Chemicals: trade name carbinoxamine maleate
  • Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1590.4mg
  • Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Magnesium stearate 24.3mg
  • Example 138 Formulation in which loxoprofen sodium hydrate and carbinoxamine maleate are not substantially in contact 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured by.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Carbinoxamine maleate manufactured by Kongo Chemicals: trade name carbinoxamine maleate
  • Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg Magnesium stearate 24.3mg
  • Example 139 Preparation in which loxoprofen sodium hydrate and diphenylpyraline hydrochloride are not substantially in contact with each other
  • Nine tablets (daily dose) containing the following ingredients were prepared in the same manner as in Example 117 did.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Diphenylpyraline hydrochloride (product of Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 4mg Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1593.9mg Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Magnesium stearate 24.3mg
  • Example 140 Preparation in which loxoprofen sodium hydrate and diphenylpyraline hydrochloride are not substantially in contact with each other 9 tablets (daily dose) containing the following ingredients were prepared in the same manner as in Example 117 did.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Diphenylpyraline hydrochloride (product of Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 4mg Hardened oil 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1593.9mg Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Magnesium stearate 24.3mg
  • Example 141 Preparation in which loxoprofen sodium hydrate and bromhexine hydrochloride are not substantially in contact
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 12mg Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1585.9mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Magnesium stearate 24.3mg
  • Example 142 Preparation in which loxoprofen sodium hydrate and bromhexine hydrochloride are not substantially in contact
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Bromhexine hydrochloride manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2
  • Magnesium aluminate metasilicate manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2
  • Example 143 Formulation in which loxoprofen sodium hydrate and bromhexine hydrochloride are not substantially in contact
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Bromhexine hydrochloride manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride
  • Precipitated calcium carbonate Surankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Magnesium stearate 24.3mg
  • Example 144 Formulation in which loxoprofen sodium hydrate and ambroxol hydrochloride do not substantially contact each other 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1552.9mg Anhydrous calcium hydrogen phosphate (Kyowa Chemical Industry, trade name: anhydrous calcium hydrogen phosphate) 200mg Magnesium stearate 24.3mg
  • Example 145 Formulation in which loxoprofen sodium hydrate and ambroxol hydrochloride do not substantially contact each other 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg Hardened oil 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1552.9mg Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg Magnesium stearate 24.3mg
  • Example 146 Formulation in which loxoprofen sodium hydrate and ambroxol hydrochloride do not substantially contact each other 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1552.9mg Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg Magnesium stearate 24.3mg
  • Example 147 Formulation in which loxoprofen sodium hydrate and potassium guaiacol sulfonate are not substantially in contact
  • Nine tablets (daily dose) containing the following ingredients were produced in the same manner as in Example 117 did.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate) Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1347.9mg Magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg Magnesium stearate 24.3mg
  • Example 148 Formulation in which loxoprofen sodium hydrate and potassium guaiacol sulfonate are not substantially in contact
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Potassium guaiacol sulfonate manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate
  • Magnesium aluminate silicate Tonda Pharmaceutical: Brand name Magnesium aluminate
  • Example 149 Formulation in which loxoprofen sodium hydrate and sodium caffeine benzoate do not substantially contact each other 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured.
  • Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
  • Sodium benzoate caffeine (manufactured by Shizuoka Caffeine: trade name sodium benzoate caffeine) 300mg Macrogol 6000 87.6mg Corn starch 72.9mg Carmellose calcium 243mg Lactose hydrate 1297.9mg
  • Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg Magnesium stearate 24.3mg
  • Example 150 Preparation in which loxoprofen sodium hydrate and bromvaleryl urea do not substantially contact each other In 9 tablets (daily dose), tablets containing the following components were produced in the same manner as in Example 117.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Bromvalerylurea product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P
  • Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg Magnesium stearate 24.3mg
  • Example 151 Formulation in which loxoprofen sodium hydrate and butylscopolamine bromide are not substantially in contact with each other Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 parts by mass, Calcium silicate (manufactured by Tokuyama: trade name FLORITE RE) 8.1 parts by mass, 16.2 parts by mass of hydroxypropylcellulose, 24.3 parts by mass of sodium carboxymethyl starch and 50.4 parts by mass of crystalline cellulose are mixed and purified After kneading and granulating with water, the granules were sized to obtain a granulated product.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • Calcium silicate manufactured by Tokuyama: trade name FLORITE RE
  • butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia butyl scopolamine bromide) 30 parts by mass, tranexamic acid 750 parts by mass, hydroxypropylcellulose 16.2 parts by mass, carmellose calcium 24.3 parts by mass and lactose water 60 parts by mass of a Japanese product 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 granule for tableting was tableted to obtain a tablet in which loxoprofen sodium hydrate and butyl scopolamine bromide were not substantially in contact with each other.
  • Example 152 Formulation in which loxoprofen sodium hydrate and butyl scopolamine bromide are not substantially in contact with each other Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 parts by mass, 16.2 parts by mass of hydroxypropylcellulose, 24.3 parts by mass of croscarmellose sodium, 8.1 parts by mass of light anhydrous silicic acid and 65.2 parts by mass of crystalline cellulose were mixed and kneaded using purified water. After granulation, the granules were sized to obtain a granulated product.
  • Loxoprofen sodium hydrate manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate
  • butyl scopolamine bromide manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia butyl scopolamine bromide
  • magnesium metasilicate aluminate trade name: Neusilin UFL2
  • tranexamic acid 750 parts by mass 16.2 parts by mass of hydroxypropylcellulose
  • 24.3 parts by mass of croscarmellose sodium and 6 parts by mass of lactose hydrate are mixed, kneaded using ethanol, granulated, and then granulated and granulated.
  • the interaction between loxoprofen or a salt thereof and an interactive component can be suppressed. Therefore, it is possible to provide a pharmaceutical composition comprising loxoprofen or a salt thereof and an interactive component, which has excellent storage stability.

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Abstract

Provided is a pharmaceutical composition in which the interaction between loxoprofen or a salt thereof and an interacting component is suppressed. The pharmaceutical composition contains loxoprofen or a salt thereof, an interacting component, and a basic compound capable of acid neutralization.

Description

ロキソプロフェンを含有する医薬組成物Pharmaceutical composition containing loxoprofen
　本発明は、ロキソプロフェン又はその塩を含有する医薬組成物に関する。 The present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof.
　ロキソプロフェンは、非ステロイド性消炎鎮痛剤（ＮＳＡＩＤ）の一種であり、関節リウマチ、変形性関節症、腰痛症、肩関節周囲炎、頸肩腕症候群、歯痛、急性上気道炎、手術後・外傷後・抜歯後等の消炎・鎮痛・解熱に有効なものとして知られており（非特許文献１）、その優れた解熱鎮痛作用から、総合感冒薬や解熱鎮痛剤等への配合も期待される。 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), and its excellent antipyretic analgesic action is expected to be incorporated into a general cold medicine, antipyretic analgesic, and the like.
　一方、これまでに、総合感冒薬、解熱鎮痛剤においては、解熱鎮痛成分のほか、抗ヒスタミン成分、去痰成分、消炎酵素成分、鎮咳成分、中枢神経興奮成分、催眠鎮静成分、抗アセチルコリン成分、抗プラスミン成分、生薬成分など多種多様の成分の組み合わせが配合されている。 On the other hand, so far, in general cold medicine and antipyretic analgesics, in addition to antipyretic analgesic components, antihistamine component, expectorant component, anti-inflammatory enzyme component, antitussive component, central nervous excitable component, hypnotic sedative component, antiacetylcholine component, anti Various combinations of ingredients such as plasmin ingredients and herbal medicine ingredients are blended.
　抗ヒスタミン成分としては、具体的には例えば、クロルフェニラミン又はその塩；クレマスチン又はその塩；カルビノキサミン又はその塩；ジフェニルピラリン又はその塩等が挙げられ、総合感冒薬のほか、鼻炎用内服薬、アレルギー用剤など様々の医薬品に用いられている（非特許文献２～５）。
　上記のうち、クロルフェニラミンは、下記式 Specific examples of the antihistamine component include chlorpheniramine or a salt thereof; clemastine or a salt thereof; carbinoxamine or a salt thereof; diphenylpyraline or a salt thereof, etc. It is used in various pharmaceuticals such as pharmaceuticals (Non-Patent Documents 2 to 5).
Of the above, chlorpheniramine has the following formula:
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
で表される化合物である。
　また、クレマスチンは、下記式 It is a compound represented by these.
In addition, clemastine has the following formula:
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
で表される化合物である。
　また、カルビノキサミンは、下記式 It is a compound represented by these.
Carbinoxamine has the following formula:
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
で表される化合物である。
　また、ジフェニルピラリンは、下記式 It is a compound represented by these.
In addition, diphenylpyraline has the following formula:
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
で表される化合物である。これらの化合物はいずれもジアリールメチル構造をその共通骨格として有し、化学構造が相互に極めて類似している。 It is a compound represented by these. These compounds all have a diarylmethyl structure as a common skeleton, and their chemical structures are very similar to each other.
　去痰成分としては、具体的には例えば、ブロムヘキシン又はその塩；アンブロキソール又はその塩；グアヤコールスルホン酸又はその塩、グアイフェネシン、クレゾールスルホン酸又はその塩等のフェノール誘導体又はその塩などが挙げられる。
　上記のうち、ブロムヘキシンは、下記式 Specific examples of the expectorant component include bromhexine or a salt thereof; ambroxol or a salt thereof; phenol derivative such as guaiacol sulfonic acid or a salt thereof, guaifenesin, cresolsulfonic acid or a salt thereof, or the like.
Of the above, bromhexine has the following formula:
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
で表される化合物であり、気道粘膜の分泌促進による粘液の希釈をはかる粘稠調整作用に基づく去痰作用を有し、スイッチＯＴＣ薬物として認可され、総合感冒薬に用いられるほか、医療用としては、急性・慢性気管支炎や塵肺症等の去痰に用いられている（非特許文献６）。
　また、アンブロキソールは、下記式 It has the expectorant action based on the viscosity adjustment action to dilute mucus by promoting secretion of the respiratory tract mucosa, and is approved as a switch OTC drug, used for general cold medicine, and for medical use It is used for expectoration such as acute and chronic bronchitis and pneumoconiosis (Non-patent Document 6).
Ambroxol has the following formula:
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
で表される化合物であり、去痰成分である上記ブロムヘキシンの活性代謝物として知られ、粘膜潤滑成分とも呼ばれている。スイッチＯＴＣ薬物として認可され、総合感冒薬に用いられるほか、医療用としては、急性・慢性気管支炎や塵肺症等の去痰に用いられる（非特許文献７）。 Is known as an active metabolite of the above bromhexine, which is an expectorant component, and is also called a mucosal lubricating component. In addition to being approved as a switch OTC drug and used for general cold medicine, it is used for expectoration of acute and chronic bronchitis, pneumoconiosis, etc. for medical use (Non-patent Document 7).
　また、グアヤコールスルホン酸又はその塩、グアイフェネシン、クレゾールスルホン酸又はその塩等のフェノール誘導体又はその塩は、気道分泌促進作用等を有する成分である（非特許文献８）。 Further, phenol derivatives or salts thereof such as guaiacol sulfonic acid or its salt, guaifenesin, cresol sulfonic acid or its salt are components having airway secretion promoting action and the like (Non-patent Document 8).
　消炎酵素成分としては、具体的には例えば、リゾチーム又はその塩などが挙げられる。これらは、ムコ多糖分解作用や抗炎症作用等を示し、ムコ多糖分解作用による痰や鼻汁の膿粘液の分解や抗炎症作用を期待して、総合感冒薬のほか、鎮咳去痰剤や鼻炎用内服薬等にも用いられる薬物である（非特許文献９）。 Specific examples of the anti-inflammatory enzyme component include lysozyme or a salt thereof. These have mucopolysaccharide decomposing action, anti-inflammatory action, etc. In addition to comprehensive cold medicine, antitussive expectorant and rhinitis oral medicine, in anticipation of mucopolysaccharide decomposing action to decompose sputum and nasal pus mucus and anti-inflammatory action (Non-patent document 9).
　鎮咳成分としては、具体的には例えば、コデイン類；エフェドリン類；デキストロメトルファン又はその塩等が挙げられる。
　上記のうち、コデイン類は、咳中枢の機能を抑制することによる鎮咳作用を有する麻薬性鎮咳成分であることが知られている。そして、この作用に基づき、総合感冒薬のほか、鎮咳去痰薬等にも用いられている薬物である（非特許文献１０）。
　また、エフェドリン類は、交感神経興奮作用に基づく気管支拡張作用により、鎮咳作用をもたらすことが知られている。そして、鎮咳成分として、総合感冒薬、鎮咳去痰薬に用いられるほか、血管収縮作用による鼻づまりの緩和を目的として鼻炎用内服薬等にも用いられている薬物である（非特許文献１１及び１２）。
　また、デキストロメトルファン又はその塩は、中枢性非麻薬性鎮咳成分であり、咳中枢に直接作用し、咳反射を抑制することで鎮咳作用を示すことが知られている。そして、この作用に基づき、総合感冒薬のほか、鎮咳去痰薬にも用いられている薬物である（非特許文献１１）。 Specific examples of the antitussive component include codeines; ephedrines; dextromethorphan or a salt thereof.
Among the above, codeines are known to be narcotic antitussive components having an antitussive action by suppressing the function of the cough center. And based on this effect | action, it is a drug used for an antitussive expectorant etc. other than a general cold medicine (nonpatent literature 10).
In addition, ephedrines are known to have an antitussive effect by bronchodilating action based on sympathomimetic action. In addition to being used as a general cold medicine and antitussive expectorant as an antitussive component, it is a drug that is also used as an internal medicine for rhinitis for the purpose of alleviating nasal congestion due to vasoconstriction (Non-patent Documents 11 and 12).
Moreover, dextromethorphan or a salt thereof is a central non-narcotic antitussive component, and is known to exhibit an antitussive action by acting directly on the cough center and suppressing the cough reflex. And based on this effect | action, it is a drug used also for an antitussive expectorant besides a general cold medicine (nonpatent literature 11).
　中枢神経興奮成分としては、具体的には例えば、カフェインを始めとするキサンチン誘導体が挙げられる。カフェインは中枢興奮作用、強心・利尿作用、胃酸分泌亢進作用、平滑筋弛緩作用等を示し、総合感冒薬のほか、解熱鎮痛剤、鎮咳去痰薬等に用いられる薬物である（非特許文献１３）。また、カフェインと類似の構造を有するテオフィリン、パラキサンチン、テオブロミン、アミノフィリン、ジプロフィリン、プロキシフィリン等の他のキサンチン誘導体も、カフェインと類似の薬理作用を有する。テオフィリンは中枢興奮作用、強心・利尿作用、平滑筋弛緩作用等を示し、鎮咳去痰薬や鎮暈薬等に用いられる薬物である。アミノフィリンはテオフィリンとエチレンジアミンの複塩であり、テオフィリンと同様の作用を示し、ジプロフィリンも、テオフィリンと同様の作用を示す（非特許文献１４）。プロキシフィリンもテオフィリンと同様の作用を示し（非特許文献１５）、パラキサンチンやテオブロミンも同様の作用を示す。 Specific examples of central nervous excitatory components include xanthine derivatives such as caffeine. Caffeine exhibits central excitatory action, cardiotonic / diuretic action, gastric acid secretion enhancing action, smooth muscle relaxing action, etc., and is a drug used for antipyretic analgesics, antitussive expectorants, etc. in addition to general cold medicine (Non-patent Document 13) ). In addition, other xanthine derivatives such as theophylline, paraxanthine, theobromine, aminophylline, diprofylline, and proxyphylline having a structure similar to caffeine have pharmacological effects similar to caffeine. Theophylline exhibits central excitatory action, cardiotonic / diuretic action, smooth muscle relaxing action, etc., and is a drug used for antitussive expectorant, antipruritics and the like. Aminophylline is a double salt of theophylline and ethylenediamine, and exhibits the same action as theophylline, and diprofylline also exhibits the same action as theophylline (Non-patent Document 14). Proxyphyrin also shows the same action as theophylline (Non-patent Document 15), and paraxanthine and theobromine show the same action.
　催眠鎮静成分としては、具体的には例えば、ブロムワレリル尿素、アリルイソプロピルアセチル尿素等のイソバレリル尿素誘導体が挙げられる。
　上記のうち、ブロムワレリル尿素は、下記式 Specific examples of the hypnotic sedative component include isovaleryl urea derivatives such as bromovalerylurea and allylisopropylacetylurea.
Of the above, bromvalerylurea has the following formula:
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
で表される化合物である。
　また、アリルイソプロピルアセチル尿素は、下記式 It is a compound represented by these.
Allyl isopropyl acetyl urea is represented by the following formula:
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
で表される化合物である。これらのイソバレリル尿素誘導体はいずれも鎮静作用を有し、解熱鎮痛剤等に配合される薬物である（非特許文献１６）。 It is a compound represented by these. All of these isovaleryl urea derivatives have a sedative effect and are drugs that are blended in antipyretic analgesics and the like (Non-patent Document 16).
　抗アセチルコリン成分としては、具体的には例えば、ダツラエキス、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ベラドンナエキス、ロートエキス、メチルスコポラミン又はその塩、ブチルスコポラミン又はその塩等のトロパンアルカロイド類が挙げられ、鼻水（鼻汁）の抑制のほか、鎮痛・鎮痙作用を目的として総合感冒薬等に用いられる。 Specific examples of the anti-acetylcholine component include drip extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, funnel extract, methyl scopolamine or a salt thereof, tropane alkaloids such as butyl scopolamine or a salt thereof, ), As well as general cold medicine for the purpose of analgesia and antispasmodic action.
　ロキソプロフェンは、その優れた薬理作用から、様々な薬物と組み合せることが検討されており、上述した総合感冒薬に用いられる成分等との組み合わせも種々知られている。
　例えば、特許文献１には、（１）クレマスチン類、フェニラミン類、マレイン酸カルビノキサミン、エフェドリン類、コデイン類、塩酸フェニルプロパノールアミン、セラペプターゼ、塩化リゾチーム及び塩酸ブロムヘキシンより選択される１種又は２種以上の薬剤、並びに（２）ロキソプロフェン類を有効成分として含有する医薬組成物が記載され、当該文献には、マレイン酸カルビノキサミン、ｄ－マレイン酸クロルフェニラミン又は塩酸フェニルプロパノールアミンと組み合わせることによる鎮痛作用の増強作用；リン酸ジヒドロコデイン、マレイン酸カルビノキサミン又は塩酸ブロムヘキシンと組み合わせることによる抗炎症作用の増強作用；マレイン酸カルビノキサミン又は塩化リゾチームと組合わせることによる解熱作用の増強作用；フマル酸クレマスチン又はｄ－マレイン酸クロルフェニラミンと組合わせることによる抗ヒスタミン作用の増強作用などが開示されている。 Loxoprofen has been studied to be combined with various drugs because of its excellent pharmacological action, and various combinations with the components used in the above-mentioned general cold medicine are also known.
For example, Patent Document 1 includes (1) one or more selected from clemastines, phenylamines, carbinoxamine maleate, ephedrines, codeines, phenylpropanolamine hydrochloride, serrapeptase, lysozyme chloride, and bromhexine hydrochloride. A pharmaceutical composition and (2) a pharmaceutical composition containing loxoprofen as an active ingredient is described, and this document enhances analgesic action by combining with carbinoxamine maleate, chlorpheniramine maleate or phenylpropanolamine hydrochloride Action; potentiation of anti-inflammatory action by combining with dihydrocodeine phosphate, carbinoxamine maleate or bromohexine hydrochloride; enhancement of antipyretic action by combining with carbinoxamine maleate or lysozyme chloride Use; and potentiation of anti-histamine action it has been disclosed by be combined with clemastine fumarate or d- chlorpheniramine maleate.
　また、特許文献２には、（ａ）ロキソプロフェン類並びに（ｂ）抗アレルギー薬及び抗ヒスタミン薬からなる群から選ばれる少なくとも１種を配合してなる感冒・鼻炎用組成物が記載されており、マレイン酸カルビノキサミン又はマレイン酸クロルフェニラミンと組み合わせることによる鼻閉症状の改善作用が開示されている。
　また、特許文献３には、去痰薬、及びロキソプロフェン又はその塩類を配合することを特徴とする風邪用組成物が記載されており、塩酸ブロムヘキシン又はアンブロキソールと組み合わせることによる咳嗽症状に対する効果の増強作用が開示されている。 Patent Document 2 describes a composition for cold and rhinitis comprising at least one selected from the group consisting of (a) loxoprofen and (b) an antiallergic agent and an antihistamine, An effect of improving nasal congestion by combining with carbinoxamine maleate or chlorpheniramine maleate is disclosed.
Patent Document 3 describes a composition for colds containing an expectorant and loxoprofen or a salt thereof, and enhances the effect on cough symptoms by combining with bromhexine hydrochloride or ambroxol. The effect is disclosed.
　また、特許文献４には、ロキソプロフェンと、アンブロキソールやブロムヘキシンとを含有する去痰又は気道の杯細胞過形成を抑制するための医薬組成物が記載され、塩酸アンブロキソール又は塩酸ブロムヘキシンと組み合わせることにより杯細胞過形成抑制作用が発現することが開示されている。
　また、特許文献５には、ロキソプロフェン並びに、カフェイン類、エフェドリン類及びコデイン類から選ばれる１種又は２種以上を含有する鎮咳又は去痰のための医薬組成物が記載され、リン酸コデイン又は無水カフェインと組み合わせることによる杯細胞過形成抑制作用の発現が開示されている。
　また、特許文献６には、非ステロイド系抗炎症剤が引き起こす消化管運動亢進作用に対する抑制剤であって、四級アンモニウム系抗コリン剤を有効成分として含む抑制剤が記載され、ロキソプロフェンとブチルスコポラミン臭化物を含有するカプセル剤が開示されている。
　さらに、特許文献７には、ベラドンナアルカロイド、ベラドンナ総アルカロイド及びベラドンナエキスからなる群より選ばれる１種以上とロキソプロフェン又はその塩とを含有する医薬組成物が記載され、ベラドンナアルカロイド等と組み合わせることにより、ロキソプロフェン又はその塩に起因する消化管障害が軽減・抑制されることが開示されている。 Patent Document 4 describes a pharmaceutical composition containing loxoprofen and ambroxol or bromhexine to suppress expectoration or airway goblet cell hyperplasia, which is combined with ambroxol hydrochloride or bromhexine hydrochloride. It is disclosed that a goblet cell hyperplasia inhibitory action is expressed.
Patent Document 5 describes a pharmaceutical composition for antitussive or expectorant containing loxoprofen, and one or more selected from caffeine, ephedrine and codeine, and contains codeine phosphate or anhydrous Expression of goblet cell hyperplasia inhibitory action by combining with caffeine is disclosed.
Further, Patent Document 6 describes an inhibitor against gastrointestinal motility-promoting action caused by a nonsteroidal anti-inflammatory agent, which contains a quaternary ammonium anticholinergic agent as an active ingredient. Loxoprofen and butylscopolamine Capsules containing bromide are disclosed.
Furthermore, Patent Document 7 describes a pharmaceutical composition containing at least one selected from the group consisting of belladonna alkaloids, belladonna total alkaloids and belladonna extracts and loxoprofen or a salt thereof, and in combination with belladonna alkaloids, etc. It is disclosed that gastrointestinal disorders caused by loxoprofen or a salt thereof are reduced / suppressed.
特開２０００－１４３５０５号公報JP 2000-143505 A 特開２００１－１９９８８２号公報JP 2001-199882 A 特開２００１－１７２１７５号公報JP 2001-172175 A 特開２００８－１３５４２号公報JP 2008-13542 A 特開２００７－３１４５１７号公報JP 2007-314517 A 特開２０００－２６３１３号公報Japanese Patent Laid-Open No. 2000-26313 特開２０１０－１６８３７３号公報JP 2010-168373 A
　しかしながら、ロキソプロフェン又はその塩と下記の１～１０から選ばれる成分の１種以上との間に、保存安定性に影響を与えるような相互作用が生じるか否かについては、一切知られていない。
　そこで、本発明者らは、まず、ロキソプロフェン又はその塩と種々の成分の保存安定性について検討したところ、ロキソプロフェン又はその塩と以下の成分１～１０のうちいずれか： However, it is not known at all whether or not an interaction that affects storage stability occurs between loxoprofen or a salt thereof and one or more components selected from the following 1 to 10.
Therefore, the present inventors first examined the storage stability of loxoprofen or a salt thereof and various components, and as a result, any one of the following components 1 to 10:
１　クロルフェニラミン又はその塩、クレマスチン又はその塩、カルビノキサミン又はその塩、ジフェニルピラリン又はその塩などを包含する、下記一般式（１） 1 The following general formula (1) including chlorpheniramine or a salt thereof, clemastine or a salt thereof, carbinoxamine or a salt thereof, diphenylpyraline or a salt thereof, and the like
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
［式（１）中、Ｘは単結合又は酸素原子を示し、Ｙはメチン基又は窒素原子を示し、Ｒ１は水素原子、水酸基又はアルキル基を示し、Ｒ２は置換基を有していてもよい環状アミノ基、又は置換基を有していてもよいアミノアルキル基を示し、Ｒ３は水素原子又はハロゲン原子を示す。］
で表される化合物又はその塩
２　ブロムヘキシン又はその塩、アンブロキソール又はその塩などを包含する、下記一般式（２） [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group, and R 2 has a substituent. A cyclic amino group which may be substituted, or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom. ]
Or a salt thereof 2 represented by the following general formula (2), including bromhexine or a salt thereof, ambroxol or a salt thereof
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
［式（２）中、Ｒ４は水素原子又はメチル基を示し、Ｒ５は水素原子又は水酸基を示す。］
で表される化合物又はその塩
３　グアヤコールスルホン酸又はその塩、グアイフェネシン、クレゾールスルホン酸又はその塩などを包含する、下記一般式（３） [In the formula (2), R 4 represents a hydrogen atom or a methyl group, and R 5 represents a hydrogen atom or a hydroxyl group. ]
Or a salt thereof 3 including guaiacolsulfonic acid or a salt thereof, guaifenesin, cresolsulfonic acid or a salt thereof, and the like.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
［式（３）中、Ｒ６はアルキル基又は置換基を有していてもよいアルコキシ基を示し、Ｒ７は水素原子又はスルホ基を示す。なお、式（３）中のフェノール性水酸基はエーテル化されていてもよい。］
で表される化合物又はその塩
４　リゾチーム又はその塩
５　コデイン類
６　エフェドリン類
７　デキストロメトルファン又はその塩
８　キサンチン誘導体
９　イソバレリル尿素誘導体
１０　トロパンアルカロイド類
（なお、本明細書において、上記１～１０から選ばれる成分の１種以上を「相互作用性成分」と称することがある。） [In Formula (3), R 6 represents an alkyl group or an alkoxy group which may have a substituent, and R 7 represents a hydrogen atom or a sulfo group. In addition, the phenolic hydroxyl group in Formula (3) may be etherified. ]
Or a salt thereof 4 lysozyme or a salt thereof 5 codeine 6 ephedrine 7 dextromethorphan or a salt 8 xanthine derivative 9 isovaleryl urea derivative 10 tropane alkaloids (in the present specification, from 1 to 10 above) (One or more selected components may be referred to as “interactive components”.)
とを混合して保存すると、意外にも、これらの成分の間に相互作用が生じ、この相互作用により、混合物の経時的な湿潤、固化及び変色等の状態変化が生じ、安定性に問題が生じることを見出した。 When mixed and stored, unexpectedly, an interaction occurs between these components, and this interaction causes changes in the state of the mixture such as wetting, solidification, and discoloration over time, which causes problems in stability. Found out that it would occur.
　従って、本発明の課題は、ロキソプロフェン又はその塩と上記相互作用性成分との間の相互作用が抑制された医薬組成物を提供することである。 Therefore, an object of the present invention is to provide a pharmaceutical composition in which the interaction between loxoprofen or a salt thereof and the interactive component is suppressed.
　そこで、本発明者らは、この問題を解決すべくさらに検討したところ、ロキソプロフェン又はその塩及び上記相互作用性成分に、酸中和能を有する塩基性化合物を共存せしめることにより、相互作用を抑制することができることを見出し、本発明を完成した。 Therefore, the present inventors further studied to solve this problem, and as a result, the interaction was suppressed by allowing loxoprofen or a salt thereof and the interactive component to coexist with a basic compound having acid neutralizing ability. As a result, the present invention was completed.
　すなわち、本発明は、次の成分（Ａ）、（Ｂ）及び（Ｃ）：
（Ａ）ロキソプロフェン又はその塩
（Ｂ）次の成分（Ｂ－１）～（Ｂ－１０）からなる群より選ばれる１種又は２種以上
　（Ｂ－１）下記一般式（１） That is, the present invention includes the following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof (B) One or more selected from the group consisting of the following components (B-1) to (B-10) (B-1) The following general formula (1)
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
［式（１）中、Ｘは単結合又は酸素原子を示し、Ｙはメチン基又は窒素原子を示し、Ｒ１は水素原子、水酸基又はアルキル基を示し、Ｒ２は置換基を有していてもよい環状アミノ基、又は置換基を有していてもよいアミノアルキル基を示し、Ｒ３は水素原子又はハロゲン原子を示す。］
で表される化合物又はその塩
　（Ｂ－２）下記一般式（２） [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group, and R 2 has a substituent. A cyclic amino group which may be substituted, or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom. ]
(B-2) The following general formula (2)
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
［式（２）中、Ｒ４は水素原子又はメチル基を示し、Ｒ５は水素原子又は水酸基を示す。］
で表される化合物又はその塩
　（Ｂ－３）下記一般式（３） [In the formula (2), R 4 represents a hydrogen atom or a methyl group, and R 5 represents a hydrogen atom or a hydroxyl group. ]
(B-3) The following general formula (3)
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
［式（３）中、Ｒ６はアルキル基又は置換基を有していてもよいアルコキシ基を示し、Ｒ７は水素原子又はスルホ基を示す。なお、式（３）中のフェノール性水酸基はエーテル化されていてもよい。］
で表される化合物又はその塩
　（Ｂ－４）リゾチーム又はその塩
　（Ｂ－５）コデイン類
　（Ｂ－６）エフェドリン類
　（Ｂ－７）デキストロメトルファン又はその塩
　（Ｂ－８）キサンチン誘導体
　（Ｂ－９）イソバレリル尿素誘導体
　（Ｂ－１０）トロパンアルカロイド類
（Ｃ）酸中和能を有する塩基性化合物
を含有する医薬組成物を提供するものである。 [In Formula (3), R 6 represents an alkyl group or an alkoxy group which may have a substituent, and R 7 represents a hydrogen atom or a sulfo group. In addition, the phenolic hydroxyl group in Formula (3) may be etherified. ]
(B-4) Lysozyme or its salt (B-5) Codeine (B-6) Ephedrine (B-7) Dextromethorphan or its salt (B-8) Xanthine derivative B-9) Isovaleryl urea derivative (B-10) A tropane alkaloid (C) A pharmaceutical composition containing a basic compound having an acid neutralizing ability is provided.
　本発明によれば、ロキソプロフェン又はその塩と相互作用性成分との相互作用を抑制できる。従って、保存安定性が優れた、ロキソプロフェン又はその塩、及び相互作用性成分を含有する医薬組成物を提供することができる。
　また、複雑な工程を経ることなく、簡便かつ安価に、ロキソプロフェン又はその塩、及び相互作用性成分を含有する、相互作用が抑制された医薬組成物を提供することができる。 According to the present invention, the interaction between loxoprofen or a salt thereof and an interactive component can be suppressed. Therefore, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and an interactive component having excellent storage stability.
In addition, a pharmaceutical composition containing loxoprofen or a salt thereof and an interactive component, in which interaction is suppressed, can be provided easily and inexpensively without going through complicated steps.
　＜医薬組成物＞
　まず、本発明の医薬組成物について説明する。
　本発明の成分（Ａ）は、ロキソプロフェン又はその塩である。
　本発明において、「ロキソプロフェン又はその塩」には、ロキソプロフェンそのもののほか、ロキソプロフェンの薬学上許容される塩、さらにはロキソプロフェンやその薬学上許容される塩と水やアルコール等との溶媒和物も含まれる。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。本発明において、ロキソプロフェン又はその塩としては、ロキソプロフェンナトリウム水和物（化学名：Ｍｏｎｏｓｏｄｉｕｍ　２－［４－［（２－ｏｘｏｃｙｃｌｏｐｅｎｔｙｌ）ｍｅｔｈｙｌ］ｐｈｅｎｙｌ］ｐｒｏｐａｎｏａｔｅ　ｄｉｈｙｄｒａｔｅ）が好ましい。 <Pharmaceutical composition>
First, the pharmaceutical composition of the present invention will be described.
Component (A) of the present invention is loxoprofen or a salt thereof.
In the present invention, “loxoprofen or a salt thereof” includes not only loxoprofen itself but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol or the like. It is. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).
　本発明の医薬組成物におけるロキソプロフェン又はその塩の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、１日あたり、ロキソプロフェンナトリウム無水物換算で１０～３００ｍｇ、より好適には３０～２４０ｍｇ、特に好適には６０～１８０ｍｇ服用できる量を含有せしめることができる。本発明においては、ロキソプロフェン又はその塩を医薬組成物全質量に対して、ロキソプロフェンナトリウム無水物換算で０．４～５０質量％含有するのが好ましく、１．２～３０質量％含有するのがより好ましく、１．２～２５質量％含有するのがさらに好ましい。このうち、１．２～２０質量％含有するのがより好ましく、２．４～１５質量％含有するのがさらにより好ましく、２．４～１２質量％含有するのが特に好ましい。 The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, 10 to 300 mg, more preferably 30 to 240 mg, particularly preferably 60 to 180 mg in terms of loxoprofen sodium anhydride can be contained per day. In the present invention, loxoprofen or a salt thereof is preferably contained in an amount of 0.4 to 50% by mass in terms of anhydrous loxoprofen sodium, more preferably 1.2 to 30% by mass, based on the total mass of the pharmaceutical composition. Preferably, the content is 1.2 to 25% by mass. Among these, the content is preferably 1.2 to 20% by mass, more preferably 2.4 to 15% by mass, and particularly preferably 2.4 to 12% by mass.
　次に、本発明の成分（Ｂ）について詳細に説明する。
　本発明において、一般式（１） Next, the component (B) of the present invention will be described in detail.
In the present invention, the general formula (1)
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
［式（１）中、Ｘは単結合又は酸素原子を示し、Ｙはメチン基又は窒素原子を示し、Ｒ１は水素原子、水酸基又はアルキル基を示し、Ｒ２は置換基を有していてもよい環状アミノ基、又は置換基を有していてもよいアミノアルキル基を示し、Ｒ３は水素原子又はハロゲン原子を示す。］
で表される化合物又はその塩には、上記一般式（１）で表される化合物そのもののほか、一般式（１）で表される化合物の薬学上許容される塩も含まれる。一般式（１）で表される化合物又はその塩の具体例としては例えば、一般式（１）で表される化合物、一般式（１）で表される化合物の無機酸塩や有機酸塩（例えば、塩酸塩、マレイン酸塩、フマル酸塩、ジフェニルジスルホン酸塩、テオクル酸塩、サリチル酸塩、タンニン酸塩、ベシル酸塩、リン酸塩など）等が挙げられる。また、一般式（１）で表される化合物の化学構造中、不斉炭素が存する場合は、種々の光学異性体を有するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。さらに、一般式（１）で表される化合物又はその塩は溶媒和物の状態にあってもよく、一般式（１）で表される化合物やその塩と水やアルコール等との溶媒和物も「一般式（１）で表される化合物又はその塩」に含まれる。 [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group, and R 2 has a substituent. A cyclic amino group which may be substituted, or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom. ]
In addition to the compound itself represented by the general formula (1), a pharmaceutically acceptable salt of the compound represented by the general formula (1) is also included. Specific examples of the compound represented by the general formula (1) or a salt thereof include, for example, a compound represented by the general formula (1), an inorganic acid salt or an organic acid salt of the compound represented by the general formula (1) ( For example, hydrochloride, maleate, fumarate, diphenyl disulfonate, theocrate, salicylate, tannate, besylate, phosphate, etc.). In addition, in the chemical structure of the compound represented by the general formula (1), when an asymmetric carbon exists, it has various optical isomers. Or a mixture of various optical isomers. Further, the compound represented by the general formula (1) or a salt thereof may be in the form of a solvate, and a solvate of the compound represented by the general formula (1) or a salt thereof with water, alcohol or the like. Are also included in the “compound represented by the general formula (1) or a salt thereof”.
　上記Ｒ１において、アルキル基としては、直鎖又は分枝鎖の炭素数１～３のアルキル基が好ましい。具体的には、メチル基、エチル基、ｎ－プロピル基、イソプロピル基が挙げられるが、メチル基が好ましい。
　また、上記Ｒ１としては、水素原子、アルキル基が好ましく、水素原子、メチル基がより好ましい。 In the above R 1 , the alkyl group is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, and a methyl group is preferable.
Further, as the R 1, a hydrogen atom, preferably an alkyl group, a hydrogen atom, more preferably a methyl group.
　上記Ｒ２において、置換基を有していてもよい環状アミノ基における「環状アミノ基」とは、環構成原子として窒素原子を少なくとも１個、好適には１又は２個有する５～７員の脂環式基を意味する。
　このような環状アミノ基としては、具体的には例えば、ピロリジニル基、ピラゾリジニル基、ピペリジニル基、ピペラジニル基、モルホリニル基、ホモピペリジニル基、ホモピペラジニル基等が挙げられる。中でも、ピペリジニル基、ピペラジニル基、ホモピペラジニル基が好ましく、ピペリジニル基、ピペラジニル基がより好ましい。 In the above R 2 , the “cyclic amino group” in the cyclic amino group which may have a substituent is a 5- to 7-membered member having at least one, preferably 1 or 2, nitrogen atoms as ring-constituting atoms. An alicyclic group is meant.
Specific examples of such cyclic amino groups include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, and homopiperazinyl groups. Among these, a piperidinyl group, a piperazinyl group, and a homopiperazinyl group are preferable, and a piperidinyl group and a piperazinyl group are more preferable.
　また、置換基を有していてもよい環状アミノ基における「置換基」としては、例えば、アルキルベンゾイル基、１，３－ジヒドロ－２Ｈ－ベンゾイミダゾール－２－オン－１－イル基、カルボキシアルコキシ基、カルボキシル基、カルボキシアルキルフェニル基及び水酸基から選ばれる１種以上の基が置換していてもよいアルキル基等が挙げられる。中でも、アルキル基、カルボキシアルコキシアルキル基、カルボキシアルキルフェニル（ヒドロキシ）アルキル基が好ましい。
　上記「置換基」の具体例としては、例えば、メチル基、３－（４－ｔｅｒｔ－ブチルベンゾイル）プロピル基、３－（１，３－ジヒドロ－２Ｈ－ベンゾイミダゾール－２－オン－１－イル）プロピル基、２－（カルボキシメトキシ）エチル基、４－［４－（２－カルボキシプロパン－２－イル）フェニル］－４－ヒドロキシブチル基、３－カルボキシプロピル基等が挙げられる。 Examples of the “substituent” in the cyclic amino group which may have a substituent include, for example, an alkylbenzoyl group, a 1,3-dihydro-2H-benzimidazol-2-one-1-yl group, and a carboxyalkoxy group. Examples thereof include an alkyl group which may be substituted with one or more groups selected from a group, a carboxyl group, a carboxyalkylphenyl group and a hydroxyl group. Among these, an alkyl group, a carboxyalkoxyalkyl group, and a carboxyalkylphenyl (hydroxy) alkyl group are preferable.
Specific examples of the “substituent” include, for example, methyl group, 3- (4-tert-butylbenzoyl) propyl group, 3- (1,3-dihydro-2H-benzimidazol-2-one-1-yl ) Propyl group, 2- (carboxymethoxy) ethyl group, 4- [4- (2-carboxypropan-2-yl) phenyl] -4-hydroxybutyl group, 3-carboxypropyl group and the like.
　上記Ｒ２において、「置換基を有していてもよい環状アミノ基」としては、１－メチルピペリジン－４－イル基、４－メチルホモピペラジン－１－イル基、１－［３－（４－ｔｅｒｔ－ブチルベンゾイル）プロピル］ピペリジン－４－イル基、４－［３－（１，３－ジヒドロ－２Ｈ－ベンゾイミダゾール－２－オン－１－イル）プロピル］ピペラジン－１－イル基、４－［２－（カルボキシメトキシ）エチル］ピペラジン－１－イル基、１－｛４－［４－（２－カルボキシプロパン－２－イル）フェニル］－４－ヒドロキシブチル｝ピペリジン－４－イル基、１－（３－カルボキシプロピル）ピペリジン－４－イル基が好ましい。 In the above R 2 , the “optionally substituted cyclic amino group” includes a 1-methylpiperidin-4-yl group, a 4-methylhomopiperazin-1-yl group, 1- [3- (4 -Tert-butylbenzoyl) propyl] piperidin-4-yl group, 4- [3- (1,3-dihydro-2H-benzoimidazol-2-one-1-yl) propyl] piperazin-1-yl group, 4 -[2- (carboxymethoxy) ethyl] piperazin-1-yl group, 1- {4- [4- (2-carboxypropan-2-yl) phenyl] -4-hydroxybutyl} piperidin-4-yl group, The 1- (3-carboxypropyl) piperidin-4-yl group is preferred.
　上記Ｒ２において、置換基を有していてもよいアミノアルキル基における「アミノアルキル基」は、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基又は環状アミノ基（当該「環状アミノ基」は、上記した「置換基を有していてもよい環状アミノ基」における「環状アミノ基」と同義である。）が置換したアルキル基を意味する。中でも、ジアルキルアミノ基又は環状アミノ基が置換したアルキル基が好ましい。なお、当該環状アミノ基としては、ピロリジニル基が好ましい。
　このようなアミノアルキル基としては、具体的には例えば、２－（ジメチルアミノ）エチル基、２－（ピロリジン－２－イル）エチル基、２－［（イソプロピル）（メチル）アミノ］エチル基等が挙げられる。また、置換基を有していてもよいアミノアルキル基における「置換基」としては、例えば、水酸基、フェニル基、アルキル基等が挙げられる。 In the above R 2 , the “aminoalkyl group” in the aminoalkyl group which may have a substituent is an amino group, a monoalkylamino group, a dialkylamino group or a cyclic amino group (the “cyclic amino group” is the above The same as the “cyclic amino group” in the “cyclic amino group which may have a substituent”. Among these, an alkyl group substituted with a dialkylamino group or a cyclic amino group is preferable. The cyclic amino group is preferably a pyrrolidinyl group.
Specific examples of such aminoalkyl groups include 2- (dimethylamino) ethyl group, 2- (pyrrolidin-2-yl) ethyl group, 2-[(isopropyl) (methyl) amino] ethyl group, and the like. Is mentioned. Examples of the “substituent” in the aminoalkyl group which may have a substituent include a hydroxyl group, a phenyl group, and an alkyl group.
　上記Ｒ２において、「置換基を有していてもよいアミノアルキル基」としては、２－（ジメチルアミノ）エチル基、２－（１－メチルピロリジン－２－イル）エチル基、２－［（メチル）（１－フェニル－１－ヒドロキシプロパン－２－イル）アミノ］エチル基が好ましい。 In the above R 2 , the “optionally substituted aminoalkyl group” includes 2- (dimethylamino) ethyl group, 2- (1-methylpyrrolidin-2-yl) ethyl group, 2-[( A methyl) (1-phenyl-1-hydroxypropan-2-yl) amino] ethyl group is preferred.
　なお、上記Ｒ２において、「アルキル基」、「アルキルベンゾイル基」、「カルボキシアルキルフェニル基」、「アミノアルキル基」、「モノアルキルアミノ基」、「ジアルキルアミノ基」におけるアルキル基部分としては、炭素数１～６の直鎖又は分枝鎖のアルキル基が好ましく、具体例としては、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基等が挙げられる。
　また、上記Ｒ２において、「カルボキシアルコキシ基」におけるアルコキシ基部分としては、炭素数１～６の直鎖又は分枝鎖のアルコキシ基が好ましく、具体例としては、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基等が挙げられる。 In the above R 2 , as the alkyl group moiety in the “alkyl group”, “alkylbenzoyl group”, “carboxyalkylphenyl group”, “aminoalkyl group”, “monoalkylamino group”, “dialkylamino group”, A straight-chain or branched alkyl group having 1 to 6 carbon atoms is preferable, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
In the above R 2 , the alkoxy group moiety in the “carboxyalkoxy group” is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, and a propoxy group. , Butoxy group, pentyloxy group, hexyloxy group and the like.
　上記Ｒ３において、「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられ、本発明においては、塩素原子が好ましい。また、一般式（１）においてＲ３のフェニル基上の置換位置は特に限定されないが、４位に置換するのが好ましい。 In the above R 3 , examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the present invention, a chlorine atom is preferable. In the general formula (1), the substitution position on the phenyl group of R 3 is not particularly limited, but substitution at the 4-position is preferable.
　また、Ｘ、Ｙ、Ｒ１、Ｒ２及びＲ３の組み合わせとしては、以下の（ｉ）～（ｉｖ）が好ましい。
　（ｉ）Ｘが単結合であり、Ｙが窒素原子であり、Ｒ１が水素原子であり、Ｒ２が置換基を有していてもよいアミノアルキル基であり、Ｒ３がハロゲン原子である組み合わせ
　（ｉｉ）Ｘが酸素原子であり、Ｙがメチン基であり、Ｒ１がアルキル基であり、Ｒ２が置換基を有していてもよいアミノアルキル基であり、Ｒ３がハロゲン原子である組み合わせ
　（ｉｉｉ）Ｘが酸素原子であり、Ｙが窒素原子であり、Ｒ１が水素原子であり、Ｒ２が置換基を有していてもよいアミノアルキル基であり、Ｒ３がハロゲン原子である組み合わせ
　（ｉｖ）Ｘが酸素原子であり、Ｙがメチン基であり、Ｒ１が水素原子であり、Ｒ２が置換基を有していてもよい環状アミノ基であり、Ｒ３が水素原子である組み合わせ Further, the following combinations (i) to (iv) are preferable as the combination of X, Y, R 1 , R 2 and R 3 .
(I) X is a single bond, Y is a nitrogen atom, R 1 is a hydrogen atom, R 2 is an aminoalkyl group which may have a substituent, and R 3 is a halogen atom. Combination (ii) X is an oxygen atom, Y is a methine group, R 1 is an alkyl group, R 2 is an aminoalkyl group which may have a substituent, and R 3 is a halogen atom A certain combination (iii) X is an oxygen atom, Y is a nitrogen atom, R 1 is a hydrogen atom, R 2 is an aminoalkyl group which may have a substituent, and R 3 is a halogen atom (Iv) X is an oxygen atom, Y is a methine group, R 1 is a hydrogen atom, R 2 is an optionally substituted cyclic amino group, and R 3 is hydrogen A combination that is an atom
　本発明において、一般式（１）で表される化合物又はその塩としては、ジアリールメチル構造をその共通骨格として有する化合物、具体的には例えば、エバスチン又はその塩；オキサトミド又はその塩；カルビノキサミンジフェニルジスルホン酸塩、カルビノキサミンマレイン酸塩等のカルビノキサミン又はその塩；クレマスチンフマル酸塩等のクレマスチン又はその塩；ｄ－クロルフェニラミンマレイン酸塩、ｄｌ－クロルフェニラミンマレイン酸塩等のクロルフェニラミン又はその塩；ジフェテロール塩酸塩、ジフェテロールリン酸塩等のジフェテロール又はその塩；ジフェニルピラリン塩酸塩、ジフェニルピラリンテオクル酸塩等のジフェニルピラリン又はその塩；ジフェンヒドラミン塩酸塩、ジフェンヒドラミンサリチル酸塩、ジフェンヒドラミンタンニン酸塩等のジフェンヒドラミン又はその塩；セチリジン塩酸塩等のセチリジン又はその塩；フェキソフェナジン又はその塩；ベポタスチンベシル酸塩等のベポタスチン又はその塩；ホモクロルシクリジン塩酸塩等のホモクロルシクリジン又はその塩等が挙げられる。
　上記一般式（１）で表される化合物及びその塩、特に上記した化合物及びその塩は公知であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, as the compound represented by the general formula (1) or a salt thereof, a compound having a diarylmethyl structure as a common skeleton thereof, specifically, for example, ebastine or a salt thereof; oxatomide or a salt thereof; Carbinoxamine such as diphenyldisulfonate and carbinoxamine maleate or a salt thereof; clemastine or a salt thereof such as clemastine fumarate; chlorpheny such as d-chlorpheniramine maleate and dl-chlorpheniramine maleate Lamin or a salt thereof; Dipheterol or a salt thereof such as dipheterol hydrochloride or dipheterol phosphate; Diphenylpyrine or a salt thereof such as diphenylpyraline hydrochloride or diphenylpyraline theocrate; Diphenhydramine hydrochloride, diphenhydramine salicylate, diph Diphenhydramine or its salt such as hydramine tannate; cetirizine or its salt such as cetirizine hydrochloride; fexofenadine or its salt; bepotastine such as bepotastine besylate or its salt; homochlorcyclidine hydrochloride Homochlorocyclidine or a salt thereof.
The compounds represented by the above general formula (1) and salts thereof, in particular, the above-described compounds and salts thereof are known and can be produced by known methods, and commercially available products can be used.
　本発明の医薬組成物における一般式（１）で表される化合物又はその塩の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、１日あたり、一般式（１）で表される化合物又はその塩を０．０１～４００ｍｇ、より好適には０．０３～３００ｍｇ、特に好適には０．１～２００ｍｇ服用できる量を含有せしめることができる。なお、一般式（１）で表される化合物又はその塩として具体的な成分を用いる場合における好適な含有量を以下に例示するが、本発明は何らこれに限定されるものではない。 The content of the compound represented by the general formula (1) or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. . For example, it contains 0.01 to 400 mg, more preferably 0.03 to 300 mg, particularly preferably 0.1 to 200 mg of a compound represented by the general formula (1) or a salt thereof per day. It can be shown. In addition, although suitable content in the case of using a specific component as a compound represented by General formula (1) or its salt is illustrated below, this invention is not limited to this at all.
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてエバスチン又はその塩を用いる場合、その含有量は、１日あたり、０．１～５０ｍｇ服用できる量が好ましく、０．５～３０ｍｇ服用できる量がより好ましく、１～２０ｍｇ服用できる量がさらに好ましい。
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてオキサトミド又はその塩を用いる場合、その含有量は、１日あたり、０．３～２００ｍｇ服用できる量が好ましく、１～１００ｍｇ服用できる量がより好ましく、６～６０ｍｇ服用できる量がさらに好ましい。
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてカルビノキサミン又はその塩を用いる場合、その含有量は、１日あたり、０．１～６０ｍｇ服用できる量が好ましく、０．５～３０ｍｇ服用できる量がより好ましく、１～１６ｍｇ服用できる量がさらに好ましい。 In the pharmaceutical composition of the present invention, when ebastine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.1 to 50 mg per day, The amount that can be taken from 0.5 to 30 mg is more preferred, and the amount that can be taken from 1 to 20 mg is even more preferred.
In the pharmaceutical composition of the present invention, when oxatomide or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.3 to 200 mg per day, The amount that can be taken 1 to 100 mg is more preferred, and the amount that can be taken 6 to 60 mg is more preferred.
In the pharmaceutical composition of the present invention, when carbinoxamine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content thereof is preferably an amount that can be taken from 0.1 to 60 mg per day, The amount that can be taken from 0.5 to 30 mg is more preferred, and the amount that can be taken from 1 to 16 mg is even more preferred.
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてクレマスチン又はその塩を用いる場合、その含有量は、１日あたり、クレマスチンのフリー体換算で、０．０１～５ｍｇ服用できる量が好ましく、０．０５～３ｍｇ服用できる量がより好ましく、０．１～２ｍｇ服用できる量がさらに好ましい。なお、クレマスチンフマル酸塩１．３４ｍｇはクレマスチンのフリー体として１ｍｇに相当するものである。
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてクロルフェニラミン又はその塩を用いる場合、その含有量は、１日あたり、０．１～２０ｍｇ服用できる量が好ましく、０．６～１２ｍｇ服用できる量がより好ましい。なお、クロルフェニラミン又はその塩として、ｄ－クロルフェニラミンマレイン酸塩を用いる場合、１日あたり、０．１～１５ｍｇ服用できる量が好ましく、０．６～６ｍｇ服用できる量がより好ましく、１～５ｍｇ服用できる量がさらに好ましい。ｄｌ－クロルフェニラミンマレイン酸塩を用いる場合は、１日あたり、０．５～２０ｍｇ服用できる量が好ましく、１～１２ｍｇ服用できる量がより好ましく、２～１０ｍｇ服用できる量がさらに好ましい。
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてジフェテロール又はその塩を用いる場合、その含有量は、１日あたり、１～３００ｍｇ服用できる量が好ましく、５～１５０ｍｇ服用できる量がより好ましく、１０～１００ｍｇ服用できる量がさらに好ましい。 In the pharmaceutical composition of the present invention, when clemastine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content thereof is 0.01 to The amount that can be taken 5 mg is preferred, the amount that can be taken 0.05 to 3 mg is more preferred, and the amount that can be taken 0.1 to 2 mg is more preferred. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
In the pharmaceutical composition of the present invention, when chlorpheniramine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is 0.1 to 20 mg per day. The amount that can be taken 0.6 to 12 mg is more preferable. In addition, when d-chlorpheniramine maleate is used as chlorpheniramine or a salt thereof, an amount that can be taken 0.1 to 15 mg per day is preferable, and an amount that can be taken 0.6 to 6 mg is more preferable. An amount that can be taken up to 5 mg is more preferred. When dl-chlorpheniramine maleate is used, the amount that can be taken from 0.5 to 20 mg per day is preferred, the amount that can be taken from 1 to 12 mg is more preferred, and the amount that can be taken from 2 to 10 mg is even more preferred.
In the pharmaceutical composition of the present invention, when difeterol or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken in an amount of 1 to 300 mg per day. The amount that can be taken 150 mg is more preferred, and the amount that can be taken 10 to 100 mg is more preferred.
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてジフェニルピラリン又はその塩を用いる場合、その含有量は、１日あたり、０．１～１３．５ｍｇ服用できる量が好ましく、１～４．５ｍｇ服用できる量がより好ましい。なお、ジフェニルピラリン又はその塩として、ジフェニルピラリン塩酸塩を用いる場合、１日あたり、０．１～１２ｍｇ服用できる量が好ましく、１～４ｍｇ服用できる量がより好ましい。ジフェニルピラリンテオクル酸塩を用いる場合は、１日あたり、０．１～１３．５ｍｇ服用できる量が好ましく、１～４．５ｍｇ服用できる量がより好ましい。
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてジフェンヒドラミン又はその塩を用いる場合、その含有量は、１日あたり、１～３００ｍｇ服用できる量が好ましく、５～２００ｍｇ服用できる量がより好ましく、１５～１５０ｍｇ服用できる量がさらに好ましい。
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてセチリジン又はその塩を用いる場合、その含有量は、１日あたり、０．１～５０ｍｇ服用できる量が好ましく、０．３～３０ｍｇ服用できる量がより好ましく、１～２０ｍｇ服用できる量がさらに好ましい。 In the pharmaceutical composition of the present invention, when diphenylpyrine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is an amount that can be taken from 0.1 to 13.5 mg per day. The amount that can be taken 1 to 4.5 mg is more preferable. When diphenylpyraline hydrochloride is used as diphenylpyraline or a salt thereof, the amount that can be taken 0.1 to 12 mg per day is preferable, and the amount that can be taken 1 to 4 mg is more preferable. When using diphenylpyraline theocuroate, the amount that can be taken 0.1 to 13.5 mg per day is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred.
In the pharmaceutical composition of the present invention, when diphenhydramine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken from 1 to 300 mg per day. An amount that can be taken at 200 mg is more preferred, and an amount that can be taken at 15 to 150 mg is even more preferred.
In the pharmaceutical composition of the present invention, when cetirizine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.1 to 50 mg per day, The amount that can be taken 0.3 to 30 mg is more preferred, and the amount that can be taken 1 to 20 mg is more preferred.
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてフェキソフェナジン又はその塩を用いる場合、その含有量は、１日あたり、０．３～２００ｍｇ服用できる量が好ましく、１～１００ｍｇ服用できる量がより好ましく、６～６０ｍｇ服用できる量がさらに好ましい。
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてベポタスチン又はその塩を用いる場合、その含有量は、１日あたり、０．１～４０ｍｇ服用できる量が好ましく、０．５～３０ｍｇ服用できる量がより好ましく、２～２０ｍｇ服用できる量がさらに好ましい。
　本発明の医薬組成物において、一般式（１）で表される化合物又はその塩としてホモクロルシクリジン又はその塩を用いる場合、その含有量は、１日あたり、０．３～１８０ｍｇ服用できる量が好ましく、１～９０ｍｇ服用できる量がより好ましく、３～６０ｍｇ服用できる量がさらに好ましい。 In the pharmaceutical composition of the present invention, when fexofenadine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content thereof can be taken in an amount of 0.3 to 200 mg per day. The amount that can be taken 1 to 100 mg is more preferable, and the amount that can be taken 6 to 60 mg is more preferable.
In the pharmaceutical composition of the present invention, when bepotastine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.1 to 40 mg per day, The amount that can be taken from 0.5 to 30 mg is more preferred, and the amount that can be taken from 2 to 20 mg is even more preferred.
In the pharmaceutical composition of the present invention, when homochlorocyclidine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is an amount that can be taken 0.3 to 180 mg per day. The amount that can be taken 1 to 90 mg is more preferred, the amount that can be taken 3 to 60 mg is more preferred.
　本発明においては、一般式（１）で表される化合物又はその塩として、「クロルフェニラミン又はその塩」、「クレマスチン又はその塩」、「カルビノキサミン又はその塩」又は「ジフェニルピラリン又はその塩」を用いるのが好ましい。 In the present invention, as the compound represented by the general formula (1) or a salt thereof, “chlorpheniramine or a salt thereof”, “clemastine or a salt thereof”, “carbinoxamine or a salt thereof” or “diphenylpyrine or a salt thereof” Is preferably used.
　本発明において、「クロルフェニラミン又はその塩」には、クロルフェニラミンそのもののほか、クロルフェニラミンの薬学上許容される塩も含まれる。
　クロルフェニラミンには不斉炭素が存するため、光学異性体を有するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。これらのうち、本発明においては、ｄ－体、ｄｌ－体が好ましい。当該クロルフェニラミン又はその塩の具体例としては例えば、クロルフェニラミン、クロルフェニラミンマレイン酸塩、ｄ－クロルフェニラミンマレイン酸塩、ｄｌ－クロルフェニラミンマレイン酸塩等が挙げられる。本発明においては、ｄ－クロルフェニラミンマレイン酸塩、ｄｌ－クロルフェニラミンマレイン酸塩が好ましく、ｄ－クロルフェニラミンマレイン酸塩が特に好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, “chlorpheniramine or a salt thereof” includes not only chlorpheniramine itself but also a pharmaceutically acceptable salt of chlorpheniramine.
Since chlorpheniramine has an asymmetric carbon, it has optical isomers. However, in the present invention, any optical isomer may be included, which may be a single optical isomer or a mixture of various optical isomers. . Of these, d-form and dl-form are preferred in the present invention. Specific examples of the chlorpheniramine or a salt thereof include chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate and the like. In the present invention, d-chlorpheniramine maleate and dl-chlorpheniramine maleate are preferable, and d-chlorpheniramine maleate is particularly preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　本発明の医薬組成物におけるクロルフェニラミン又はその塩の含有量は特に限定されず、上述した１日あたりの服用量に応じて適宜検討して決定すればよいが、クロルフェニラミン又はその塩を医薬組成物全質量に対して０．００４～１．５質量％含有するのが好ましい。このうち、０．０２～１質量％含有するのが好ましく、０．０４～０．９質量％含有するのがより好ましい。 The content of chlorpheniramine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose. The content is preferably 0.004 to 1.5% by mass with respect to the total mass of the pharmaceutical composition. Of these, 0.02 to 1% by mass is preferably contained, and 0.04 to 0.9% by mass is more preferred.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びクロルフェニラミン又はその塩の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、クロルフェニラミン又はその塩を０．０００１～１．５質量部含有するものが好ましく、０．０００５～０．７質量部含有するものがより好ましく、０．００１～０．５質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and chlorpheniramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof contains 0.0001 to 1.5 parts by mass of chlorpheniramine or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 0.7 Those containing parts by mass are more preferred, and those containing 0.001 to 0.5 parts by mass are particularly preferred.
　本発明において、「クレマスチン又はその塩」には、クレマスチンそのもののほか、クレマスチンの薬学上許容される塩も含まれる。クレマスチン又はその塩の具体例としては例えば、クレマスチン、クレマスチンの鉱酸塩（塩酸塩、硝酸塩、硫酸塩など）、クレマスチンの有機酸塩（フマル酸塩、メタンスルホン酸塩など）等が挙げられ、本発明においては、クレマスチンフマル酸塩が好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, “clemastine or a salt thereof” includes not only clemastine itself but also a pharmaceutically acceptable salt of clemastine. Specific examples of clemastine or a salt thereof include, for example, clemastine, a mineral salt of clemastine (hydrochloride, nitrate, sulfate, etc.), an organic acid salt of clemastine (fumarate, methanesulfonate, etc.), etc. In the present invention, clemastine fumarate is preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　本発明の医薬組成物におけるクレマスチン又はその塩の含有量は特に限定されず、上述した１日あたりの服用量に応じて適宜検討して決定すればよいが、クレマスチン又はその塩を医薬組成物全質量に対してクレマスチンのフリー体換算で０．００８～０．４質量％含有するのが好ましい。このうち、０．０１～０．３質量％含有するのが好ましく、０．０１５～０．２５質量％含有するのがより好ましい。なお、クレマスチンフマル酸塩１．３４ｍｇはクレマスチンのフリー体として１ｍｇに相当するものである。 The content of clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose, but clemastine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.008 to 0.4% by mass in terms of free mass of clemastine relative to the mass. Of these, 0.01 to 0.3% by mass is preferable, and 0.015 to 0.25% by mass is more preferable. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
　本発明の医薬組成物におけるロキソプロフェン又はその塩とクレマスチン又はその塩の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、クレマスチン又はその塩をクレマスチンのフリー体換算で０．０００６～０．５質量部含有するものが好ましく、０．００１２～０．３質量部含有するものがより好ましく、０．００２～０．１質量部含有するものがさらに好ましい。 The content ratio of loxoprofen or a salt thereof and clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the daily dose of each component described above. Alternatively, it is preferable to contain 0.0006 to 0.5 parts by mass of clemastine or a salt thereof in terms of free form of clemastine with respect to 1 part by mass of loxoprofen sodium anhydride in terms of its salt. More preferred are those containing 0.002 to 0.1 parts by mass.
　本発明において、「カルビノキサミン又はその塩」には、カルビノキサミンそのもののほか、カルビノキサミンの薬学上許容される塩も含まれる。カルビノキサミン又はその塩の具体例としては例えば、カルビノキサミン、カルビノキサミンマレイン酸塩、カルビノキサミンジフェニルジスルホン酸塩等が挙げられ、本発明においては、カルビノキサミンマレイン酸塩がより好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, “carbinoxamine or a salt thereof” includes not only carbinoxamine itself but also a pharmaceutically acceptable salt of carbinoxamine. Specific examples of carbinoxamine or a salt thereof include carbinoxamine, carbinoxamine maleate, carbinoxamine diphenyl disulfonate, and the like, and carbinoxamine maleate is more preferable in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　本発明の医薬組成物におけるカルビノキサミン又はその塩の含有量は特に限定されず、上述した１日あたりの服用量に応じて適宜検討して決定すればよいが、カルビノキサミン又はその塩を医薬組成物全質量に対して０．００４～４質量％含有するのが好ましく、０．０２～２質量％含有するのがより好ましく、０．０４～１．８質量％含有するのがさらに好ましい。 The content of carbinoxamine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose. Carbinoxamine or a salt thereof may be added to the entire pharmaceutical composition. The content is preferably 0.004 to 4% by mass, more preferably 0.02 to 2% by mass, and still more preferably 0.04 to 1.8% by mass.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びカルビノキサミン又はその塩の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、カルビノキサミン又はその塩を０．０００３～６質量部含有するものが好ましく、０．００２～１質量部含有するものがより好ましく、０．００５～０．３質量部含有するものがさらに好ましい。 The content ratio of loxoprofen or a salt thereof and carbinoxamine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof is contained in an amount of 0.0003 to 6 parts by mass, more preferably 0.002 to 1 part by mass with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. More preferably, 0.005 to 0.3 parts by mass is contained.
　本発明において、「ジフェニルピラリン又はその塩」には、ジフェニルピラリンそのもののほか、ジフェニルピラリンの薬学上許容される塩も含まれる。ジフェニルピラリン又はその塩の具体例としては例えば、ジフェニルピラリン、ジフェニルピラリン塩酸塩、ジフェニルピラリンテオクル酸塩等が挙げられ、本発明においては、ジフェニルピラリン塩酸塩、ジフェニルピラリンテオクル酸塩が好ましく、ジフェニルピラリン塩酸塩が特に好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, “diphenylpyrine or a salt thereof” includes not only diphenylpyraline itself but also a pharmaceutically acceptable salt of diphenylpyraline. Specific examples of diphenylpyraline or a salt thereof include, for example, diphenylpyraline, diphenylpyraline hydrochloride, diphenylpyraline theocuroate and the like. In the present invention, diphenylpyraline hydrochloride and diphenylpyraline theocuroate are preferable, Diphenylpyraline hydrochloride is particularly preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　本発明の医薬組成物におけるジフェニルピラリン又はその塩の含有量は特に限定されず、上述した１日あたりの服用量に応じて適宜検討して決定すればよいが、ジフェニルピラリン又はその塩を医薬組成物全質量に対して０．００４～１質量％含有するのが好ましく、０．００４～１質量％含有するのがより好ましく、０．０４～１質量％含有するのがさらに好ましく、０．０６～１質量％含有するのが特に好ましい。 The content of diphenylpyralin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the above-mentioned daily dose. The content is preferably 0.004 to 1% by mass, more preferably 0.004 to 1% by mass, still more preferably 0.04 to 1% by mass, more preferably 0.06% by mass based on the total mass of the product. It is particularly preferable to contain 1 to 1% by mass.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びジフェニルピラリン又はその塩の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、ジフェニルピラリン又はその塩を０．０００１～３質量部含有するものが好ましく、０．０００５～２．５質量部含有するものがより好ましく、０．００１～１質量部含有するものがさらに好ましく、０．００１～０．５質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and diphenylpyraline or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof contains 0.0001 to 3 parts by mass of diphenylpyraline or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 2.5 parts by mass. More preferred are those containing 0.001 to 1 part by mass, and particularly preferred are those containing 0.001 to 0.5 part by mass.
　本発明において、一般式（２） In the present invention, the general formula (2)
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
［式（２）中、Ｒ４は水素原子又はメチル基を意味し、Ｒ５は水素原子又は水酸基を示す。］
で表される化合物又はその塩には、一般式（２）で表される化合物そのもののほか、一般式（２）で表される化合物の薬学上許容される塩も含まれる。一般式（２）で表される化合物又はその塩の具体例としては例えば、一般式（２）で表される化合物、一般式（２）で表される化合物の塩酸塩等の無機酸塩や有機酸塩が挙げられ、一般式（２）で表される化合物の塩酸塩がより好ましい。 [In Formula (2), R 4 represents a hydrogen atom or a methyl group, and R 5 represents a hydrogen atom or a hydroxyl group. ]
In addition to the compound itself represented by the general formula (2), a pharmaceutically acceptable salt of the compound represented by the general formula (2) is also included in the compound represented by general formula (2). Specific examples of the compound represented by the general formula (2) or a salt thereof include, for example, an inorganic acid salt such as a compound represented by the general formula (2), a hydrochloride of the compound represented by the general formula (2), and the like. Organic acid salt is mentioned, The hydrochloride of the compound represented by General formula (2) is more preferable.
　一般式（２）で表される化合物又はその塩としては、
（ａ）ブロムヘキシン（Ｒ４がメチル基であり、Ｒ５が水素原子である化合物）又はその塩
（ｂ）アンブロキソール（Ｒ４が水素原子であり、Ｒ５が水酸基である化合物）又はその塩
（ｃ）Ｒ４がメチル基であり、Ｒ５が水酸基である化合物又はその塩
（ｄ）Ｒ４及びＲ５が水素原子である化合物又はその塩
が挙げられるが、（ａ）ブロムヘキシン又はその塩、（ｂ）アンブロキソール又はその塩が好ましく、ブロムヘキシン塩酸塩、アンブロキソール塩酸塩が特に好ましい。 As the compound represented by the general formula (2) or a salt thereof,
(A) Bromohexine (a compound in which R 4 is a methyl group and R 5 is a hydrogen atom) or a salt thereof (b) Ambroxol (a compound in which R 4 is a hydrogen atom and R 5 is a hydroxyl group) or a salt thereof Salt (c) a compound in which R 4 is a methyl group and R 5 is a hydroxyl group or a salt thereof (d) a compound in which R 4 and R 5 are hydrogen atoms or a salt thereof, (a) bromohexine or a salt thereof Salt, (b) ambroxol or a salt thereof is preferable, and bromohexine hydrochloride or ambroxol hydrochloride is particularly preferable.
　また、一般式（２）において、Ｒ５が水酸基である場合は、当該置換基のα炭素は不斉中心となり、Ｓ体及びＲ体から選ばれる異性体が存在するが、本発明においては、それらのいずれでもよく、また、それらの混合物であってもよい。なお、これらの化合物は、単独で用いてもよく、二種以上を混合して用いてもよい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the general formula (2), when R 5 is a hydroxyl group, the α carbon of the substituent is an asymmetric center, and there are isomers selected from the S and R isomers. In the present invention, Any of them may be sufficient, and a mixture thereof may be sufficient. In addition, these compounds may be used independently and may mix and use 2 or more types. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　本発明の医薬組成物における一般式（２）で表される化合物又はその塩の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、一般式（２）で表される化合物又はその塩がブロムヘキシン又はその塩の場合、１日あたり、ブロムヘキシン又はその塩をブロムヘキシン塩酸塩に換算して０．１～５０ｍｇ、より好適には０．５～２５ｍｇ、特に好適には１～１５ｍｇ服用できる量を含有せしめることができる。また、一般式（２）で表される化合物又はその塩がアンブロキソール又はその塩の場合、１日あたり、アンブロキソール又はその塩をアンブロキソール塩酸塩に換算して０．１～１５０ｍｇ、より好適には０．５～１００ｍｇ、特に好適には１～５０ｍｇ服用できる量を含有せしめることができる。 The content of the compound represented by the general formula (2) or the salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. . For example, when the compound represented by the general formula (2) or a salt thereof is bromohexine or a salt thereof, 0.1 to 50 mg, more preferably 0, of bromhexine or a salt thereof converted into bromohexine hydrochloride per day. It can be contained in an amount of 5 to 25 mg, particularly preferably 1 to 15 mg. In addition, when the compound represented by the general formula (2) or a salt thereof is ambroxol or a salt thereof, 0.1 to 150 mg of ambroxol or a salt thereof is converted into ambroxol hydrochloride per day. More preferably, it can be contained in an amount of 0.5 to 100 mg, particularly preferably 1 to 50 mg.
　本発明においては、一般式（２）で表される化合物又はその塩を医薬組成物全質量に対して０．００１～２０質量％含有するのが好ましい。また、一般式（２）で表される化合物又はその塩がブロムヘキシン又はその塩の場合、医薬組成物全質量に対してブロムヘキシン塩酸塩に換算して０．００４～５質量％含有するのが好ましく、０．０２～４質量％含有するのがより好ましく、０．０４～３質量％含有するのが特に好ましい。さらに、一般式（２）で表される化合物又はその塩がアンブロキソール又はその塩の場合、医薬組成物全質量に対してアンブロキソール塩酸塩に換算して０．００４～２０質量％含有するのが好ましく、０．０２～１５質量％含有するのがより好ましく、０．０４～１０質量％含有するのがさらに好ましい。 In the present invention, the compound represented by the general formula (2) or a salt thereof is preferably contained in an amount of 0.001 to 20% by mass with respect to the total mass of the pharmaceutical composition. In addition, when the compound represented by the general formula (2) or a salt thereof is bromohexine or a salt thereof, it is preferably contained in an amount of 0.004 to 5% by mass in terms of bromohexine hydrochloride with respect to the total mass of the pharmaceutical composition. 0.02 to 4% by mass is more preferable, and 0.04 to 3% by mass is particularly preferable. Further, when the compound represented by the general formula (2) or a salt thereof is ambroxol or a salt thereof, 0.004 to 20% by mass in terms of ambroxol hydrochloride is contained with respect to the total mass of the pharmaceutical composition. The content is preferably 0.02 to 15% by mass, more preferably 0.04 to 10% by mass.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及び一般式（２）で表される化合物又はその塩の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて適宜検討して決定すればよいが、一般式（２）で表される化合物又はその塩がブロムヘキシン又はその塩である場合、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、ブロムヘキシン又はその塩をブロムヘキシン塩酸塩に換算して０．０００１～１０質量部含有するものが好ましく、０．０００５～２質量部含有するものがより好ましく、０．００１～１質量部含有するものが特に好ましい。また、一般式（２）で表される化合物又はその塩がアンブロキソール又はその塩である場合、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、アンブロキソール又はその塩をアンブロキソール塩酸塩に換算して０．０００１～１０質量部含有するものが好ましく、０．０００５～５質量部含有するものがより好ましく、０．００１～３質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and the compound represented by the general formula (2) or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and depends on the daily dose of each component described above. However, when the compound represented by the general formula (2) or a salt thereof is bromhexine or a salt thereof, loxoprofen or a salt thereof is added to 1 part by mass in terms of anhydrous loxoprofen sodium, Those containing 0.0001 to 10 parts by mass of bromhexine or a salt thereof in terms of bromohexine hydrochloride are preferred, those containing 0.0005 to 2 parts by mass are more preferred, and those containing 0.001 to 1 part by mass. Particularly preferred. In addition, when the compound represented by the general formula (2) or a salt thereof is ambroxol or a salt thereof, loxoprofen or a salt thereof is added to 1 part by mass in terms of loxoprofen sodium anhydride with respect to an ambroxol or a salt thereof. Those containing 0.0001 to 10 parts by mass in terms of ambroxol hydrochloride are preferred, those containing 0.0005 to 5 parts by mass are more preferred, and those containing 0.001 to 3 parts by mass are particularly preferred.
　本発明において、下記一般式（３） In the present invention, the following general formula (3)
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
［式（３）中、Ｒ６はアルキル基又は置換基を有していてもよいアルコキシ基を示し、Ｒ７は水素原子又はスルホ基を示す。なお、式中のフェノール性水酸基はエーテル化されても良い。］
で表される化合物又はその塩には、一般式（３）で表される化合物そのもののほか、一般式（３）で表される化合物の薬学上許容される塩も含まれる。当該一般式（３）で表される化合物又はその塩の具体例としては例えば、一般式（３）で表される化合物、一般式（３）で表される化合物のカリウム塩等のアルカリ金属塩が挙げられ、一般式（３）で表される化合物のカリウム塩がより好ましい。 [In Formula (3), R 6 represents an alkyl group or an alkoxy group which may have a substituent, and R 7 represents a hydrogen atom or a sulfo group. The phenolic hydroxyl group in the formula may be etherified. ]
In addition to the compound itself represented by the general formula (3), a pharmaceutically acceptable salt of the compound represented by the general formula (3) is also included in the compound represented by general formula (3). Specific examples of the compound represented by the general formula (3) or a salt thereof include, for example, an alkali metal salt such as a compound represented by the general formula (3) and a potassium salt of the compound represented by the general formula (3). The potassium salt of the compound represented by the general formula (3) is more preferable.
　上記Ｒ６において、アルキル基としては、直鎖又は分枝鎖の炭素数１～６のアルキル基が好ましく、具体例としては、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基等が挙げられる。本発明においては、メチル基が好ましい。
　また、アルコキシ基としては、直鎖又は分枝鎖の炭素数１～６のアルコキシ基が好ましく、具体例としては、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基等が挙げられる。本発明においては、メトキシ基が好ましい。
　当該アルコキシ基に置換し得る基としては、水酸基；臭素原子、塩素原子、フッ素原子、ヨウ素原子等のハロゲン原子が挙げられ、これらを１個又は複数個有していてもよい。 In the above R 6 , the alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Etc. In the present invention, a methyl group is preferred.
The alkoxy group is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, and the like. Is mentioned. In the present invention, a methoxy group is preferred.
Examples of the group that can be substituted with the alkoxy group include a hydroxyl group; a halogen atom such as a bromine atom, a chlorine atom, a fluorine atom, and an iodine atom, and may have one or more of these.
　上記一般式（３）において、フェノール性水酸基がエーテル化された場合としては、例えば、直鎖又は分枝鎖の炭素数１～３の一価アルコールでフェノール性水酸基がエーテル化されたもの、直鎖又は分枝鎖の炭素数１～３の多価アルコールでフェノール性水酸基がエーテル化されたもの等が挙げられる。一価アルコールとしては、メタノール、エタノール、プロパノールが挙げられる。また、多価アルコールとしては、エチレングリコール、プロピレングリコール、グリセリン等が挙げられる。本発明においては、直鎖又は分枝鎖の炭素数１～３の多価アルコール、中でもグリセリンでフェノール性水酸基がエーテル化されたものが好ましい。なお、フェノール性水酸基がエーテル化された場合において、エーテル化反応は特に限定されるものではない。 In the above general formula (3), examples of the case where the phenolic hydroxyl group is etherified include, for example, those in which the phenolic hydroxyl group is etherified with a linear or branched monohydric alcohol having 1 to 3 carbon atoms. Examples thereof include those in which a phenolic hydroxyl group is etherified with a chain or branched polyhydric alcohol having 1 to 3 carbon atoms. Examples of the monohydric alcohol include methanol, ethanol, and propanol. Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, and glycerin. In the present invention, linear or branched polyhydric alcohols having 1 to 3 carbon atoms, particularly those obtained by etherifying a phenolic hydroxyl group with glycerin are preferred. When the phenolic hydroxyl group is etherified, the etherification reaction is not particularly limited.
　また、式（３）中のフェノール性水酸基、Ｒ６及びＲ７の組み合わせとしては、以下の（ｖ）～（ｖｉｉ）が好ましい。
　（ｖ）フェノール性水酸基が、エーテル化されていないフェノール性水酸基であり、Ｒ６が、置換基を有していてもよいアルコキシ基であり、Ｒ７が、スルホ基である組み合わせ
　（ｖｉ）フェノール性水酸基が、エーテル化されているフェノール性水酸基であり、Ｒ６が、置換基を有していてもよいアルコキシ基であり、Ｒ７が、水素原子である組み合わせ
　（ｖｉｉ）フェノール性水酸基が、エーテル化されていないフェノール性水酸基であり、Ｒ６が、アルキル基であり、Ｒ７が、スルホ基である組み合わせ Further, the following (v) to (vii) are preferable as the combination of the phenolic hydroxyl group, R 6 and R 7 in the formula (3).
(V) A combination in which the phenolic hydroxyl group is a non-etherified phenolic hydroxyl group, R 6 is an optionally substituted alkoxy group, and R 7 is a sulfo group (vi) phenol A combination in which the functional hydroxyl group is a phenolic hydroxyl group that is etherified, R 6 is an alkoxy group that may have a substituent, and R 7 is a hydrogen atom (vii) Combination of phenolic hydroxyl group not etherified, R 6 is an alkyl group, and R 7 is a sulfo group
　本発明の一般式（３）で表される化合物又はその塩としては、２－メトキシフェノール誘導体（グアヤコール誘導体）又はその塩、２－メチルフェノール誘導体（クレゾール誘導体）又はその塩が好適な具体例として挙げられる。
　グアヤコール誘導体又はその塩としては、グアイフェネシン（グアヤコールグリセリンエーテル；（２ＲＳ）－３－（２－メトキシフェノキシ）プロパン－１，２－ジオール）又はその塩；グアヤコールスルホン酸、グアヤコールスルホン酸カリウム等のグアヤコールスルホン酸又はその塩が好ましい。また、クレゾール誘導体又はその塩としては、クレゾールスルホン酸（２－メチルフェノールスルホン酸）、クレゾールスルホン酸カリウム等のクレゾールスルホン酸又はその塩が好ましい。
　また、一般式（３）で表される化合物又はその塩としては、グアヤコール誘導体又はその塩が好ましく、グアヤコールスルホン酸又はその塩、グアイフェネシンがより好ましく、グアヤコールスルホン酸カリウム、グアイフェネシンが特に好ましい。
　これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 Preferred examples of the compound represented by the general formula (3) of the present invention or a salt thereof include 2-methoxyphenol derivatives (guaiacol derivatives) or salts thereof, 2-methylphenol derivatives (cresol derivatives) or salts thereof. Can be mentioned.
Examples of guaiacol derivatives or salts thereof include guaifenesin (guaiacol glycerol ether; (2RS) -3- (2-methoxyphenoxy) propane-1,2-diol) or salts thereof; guaiacol sulfones such as guaiacol sulfonic acid and potassium guaiacol sulfonate. An acid or a salt thereof is preferred. Further, the cresol derivative or a salt thereof is preferably a cresol sulfonic acid such as cresol sulfonic acid (2-methylphenol sulfonic acid) or potassium cresol sulfonate or a salt thereof.
The compound represented by the general formula (3) or a salt thereof is preferably a guaiacol derivative or a salt thereof, more preferably guaiacol sulfonic acid or a salt thereof, or guaifenesin, and particularly preferably potassium guaiacol sulfonate or guaifenesin.
These are known compounds, and can be produced by known methods, or commercially available products can be used.
　本発明の医薬組成物における一般式（３）で表される化合物又はその塩の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、１日あたり、一般式（３）で表される化合物又はその塩を５～６００ｍｇ、より好適には１０～４５０ｍｇ、特に好適には２５～３００ｍｇ服用できる量を含有せしめることができる。なお、一般式（３）で表される化合物又はその塩として、グアヤコール誘導体又はその塩を用いる場合、１日あたり、グアヤコール誘導体又はその塩を１０～６００ｍｇ、より好適には２０～４５０ｍｇ、特に好適には３０～３００ｍｇ服用できる量を含有せしめるのが好ましい。また、一般式（３）で表される化合物又はその塩として、クレゾール誘導体又はその塩を用いる場合、１日あたり、クレゾール誘導体又はその塩を５～５５０ｍｇ、より好適には１０～４００ｍｇ、特に好適には２５～２７０ｍｇ服用できる量を含有せしめるのが好ましい。
　本発明においては、一般式（３）で表される化合物又はその塩を医薬組成物全質量に対して０．２～４０質量％含有するのが好ましい。また、一般式（３）で表される化合物又はその塩がグアヤコール誘導体又はその塩である場合、医薬組成物全質量に対して０．４～４０質量％含有するのが好ましく、０．８～３５質量％含有するのがより好ましく、１．２～３０質量％含有するのがさらに好ましい。さらに、一般式（３）で表される化合物又はその塩がクレゾール誘導体又はその塩である場合、医薬組成物全質量に対して０．２～３５質量％含有するのが好ましく、０．４～２５質量％含有するのがより好ましく、１～２０質量％含有するのが特に好ましい。 The content of the compound represented by the general formula (3) or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. . For example, the compound represented by the general formula (3) or a salt thereof can be contained in an amount that can be taken from 5 to 600 mg, more preferably from 10 to 450 mg, particularly preferably from 25 to 300 mg per day. When a guaiacol derivative or a salt thereof is used as the compound represented by the general formula (3) or a salt thereof, the guaiacol derivative or a salt thereof is preferably 10 to 600 mg, more preferably 20 to 450 mg, particularly preferably per day. It is preferable to contain an amount of 30 to 300 mg that can be taken. When a cresol derivative or a salt thereof is used as the compound represented by the general formula (3) or a salt thereof, the cresol derivative or a salt thereof is preferably 5 to 550 mg, more preferably 10 to 400 mg, particularly preferably per day. It is preferable to contain an amount that can be taken from 25 to 270 mg.
In the present invention, the compound represented by the general formula (3) or a salt thereof is preferably contained in an amount of 0.2 to 40% by mass based on the total mass of the pharmaceutical composition. Further, when the compound represented by the general formula (3) or a salt thereof is a guaiacol derivative or a salt thereof, it is preferably contained in an amount of 0.4 to 40% by mass relative to the total mass of the pharmaceutical composition, 0.8 to The content is more preferably 35% by mass, and even more preferably 1.2 to 30% by mass. Further, when the compound represented by the general formula (3) or a salt thereof is a cresol derivative or a salt thereof, it is preferably contained in an amount of 0.2 to 35% by mass relative to the total mass of the pharmaceutical composition, 0.4 to The content is more preferably 25% by mass, and particularly preferably 1 to 20% by mass.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及び一般式（３）で表される化合物又はその塩の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、一般式（３）で表される化合物又はその塩を０．０１５～６０質量部含有するものが好ましく、０．０４～１５質量部含有するものがより好ましく、０．１３～５質量部含有するものがさらに好ましい。 The content ratio of loxoprofen or a salt thereof and the compound represented by the general formula (3) or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and depends on the daily dose of each component described above. The amount of loxoprofen or a salt thereof contained in 0.015 to 60 parts by mass of the compound represented by the general formula (3) or a salt thereof is 1 part by mass in terms of loxoprofen sodium anhydride. Those containing 0.04 to 15 parts by mass are more preferred, and those containing 0.13 to 5 parts by mass are more preferred.
　本発明において、「リゾチーム又はその塩」には、リゾチームそのもののほか、リゾチームの薬学上許容される塩も含まれる。当該リゾチーム又はその塩の具体例としては例えば、リゾチーム、リゾチーム塩酸塩等が挙げられ、リゾチーム塩酸塩が好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, “lysozyme or a salt thereof” includes not only lysozyme itself but also a pharmaceutically acceptable salt of lysozyme. Specific examples of the lysozyme or a salt thereof include lysozyme and lysozyme hydrochloride, and lysozyme hydrochloride is preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　本発明の医薬組成物におけるリゾチーム又はその塩の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、１日あたり、リゾチーム又はその塩をリゾチーム塩酸塩の力価換算で、５～４５０ｍｇ（力価）、より好適には１０～３６０ｍｇ（力価）、特に好適には１５～２７０ｍｇ（力価）服用できる量を含有せしめることができる。なお、リゾチーム又はその塩として、リゾチーム塩酸塩を用いる場合、１日あたり、リゾチーム塩酸塩を５～４５０ｍｇ（力価）、より好適には１０～３６０ｍｇ（力価）、特に好適には１５～２７０ｍｇ（力価）服用できる量を含有せしめるのが好ましい。
　本発明においては、リゾチーム又はその塩を医薬組成物全質量に対してリゾチーム塩酸塩の力価換算で、０．２～３０質量％（力価）含有するのが好ましく、０．４～２５質量％（力価）含有するのがより好ましく、０．６～２０質量％（力価）含有するのが特に好ましい。 The content of lysozyme or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, per day, lysozyme or a salt thereof is converted to a lysozyme hydrochloride titer of 5 to 450 mg (titer), more preferably 10 to 360 mg (titer), particularly preferably 15 to 270 mg (titer). ) Can be taken in an amount that can be taken. When lysozyme hydrochloride is used as lysozyme or a salt thereof, lysozyme hydrochloride is 5 to 450 mg (titer), more preferably 10 to 360 mg (titer), particularly preferably 15 to 270 mg per day. (Titer) It is preferable to include an amount that can be taken.
In the present invention, lysozyme or a salt thereof is preferably contained in an amount of 0.2 to 30% by mass (titer) in terms of titer of lysozyme hydrochloride with respect to the total mass of the pharmaceutical composition, and 0.4 to 25% by mass. % (Titer) is more preferable, and 0.6 to 20% by mass (titer) is particularly preferable.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びリゾチーム又はその塩の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、リゾチーム又はその塩をリゾチーム塩酸塩の力価換算で、０．０１～４５質量部（力価）含有するものが好ましく、０．０３～３０質量部（力価）含有するものがより好ましく、０．０４～１２質量部（力価）含有するものがさらに好ましく、０．０８～５質量部（力価）含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and lysozyme or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof contains 0.01 to 45 parts by mass (titer) of lysozyme or a salt thereof in terms of titer of lysozyme hydrochloride with respect to 1 part by mass of loxoprofen sodium anhydride. Those containing 0.03 to 30 parts by mass (titer) are more preferable, those containing 0.04 to 12 parts by mass (titer) are more preferable, and those containing 0.08 to 5 parts by mass (titer) Is particularly preferred.
　本発明において、「コデイン類」とは、コデイン、ジヒドロコデイン及びこれらの塩並びにこれらの溶媒和物からなる群より選ばれる１種以上のものを意味する。この群にはコデインやジヒドロコデインそのもののほか、コデインやジヒドロコデインの薬学上許容される塩やこれらの溶媒和物も含まれる。コデイン類の具体例としては例えば、コデイン、ジヒドロコデイン、コデインリン酸塩水和物、ジヒドロコデインリン酸塩等が挙げられ、本発明の医薬組成物を総合感冒薬等として利用した場合の観点から、コデインリン酸塩水和物、ジヒドロコデインリン酸塩がより好ましく、ジヒドロコデインリン酸塩がさらに好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, “codeines” means one or more selected from the group consisting of codeine, dihydrocodeine, salts thereof, and solvates thereof. This group includes codeine and dihydrocodeine itself, as well as pharmaceutically acceptable salts of codeine and dihydrocodeine and solvates thereof. Specific examples of codeines include, for example, codeine, dihydrocodeine, codeine phosphate hydrate, dihydrocodeine phosphate and the like. From the viewpoint of using the pharmaceutical composition of the present invention as a general cold medicine, codeine phosphate water More preferred are Japanese and dihydrocodeine phosphate, and more preferred is dihydrocodeine phosphate. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　本発明の医薬組成物におけるコデイン類の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、１日あたり、コデイン類を２～６０ｍｇ、より好適には４～４８ｍｇ、特に好適には６～３６ｍｇ服用できる量を含有せしめることができる。なお、コデイン類として、コデインリン酸塩水和物を用いる場合、１日あたり、コデインリン酸塩水和物を４～６０ｍｇ、より好適には８～４８ｍｇ、特に好適には１２～３６ｍｇ服用できる量を含有せしめるのが好ましい。また、ジヒドロコデインリン酸塩を用いる場合は、１日あたり、ジヒドロコデインリン酸塩を２～３０ｍｇ、より好適には４～２４ｍｇ、特に好適には６～２４ｍｇ服用できる量を含有せしめるのが好ましい。
　本発明においては、コデイン類を医薬組成物全質量に対して、０．０８～８質量％含有するのが好ましく、０．０８～７質量％含有するのがより好ましい。また、コデイン類がコデインリン酸塩水和物である場合、医薬組成物全質量に対して０．１５～４質量％含有するのが好ましく、０．３～３質量％含有するのがより好ましく、０．５～２．５質量％含有するのが特に好ましい。さらに、コデイン類がジヒドロコデインリン酸塩である場合、医薬組成物全質量に対して０．０８～６．５質量％含有するのが好ましく、０．１６～６質量％含有するのがより好ましく、０．２４～５．５質量％含有するのがさらに好ましい。 The content of codeine in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, 2-60 mg of codeine can be contained per day, more preferably 4-48 mg, particularly preferably 6-36 mg. When codeine phosphate hydrate is used as codeine, 4-60 mg, more preferably 8-48 mg, particularly preferably 12-36 mg of codeine phosphate hydrate is contained per day. Is preferred. When dihydrocodeine phosphate is used, it is preferable to contain 2 to 30 mg, more preferably 4 to 24 mg, particularly preferably 6 to 24 mg of dihydrocodeine phosphate per day.
In the present invention, the codeine is preferably contained in an amount of 0.08 to 8% by mass, more preferably 0.08 to 7% by mass, based on the total mass of the pharmaceutical composition. When codeine is codeine phosphate hydrate, it is preferably contained in an amount of 0.15 to 4% by mass, more preferably 0.3 to 3% by mass, based on the total mass of the pharmaceutical composition. It is particularly preferable to contain 5 to 2.5% by mass. Further, when the codeine is dihydrocodeine phosphate, it is preferably contained in an amount of 0.08 to 6.5% by mass, more preferably 0.16 to 6% by mass, based on the total mass of the pharmaceutical composition, More preferably, the content is 0.24 to 5.5% by mass.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びコデイン類の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて、適宜検討して決定すればよいが、ロキソプロフェン又はその塩を、ロキソプロフェンナトリウム無水物換算で１質量部に対し、コデイン類を０．００５～４質量部含有するものが好ましく、０．０１～２質量部含有するものがより好ましく、０．０２～１質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and codeines contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the daily dose of each component described above. , Loxoprofen or a salt thereof is preferably 0.005 to 4 parts by mass of codeine, more preferably 0.01 to 2 parts by mass with respect to 1 part by mass of loxoprofen sodium anhydride. Those containing 0.02 to 1 part by mass are particularly preferred.
　本発明において、「エフェドリン類」とは、エフェドリン及びエフェドリンの誘導体並びにそれらの塩からなる群より選ばれる１種以上を意味する。ここで、エフェドリンの誘導体としては、ノルエフェドリン（フェニルプロパノールアミン）、メチルエフェドリン等が挙げられる。また、塩としては、薬学上許容される無機酸や有機酸の塩が挙げられ、好適な具体例としては、塩酸塩、硫酸塩、サッカリン塩が挙げられる。また、エフェドリンには２つの不斉炭素が存するため、種々の光学異性体が存するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。本発明においては、ｌ－体、ｄｌ－体が好ましい。 In the present invention, “ephedrines” mean one or more selected from the group consisting of ephedrine, ephedrine derivatives, and salts thereof. Here, examples of derivatives of ephedrine include norephedrine (phenylpropanolamine) and methylephedrine. Examples of the salt include salts of pharmaceutically acceptable inorganic acids and organic acids, and preferred specific examples include hydrochloride, sulfate, and saccharin salt. In addition, since ephedrine has two asymmetric carbons, there are various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used. A mixture of In the present invention, l-form and dl-form are preferable.
　本発明において、エフェドリン類の具体例としては例えば、ｌ－メチルエフェドリン塩酸塩、ｄｌ－メチルエフェドリン塩酸塩、ｌ－メチルエフェドリンサッカリン塩、ｄｌ－メチルエフェドリンサッカリン塩、プソイドエフェドリン塩酸塩、プソイドエフェドリン硫酸塩等が挙げられ、これらを単独で、又は２種以上を組合わせて用いることができる。なお、エフェドリンとプソイドエフェドリンは互いにエナンチオマーの関係にあるものである。これらのうち、本発明においては、ｄｌ－メチルエフェドリン塩酸塩が好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, specific examples of ephedrines include, for example, 1-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, 1-methylephedrine saccharin salt, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, pseudoephedrine sulfate and the like. These may be used alone or in combination of two or more. Ephedrine and pseudoephedrine are in an enantiomeric relationship with each other. Of these, dl-methylephedrine hydrochloride is preferred in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　また、本発明において「エフェドリン類」としては、これらを成分として含有するマオウ（麻黄）も用いることができる。
　マオウは、第十五改正日本薬局方に掲載されているとおり、Ｅｐｈｅｄｒａ　ｓｉｎｉｃａ　Ｓｔａｐｆ、Ｅｐｈｅｄｒａ　ｉｎｔｅｒｍｅｄｉａ　Ｓｃｈｒｅｎｋ　ｅｔ　Ｃ．　Ａ．　Ｍｅｙｅｒ又はＥｐｈｅｄｒａ　ｅｑｕｉｓｅｔｉｎａ　Ｂｕｎｇｅ　（Ｅｐｈｅｄｒａｃｅａｅ）の地上茎を意味する。マオウは必要に応じてその形態を調節することができ、小片、小塊に切断若しくは破砕、又は粉末に粉砕することができる。例えば、マオウの粉末は「マオウ末」という。
　また、マオウは、第十五改正日本薬局方　製剤総則等に記載の公知の方法に基づき、適当な大きさとした後に、適当な浸出剤を加えて浸出した液や浸出液を濃縮した液、すなわち「エキス」や「チンキ」等としてもよい。浸出剤としては、メタノール、エタノール及びｎ－ブタノール等の低級一価アルコール；エチレングリコール、プロピレングリコール、１，３－ブチレングリコール及びグリセリン等の低級多価アルコール；ジエチルエーテル等のエーテル類；アセトン及びエチルメチルケトン等のケトン類；酢酸エチルエステル等のエステル類；ジクロロメタン及びクロロホルム等のハロゲノアルカン類；ベンゼン及びトルエン等の芳香族炭化水素；及び水等が挙げられる。これらは各々単独で用いてもよいし、２種以上を混合して用いてもよい。さらにエキスは乾燥することもできる。 In the present invention, “ephedrines” can also be used mah (mao) containing these as ingredients.
As described in the Fifteenth Amendment Japanese Pharmacopoeia, Maou is a member of Ephedra sinica Stapf, Ephdra intermedia Schrenk et C. A. Means the ground stem of Meyer or Ephedra equisetina Bunge (Ephedlacea). Maow can be adjusted in shape as needed, and can be cut or crushed into small pieces, lumps, or ground into powder. For example, Maow powder is called “Maow powder”.
In addition, Maou is a liquid obtained by adding an appropriate leaching agent after concentrating to an appropriate size based on a known method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations, etc. It may be “extract” or “tinced”. Leaching agents include lower monohydric alcohols such as methanol, ethanol and n-butanol; lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol and glycerine; ethers such as diethyl ether; acetone and ethyl Ketones such as methyl ketone; esters such as ethyl acetate; halogenoalkanes such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene and toluene; and water. These may be used alone or in combination of two or more. Furthermore, the extract can be dried.
　本発明において、エフェドリン類としてマオウを用いる場合、マオウ末、マオウ流エキス、マオウ軟エキス、マオウ乾燥エキス、マオウエキス等が好ましく、これらを単独で、又は２種以上を組み合わせて用いることができる。さらに、マオウを用いる場合は、マオウを含む漢方処方である、カッコントウ（葛根湯）、ショウセイリュウトウ（小青竜湯）、マオウトウ（麻黄湯）等を用いることもできる。これらは、公知の方法により製造してもよいし、市販品を用いてもよい。 In the present invention, when maou is used as the ephedrine, maou powder, maou stream extract, maou soft extract, mao dry extract, mao extract and the like are preferable, and these can be used alone or in combination of two or more. Furthermore, when using maou, Chinese herbal prescriptions including maou, kakonto (Kakkonto), shosei ryoutou (Sho Seiryuto), maoutou (maoyuto), etc. can also be used. These may be produced by known methods, or commercially available products may be used.
　本発明の医薬組成物におけるエフェドリン類の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、１日あたり、エフェドリン類を５～５００ｍｇ、より好適には１０～３６０ｍｇ、特に好適には２０～２４０ｍｇ服用できる量を含有せしめることができる。
　なお、エフェドリン類の一部又は全ては、上述のマオウに代替することができる。エフェドリン類としてマオウを用いる場合は、例えば、１日あたり、マオウを０．１～２５ｇ（原生薬換算量）、より好適には０．２５～１０ｇ（原生薬換算量）、特に好適には０．４～４ｇ（原生薬換算量）服用できる量を含有せしめることができる。
　本発明においては、エフェドリン類を医薬組成物全質量に対して０．１～４０質量％含有するのが好ましく、０．５～２０質量％含有するのがより好ましく、１～１０質量％含有するのがさらに好ましく、２～１０質量％含有するのが特に好ましい。また、エフェドリン類としてマオウを用いる場合は、マオウを医薬組成物全質量に対して１～９８質量％含有するのが好ましく、２～５０質量％含有するのがより好ましく、４～２０質量％含有するのが特に好ましい。 The content of ephedrines in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, an amount of ephedrines that can be taken in an amount of 5 to 500 mg, more preferably 10 to 360 mg, and particularly preferably 20 to 240 mg per day can be included.
In addition, a part or all of ephedrines can be substituted for the above-mentioned maou. When using ephedrine as ephedrines, for example, 0.1 to 25 g (powder equivalent) of maow per day, more preferably 0.25 to 10 g (powder equivalent), particularly preferably 0 4 to 4 g (concentration in bulk drug substance) can be included.
In the present invention, the ephedrine is preferably contained in an amount of 0.1 to 40% by weight, more preferably 0.5 to 20% by weight, and more preferably 1 to 10% by weight based on the total weight of the pharmaceutical composition. More preferably, the content is 2 to 10% by mass. Further, when using maou as the ephedrine, it is preferable to contain 1 to 98% by mass, more preferably 2 to 50% by mass, and more preferably 4 to 20% by mass with respect to the total mass of the pharmaceutical composition. It is particularly preferable to do this.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びエフェドリン類の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて、適宜検討して決定すればよいが、ロキソプロフェン又はその塩を、ロキソプロフェンナトリウム無水物換算で１質量部に対し、エフェドリン類を、０．００１～５０質量部含有するものが好ましく、０．００５～５０質量部含有するものがより好ましく、０．０１５～５０質量部含有するものがさらに好ましい。このうち、０．０５～１２質量部含有するものがより好ましく、０．１～４質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and ephedrine contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the daily dose of each component described above. , Loxoprofen or a salt thereof is preferably 0.001 to 50 parts by mass, more preferably 0.005 to 50 parts by mass of ephedrine, relative to 1 part by mass of loxoprofen sodium anhydride. Those containing 0.015 to 50 parts by mass are more preferable. Of these, those containing 0.05 to 12 parts by mass are more preferred, and those containing 0.1 to 4 parts by mass are particularly preferred.
　本発明において、「デキストロメトルファン又はその塩」には、デキストロメトルファンそのもののほか、デキストロメトルファンの薬学上許容される塩、さらにはデキストロメトルファンやデキストロメトルファンの薬学上許容される塩と水やアルコール等との溶媒和物も含まれる。デキストロメトルファン又はその塩の具体例としては例えば、デキストロメトルファン、デキストロメトルファン臭化水素酸塩水和物、デキストロメトルファンフェノールフタリン塩等が挙げられ、デキストロメトルファン臭化水素酸塩水和物、デキストロメトルファンフェノールフタリン塩が好ましく、デキストロメトルファン臭化水素酸塩水和物が特に好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, the term “dextromethorphan or a salt thereof” includes dextromethorphan itself, pharmaceutically acceptable salts of dextromethorphan, and pharmaceutically acceptable salts of dextromethorphan and dextromethorphan. Solvates with water or alcohol are also included. Specific examples of dextromethorphan or a salt thereof include, for example, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenol phthaline salt, etc., and dextromethorphan hydrobromide hydrate. Dextromethorphan phenol phthaline salt is preferred, and dextromethorphan hydrobromide hydrate is particularly preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　本発明の医薬組成物におけるデキストロメトルファン又はその塩の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、１日あたり、デキストロメトルファン又はその塩を０．１～２７０ｍｇ、より好適には０．５～１８０ｍｇ、特に好適には１～９０ｍｇ服用できる量を含有せしめることができる。なお、デキストロメトルファン又はその塩がデキストロメトルファン臭化水素酸塩水和物である場合、１日あたり、デキストロメトルファン臭化水素酸塩水和物を６～６０ｍｇ、より好適には１５～６０ｍｇ、特に好適には２０～６０ｍｇ服用できる量を含有せしめるのが好ましい。また、デキストロメトルファン又はその塩がデキストロメトルファンフェノールフタリン塩である場合、１日あたり、デキストロメトルファンフェノールフタリン塩を９～９０ｍｇ、より好適には２２～９０ｍｇ、特に好適には３０～９０ｍｇ服用できる量を含有せしめるのが好ましい。
　本発明においては、デキストロメトルファン又はその塩を医薬組成物全質量に対して０．００４～２０質量％含有するのが好ましく、０．０２～１５質量％含有するのがより好ましく、０．０４～１０質量％含有するのが特に好ましい。 The content of dextromethorphan or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, 0.1 to 270 mg, more preferably 0.5 to 180 mg, and particularly preferably 1 to 90 mg of dextromethorphan or a salt thereof can be contained per day. When dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate, 6 to 60 mg, more preferably 15 to 60 mg of dextromethorphan hydrobromide hydrate per day, It is particularly preferable to add an amount that can be taken from 20 to 60 mg. In addition, when dextromethorphan or a salt thereof is dextromethorphan phenol phthalin salt, 9 to 90 mg, more preferably 22 to 90 mg, particularly preferably 30 to 90 mg of dextromethorphan phenol phthalin salt per day. It is preferable to contain an amount that can be taken by 90 mg.
In the present invention, dextromethorphan or a salt thereof is preferably contained in an amount of 0.004 to 20% by mass, more preferably 0.02 to 15% by mass, more preferably 0.04%, based on the total mass of the pharmaceutical composition. The content is particularly preferably 10 to 10% by mass.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びデキストロメトルファン又はその塩の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて、適宜検討して決定すればよいが、ロキソプロフェン又はその塩を、ロキソプロフェンナトリウム無水物換算で１質量部に対し、デキストロメトルファン又はその塩を、０．０００１～２０質量部含有するものが好ましく、０．０００５～１０質量部含有するものがより好ましく、０．００１～５質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and dextromethorphan or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and is determined by appropriate examination according to the daily dose of each component described above. It is preferable that loxoprofen or a salt thereof contains 0.0001 to 20 parts by mass of dextromethorphan or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 10 masses. More preferred are those containing 0.001 to 5 parts by mass.
　本発明において、「キサンチン誘導体」としては、下記一般式（４）で表される化合物が好ましい。 In the present invention, the “xanthine derivative” is preferably a compound represented by the following general formula (4).
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
［式（４）中、Ｒ８及びＲ９は各々独立して水素原子又はメチル基を示し、Ｒ１０は水素原子、メチル基、モノヒドロキシプロピル基又はジヒドロキシプロピル基を示す。］ [In Formula (4), R 8 and R 9 each independently represent a hydrogen atom or a methyl group, and R 10 represents a hydrogen atom, a methyl group, a monohydroxypropyl group, or a dihydroxypropyl group. ]
　式（４）中、Ｒ１０において、モノヒドロキシプロピル基としては、２－ヒドロキシプロピル基が好ましい。また、ジヒドロキシプロピル基としては、２，３－ジヒドロキシプロピル基が好ましい。 In formula (4), in R 10 , the monohydroxypropyl group is preferably a 2-hydroxypropyl group. The dihydroxypropyl group is preferably a 2,3-dihydroxypropyl group.
　なお、上記一般式（４）において、
（１）Ｒ８がメチル基であり、Ｒ９がメチル基であり、Ｒ１０がメチル基であるものは、カフェインを意味するものである。
（２）Ｒ８がメチル基であり、Ｒ９がメチル基であり、Ｒ１０が水素原子であるものは、テオフィリンを意味するものである。
（３）Ｒ８が水素原子であり、Ｒ９がメチル基であり、Ｒ１０がメチル基であるものは、テオブロミンを意味するものである。
（４）Ｒ８がメチル基であり、Ｒ９が水素原子であり、Ｒ１０がメチル基であるものは、パラキサンチンを意味するものである。
（５）Ｒ８がメチル基であり、Ｒ９がメチル基であり、Ｒ１０が２－ヒドロキシプロピル基であるものは、プロキシフィリンを意味するものである。
（６）Ｒ８がメチル基であり、Ｒ９がメチル基であり、Ｒ１０が２，３－ジヒドロキシプロピル基であるものは、ジプロフィリンを意味するものである。 In the general formula (4),
(1) R 8 is a methyl group, R 9 is a methyl group, and R 10 is a methyl group means caffeine.
(2) R 8 is a methyl group, R 9 is a methyl group, and R 10 is a hydrogen atom means theophylline.
(3) The case where R 8 is a hydrogen atom, R 9 is a methyl group, and R 10 is a methyl group means theobromine.
(4) R 8 is a methyl group, R 9 is a hydrogen atom and R 10 is a methyl group is intended to mean a paraxanthine.
(5) A compound in which R 8 is a methyl group, R 9 is a methyl group, and R 10 is a 2-hydroxypropyl group means proxyphylline.
(6) The case where R 8 is a methyl group, R 9 is a methyl group, and R 10 is a 2,3-dihydroxypropyl group means diprofylline.
　一般式（４）の化合物、とりわけ上述の化合物は公知であり、本発明においては、公知の方法により製造したもののほか、市販のものを用いることができる。
　なお、キサンチン誘導体としては、上記一般式（４）で表される化合物そのもののほか、その薬学上許容される塩（例えば、複塩を形成したもの（安息香酸ナトリウムカフェイン（安息香酸ナトリウムとカフェインの複塩）、アミノフィリン（テオフィリンとエチレンジアミンとの複塩））等）、一般式（４）で表される化合物又はその塩と水やアルコール等との溶媒和物を用いることもでき、これらも「キサンチン誘導体」に包含され、上述の化合物（カフェイン、テオフィリン、テオブロミン、パラキサンチン、プロキシフィリン及びジプロフィリン）には、当該化合物、その塩やそれらの溶媒和物も包含される。なお、本発明においては、これらキサンチン誘導体のうち、１種又は２種以上を用いることができる。 The compounds of the general formula (4), especially the above-mentioned compounds are known. In the present invention, commercially available products can be used in addition to those produced by known methods.
As the xanthine derivative, in addition to the compound itself represented by the general formula (4), a pharmaceutically acceptable salt thereof (for example, a double salt formed (sodium benzoate caffeine (sodium benzoate and caffeine)). Indium), aminophylline (theophylline and ethylenediamine double salt))), compounds represented by the general formula (4) or a solvate of the salt thereof with water or alcohol, etc. Are also included in the “xanthine derivative”, and the above-mentioned compounds (caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprofylline) also include the compound, a salt thereof, and a solvate thereof. In the present invention, one or more of these xanthine derivatives can be used.
　本発明においてキサンチン誘導体としては、カフェイン、テオフィリン、テオブロミン、パラキサンチン、プロキシフィリン及びジプロフィリンからなる群より選ばれる１種以上が好ましく、特に、本発明の医薬組成物を解熱鎮痛剤や総合感冒薬等として利用した場合の観点から、カフェインが好ましい。当該カフェインとしては、カフェイン水和物、無水カフェイン、安息香酸ナトリウムカフェイン、クエン酸カフェインが好適な具体例として挙げられ、このうち、カフェイン水和物、無水カフェイン、安息香酸ナトリウムカフェインが特に好ましい。 In the present invention, the xanthine derivative is preferably one or more selected from the group consisting of caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprofylline. In particular, the pharmaceutical composition of the present invention is used as an antipyretic analgesic or a general cold medicine. Caffeine is preferred from the standpoint of use as a etc. Specific examples of the caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. Among these, caffeine hydrate, caffeine anhydride, benzoic acid are preferable. Sodium caffeine is particularly preferred.
　本発明の医薬組成物におけるキサンチン誘導体の含有量は、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、１日あたり、キサンチン誘導体を１０～１０００ｍｇ、より好適には２０～８００ｍｇ、特に好適には３０～６００ｍｇ服用できる量を含有せしめることができる。本発明においては、キサンチン誘導体を医薬組成物全質量に対して０．４～６５質量％含有するのが好ましく、０．８～５０質量％含有するのがより好ましく、１．６～４０質量％含有するのが特に好ましい。 The content of the xanthine derivative in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, 10 to 1000 mg, more preferably 20 to 800 mg, particularly preferably 30 to 600 mg of xanthine derivative can be contained per day. In the present invention, the xanthine derivative is preferably contained in an amount of 0.4 to 65% by mass relative to the total mass of the pharmaceutical composition, more preferably 0.8 to 50% by mass, and 1.6 to 40% by mass. It is particularly preferable to contain it.
　また、本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びキサンチン誘導体の配合比は、上述した各成分の１日あたりの服用量に応じて、適宜検討して決定すればよいが、ロキソプロフェン又はその塩を、ロキソプロフェンナトリウム無水物換算で１質量部に対し、キサンチン誘導体を、０．０３～１００質量部含有するものが好ましく、０．０８～２７質量部含有するものがより好ましく、０．２～１０質量部含有するものがさらに好ましい。 In addition, the blending ratio of loxoprofen or a salt thereof and xanthine derivative 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. Alternatively, the salt thereof preferably contains 0.03 to 100 parts by mass, more preferably 0.08 to 27 parts by mass of xanthine derivative with respect to 1 part by mass of loxoprofen sodium anhydride. Those containing 2 to 10 parts by mass are more preferable.
　本発明において「イソバレリル尿素誘導体」とは、ブロムワレリル尿素及びアリルイソプロピルアセチル尿素並びにそれらの塩からなる群より選ばれる１種以上を意味する。このうち、ブロムワレリル尿素が好ましい。
　なお、イソバレリル尿素誘導体には不斉炭素が存するため、種々の光学異性体が存するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。 In the present invention, the “isovaleryl urea derivative” means one or more selected from the group consisting of bromovalerylurea, allylisopropylacetylurea and salts thereof. Of these, bromovalerylurea is preferred.
Since the isovaleryl urea derivative has an asymmetric carbon, there are various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used. A mixture of
　本発明の医薬組成物におけるイソバレリル尿素誘導体の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて適宜検討して決定すればよい。例えば、イソバレリル尿素誘導体がブロムワレリル尿素又はその塩である場合、１日あたり、ブロムワレリル尿素をフリー体換算で１０～１０００ｍｇ、より好適には３０～８００ｍｇ、特に好適には６０～６００ｍｇ服用できる量を含有せしめることができる。また、イソバレリル尿素誘導体がアリルイソプロピルアセチル尿素又はその塩である場合、１日あたり、アリルイソプロピルアセチル尿素をフリー体換算で１～５００ｍｇ、より好適には１０～３００ｍｇ、特に好適には２０～１８０ｍｇ服用できる量を含有せしめることができる。 The content of the isovaleryl urea derivative in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, when the isovaleryl urea derivative is bromvaleryl urea or a salt thereof, it contains 10 to 1000 mg, more preferably 30 to 800 mg, particularly preferably 60 to 600 mg of bromvalerylurea per day in terms of free form. It can be shown. In addition, when the isovaleryl urea derivative is allyl isopropyl acetyl urea or a salt thereof, 1 to 500 mg, more preferably 10 to 300 mg, particularly preferably 20 to 180 mg of allyl isopropyl acetyl urea per day is converted in free form. An amount that can be contained can be included.
　本発明においては、イソバレリル尿素誘導体を医薬組成物全質量に対して０．１～９５質量％含有するのが好ましい。特に、イソバレリル尿素誘導体がブロムワレリル尿素又はその塩である場合、医薬組成物全質量に対してブロムワレリル尿素をフリー体換算で１～９５質量％含有するのが好ましく、４～９０質量％含有するのがより好ましく、８～８０質量％含有するのが特に好ましい。また、イソバレリル尿素誘導体がアリルイソプロピルアセチル尿素又はその塩である場合、医薬組成物全質量に対してアリルイソプロピルアセチル尿素をフリー体換算で０．１～７０質量％含有するのが好ましく、１～４０質量％含有するのがより好ましく、２～２４質量％含有するのが特に好ましい。 In the present invention, it is preferable to contain 0.1 to 95% by mass of the isovaleryl urea derivative with respect to the total mass of the pharmaceutical composition. In particular, when the isovaleryl urea derivative is bromvaleryl urea or a salt thereof, it is preferable to contain 1 to 95% by mass of bromvaleryl urea in terms of free form, and preferably 4 to 90% by mass with respect to the total mass of the pharmaceutical composition. More preferably, the content is particularly preferably 8 to 80% by mass. Further, when the isovaleryl urea derivative is allyl isopropyl acetyl urea or a salt thereof, it is preferable to contain 0.1 to 70% by mass of allyl isopropyl acetyl urea in terms of free form based on the total mass of the pharmaceutical composition. More preferably, it is contained in an amount of 2 to 24% by mass.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びイソバレリル尿素誘導体の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて適宜検討して決定すればよいが、イソバレリル尿素誘導体がブロムワレリル尿素又はその塩である場合、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、ブロムワレリル尿素又はその塩をフリー体換算で０．０３～１００質量部含有するものが好ましく、０．０５～５０質量部含有するものがより好ましく、０．１～３０質量部含有するものがさらに好ましく、０．３～１０質量部含有するものが特に好ましい。また、イソバレリル尿素誘導体がアリルイソプロピルアセチル尿素又はその塩である場合、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、アリルイソプロピルアセチル尿素又はその塩をフリー体換算で０．００３～５０質量部含有するものが好ましく、０．０４～１０質量部含有するものがより好ましく、０．１～３質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and isovaleryl urea derivative contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. When the isovaleryl urea derivative is bromvaleryl urea or a salt thereof, 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium is contained in an amount of 0.03 to 100 parts by mass of bromvaleryl urea or a salt thereof in terms of free form Those containing 0.05 to 50 parts by mass are more preferred, those containing 0.1 to 30 parts by mass are more preferred, and those containing 0.3 to 10 parts by mass are particularly preferred. When the isovaleryl urea derivative is allyl isopropyl acetyl urea or a salt thereof, 1 part by mass of loxoprofen or a salt thereof in terms of loxoprofen sodium anhydride is 0.003 to Those containing 50 parts by mass are preferred, those containing 0.04 to 10 parts by mass are more preferred, and those containing 0.1 to 3 parts by mass are particularly preferred.
　本発明において「トロパンアルカロイド類」とは、トロパン骨格を持つアルカロイド又はその誘導体を意味し、具体的にはトロパンアルカロイド（アトロピン、スコポラミン、ヒヨスチアミンなど）及びその誘導体（例えば、メチルアトロピン、メチルスコポラミン、ブチルスコポラミンなどの四級アンモニウム化誘導体など）並びにそれらのアルカロイドを含有する成分（ダツラエキス、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ベラドンナコン、ベラドンナエキス、ロートコン総アルカロイド、ロートコン、ロートエキス）が挙げられる。なお、これらは、薬学上許容される塩や溶媒和物の状態であってもよい。
　ここで、塩としては、好適な具体例としては、臭化物塩（例えば、ブチルスコポラミン臭化物など）、臭化水素酸塩（例えば、スコポラミン臭化水素酸塩水和物など）、クエン酸塩（例えば、ロートコン総アルカロイドクエン酸塩など）などが挙げられる。また、溶媒和物としては、水和物等が挙げられる。 In the present invention, “tropane alkaloids” mean alkaloids having a tropane skeleton or derivatives thereof. Specifically, tropane alkaloids (atropine, scopolamine, hyoscyamine, etc.) and derivatives thereof (for example, methylatropine, methylscopolamine, And quaternary ammonium derivatives such as butyl scopolamine) and components containing these alkaloids (datsura extract, belladonna alkaloid, belladonna total alkaloid, belladonnacon, belladonna extract, rotocon total alkaloid, rotocon, funnel extract). These may be in the form of a pharmaceutically acceptable salt or solvate.
Here, suitable specific examples of the salt include bromide salts (for example, butyl scopolamine bromide), hydrobromides (for example, scopolamine hydrobromide hydrate), citrates (for example, Rotcon total alkaloid citrate, etc.). Examples of solvates include hydrates.
　本発明においてトロパンアルカロイド類としては、ダツラエキス、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ベラドンナエキス、ロートコン総アルカロイドクエン酸塩、ロートエキス及びブチルスコポラミン臭化物からなる群より選ばれる１種以上が好ましく、ブチルスコポラミン臭化物が特に好ましい。
　これらは公知の成分であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, the tropane alkaloid is preferably one or more selected from the group consisting of datsura extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, rotcon total alkaloid citrate, funnel extract and butyl scopolamine bromide, and butyl scopolamine bromide. Particularly preferred.
These are known components, which can be produced by a known method or commercially available.
　本発明の医薬組成物におけるトロパンアルカロイド類の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて適宜検討して決定すればよい。例えば、１日あたり、トロパンアルカロイド類を、１日あたり０．０５～１０００ｍｇ、より好適には０．１～５００ｍｇ、特に好適には０．１２～１００ｍｇ服用できる量を含有せしめることができる。なお、トロパンアルカロイド類として、ブチルスコポラミン臭化物を用いる場合、１日あたり３～１０００ｍｇ、より好適には５～５００ｍｇ、特に好適には３０～１００ｍｇ服用できる量を含有せしめることができる。また、トロパンアルカロイド類として、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ロートコン総アルカロイドを用いる場合、１日あたり０．０５～２ｍｇ、より好適には０．１～１ｍｇ、特に好適には０．１２～０．８ｍｇ服用できる量を含有せしめることができる。また、トロパンアルカロイド類として、ダツラエキス、ベラドンナエキス、ロートエキスを用いる場合、１日あたり１～２００ｍｇ、より好適には５～１００ｍｇ、特に好適には１０～８０ｍｇ服用できる量を含有せしめることができる。 The content of tropane alkaloids in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, the amount of tropane alkaloids that can be taken per day is 0.05 to 1000 mg, more preferably 0.1 to 500 mg, and particularly preferably 0.12 to 100 mg per day. When butyl scopolamine bromide is used as the tropane alkaloids, it can be contained in an amount of 3 to 1000 mg, more preferably 5 to 500 mg, particularly preferably 30 to 100 mg per day. Further, when using belladonna alkaloids, belladonna total alkaloids, rotcon total alkaloids as tropane alkaloids, 0.05 to 2 mg per day, more preferably 0.1 to 1 mg, particularly preferably 0.12 to 0.00. The amount that can be taken 8 mg can be included. In addition, when datsura extract, belladonna extract, or funnel extract is used as the tropane alkaloids, it can contain 1 to 200 mg, more preferably 5 to 100 mg, and particularly preferably 10 to 80 mg per day.
　本発明においては、トロパンアルカロイド類を医薬組成物全質量に対して合計で０．００５～６０質量％含有するものが好ましく、０．０１～５０質量％含有するものがより好ましく、０．０２～４０質量％含有するものが好ましい。特に、トロパンアルカロイド類としてブチルスコポラミン臭化物を用いる場合においては、ブチルスコポラミン臭化物を医薬組成物全質量に対して１～１０質量％含有するものが好ましく、２～８質量％含有するものがより好ましく、３～７質量％含有するものが特に好ましい。 In the present invention, the tropane alkaloids are preferably contained in a total amount of 0.005 to 60% by mass, more preferably 0.01 to 50% by mass, more preferably 0.02 to What contains 40 mass% is preferable. In particular, when butyl scopolamine bromide is used as the tropane alkaloids, it preferably contains 1 to 10% by mass of butyl scopolamine bromide with respect to the total mass of the pharmaceutical composition, and more preferably contains 2 to 8% by mass. Those containing 3 to 7% by mass are particularly preferred.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びトロパンアルカロイド類の含有比は特に限定されず、上述した各成分の１日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、トロパンアルカロイド類を０．０００１～１０００質量部含有するものが好ましく、０．０００５～５００質量部含有するものがより好ましく、０．００１～３００質量部含有するものが特に好ましい。特に、トロパンアルカロイド類としてブチルスコポラミン臭化物を用いる場合においては、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で１質量部に対し、ブチルスコポラミン臭化物を０．０１～１００質量部含有するものが好ましく、０．０２～２０質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and tropane alkaloids contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. , Preferably containing 0.0001 to 1000 parts by mass of tropane alkaloids, more preferably 0.0005 to 500 parts by mass with respect to 1 part by mass of loxoprofen sodium salt in terms of loxoprofen sodium anhydride. Those containing 0.001 to 300 parts by mass are particularly preferable. In particular, when butyl scopolamine bromide is used as the tropane alkaloids, it is preferable that loxoprofen or a salt thereof contains 0.01 to 100 parts by mass of butyl scopolamine bromide with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. Those containing 0.02 to 20 parts by mass are particularly preferable.
　次に、本発明の成分（Ｃ）について詳細に説明する。
　成分（Ｃ）は、酸中和能を有する塩基性化合物である。ここで、本発明において「酸中和能を有する塩基性化合物」とは、酸中和能を有する塩基性の化合物を意味する。ここで、「酸中和能」は、第十五改正日本薬局方　一般試験法に記載の制酸力試験法に従い試験を行なうことにより判定することができる。 Next, the component (C) of the present invention will be described in detail.
Component (C) is a basic compound having acid neutralizing ability. Here, in the present invention, the “basic compound having acid neutralizing ability” means a basic compound having acid neutralizing ability. Here, the “acid neutralizing ability” can be determined by conducting a test according to the antacid test method described in the Fifteenth Amendment Japanese Pharmacopoeia General Test Method.
　本発明において、酸中和能を有する塩基性化合物としては例えば、マグネシウム、アルミニウム、カルシウム等のアルカリ土類金属及び／又は土類金属系塩基性無機化合物、ナトリウム、カリウム等のアルカリ金属系塩基性無機化合物、アミン系塩基性無機化合物等の塩基性無機化合物；マグネシウム、アルミニウム、カルシウム等のアルカリ土類金属及び／又は土類金属系塩基性有機化合物、ナトリウム、カリウム等のアルカリ金属系塩基性有機化合物、アミン系塩基性有機化合物等の塩基性有機化合物が挙げられる。 In the present invention, examples of the basic compound having an acid neutralizing ability include alkaline earth metals such as magnesium, aluminum and calcium and / or alkaline metal basic inorganic compounds such as magnesium and aluminum, and alkali metal basics such as sodium and potassium. Basic inorganic compounds such as inorganic compounds and amine basic inorganic compounds; alkaline earth metals such as magnesium, aluminum and calcium and / or earth metal basic organic compounds, alkali metal basic organic such as sodium and potassium Examples thereof include basic organic compounds such as compounds and amine basic organic compounds.
　上記塩基性無機化合物において、アルカリ土類金属及び／又は土類金属系塩基性無機化合物としては、例えば、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウムアルミニウム、酸化マグネシウム、水酸化マグネシウム、水酸化マグネシウム・硫酸アルミニウムカリウムの共沈生成物、炭酸マグネシウム、合成ヒドロタルサイト、メタケイ酸アルミン酸マグネシウム、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、合成ケイ酸アルミニウム・ヒドロキシプロピルスターチ・結晶セルロース、水酸化アルミナマグネシウム、水酸化アルミニウムゲル、水酸化アルミニウム・炭酸水素ナトリウム共沈生成物、水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲル、水酸化アルミニウム・炭酸マグネシウム・炭酸カルシウム共沈生成物、ベントナイト、ケイ酸カルシウム、炭酸カルシウム、沈降炭酸カルシウム、リン酸水素カルシウム、無水リン酸水素カルシウム等のマグネシウム、アルミニウム及びカルシウムから選ばれる金属の無機塩等が挙げられる。
　また、アルカリ金属系塩基性無機化合物としては、例えば、乾燥炭酸ナトリウム、水酸化ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム水和物、ピロリン酸四ナトリウム、リン酸三ナトリウム、リン酸水素ナトリウム水和物、無水ピロリン酸ナトリウム、無水リン酸一水素ナトリウム、水酸化カリウム、炭酸水素カリウム、炭酸カリウム等のナトリウム及びカリウムから選ばれる金属の無機塩等が挙げられる。 In the basic inorganic compound, examples of the alkaline earth metal and / or earth metal-based basic inorganic compound include magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, and water. Coprecipitation product of magnesium oxide and potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminate metasilicate, dry aluminum hydroxide gel, synthetic aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, water Alumina magnesium oxide, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / carbonic acid Calcium coprecipitation product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, magnesium such as anhydrous calcium hydrogen phosphate, metal inorganic salts selected from aluminum and calcium and the like.
Examples of the alkali metal basic inorganic compound include dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, tetrasodium pyrophosphate, trisodium phosphate, sodium hydrogen phosphate hydrate, Examples thereof include inorganic salts of metals selected from sodium and potassium, such as anhydrous sodium pyrophosphate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, and potassium carbonate.
　本発明において、酸中和能を有する塩基性無機化合物としては、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウムアルミニウム、酸化マグネシウム、水酸化マグネシウム、水酸化マグネシウム・硫酸アルミニウムカリウムの共沈生成物、炭酸マグネシウム、合成ヒドロタルサイト、メタケイ酸アルミン酸マグネシウム、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、合成ケイ酸アルミニウム・ヒドロキシプロピルスターチ・結晶セルロース、水酸化アルミナマグネシウム、水酸化アルミニウムゲル、水酸化アルミニウム・炭酸水素ナトリウム共沈生成物、水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲル、水酸化アルミニウム・炭酸マグネシウム・炭酸カルシウム共沈生成物、ベントナイト、ケイ酸カルシウム、炭酸カルシウム、沈降炭酸カルシウム、リン酸水素カルシウム、無水リン酸水素カルシウム、炭酸水素ナトリウムが好ましい。 In the present invention, the basic inorganic compound having acid neutralizing ability includes magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide / potassium aluminum sulfate , Magnesium carbonate, Synthetic hydrotalcite, Magnesium aluminate metasilicate, Dry aluminum hydroxide gel, Synthetic aluminum silicate, Synthetic aluminum silicate, Hydroxypropyl starch, Crystalline cellulose, Magnesium aluminate hydroxide, Aluminum hydroxide gel, Water Aluminum oxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, bentonite, silica Calcium, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, calcium hydrogen phosphate anhydrous, sodium bicarbonate is preferred.
　また、上記塩基性有機化合物において、アルカリ土類金属及び／又は土類金属系塩基性有機化合物としては、例えば、アルジオキサ、ジヒドロキシアルミニウムアミノアセテート、スクラルファート水和物、パントテン酸カルシウム等が挙げられる。
　また、アルカリ金属系塩基性有機化合物としては、例えば、クエン酸ナトリウム水和物、コハク酸二ナトリウム六水和物、ＤＬ－酒石酸ナトリウム、Ｌ－酒石酸ナトリウム、銅クロロフィリンナトリウム、ポリアクリル酸ナトリウム、５’－リボヌクレオチド二ナトリウム、銅クロロフィリンカリウム等が挙げられる。
　また、アミン系塩基性有機化合物としては、例えば、アミノ酢酸、Ｌ－アルギニン、メグルミン等が挙げられる。 In the basic organic compound, examples of the alkaline earth metal and / or earth metal-based basic organic compound include aldioxa, dihydroxyaluminum aminoacetate, sucralfate hydrate, calcium pantothenate, and the like.
Examples of the alkali metal basic organic compound include sodium citrate hydrate, disodium succinate hexahydrate, DL-sodium tartrate, sodium L-tartrate, copper chlorophyllin sodium, sodium polyacrylate, 5 '-Ribonucleotide disodium, copper chlorophyllin potassium and the like.
Examples of the amine basic organic compound include aminoacetic acid, L-arginine, meglumine and the like.
　本発明において、酸中和能を有する塩基性有機化合物としては、アルジオキサ、ジヒドロキシアルミニウムアミノアセテート、スクラルファート水和物が好ましい。 In the present invention, as the basic organic compound having acid neutralizing ability, aldioxa, dihydroxyaluminum aminoacetate and sucralfate hydrate are preferable.
　なお、本発明においては、前記塩基性化合物として、烏賊骨、石決明、ボレイ（牡蠣）等の塩基性化合物を含有する生薬を用いてもよい。 In the present invention, a crude drug containing a basic compound such as bandit bone, stone decision, or oyster may be used as the basic compound.
　本発明において、前記酸中和能を有する塩基性化合物の好適な具体例としては、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウムアルミニウム、酸化マグネシウム、水酸化マグネシウム、沈降炭酸カルシウム、無水リン酸水素カルシウム及びメタケイ酸アルミン酸マグネシウムからなる群より選ばれる１種以上が挙げられ、特に好ましくは、相互作用抑制の点で、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、ケイ酸カルシウム、酸化マグネシウム、水酸化マグネシウム、沈降炭酸カルシウム、無水リン酸水素カルシウム及びメタケイ酸アルミン酸マグネシウムからなる群より選ばれる１種以上が挙げられる。
　なお、前記塩基性化合物は単独でもよく、２種以上を組み合わせてもよい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, preferred specific examples of the basic compound having acid neutralizing ability include magnesium aluminate silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, precipitated carbonic acid. 1 or more types selected from the group consisting of calcium, anhydrous calcium hydrogen phosphate and magnesium aluminate metasilicate are mentioned, and particularly preferred are magnesium aluminate silicate, magnesium silicate, and calcium silicate in terms of inhibition of interaction. And one or more selected from the group consisting of magnesium oxide, magnesium hydroxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, and magnesium aluminate metasilicate.
In addition, the said basic compound may be individual, and may combine 2 or more types. These are known compounds, and can be produced by known methods, or commercially available products can be used.
　また、前記酸中和能を有する塩基性化合物としては、制酸剤として用いられ得るものが好ましい具体例として挙げられる。制酸剤として用いられ得る酸中和能を有する塩基性化合物としては、具体的には例えば、アミノ酢酸、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、合成ケイ酸アルミニウム、合成ヒドロタルサイト、酸化マグネシウム、ジヒドロキシアルミニウムアミノアセテート、水酸化アルミナマグネシウム、水酸化アルミニウムゲル、乾燥水酸化アルミニウムゲル、水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲル、水酸化アルミニウム・炭酸水素ナトリウムの共沈生成物、水酸化アルミニウム・炭酸カルシウム・炭酸マグネシウムの共沈生成物、水酸化マグネシウム、水酸化マグネシウム・硫酸アルミニウムカリウムの共沈生成物、炭酸マグネシウム、炭酸水素ナトリウム、沈降炭酸カルシウム、メタケイ酸アルミン酸マグネシウム、無水リン酸水素カルシウム、リン酸水素カルシウム、烏賊骨、石決明、ボレイ等が挙げられる。制酸剤は、その性質から吸収性制酸剤と局所性制酸剤とに大別されるが、本発明においては、アルカローシス予防の観点で、局所性制酸剤が好ましい。 As the basic compound having acid neutralizing ability, those which can be used as an antacid are mentioned as preferred specific examples. Specific examples of basic compounds having acid neutralizing ability that can be used as antacids include aminoacetic acid, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, and magnesium oxide. , Dihydroxyaluminum aminoacetate, magnesium hydroxide hydroxide, aluminum hydroxide gel, dry aluminum hydroxide gel, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / carbonate Coprecipitation product of calcium / magnesium carbonate, magnesium hydroxide, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium aluminate metasilicate, Water calcium hydrogen phosphate, calcium hydrogen phosphate, cuttlefish bone, stone Ke'Akira, Borei like. Antacids are broadly classified into absorbent antacids and local antacids due to their properties. In the present invention, local antacids are preferred from the viewpoint of preventing alkalosis.
　本発明の医薬組成物における酸中和能を有する塩基性化合物の含有量は特に限定されず、ロキソプロフェンと相互作用性成分との相互作用の抑制効果に応じて、適宜検討して決定すればよい。例えば、１日あたり、１～２００００ｍｇ服用する量が好ましく、１０～１００００ｍｇ服用する量がより好ましく、２０～５０００ｍｇ服用する量が特に好ましい。本発明においては、酸中和能を有する塩基性化合物を医薬組成物全質量に対して０．０４～９９．９質量％含有するのが好ましく、０．４～９９．９質量％含有するのがより好ましく、０．８～９９．９質量％含有するのがより好ましく、２５～７５質量％含有するのが特に好ましい。 The content of the basic compound having acid neutralization ability in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the inhibitory effect of the interaction between loxoprofen and the interactive component. . For example, the amount taken from 1 to 20000 mg per day is preferred, the amount taken from 10 to 10000 mg is more preferred, and the amount taken from 20 to 5000 mg is particularly preferred. In the present invention, the basic compound having acid neutralizing ability is preferably contained in an amount of 0.04 to 99.9% by mass, and preferably 0.4 to 99.9% by mass, based on the total mass of the pharmaceutical composition. Is more preferable, 0.8 to 99.9% by mass is more preferable, and 25 to 75% by mass is particularly preferable.
　なお、酸中和能を有する塩基性化合物として、アルジオキサを用いる場合、１日あたり１０～８００ｍｇ服用する量が好ましく、３０～４００ｍｇ服用する量がより好ましい。
　烏賊骨を用いる場合、１日あたり１０～６０００ｍｇ服用する量が好ましく、３０～３０００ｍｇ服用する量がより好ましい。
　乾燥水酸化アルミニウムゲルを用いる場合、１日あたり１０～６０００ｍｇ服用する量が好ましく、３０～３０００ｍｇ服用する量がより好ましい。
　ケイ酸アルミン酸マグネシウムを用いる場合、１日あたり１０～８０００ｍｇ服用する量が好ましく、３０～４０００ｍｇ服用する量がより好ましい。
　ケイ酸カルシウムを用いる場合、１日あたり１～６００ｍｇ服用する量が好ましく、３０～３００ｍｇ服用する量がより好ましい。
　ケイ酸マグネシウムを用いる場合、１日あたり１０～１２０００ｍｇ服用する量が好ましく、３０～６０００ｍｇ服用する量がより好ましい。
　ケイ酸マグネシウムアルミニウムを用いる場合、１日あたり１～５００ｍｇ服用する量が好ましく、２０～２２５ｍｇ服用する量がより好ましい。
　合成ケイ酸アルミニウムを用いる場合、１日あたり１０～２００００ｍｇ服用する量が好ましく、３０～１００００ｍｇ服用する量がより好ましい。
　合成ケイ酸アルミニウム・ヒドロキシプロピルスターチ・結晶セルロースを用いる場合、１日あたり１０～３５００ｍｇ服用する量が好ましく、３０～１８００ｍｇ服用する量がより好ましい。 When aldioxa is used as the basic compound having acid neutralizing ability, the amount taken from 10 to 800 mg per day is preferred, and the amount taken from 30 to 400 mg is more preferred.
In the case of using the bandage bone, the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred.
When using dry aluminum hydroxide gel, the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred.
When using magnesium aluminate silicate, the amount taken from 10 to 8000 mg per day is preferred, and the amount taken from 30 to 4000 mg per day is more preferred.
When calcium silicate is used, the dose taken from 1 to 600 mg per day is preferred, and the dose taken from 30 to 300 mg is more preferred.
When using magnesium silicate, the amount taken from 10 to 12000 mg per day is preferred, and the amount taken from 30 to 6000 mg is more preferred.
When using magnesium aluminum silicate, the amount taken from 1 to 500 mg per day is preferred, and the amount taken from 20 to 225 mg is more preferred.
When using synthetic aluminum silicate, the amount taken from 10 to 20000 mg per day is preferred, and the amount taken from 30 to 10,000 mg is more preferred.
When using synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose, the amount taken from 10 to 3500 mg per day is preferred, and the amount taken from 30 to 1800 mg is more preferred.
　合成ヒドロタルサイトを用いる場合、１日あたり１０～８０００ｍｇ服用する量が好ましく、３０～４０００ｍｇ服用する量がより好ましい。
　酸化マグネシウムを用いる場合、１日あたり１０～２０００ｍｇ服用する量が好ましく、３０～１０００ｍｇ服用する量がより好ましい。
　ジヒドロキシアルミニウムアミノアセテートを用いる場合、１日あたり１０～６０００ｍｇ服用する量が好ましく、３０～３０００ｍｇ服用する量がより好ましい。
　水酸化アルミナマグネシウムを用いる場合、１日あたり１０～８０００ｍｇ服用する量が好ましく、３０～４０００ｍｇ服用する量がより好ましい。
　水酸化アルミニウムゲルを用いる場合、乾燥水酸化アルミニウムゲル換算で１日あたり１０～６０００ｍｇ服用する量が好ましく、３０～３０００ｍｇ服用する量がより好ましい。
　水酸化アルミニウム・炭酸水素ナトリウム共沈生成物を用いる場合、１日あたり１０～４０００ｍｇ服用する量が好ましく、３０～２０００ｍｇ服用する量がより好ましい。
　水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲルを用いる場合、１日あたり１０～６０００ｍｇ服用する量が好ましく、３０～３０００ｍｇ服用する量がより好ましい。
　水酸化アルミニウム・炭酸マグネシウム・炭酸カルシウム共沈生成物を用いる場合、１日あたり１０～８０００ｍｇ服用する量が好ましく、３０～４０００ｍｇ服用する量がより好ましい。
　水酸化マグネシウムを用いる場合、１日あたり１０～５０００ｍｇ服用する量が好ましく、３０～２４００ｍｇ服用する量がより好ましい。
　水酸化マグネシウム・硫酸アルミニウムカリウムの共沈生成物を用いる場合、１日あたり１０～４０００ｍｇ服用する量が好ましく、３０～２０００ｍｇ服用する量がより好ましい。 When using synthetic hydrotalcite, the amount taken from 10 to 8000 mg per day is preferred, and the amount taken from 30 to 4000 mg is more preferred.
In the case of using magnesium oxide, the amount taken from 10 to 2000 mg per day is preferred, and the amount taken from 30 to 1000 mg is more preferred.
When dihydroxyaluminum aminoacetate is used, the dose taken from 10 to 6000 mg per day is preferred, and the dose taken from 30 to 3000 mg is more preferred.
When using alumina magnesium hydroxide, the amount taken from 10 to 8000 mg per day is preferred, and the amount taken from 30 to 4000 mg is more preferred.
In the case of using aluminum hydroxide gel, the amount taken from 10 to 6000 mg per day in terms of dry aluminum hydroxide gel is preferred, and the amount taken from 30 to 3000 mg is more preferred.
When the aluminum hydroxide / sodium hydrogen carbonate coprecipitation product is used, the dose taken is preferably 10 to 4000 mg per day, more preferably 30 to 2000 mg.
When using an aluminum hydroxide / magnesium carbonate mixed dry gel, the dose taken is preferably 10 to 6000 mg per day, more preferably 30 to 3000 mg.
When an aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product is used, the amount taken is preferably 10 to 8000 mg per day, and more preferably 30 to 4000 mg.
When using magnesium hydroxide, the amount taken from 10 to 5000 mg per day is preferred, and the amount taken from 30 to 2400 mg is more preferred.
When a coprecipitation product of magnesium hydroxide and potassium aluminum sulfate is used, the amount taken is preferably 10 to 4000 mg per day, more preferably 30 to 2000 mg.
　スクラルファート水和物を用いる場合、１日あたり１０～６５００ｍｇ服用する量が好ましく、３０～３２５０ｍｇ服用する量がより好ましい。
　石決明を用いる場合、１日あたり１０～６０００ｍｇ服用する量が好ましく、３０～３０００ｍｇ服用する量がより好ましい。
　炭酸水素ナトリウムを用いる場合、１日あたり１０～１００００ｍｇ服用する量が好ましく、３０～５０００ｍｇ服用する量がより好ましい。
　炭酸カルシウムを用いる場合、１日あたり１０～１５００ｍｇ服用する量が好ましく、３０～７００ｍｇ服用する量がより好ましい。
　炭酸マグネシウムを用いる場合、１日あたり１０～４０００ｍｇ服用する量が好ましく、３０～２０００ｍｇ服用する量がより好ましい。
　沈降炭酸カルシウムを用いる場合、１日あたり１０～６０００ｍｇ服用する量が好ましく、３０～３０００ｍｇ服用する量がより好ましい。
　ベントナイトを用いる場合、１日あたり１～２００ｍｇ服用する量が好ましく、１０～１００ｍｇ服用する量がより好ましい。
　ボレイ（牡蠣）を用いる場合、１日あたり１０～６０００ｍｇ服用する量が好ましく、３０～３０００ｍｇ服用する量がより好ましい。 When using sucralfate hydrate, the amount taken from 10 to 6500 mg per day is preferred, and the amount taken from 30 to 3250 mg is more preferred.
When using stone decision, the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred.
In the case of using sodium bicarbonate, the amount taken from 10 to 10,000 mg per day is preferred, and the amount taken from 30 to 5000 mg is more preferred.
When calcium carbonate is used, the amount taken is preferably 10 to 1500 mg per day, and more preferably 30 to 700 mg.
When using magnesium carbonate, the dose taken from 10 to 4000 mg per day is preferred, and the dose taken from 30 to 2000 mg is more preferred.
When using precipitated calcium carbonate, the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred.
When bentonite is used, the amount taken is preferably 1 to 200 mg per day, and more preferably 10 to 100 mg.
When using oysters, the amount taken from 10 to 6000 mg per day is preferred, and the amount taken from 30 to 3000 mg is more preferred.
　無水リン酸水素カルシウムを用いる場合、１日あたり１０～５０００ｍｇ服用する量が好ましく、３０～２４００ｍｇ服用する量がより好ましい。
　メタケイ酸アルミン酸マグネシウムを用いる場合、１日あたり１０～８０００ｍｇ服用する量が好ましく、３０～４０００ｍｇ服用する量がより好ましい。
　リン酸水素カルシウムを用いる場合、１日あたり１０～９０００ｍｇ服用する量が好ましく、３０～４５００ｍｇ服用する量がより好ましい。 When anhydrous calcium hydrogen phosphate is used, the amount taken is preferably 10 to 5000 mg per day, and more preferably 30 to 2400 mg.
When using magnesium aluminate metasilicate, an amount taken from 10 to 8000 mg per day is preferred, and an amount taken from 30 to 4000 mg per day is more preferred.
When calcium hydrogen phosphate is used, the amount taken from 10 to 9000 mg per day is preferred, and the amount taken from 30 to 4500 mg is more preferred.
　本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及び酸中和能を有する塩基性化合物の含有比は特に限定されず、ロキソプロフェンと相互作用性成分の相互作用の抑制効果に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩を、ロキソプロフェンナトリウム無水物換算で１質量部に対し、酸中和能を有する塩基性化合物を０．００３～２０００質量部含有するものが好ましく、０．０１～１００質量部含有するものがより好ましく、０．０２～３０質量部含有するものがさらに好ましく、０．０４～１０質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and a basic compound having acid neutralizing ability contained in the pharmaceutical composition of the present invention is not particularly limited, and is appropriately examined according to the inhibitory effect of the interaction between loxoprofen and the interactive component. However, it is preferable that loxoprofen or a salt thereof contains 0.003 to 2000 parts by mass of a basic compound having an acid neutralizing ability with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. Those containing 0.01 to 100 parts by mass are more preferred, those containing 0.02 to 30 parts by mass are more preferred, and those containing 0.04 to 10 parts by mass are particularly preferred.
　本発明の医薬組成物としては、次の成分（Ａ）、（Ｂ）及び（Ｃ）：
（Ａ）ロキソプロフェン又はその塩；
（Ｂ）次の成分（Ｂ－１－１）～（Ｂ－１０－１）からなる群より選ばれる１種又は２種以上；
　（Ｂ－１－１）クロルフェニラミン又はその塩、（Ｂ－１－２）クレマスチン又はその塩、（Ｂ－１－３）カルビノキサミン又はその塩、（Ｂ－１－４）ジフェニルピラリン又はその塩、（Ｂ－２－１）ブロムヘキシン又はその塩、（Ｂ－２－２）アンブロキソール又はその塩、（Ｂ－３－１）グアヤコール誘導体又はその塩、（Ｂ－３－２）クレゾール誘導体又はその塩、（Ｂ－４）リゾチーム又はその塩、（Ｂ－５－１）コデイン、ジヒドロコデイン及びこれらの塩並びにこれらの溶媒和物からなる群より選ばれる１種以上、（Ｂ－６－１）エフェドリン、ノルエフェドリン及びメチルエフェドリン並びにこれらの塩からなる群より選ばれる１種以上、（Ｂ－７）デキストロメトルファン又はその塩、（Ｂ－８－１）カフェイン、（Ｂ－９－１）ブロムワレリル尿素及びアリルイソプロピルアセチル尿素からなる群より選ばれる１種以上、（Ｂ－１０－１）ダツラエキス、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ベラドンナエキス、ロートコン総アルカロイドクエン酸塩、ロートエキス及びブチルスコポラミン臭化物からなる群より選ばれる１種以上
（Ｃ）酸中和能を有する塩基性化合物；
を含有する医薬組成物が好ましく、 The pharmaceutical composition of the present invention includes the following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof;
(B) one or more selected from the group consisting of the following components (B-1-1) to (B-10-1);
(B-1-1) Chlorpheniramine or a salt thereof, (B-1-2) Clemastine or a salt thereof, (B-1-3) Carbinoxamine or a salt thereof, (B-1-4) Diphenylpyramine or a salt thereof (B-2-1) bromohexine or a salt thereof, (B-2-2) ambroxol or a salt thereof, (B-3-1) a guaiacol derivative or a salt thereof, (B-3-2) a cresol derivative or a salt thereof One or more selected from the group consisting of a salt thereof, (B-4) lysozyme or a salt thereof, (B-5-1) codeine, dihydrocodeine and a salt thereof, and a solvate thereof, (B-6-1) One or more selected from the group consisting of ephedrine, norephedrine, methylephedrine and salts thereof, (B-7) dextromethorphan or a salt thereof, (B-8-1) caffeine, (B- -1) one or more selected from the group consisting of bromvalerylurea and allylisopropylacetylurea, (B-10-1) duck extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, rotcon total alkaloid citrate, funnel extract and butyl One or more (C) basic compounds having acid neutralizing ability selected from the group consisting of scopolamine bromides;
A pharmaceutical composition containing
次の成分（Ａ）、（Ｂ）及び（Ｃ）：
（Ａ）ロキソプロフェン又はその塩；
（Ｂ）次の成分（Ｂ－１－１）～（Ｂ－１０－１－１）からなる群より選ばれる１種又は２種以上；
　（Ｂ－１－１）クロルフェニラミン又はその塩、（Ｂ－１－２）クレマスチン又はその塩、（Ｂ－１－３）カルビノキサミン又はその塩、（Ｂ－１－４）ジフェニルピラリン又はその塩、（Ｂ－２－１）ブロムヘキシン又はその塩、（Ｂ－２－２）アンブロキソール又はその塩、（Ｂ－３－１－１）グアイフェネシン又はその塩、（Ｂ－３－１－２）グアヤコールスルホン酸又はその塩、（Ｂ－３－２－１）クレゾールスルホン酸又はその塩、（Ｂ－４）リゾチーム又はその塩、（Ｂ－５－１－１）ジヒドロコデイン又はその塩、（Ｂ－６－１－１）メチルエフェドリン又はその塩、（Ｂ－７）デキストロメトルファン又はその塩、（Ｂ－８－１）カフェイン、（Ｂ－９－１－１）ブロムワレリル尿素、（Ｂ－１０－１－１）ブチルスコポラミン臭化物
（Ｃ）酸中和能を有する塩基性化合物；
を含有する医薬組成物が特に好ましい。 The following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof;
(B) one or more selected from the group consisting of the following components (B-1-1) to (B-10-1-1);
(B-1-1) Chlorpheniramine or a salt thereof, (B-1-2) Clemastine or a salt thereof, (B-1-3) Carbinoxamine or a salt thereof, (B-1-4) Diphenylpyramine or a salt thereof (B-2-1) bromohexine or a salt thereof, (B-2-2) ambroxol or a salt thereof, (B-3-1-1) guaifenesin or a salt thereof, (B-3-1-2) Guaiacol sulfonic acid or salt thereof, (B-3-2-1) cresol sulfonic acid or salt thereof, (B-4) lysozyme or salt thereof, (B-5-1-1) dihydrocodeine or salt thereof, (B- 6-1-1) methylephedrine or a salt thereof, (B-7) dextromethorphan or a salt thereof, (B-8-1) caffeine, (B-9-1-1) bromovalerylurea, (B-10) -1-1) Butyl scopola Basic compound having an emission bromide (C) an acid neutralizing capacity;
Particularly preferred are pharmaceutical compositions containing
　本発明の医薬組成物は、例えば、第十五改正日本薬局方　製剤総則等に記載の公知の方法により製造することができる。また、剤形は、特に限定されるものではなく、固形状、半固形状、液状のいずれの形状であってもよく、その利用目的等に応じて医薬品において通常利用される形状とすることができる。当該剤形としては、具体的には例えば、錠剤（チュアブル錠、発泡錠、口腔内崩壊錠などを含む）、トローチ剤、ドロップ剤、硬カプセル剤、軟カプセル剤、顆粒剤、細粒剤、散剤、丸剤、ドライシロップ剤、坐剤、パップ剤、プラスター剤などの固形製剤；舐剤、チューインガム剤、ゼリー剤、ゼリー状ドロップ剤、ホイップ剤、軟膏剤、クリーム剤、フォーム剤、インへラー剤、ナザールジェル剤などの半固形製剤；シロップ剤、ドリンク剤、懸濁剤、酒精剤、液剤、点眼剤、エアゾール剤、噴霧剤、スプレー剤などの液状製剤などの、第十五改正日本薬局方　製剤総則等に記載の剤形が挙げられる。これらの中でも、固形製剤が好ましく、錠剤、カプセル剤、丸剤、顆粒剤、散剤及び細粒剤からなる群より選ばれる固形製剤がより好ましく、錠剤又はカプセル剤がさらに好ましく、錠剤が特に好ましい。この点に関し、固形製剤は一般的に服用の簡便性や薬物服用量の管理等の点で有利であるのみならず、下記試験例１５に具体的に記載されているとおり、本発明の医薬組成物が固形製剤である場合、その経時的な膨張が抑制されることが明らかとなった。従って、本発明によれば、コーティングや糖衣を施した場合や、カプセルへの充填等をした場合に、コーティング、糖衣やカプセルの割れや欠けが生じにくい、安定性に優れた固形製剤を提供できる。 The pharmaceutical composition of the present invention can be produced by, for example, a known method described in the 15th revision Japanese Pharmacopoeia, General Rules for Preparations. The dosage form is not particularly limited, and may be any of solid, semi-solid, and liquid shapes, and may be a shape usually used in pharmaceuticals depending on the purpose of use and the like. it can. Specific examples of the dosage form include tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets), troches, drops, hard capsules, soft capsules, granules, fine granules, Solid preparations such as powders, pills, dry syrups, suppositories, poultices, plasters; licks, chewing gums, jellies, jelly drops, whippings, ointments, creams, foams, inhalers 15th revision Japanese Pharmacy, including liquid preparations such as syrups, drinks, suspensions, spirits, liquids, eye drops, aerosols, sprays, sprays, etc. The dosage forms described in the General Rules for Preparations are listed. Among these, solid preparations are preferable, solid preparations selected from the group consisting of tablets, capsules, pills, granules, powders, and fine granules are more preferable, tablets or capsules are more preferable, and tablets are particularly preferable. In this regard, solid preparations are generally advantageous not only in terms of ease of administration and management of drug doses, but also as specifically described in Test Example 15 below, the pharmaceutical composition of the present invention. When the product was a solid preparation, it was revealed that the swelling over time was suppressed. Therefore, according to the present invention, it is possible to provide a solid preparation with excellent stability, which is less likely to cause cracking or chipping of the coating, sugar coating or capsule when the coating or sugar coating is applied or when the capsule is filled. .
　本発明の医薬組成物が固形製剤である場合においては、相互作用抑制の点で、固形製剤中のロキソプロフェン又はその塩及び相互作用性成分を実質的に互いに接触しないように含有せしめ、製造、製剤化したものがより好ましい。当該実質的に互いに接触しないように含有せしめて製した製剤とは、一般の製剤技術研究者であれば、容易に理解されうるものであり、公知の方法に基づき、適宜製剤添加物を用いて製造、製剤化できる。具体的には、固形製剤の形態としては、以下の（Ｉ）－（VI）を例示することができ、これらは公知の方法により製造、製剤化できる。 In the case where the pharmaceutical composition of the present invention is a solid preparation, in terms of inhibiting the interaction, loxoprofen or a salt thereof and the interactive component in the solid preparation are contained so as not to come into contact with each other. More preferably. The preparations prepared so as to be substantially in contact with each other can be easily understood by general pharmaceutical technology researchers, using appropriate formulation additives based on known methods. Can be manufactured and formulated. Specifically, as the form of the solid preparation, the following (I)-(VI) can be exemplified, and these can be produced and formulated by known methods.
（Ｉ）ロキソプロフェン又はその塩、及び相互作用性成分のいずれか一方を適当な方法で造粒して粒状物とし、これに他方を造粒せずに含有せしめて製した散剤や顆粒剤等、並びに当該粒状物を更に適当な方法で被覆した製剤。なお、本発明で用いられる酸中和能を有する塩基性化合物は粒状物中に含有させてもよいし、粒状物とは別に含有させてもよい。
（II）ロキソプロフェン又はその塩、及び相互作用性成分をそれぞれ適当な方法で別個に造粒して粒状物とし、これらを含有せしめて製した散剤や顆粒剤等、並びに当該粒状物を更に適当な方法で被覆した製剤。なお、本発明で用いられる酸中和能を有する塩基性化合物はいずれか一方の粒状物中に含有させてもよいし、両方の粒状物中に含有させてもよいし、また、これら粒状物とは別に含有させてもよい。
（III）上記（Ｉ）又は（II）で製した散剤や顆粒剤等をカプセルに充填したカプセル剤。
（IV）上記（Ｉ）又は（II）で製した粒状物等を製錠して得た錠剤。
（Ｖ）ロキソプロフェン又はその塩、及び相互作用性成分が互いに接触しないように製した多層錠、並びに当該多層錠を更に適当な方法で被覆した製剤。当該多層錠としては、ロキソプロフェン又はその塩、及び相互作用性成分を、互いに異なる層に位置させたものが好ましく、三層以上の多層錠として、ロキソプロフェン又はその塩を含む層と相互作用性成分を含む層が互いに接しないように位置させたものがより好ましい。なお、ロキソプロフェン又はその塩、及び相互作用性成分として、上記（Ｉ）や（II）で製した粒状物を用いることができる。多層錠において、酸中和能を有する塩基性化合物はロキソプロフェン又はその塩を含む層か、相互作用性成分を含む層のいずれかに位置させてもよいし、分けて、両方の層に位置させてもよい。さらに、いずれかの層の中間層に位置させてもよい。
（VI）ロキソプロフェン又はその塩、及び相互作用性成分のいずれか一方を核錠に配置した有核錠、並びに当該有核錠を更に適当な方法で被覆した製剤。なお、ロキソプロフェン又はその塩、及び相互作用性成分として、上記（Ｉ）や（II）で製した粒状物を用いることができる。有核錠において、酸中和能を有する塩基性化合物は核錠に位置させてもよいし、外殻に位置させてもよいし、分けて、核錠と外殻のいずれにも位置させてもよい。
　上述の固形製剤は、公知の方法により、糖衣やフィルムコーティング等により、被覆されていてもよい。 (I) Loxoprofen or a salt thereof, and any one of the interactive components are granulated by an appropriate method to form a granular material, and the other is not granulated, and the powder or granule produced by containing the other, In addition, a preparation in which the granular material is further coated by an appropriate method. In addition, the basic compound which has the acid neutralization ability used by this invention may be contained in a granular material, and may be contained separately from a granular material.
(II) Loxoprofen or a salt thereof and an interactive component are separately granulated by an appropriate method to form granules, and powders and granules produced by containing these, and the granules are further suitable. Formulation coated by the method. In addition, the basic compound having acid neutralizing ability used in the present invention may be contained in any one of the granular materials, or may be contained in both granular materials, or these granular materials. You may make it contain separately.
(III) Capsule filled with powder or granule prepared in (I) or (II) above.
(IV) A tablet obtained by tableting the granular material produced in (I) or (II) above.
(V) A multilayer tablet prepared so that loxoprofen or a salt thereof and an interactive component do not come into contact with each other, and a preparation in which the multilayer tablet is further coated by an appropriate method. The multi-layer tablet is preferably one in which loxoprofen or a salt thereof and an interactive component are located in different layers, and as a multi-layer tablet having three or more layers, a layer containing loxoprofen or a salt thereof and an interactive component are included. More preferably, the layers included are positioned so as not to contact each other. In addition, the granular material manufactured by said (I) and (II) can be used as a loxoprofen or its salt, and an interactive component. In the multilayer tablet, the basic compound having acid neutralizing ability may be located in either the layer containing loxoprofen or a salt thereof or the layer containing an interactive component, or separately in both layers. May be. Further, it may be located in an intermediate layer of any one of the layers.
(VI) A dry-coated tablet in which any one of loxoprofen or a salt thereof and an interactive component is arranged in a nuclear tablet, and a preparation in which the dry-coated tablet is further coated by an appropriate method. In addition, the granular material manufactured by said (I) and (II) can be used as a loxoprofen or its salt, and an interactive component. In the dry-coated tablet, the basic compound having acid neutralizing ability may be located in the nuclear tablet, may be located in the outer shell, or separately, located in either the nuclear tablet or the outer shell. Also good.
The above-mentioned solid preparation may be coated with sugar coating, film coating or the like by a known method.
　本発明の医薬組成物の服用経路としては、経口及び経直腸や経膣等の非経口が挙げられ、本発明においては、経口投与製剤が好ましい。また、本発明の医薬組成物は、１日につき１～４回程度に分けて、食前、食間、食後、就寝前等に服用することができる。 Examples of the route of administration of the pharmaceutical composition of the present invention include oral and parenteral such as rectal and vaginal, and in the present invention, oral preparations are preferred. In addition, the pharmaceutical composition of the present invention can be taken 1 to 4 times per day before meals, between meals, after meals, before going to bed.
　本発明の医薬組成物には、医薬成分として、ロキソプロフェン又はその塩、相互作用性成分、及び酸中和能を有する塩基性化合物以外の薬物、例えば、解熱鎮痛剤、抗ヒスタミン剤、鎮咳剤、ノスカピン類、気管支拡張剤、去痰剤、ビタミン類、抗炎症剤、胃粘膜保護剤、抗コリン剤、生薬類、漢方処方等からなる群より選ばれる１種又は２種以上を含んでいても良い。これら成分は、上記固形製剤中に配合するのが好ましい。 The pharmaceutical composition of the present invention includes, as a pharmaceutical component, a drug other than loxoprofen or a salt thereof, an interactive component, and a basic compound having acid neutralizing ability, such as antipyretic analgesics, antihistamines, antitussives, noscapines, It may contain one or more selected from the group consisting of bronchodilators, expectorants, vitamins, anti-inflammatory agents, gastric mucosal protective agents, anticholinergic agents, herbal medicines, Kampo prescriptions and the like. These components are preferably blended in the solid preparation.
　解熱鎮痛剤としては、例えば、アスピリン、アスピリンアルミニウム、アセトアミノフェン、イソプロピルアンチピリン、イブプロフェン、エテンザミド、サザピリン、サリチルアミド、サリチル酸ナトリウム、チアラミド塩酸塩、ラクチルフェネチジン等が挙げられる。 Examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, sazapyrine, salicylamide, sodium salicylate, thiaramide hydrochloride, lactylphenetidine, and the like.
　抗ヒスタミン剤としては、例えば、アゼラスチン塩酸塩、アリメマジン酒石酸塩、イソチペンジル塩酸塩、イプロヘプチン塩酸塩、エピナスチン塩酸塩、エメダスチンフマル酸塩、ケトチフェンフマル酸塩、トリプロリジン塩酸塩、トリペレナミン塩酸塩、トンジルアミン塩酸塩、フェネタジン塩酸塩、プロメタジン塩酸塩、プロメタジンメチレン二サリチル酸塩、メキタジン、メトジラジン塩酸塩、メブヒドロリンナパジシル酸塩等が挙げられる。 Antihistamines include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, ketotifen fumarate, triprolidine hydrochloride, tripelenamine hydrochloride, tondylamine hydrochloride Phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, mequitazine, methodirazine hydrochloride, mebhydroline napadisilate and the like.
　鎮咳剤としては、例えば、アロクラミド塩酸塩、エプラジノン塩酸塩、カルベタペンタンクエン酸塩、クロペラスチン塩酸塩、クロペラスチンフェンジゾ酸塩、ジブナートナトリウム、ジメモルファンリン酸塩、チペピジンクエン酸塩、チペピジンヒベンズ酸塩等が挙げられる。 Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, dibutate sodium, dimemorphan phosphate, tipepidine citrate, And tipepidine hibenzate.
　ノスカピン類としては、例えば、ノスカピン塩酸塩、ノスカピン等が挙げられる。
　気管支拡張剤としては、例えば、トリメトキノール塩酸塩、フェニレフリン塩酸塩、メトキシフェナミン塩酸塩等が挙げられる。 Examples of noscapine include noscapine hydrochloride and noscapine.
Examples of the bronchodilator include trimethquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and the like.
　去痰剤としては、例えば、アンモニア・ウイキョウ精、エチルシステイン塩酸塩、塩化アンモニウム、カルボシステイン、メチルシステイン塩酸塩、ｌ－メントール等が挙げられる。 Examples of expectorants include ammonia and fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, methylcysteine hydrochloride, l-menthol and the like.
　ビタミン類としては、ビタミンＢ１、ビタミンＢ２、ビタミンＢ５、ビタミンＢ６、ビタミンＢ１２、ビタミンＣ、ヘスペリジン及びその誘導体並びにそれらの塩類等（例えば、チアミン、チアミン塩化物塩酸塩、チアミン硝化物、ジセチアミン塩酸塩、セトチアミン塩酸塩、フルスルチアミン、フルスルチアミン塩酸塩、オクトチアミン、シコチアミン、チアミンジスルフィド、ビスイブチアミン、ビスベンチアミン、プロスルチアミン、ベンフォチアミン、リボフラビン、リボフラビンリン酸エステル、リボフラビン酪酸エステル、リン酸リボフラビンナトリウム、ピリドキシン塩酸塩、ピリドキサールリン酸エステル、シアノコバラミン、メコバラミン、アスコルビン酸、アスコルビン酸ナトリウム、アスコルビン酸カルシウム、ヘスペリジン等）が挙げられる。 Examples of vitamins 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 nitrification) , Dicetiamine hydrochloride, cetothiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisivethiamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate , Riboflavin butyrate, sodium riboflavin phosphate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate , Hesperidin, etc.).
　抗炎症剤としては、グリチルリチン酸及びその誘導体並びにそれらの塩類（例えば、グリチルリチン酸二カリウム、グリチルリチン酸モノアンモニウム等）、セアプローゼ、セミアルカリプロティナーゼ、セラペプターゼ、トラネキサム酸、プロクターゼ、プロナーゼ、ブロメライン等が挙げられる。 Examples of anti-inflammatory agents include glycyrrhizic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate and monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, bromelain and the like. .
　胃粘膜保護剤としては、ゲファルナート、セトラキサート塩酸塩、ソファルコン、テプレノン、メチルメチオニンスルホニウムクロリド等が挙げられる。 Examples of gastric mucosa protective agents include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride, and the like.
　抗コリン薬としては、オキシフェンサイクリミン塩酸塩、ジサイクロミン塩酸塩、メチキセン塩酸塩、チペピジウム臭化物、メチルベナクチジウム臭化物、ピレンゼピン塩酸塩、ヨウ化イソプロパミド、ヨウ化ジフェニルピペリジノメチルジオキソラン等が挙げられる。 Examples of anticholinergic agents include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, tipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, etc. .
　生薬類としては、アカメガシワ（赤芽柏）、アセンヤク（阿仙薬）、インヨウカク（淫羊霍）、ウイキョウ（茴香）、エンゴサク（延胡索）、オウゴン（黄岑）、オウセイ（黄精）、オウバク（黄柏）、オウヒ（桜皮）、オウレン（黄連）、オンジ（遠志）、ガジュツ（我朮）、カノコソウ（鹿子草）、カミツレ、カロニン（か楼仁）、キキョウ（桔梗）、キョウニン（杏仁）、クコシ（枸杞子）、クコヨウ（枸杞葉）、ケイガイ（荊芥）、ケイヒ（桂皮）、ケツメイシ（決明子）、ゲンチアナ、ゲンノショウコ（現証拠）、コウブシ（香附子）、ゴオウ（牛黄）、ゴミシ（五味子）、サイシン（細辛）、サンショウ（山椒）、シオン（紫苑）、ジコッピ（地骨皮）、シャクヤク（芍薬）、ジャコウ（麝香）、シャジン（沙参）、シャゼンシ（車前子）、シャゼンソウ（車前草）、獣胆（ユウタン（熊胆）を含む）、ショウキョウ（生姜）、ジリュウ（地竜）、シンイ（辛夷）、セキサン（石蒜）、セネガ、センキュウ（川きゅう）、ゼンコ（前胡）、センブリ（千振）、ソウジュツ（蒼朮）、ソウハクヒ（桑白皮）、ソヨウ（蘇葉）、タイサン（大蒜）、チクセツニンジン（竹節人参）、チョウジ（丁子）、チンピ（陳皮）、トウキ（当帰）、トコン（吐根）、ナンテンジツ（南天実）、ニンジン（人参）、バイモ（貝母）、バクモンドウ（麦門冬）、ハンゲ（半夏）、バンコウカ（番紅花）、ハンピ（反鼻）、ビャクシ（白し）、ビャクジュツ（白朮）、ブクリョウ（茯苓）、ボタンピ（牡丹皮）、ロクジョウ（鹿茸）等の生薬及びこれらの抽出物（エキス、チンキ、乾燥エキス等）等が挙げられる。 Herbal medicines include Akamegashiwa (red buds), Asenyaku (Asenyaku), Yinakukaku (Ryokan), Fennel (Yongxiang), Engosaku (Yancho), Ogon (Yellow), Ousei (Yellow), Oubak (Yellow), Spruce (Cherry bark), auren (yellow ream), onji (distant), gadgets (weather), valerian (deer grass), chamomile, caronin (karojin), kyokyo (kikyo), kyonin (kyojin), kokushi (枸杞) Child), cucumber yoi, kei gai, keihi cinnamon, katsumeishi (decided child), gentiana, gennoshouko (current evidence), kobushi (kosuke), goo (oxen yellow), trash (tasty), saishin ( Spicy), Salamander, Zion (Zhi), Ziqoppi (Skin Bark), Peonies (Glue), Musk, Shajin, Shazen (Car front child), shazensou (car front grass), beast gall (including yutan (bear gall)), gyoza (ginger), ziryu (earth dragon), shin ii (spicy potato), sexan (sarcophagus), senega, senkyu ( River Kyu), Zenko (Mae-Hu), Assembly (Senri), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Daegu), Chiksetsu carrot (Bamboo ginseng), Clove (chome) , Chimpi (Chenhide), Touki (Toshiki), Tokon (Nangen), Nantenjitsu (Nan Tenji), Carrot (Ginseng), Baimo (Shell), Bakumondou (Marimon Winter), Hange (Halfsummer), Bangkouka ( Herbal medicines such as sprouting flowers, hampi (anti-nasal), peony (white), peanuts (white moth), bukkyou (pepper), button pi (peony skin), loquat (deer moth) and their extracts (extract, tincture, dried) D Scan, etc.) and the like.
　漢方処方としては、ケイシトウ（桂枝湯）、コウソサン（香蘇散）、サイコケイシトウ（柴胡桂枝湯）、ショウサイコトウ（小柴胡湯）、バクモンドウトウ（麦門冬湯）、ハンゲコウボクトウ（半夏厚朴湯）等が挙げられる。 Herbal formulas include Keishito (Keishaeyu), Kousosan (Kousosan), Psychokeito (Shibako Keiedo), Shosai Koto (Koshisaifuto), Bakumondou (Bakumon Fuyuto), Hangekou Bokuto (Hankatsu Koboku-yu).
　なお、本発明の医薬組成物としては、以下の（ａ）～（ｌ）以外のものが好ましい。
（ａ）１錠当たりロキソプロフェンナトリウム２水和物　４５ｍｇ（無水物として換算）、エテンザミド　１２５ｍｇ、無水カフェイン　８０ｍｇ、β‐シクロデキストリン　２５４ｍｇ、アスパルテーム　３０ｍｇ、クエン酸　９６５ｍｇ、炭酸水素ナトリウム　８１３ｍｇ、乳糖　３８ｍｇ及びステアリン酸マグネシウム　５０ｍｇを含有する、２４００ｍｇの発泡錠。
（ｂ）１錠当たりロキソプロフェンナトリウム２水和物　６０ｍｇ（無水物として換算）、マレイン酸カルビノキサミン　４ｍｇ、ｄｌ－塩酸メチルエフェドリン　２０ｍｇ、セラペプターゼ　１０ｍｇ、β‐シクロデキストリン　２５４ｍｇ、アスパルテーム　３０ｍｇ、クエン酸　９６５ｍｇ、炭酸水素ナトリウム　８１３ｍｇ、乳糖　１９４ｍｇ及びステアリン酸マグネシウム　５０ｍｇを含有する、２４００ｍｇの発泡錠。
（ｃ）６錠（合計１４００ｍｇ）中に塩酸プソイドエフェドリン　１８０ｍｇ、ロキソプロフェンナトリウム　１８０ｍｇ、酸化マグネシウム　４００ｍｇ、メタケイ酸アルミン酸マグネシウム　１４０ｍｇ、結晶セルロース　１２０ｍｇ、コーンスターチ　１４０ｍｇ、ヒドロキシプロピルセルロース　６０ｍｇ、クロスカルメロースナトリウム　１５ｍｇ、ステアリン酸マグネシウム　２５ｍｇ、トリアセチン　６ｍｇ及び乳糖　適量を含有する錠剤。
（ｄ）６錠（合計１４００ｍｇ）中に塩酸プソイドエフェドリン　１８０ｍｇ、ロキソプロフェンナトリウム　９０ｍｇ、イブプロフェン　２２５ｍｇ、酸化マグネシウム　３５０ｍｇ、メタケイ酸アルミン酸マグネシウム　１４０ｍｇ、結晶セルロース　１２０ｍｇ、コーンスターチ　１４０ｍｇ、ヒドロキシプロピルセルロース　６０ｍｇ、クロスカルメロースナトリウム　１５ｍｇ、ステアリン酸マグネシウム　２５ｍｇ、トリアセチン　６ｍｇ及び乳糖　適量を含有する錠剤。
（ｅ）３包（合計４５００ｍｇ）中に塩酸プソイドエフェドリン　１８０ｍｇ、ロキソプロフェンナトリウム　１８０ｍｇ、酸化マグネシウム　４００ｍｇ、メタケイ酸アルミン酸マグネシウム　１４０ｍｇ、精製白糖　１４００ｍｇ、ステビア抽出生成物　１５ｍｇ、トウモロコシデンプン　１２００ｍｇ、ポリソルベート８０　８０ｍｇ、ステアリン酸マグネシウム　２５ｍｇ及び乳糖　適量を含有する細粒剤。
（ｆ）３包（合計４５００ｍｇ）中に塩酸プソイドエフェドリン　１８０ｍｇ、ロキソプロフェンナトリウム　９０ｍｇ、イブプロフェン　２２５ｍｇ、酸化マグネシウム　４００ｍｇ、メタケイ酸アルミン酸マグネシウム　１４０ｍｇ、精製白糖　１４００ｍｇ、ステビア抽出生成物　１５ｍｇ、トウモロコシデンプン　１１００ｍｇ、ポリソルベート８０　８０ｍｇ、ステアリン酸マグネシウム　２５ｍｇ及び乳糖　適量を含有する細粒剤。
（ｇ）６カプセル（合計２５００ｍｇ）中に塩酸プソイドエフェドリン　１８０ｍｇ、ロキソプロフェンナトリウム　１８０ｍｇ、酸化マグネシウム　４００ｍｇ、トウモロコシデンプン　６００ｍｇ、ポリソルベート８０　５０ｍｇ、ステアリン酸マグネシウム　２５ｍｇ、乳糖　適量及びカプセル　４８０ｍｇを含有する硬カプセル剤。
（ｈ）６カプセル（合計２５００ｍｇ）中に塩酸プソイドエフェドリン　１８０ｍｇ、ロキソプロフェンナトリウム　９０ｍｇ、イブプロフェン　２２５ｍｇ、酸化マグネシウム　４００ｍｇ、トウモロコシデンプン　５００ｍｇ、ポリソルベート８０　５０ｍｇ、ステアリン酸マグネシウム　２５ｍｇ、乳糖　適量及びカプセル　４８０ｍｇを含有する硬カプセル剤。
（ｉ）１乃至２錠中にロキソプロフェンナトリウム・２水和物　６０ｍｇ、酸化マグネシウム　２４０ｍｇ、カフェイン又はテオフィリン　３０ｍｇ、ヒドロキシプロピルセルロース　５０ｍｇ及びステアリン酸マグネシウム　適量を含有する錠剤。
（ｊ）１包中にロキソプロフェンナトリウム・２水和物　６０ｍｇ、酸化マグネシウム　２４０ｍｇ、カフェイン又はテオフィリン　３０ｍｇ、ヒドロキシプロピルセルロース　１００ｍｇ、ステアリン酸マグネシウム　１０ｍｇ及び低置換度ヒドロキシプロピルセルロース　適量を含有する細粒剤。
（ｋ）１乃至２カプセル中にロキソプロフェンナトリウム・２水和物　６０ｍｇ、酸化マグネシウム　２４０ｍｇ、カフェイン又はテオフィリン　３０ｍｇ、ヒドロキシプロピルセルロース　５０ｍｇ、ステアリン酸マグネシウム　１０ｍｇ、ポリソルベート８０　１５ｍｇ及びトウモロコシデンプン　適量を含有するカプセル剤。
（ｌ）６０ｍＬ中にロキソプロフェンナトリウム・２水和物　６０ｍｇ、酸化マグネシウム　２４０ｍｇ、カフェイン又はテオフィリン　３０ｍｇ、ヒドロキシプロピルセルロース　５０ｍｇ、安息香酸ナトリウム　１４０ｍｇ、クエン酸　８０ｍｇ、濃グリセリン　５３０ｍｇ、ポリビニルアルコール　１００ｍｇ、エタノール（９５％）　２２０ｍｇ及び精製水　残部を含有するシロップ剤。 As the pharmaceutical composition of the present invention, those other than the following (a) to (l) are preferable.
(A) Loxoprofen sodium dihydrate 45 mg (converted as anhydrous) per tablet, etenzaamide 125 mg, anhydrous caffeine 80 mg, β-cyclodextrin 254 mg, aspartame 30 mg, citric acid 965 mg, sodium bicarbonate 813 mg, lactose 38 mg and stearin 2400 mg effervescent tablets containing 50 mg magnesium acid.
(B) Loxoprofen sodium dihydrate 60 mg (converted as anhydrous) per tablet, carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, β-cyclodextrin 254 mg, aspartame 30 mg, citric acid 965 mg, hydrogen carbonate 2400 mg effervescent tablet containing 813 mg sodium, 194 mg lactose and 50 mg magnesium stearate.
(C) in 6 tablets (total 1400 mg) pseudoephedrine hydrochloride 180 mg, loxoprofen sodium 180 mg, magnesium oxide 400 mg, magnesium metasilicate 140 mg, crystalline cellulose 120 mg, corn starch 140 mg, hydroxypropylcellulose 60 mg, croscarmellose sodium 15 mg, stearic acid Tablets containing 25 mg of magnesium, 6 mg of triacetin and appropriate amounts of lactose.
(D) In 6 tablets (1400 mg in total) pseudoephedrine hydrochloride 180 mg, loxoprofen sodium 90 mg, ibuprofen 225 mg, magnesium oxide 350 mg, magnesium metasilicate aluminate 140 mg, crystalline cellulose 120 mg, corn starch 140 mg, hydroxypropylcellulose 60 mg, croscarmellose sodium 15 mg , 25 mg of magnesium stearate, 6 mg of triacetin and a suitable amount of lactose.
(E) Pseudoephedrine hydrochloride 180 mg, loxoprofen sodium 180 mg, magnesium oxide 400 mg, magnesium metasilicate aluminate 140 mg, purified sucrose 1400 mg, stevia extract product 15 mg, corn starch 1200 mg, polysorbate 80 80 mg, stearic acid in 3 capsules (total 4500 mg) A fine granule containing 25 mg of magnesium and an appropriate amount of lactose.
(F) Pseudoephedrine hydrochloride 180 mg, loxoprofen sodium 90 mg, ibuprofen 225 mg, magnesium oxide 400 mg, magnesium metasilicate aluminate 140 mg, purified white sugar 1400 mg, stevia extract product 15 mg, corn starch 1100 mg, polysorbate 80 80 mg in 3 capsules (total 4500 mg) A fine granule containing 25 mg of magnesium stearate and an appropriate amount of lactose.
(G) Hard capsule containing 6 mg (total 2500 mg) of pseudoephedrine hydrochloride 180 mg, loxoprofen sodium 180 mg, magnesium oxide 400 mg, corn starch 600 mg, polysorbate 80 50 mg, magnesium stearate 25 mg, lactose appropriate amount and capsule 480 mg.
(H) Hard capsule containing pseudoephedrine hydrochloride 180 mg, loxoprofen sodium 90 mg, ibuprofen 225 mg, magnesium oxide 400 mg, corn starch 500 mg, polysorbate 80 50 mg, magnesium stearate 25 mg, lactose appropriate amount and capsule 480 mg in 6 capsules (total 2500 mg) .
(I) A tablet containing loxoprofen sodium dihydrate 60 mg, magnesium oxide 240 mg, caffeine or theophylline 30 mg, hydroxypropylcellulose 50 mg and magnesium stearate in 1 to 2 tablets.
(J) Fine granules containing loxoprofen sodium dihydrate 60 mg, magnesium oxide 240 mg, caffeine or theophylline 30 mg, hydroxypropylcellulose 100 mg, magnesium stearate 10 mg and low-substituted hydroxypropylcellulose in a single package.
(K) Capsules containing loxoprofen sodium dihydrate 60 mg, magnesium oxide 240 mg, caffeine or theophylline 30 mg, hydroxypropylcellulose 50 mg, magnesium stearate 10 mg, polysorbate 80 15 mg and corn starch in 1 to 2 capsules .
(L) Loxoprofen sodium dihydrate 60 mg, magnesium oxide 240 mg, caffeine or theophylline 30 mg, hydroxypropylcellulose 50 mg, sodium benzoate 140 mg, citric acid 80 mg, concentrated glycerin 530 mg, polyvinyl alcohol 100 mg, ethanol (95 %) A syrup containing 220 mg and the balance of purified water.
　本発明の医薬組成物は、相互作用抑制の点から、さらに乾燥剤存在下で保存してもよい。以下、本発明の医薬組成物及び乾燥剤を容器中に含むものを、本発明の「医薬製剤」ということもある。 The pharmaceutical composition of the present invention may be further stored in the presence of a desiccant from the viewpoint of inhibition of interaction. Hereinafter, what contains the pharmaceutical composition and desiccant of this invention in a container may be called "pharmaceutical formulation" of this invention.
　＜医薬製剤＞
　次に、上記医薬製剤について説明する。
　本発明の医薬製剤において、乾燥剤は特に限定されるものではない。当然にその形状も限定されず、例えば、板状や袋状のシート型、円柱状（錠剤型）に成形されたもの等が挙げられ、円柱状のものにペーパーラッピングやフィルムコーティングを施したものでもよい。 <Pharmaceutical formulation>
Next, the said pharmaceutical formulation is demonstrated.
In the pharmaceutical preparation of the present invention, the desiccant is not particularly limited. Of course, the shape is not limited, for example, a plate-shaped or bag-shaped sheet type, a cylindrical shape (tablet type), etc., and a cylindrical shape with paper wrapping or film coating. But you can.
　乾燥剤としては、具体的には例えば、シリカゲル、シリカアルミナゲル（アロフェン）、天然ゼオライト、合成ゼオライト（モレキュラーシーブ）、塩化カルシウム、生石灰（酸化カルシウム）、ベントナイトクレイ（モンモリロナイト）、塩化マグネシウム、酸化マグネシウム等が挙げられ、これらと活性炭を混合したものであってもよい。これらのうち、シリカゲル、シリカアルミナゲル（アロフェン）、合成ゼオライト（モレキュラーシーブ）、及び塩化カルシウムからなる群より選ばれる１種以上がより好ましい。 Specific examples of the desiccant include silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride, magnesium oxide. Etc., and a mixture of these and activated carbon may be used. Among these, one or more selected from the group consisting of silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve), and calcium chloride is more preferable.
　乾燥剤としては市販品を用いることができ、市販品としては例えば、株式会社東海化学工業所製のシブレット、ＭＳ－タブレット、ＭＳ－セラムＷ、トーカイゲル、デシカイト２５、アルプシート、山仁薬品株式会社製のドライヤーン（登録商標）分包品、ドライヤーン（登録商標）タブレット、ドライヤーン（登録商標）シート、品川化成株式会社製のセカード、アロシート、ゼオシート、株式会社ＯＺＯ化学技研製のＯＺＯ、株式会社アイディ製のアイディシート、アイディパッキング乾燥剤等が挙げられる。 Commercially available products can be used as the desiccant. Examples of commercially available products include Siblet, MS-Tablet, MS-Serum W, Tokai Gel, Decite Kite 25, Alp Sheet, Yamanin Pharmaceutical Co., Ltd. manufactured by Tokai Chemical Industry Co., Ltd. Dryan (registered trademark) packaged product, Dryan (registered trademark) tablet, Dryan (registered trademark) sheet, Sekawa, Allosheet, Zeosheet manufactured by Shinagawa Kasei Co., Ltd., OZO manufactured by OZO Chemical Engineering Co., Ltd. An ID sheet made by the company ID, an ID packing desiccant, etc.
　本発明の医薬製剤において、乾燥剤の含有量は適宜検討して決定すればよいが、ロキソプロフェン又はその塩１質量部に対して、０．０５～３５質量部が好ましく、０．１５～１７質量部がより好ましい。
　また、本発明の医薬組成物１質量部に対しては、０．００１～１質量部が好ましく、０．００４～０．４質量部がより好ましい。 In the pharmaceutical preparation of the present invention, the content of the desiccant may be appropriately determined and determined, but is preferably 0.05 to 35 parts by weight, and 0.15 to 17 parts by weight with respect to 1 part by weight of loxoprofen or a salt thereof. Part is more preferred.
In addition, 0.001 to 1 part by mass is preferable, and 0.004 to 0.4 part by mass is more preferable with respect to 1 part by mass of the pharmaceutical composition of the present invention.
　本発明の医薬製剤に用いられる容器は、食品、サプリメント、医薬品や健康食品等の容器として使用可能なものであれば特に限定されないが、定形容器、不定形容器のいずれも用いることができ、密閉可能なものが好ましい。当該定形容器としては、例えば、瓶、缶、箱等が挙げられる。不定形容器としては、例えば、袋（ピロー包装、スティック包装、ＰＴＰ包装、ＳＰ包装等）等が挙げられる。これら容器のうち、具体的には瓶、袋が好ましい。 The container used for the pharmaceutical preparation of the present invention is not particularly limited as long as it can be used as a container for foods, supplements, pharmaceuticals, health foods, and the like, but any of a fixed container and an amorphous container can be used and sealed. What is possible is preferred. Examples of the fixed container include bottles, cans, and boxes. Examples of the amorphous container include bags (pillow packaging, stick packaging, PTP packaging, SP packaging, etc.) and the like. Of these containers, specifically, bottles and bags are preferable.
　容器の形成部材は、特に限定されるものではなく、例えば、紙、ガラス、樹脂若しくは樹脂フィルム、又は金属若しくは金属フィルム等の部材を挙げることができ、これら部材を適宜組み合わせた複合構造や多層構造としたものでもよい。また、紙などの透湿性を有する部材については透湿防止処理が施されていることが好ましい。
　当該容器は透明、半透明、不透明のいずれでもよい。 The forming member of the container is not particularly limited, and examples thereof include paper, glass, resin or resin film, or metal or metal film, and a composite structure or multilayer structure in which these members are appropriately combined. It may be a thing. Moreover, it is preferable that moisture permeation prevention processing is performed about the member which has moisture permeability, such as paper.
The container may be transparent, translucent, or opaque.
　本発明の医薬組成物と乾燥剤を容器中へ収納する方法は、特に限定されるものではなく、いずれをも容器内へ投入等の適当な手段により配置することで達成できる。 The method for storing the pharmaceutical composition of the present invention and the desiccant in a container is not particularly limited, and both can be achieved by arranging them by appropriate means such as charging into the container.
　容器内への収納は、例えば、容器が瓶の場合、乾燥剤（好ましくは、円柱状（錠剤型））を瓶内に配置、又は瓶蓋の裏側（内キャップ）に格納するとともに、本発明の医薬組成物を瓶内に格納する等により達成できる。瓶内に格納するに際して、本発明の医薬組成物の剤形としては、固形製剤であるのが好ましい。 For example, when the container is a bottle, the desiccant (preferably, a columnar shape (tablet shape)) is placed in the bottle, or stored in the back side (inner cap) of the bottle lid, and stored in the container. This can be achieved by storing the pharmaceutical composition in a bottle or the like. When stored in a bottle, the pharmaceutical composition of the present invention is preferably a solid preparation.
　また、容器が袋の場合は、乾燥剤（好ましくは、板状や袋状のシート型）と本発明の医薬組成物を袋内に格納する等により達成できる。袋内に格納するに際して、本発明の医薬組成物の剤形としては、固形製剤であるのが好ましい。 Further, when the container is a bag, it can be achieved by storing the desiccant (preferably, a plate-like or bag-like sheet type) and the pharmaceutical composition of the present invention in the bag. When stored in the bag, the pharmaceutical composition of the present invention is preferably a solid preparation.
　さらに、本発明の医薬組成物をＳＰ包装、ＰＴＰ包装や袋により一旦包装し、次いで包装された医薬組成物と乾燥剤を袋に同封した形態とすることもできる。より具体的には、ＳＰ包装又はＰＴＰ包装した医薬組成物と、板状や袋状のシート型乾燥剤とを併せてピロー包装する形態等が挙げられる。さらに当該ピロー包装形態のものは箱等に格納されてもよい。医薬組成物をＳＰ包装、ＰＴＰ包装や袋により一旦包装するに際して、本発明の医薬組成物の剤形としては、固形製剤であるのが好ましい。 Furthermore, the pharmaceutical composition of the present invention may be once packaged by SP packaging, PTP packaging or a bag, and then the packaged pharmaceutical composition and desiccant may be enclosed in a bag. More specifically, the form which carries out pillow packaging, combining the pharmaceutical composition which carried out SP packaging or PTP packaging, and a plate-shaped or bag-shaped sheet type desiccant etc. is mentioned. Further, the pillow packaging form may be stored in a box or the like. When the pharmaceutical composition is once packaged by SP packaging, PTP packaging or a bag, the pharmaceutical composition of the present invention is preferably a solid preparation.
　本発明の医薬組成物は、ＮＳＡＩＤの一種であるロキソプロフェン又はその塩を含有することから、頭痛・歯痛・抜歯後の疼痛・咽頭痛・耳痛・関節痛・神経痛・腰痛・筋肉痛・肩こり痛・打撲痛・骨折痛・ねんざ痛・月経痛（生理痛）・外傷痛の鎮痛、悪寒・発熱時の解熱、かぜの諸症状（のどの痛み、悪寒、発熱、頭痛、関節の痛み、筋肉の痛み）等に効能又は効果を有し、総合感冒薬（かぜ薬）や解熱鎮痛薬として有用である。 Since the pharmaceutical composition of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain・ Bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain), pain relief, chills, antipyretic fever, cold symptoms (throat pain, chills, fever, headache, joint pain, muscles It is useful as a general cold medicine (cold medicine) or antipyretic analgesic.
　以下に実施例を挙げて本発明を詳細に説明するが、本発明はこれら実施例に何ら限定されるものではない。
［試験例１］ロキソプロフェンナトリウム水和物とクロルフェニラミンマレイン酸塩の相互作用の検討
　以下に示す混合物１－Ａ～１－Ｅをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れ６０℃で１週間保存し、保存開始直後、１日後、２日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表１に示す。 EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
[Test Example 1] Examination of interaction between loxoprofen sodium hydrate and chlorpheniramine maleate After preparing each of the following mixtures 1-A to 1-E, they were placed in glass bottles (3K standard bottles) at 60 ° C. The samples were stored for a week and immediately after the start of storage, the state of the mixture after 1 day, 2 days, and 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 1.
〔混合物１－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４９１．６ｍｇ及びｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）８．４ｍｇを混合し、混合物１－Ａを得た。
〔混合物１－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４９１．６ｍｇ、ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）８．４ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物１－Ｂを得た。 [Mixture 1-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 491.6 mg and d-chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 8 .4 mg was mixed to obtain a mixture 1-A.
[Mixture 1-B]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 491.6 mg, d-chlorpheniramine maleate (manufactured by Kongo Chemical: trade name: D-chlorpheniramine maleate) 8 4 mg and magnesium hydroxide (trade name: Kyowasui Mug) manufactured by Kyowa Chemical Industry Co., Ltd. (500 mg) were mixed to obtain a mixture 1-B.
〔混合物１－Ｃ〕
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物１－Ｂと同様の方法により、混合物１－Ｃを得た。
〔混合物１－Ｄ〕
　水酸化マグネシウムの代わりに無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）５００ｍｇを用いたほかは混合物１－Ｂと同様の方法により、混合物１－Ｄを得た。
〔混合物１－Ｅ〕
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物１－Ｂと同様の方法により、混合物１－Ｅを得た。 [Mixture 1-C]
A mixture 1-C was obtained in the same manner as the mixture 1-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
[Mixture 1-D]
A mixture 1-D was obtained in the same manner as the mixture 1-B, except that 500 mg of anhydrous calcium hydrogen phosphate (trade name: anhydrous calcium hydrogen phosphate GS-H) was used instead of magnesium hydroxide. It was.
[Mixture 1-E]
A mixture 1-E was obtained in the same manner as the mixture 1-B, except that 500 mg of magnesium oxide (trade name, heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
　表１に示す試験結果から、ロキソプロフェンナトリウム水和物とｄ－クロルフェニラミンマレイン酸塩のみを混合した混合物１－Ａにおいては、相互作用が生じ、混合物が固化することが判明した。
　一方、ロキソプロフェンナトリウム水和物、ｄ－クロルフェニラミンマレイン酸塩に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物１－Ｂ、１－Ｃ、１－Ｄ及び１－Ｅにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、１－Ｂ～１－Ｅで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩と、クロルフェニラミン又はその塩を包含する一般式（１）で表される化合物又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 1, it was found that in the mixture 1-A in which only loxoprofen sodium hydrate and d-chlorpheniramine maleate were mixed, an interaction occurred and the mixture solidified.
On the other hand, in the mixtures 1-B, 1-C, 1-D and 1-E in which loxoprofen sodium hydrate and d-chlorpheniramine maleate were further mixed with a basic compound having acid neutralizing ability. It was found that the state of the white powder was maintained after storage for 1 week as well as immediately after the start of storage.
From the above test results, the basic compound having acid neutralizing ability used in 1-B to 1-E is represented by the general formula (1) including loxoprofen or a salt thereof and chlorpheniramine or a salt thereof. It became clear that it has the effect | action which suppresses interaction with a compound or its salt.
［試験例２］ロキソプロフェンナトリウム水和物とクレマスチンフマル酸塩の相互作用の検討
　以下に示す混合物２－Ａ～２－Ｆをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて６０℃で１週間保存し、保存開始直後、１日後、２日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表２に示す。 [Test Example 2] Examination of interaction between loxoprofen sodium hydrate and clemastine fumarate Each of the following mixtures 2-A to 2-F was prepared and then placed in a glass bottle (3K standard bottle) at 60 ° C for 1 week. The state of the mixture was evaluated immediately after the start of storage, 1 day later, 2 days later and 1 week later, and the presence or absence of interaction was confirmed. The results are shown in Table 2.
〔混合物２－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４９６．７ｍｇ及びクレマスチンフマル酸塩（ダイト製：商品名　クレマスチンフマル酸塩）３．３ｍｇを混合し、混合物２－Ａを得た。
〔混合物２－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４９６．７ｍｇ、クレマスチンフマル酸塩（ダイト製：商品名　クレマスチンフマル酸塩）３．３ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物２－Ｂを得た。
〔混合物２－Ｃ〕
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物２－Ｂと同様の方法により、混合物２－Ｃを得た。 [Mixture 2-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 496.7 mg and clemastine fumarate (trade name: product of clemastine fumarate) 3.3 mg -A was obtained.
[Mixture 2-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 496.7 mg, clemastine fumarate (trade name, made by trade name: clemastine fumarate) 3.3 mg and magnesium hydroxide (Kyowa) 500 mg of a product made by Kagaku Kogyo (trade name: Kyowasui Mug) was mixed to obtain a mixture 2-B.
[Mixture 2-C]
A mixture 2-C was obtained in the same manner as the mixture 2-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
〔混合物２－Ｄ〕
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物２－Ｂと同様の方法により、混合物２－Ｄを得た。
〔混合物２－Ｅ〕
　水酸化マグネシウムの代わりにメタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）５００ｍｇを用いたほかは混合物２－Ｂと同様の方法により、混合物２－Ｅを得た。
〔混合物２－Ｆ〕
　水酸化マグネシウムの代わりに沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）５００ｍｇを用いたほかは混合物２－Ｂと同様の方法により、混合物２－Ｆを得た。 [Mixture 2-D]
A mixture 2-D was obtained in the same manner as the mixture 2-B, except that 500 mg of magnesium oxide (trade name, heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
[Mixture 2-E]
A mixture 2-E was obtained in the same manner as the mixture 2-B, except that 500 mg of magnesium aluminate metasilicate (trade name: Neusilin UFL2) was used instead of magnesium hydroxide.
[Mixture 2-F]
A mixture 2-F was obtained in the same manner as the mixture 2-B, except that 500 mg of precipitated calcium carbonate (trade name: precipitated carbon dioxide CA, manufactured by Sankyo Seimitsu) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
　表２に示す試験結果から、ロキソプロフェンナトリウム水和物とクレマスチンフマル酸塩のみを混合した混合物２－Ａにおいては、相互作用が生じ、混合物が湿潤することが判明した。
　一方、ロキソプロフェンナトリウム、クレマスチンフマル酸塩に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物２－Ｂ、２－Ｃ、２－Ｄ、２－Ｅ及び２－Ｆにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、２－Ｂ～２－Ｆで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩と、クレマスチン又はその塩を包含する一般式（１）で表される化合物又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 2, it was found that in the mixture 2-A in which only loxoprofen sodium hydrate and clemastine fumarate were mixed, an interaction occurred and the mixture became wet.
On the other hand, in the mixtures 2-B, 2-C, 2-D, 2-E and 2-F in which loxoprofen sodium and clemastine fumarate are further mixed with a basic compound having acid neutralizing ability, 1 It was found that the white powder state was maintained after weekly storage as well as immediately after the start of storage.
From the above test results, the basic compound having acid neutralizing ability used in 2-B to 2-F is a compound represented by the general formula (1) including loxoprofen or a salt thereof and clemastine or a salt thereof. Or it became clear that it has the effect | action which suppresses interaction with the salt.
［試験例３］ロキソプロフェンナトリウム水和物とカルビノキサミンマレイン酸塩の相互作用の検討
　以下に示す混合物３－Ａ～３－Ｅをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて６０℃で１週間保存し、保存開始直後、１日後、２日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表３に示す。 [Test Example 3] Examination of interaction between loxoprofen sodium hydrate and carbinoxamine maleate After preparing each of the following mixtures 3-A to 3-E, they were placed in glass bottles (3K standard bottles) at 60 ° C. It was stored for 1 week, immediately after the start of storage, 1 day, 2 days, and 1 week later, the state of the mixture was evaluated to confirm the presence or absence of interaction. The results are shown in Table 3.
〔混合物３－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４８２．３ｍｇ及びカルビノキサミンマレイン酸塩（金剛化学製：商品名　マレイン酸カルビノキサミン）１７．７ｍｇを混合し、混合物３－Ａを得た。
〔混合物３－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４８２．３ｍｇ、カルビノキサミンマレイン酸塩（金剛化学製：商品名　マレイン酸カルビノキサミン）１７．７ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物３－Ｂを得た。 [Mixture 3-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 482.3 mg and carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) were mixed, Mixture 3-A was obtained.
[Mixture 3-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 482.3 mg, carbinoxamine maleate (manufactured by Kongo Chemical: trade name carbinoxamine maleate) 17.7 mg and magnesium hydroxide (Kyowa Chemical Industry Co., Ltd .: trade name Kyowasui Mug) 500 mg was mixed to obtain a mixture 3-B.
〔混合物３－Ｃ〕
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物３－Ｂと同様の方法により、混合物３－Ｃを得た。
〔混合物３－Ｄ〕
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物３－Ｂと同様の方法により、混合物３－Ｄを得た。
〔混合物３－Ｅ〕
　水酸化マグネシウムの代わりにメタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）５００ｍｇを用いたほかは混合物３－Ｂと同様の方法により、混合物３－Ｅを得た。 [Mixture 3-C]
A mixture 3-C was obtained in the same manner as the mixture 3-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
[Mixture 3-D]
A mixture 3-D was obtained in the same manner as the mixture 3-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
[Mixture 3-E]
A mixture 3-E was obtained in the same manner as the mixture 3-B, except that 500 mg of magnesium aluminate metasilicate (trade name: Neusilin UFL2) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
　表３に示す試験結果から、ロキソプロフェンナトリウム水和物とカルビノキサミンマレイン酸塩のみを混合した混合物３－Ａにおいては、相互作用が生じ、混合物が固化し、その後変色することが判明した。
　一方、ロキソプロフェンナトリウム水和物、カルビノキサミンマレイン酸塩に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物３－Ｂ、３－Ｃ、３－Ｄ及び３－Ｅにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、３－Ｂ～３－Ｅで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩と、カルビノキサミン又はその塩を包含する一般式（１）で表される化合物又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 3, it was found that in the mixture 3-A in which only loxoprofen sodium hydrate and carbinoxamine maleate were mixed, an interaction occurred and the mixture solidified and then changed color.
On the other hand, in the mixtures 3-B, 3-C, 3-D and 3-E in which loxoprofen sodium hydrate and carbinoxamine maleate were further mixed with a basic compound having acid neutralizing ability, It was found that the state of the white powder was maintained after the storage for 1 week as well as immediately after the start of the storage.
From the above test results, the basic compound having acid neutralizing ability used in 3-B to 3-E is a compound represented by the general formula (1) including loxoprofen or a salt thereof and carbinoxamine or a salt thereof. Or it became clear that it has the effect | action which suppresses interaction with the salt.
［試験例４］ロキソプロフェンナトリウム水和物とジフェニルピラリン塩酸塩の相互作用の検討
　以下に示す混合物４－Ａ～４－Ｅをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて６０℃で１週間保存し、保存開始直後、１日後、３日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表４に示す。 [Test Example 4] Examination of interaction between loxoprofen sodium hydrate and diphenylpyraline hydrochloride Each of the following mixtures 4-A to 4-E was prepared and then placed in a glass bottle (3K standard bottle) at 60 ° C for 1 week. The state of the mixture was evaluated immediately after the start of storage, one day later, three days later and one week later, and the presence or absence of interaction was confirmed. The results are shown in Table 4.
〔混合物４－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４９０．４ｍｇ及びジフェニルピラリン塩酸塩（金剛化学製：商品名　塩酸ジフェニルピラリン）９．６ｍｇを混合し、混合物４－Ａを得た。
〔混合物４－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４９０．４ｍｇ、ジフェニルピラリン塩酸塩（金剛化学製：商品名　塩酸ジフェニルピラリン）９．６ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物４－Ｂを得た。 [Mixture 4-A]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 490.4 mg and diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name: diphenylpyraline hydrochloride) were mixed to prepare a mixture 4 -A was obtained.
[Mixture 4-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 490.4 mg, diphenylpyraline hydrochloride (product of Kongo Chemical: trade name: diphenylpyraline hydrochloride) 9.6 mg and magnesium hydroxide (Kyowa) (Chemical Industry: trade name: Kyowasui Mug) (500 mg) was mixed to obtain a mixture 4-B.
〔混合物４－Ｃ〕
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物４－Ｂと同様の方法により、混合物４－Ｃを得た。
〔混合物４－Ｄ〕
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物４－Ｂと同様の方法により、混合物４－Ｄを得た。
〔混合物４－Ｅ〕
　水酸化マグネシウムの代わりに沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）５００ｍｇを用いたほかは混合物４－Ｂと同様の方法により、混合物４－Ｅを得た。 [Mixture 4-C]
A mixture 4-C was obtained in the same manner as the mixture 4-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
[Mixture 4-D]
A mixture 4-D was obtained in the same manner as the mixture 4-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
[Mixture 4-E]
A mixture 4-E was obtained in the same manner as the mixture 4-B, except that 500 mg of precipitated calcium carbonate (manufactured by Sankyo Seimitsu Co., Ltd .: trade name precipitated carbonated CA) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
　表４に示す試験結果から、ロキソプロフェンナトリウム水和物とジフェニルピラリン塩酸塩のみを混合した混合物４－Ａにおいては、相互作用が生じ、混合物が湿潤し、その後変色することが判明した。
　一方、ロキソプロフェンナトリウム水和物、ジフェニルピラリン塩酸塩に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物４－Ｂ、４－Ｃ、４－Ｄ及び４－Ｅにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、４－Ｂ～４－Ｅで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩と、ジフェニルピラリン又はその塩を包含する一般式（１）で表される化合物又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 4, it was found that in the mixture 4-A in which only loxoprofen sodium hydrate and diphenylpyraline hydrochloride were mixed, an interaction occurred, the mixture became wet, and then the color changed.
On the other hand, in the mixtures 4-B, 4-C, 4-D and 4-E in which loxoprofen sodium hydrate and diphenylpyraline hydrochloride were further added with a basic compound having acid neutralizing ability and mixed, one week It was found that the state of the white powder was maintained after storage as well as immediately after the start of storage.
From the above test results, the basic compound having acid neutralizing ability used in 4-B to 4-E is represented by the general formula (1) including loxoprofen or a salt thereof and diphenylpyraline or a salt thereof. It became clear that it has the effect | action which suppresses interaction with a compound or its salt.
［試験例５］ロキソプロフェンナトリウム水和物とブロムヘキシン塩酸塩の相互作用の検討
　以下に示す混合物５－Ａ～５－Ｄをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて６０℃で１週間保存し、保存開始直後、１日後、２日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表５に示す。 [Test Example 5] Examination of interaction between loxoprofen sodium hydrate and bromhexine hydrochloride After preparing each of the following mixtures 5-A to 5-D, each mixture was placed in a glass bottle (3K standard bottle) and stored at 60 ° C for 1 week. Then, immediately after the start of storage, the state of the mixture after 1 day, 2 days and 1 week was evaluated, and the presence or absence of interaction was confirmed. The results are shown in Table 5.
〔混合物５－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４７２．３ｍｇ及びブロムヘキシン塩酸塩（山洋化学製：商品名　ブロムヘキシン塩酸塩）２７．７ｍｇを混合し、混合物５－Ａを得た。
〔混合物５－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４７２．３ｍｇ、ブロムヘキシン塩酸塩（山洋化学製：商品名　ブロムヘキシン塩酸塩）２７．７ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物５－Ｂを得た。 [Mixture 5-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 472.3 mg and bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) 27.7 mg were mixed to obtain a mixture 5 -A was obtained.
[Mixture 5-B]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical: Brand name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 472.3 mg, bromhexine hydrochloride (manufactured by Sanyo Chemical: trade name bromhexine hydrochloride) 27.7 mg and magnesium hydroxide (Kyowa) 500 mg (trade name, Kyowasui Mug, manufactured by Kagaku Kogyo) was mixed to obtain a mixture 5-B.
〔混合物５－Ｃ〕
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物５－Ｂと同様の方法により、混合物５－Ｃを得た。
〔混合物５－Ｄ〕
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物５－Ｂと同様の方法により、混合物５－Ｄを得た。 [Mixture 5-C]
A mixture 5-C was obtained in the same manner as the mixture 5-B, except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
[Mixture 5-D]
A mixture 5-D was obtained in the same manner as the mixture 5-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
　表５に示す試験結果から、ロキソプロフェンナトリウム水和物とブロムヘキシン塩酸塩のみを混合した混合物５－Ａにおいては、相互作用が生じ、混合物が固化し、その後変色することが判明した。
　一方、ロキソプロフェンナトリウム水和物、ブロムヘキシン塩酸塩に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物５－Ｂ、５－Ｃ及び５－Ｄにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、５－Ｂ～５－Ｄで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩と、ブロムヘキシン又はその塩を包含する一般式（２）で表される化合物又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 5, it was found that in the mixture 5-A in which only loxoprofen sodium hydrate and bromohexine hydrochloride were mixed, an interaction occurred and the mixture solidified and then changed color.
On the other hand, in the mixtures 5-B, 5-C and 5-D, in which loxoprofen sodium hydrate and bromhexine hydrochloride were further mixed with a basic compound having an acid neutralizing ability, storage was started even after storage for 1 week. It was found that the state of the white powder was maintained as it was immediately after.
From the above test results, the basic compound having acid neutralizing ability used in 5-B to 5-D is a compound represented by the general formula (2) including loxoprofen or a salt thereof and bromhexine or a salt thereof. Or it became clear that it has the effect | action which suppresses interaction with the salt.
［試験例６］ロキソプロフェンナトリウム水和物とアンブロキソール塩酸塩の相互作用の検討
　以下に示す混合物６－Ａ～６－Ｃをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて６０℃で１週間保存し、保存開始直後、１日後、３日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表６に示す。 [Test Example 6] Examination of interaction between loxoprofen sodium hydrate and ambroxol hydrochloride Each of the following mixtures 6-A to 6-C was prepared and then placed in a glass bottle (3K standard bottle) at 60 ° C. After weekly storage, the state of the mixture was evaluated immediately after the start of storage, one day later, three days later and one week later, and the presence or absence of interaction was confirmed. The results are shown in Table 6.
〔混合物６－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４０９．８ｍｇ及びアンブロキソール塩酸塩（静岡カフェイン工業所製：商品名　塩酸アンブロキソール）９０．２ｍｇを混合し、混合物６－Ａを得た。
〔混合物６－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４０９．８ｍｇ、アンブロキソール塩酸塩（静岡カフェイン工業所製：商品名　塩酸アンブロキソール）９０．２ｍｇ及びケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを混合し、混合物６－Ｂを得た。
〔混合物６－Ｃ〕
　ケイ酸アルミン酸マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物６－Ｂと同様の方法により、混合物６－Ｃを得た。 [Mixture 6-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 409.8 mg and ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: ambroxol hydrochloride) 90.2 mg Mixing to give mixture 6-A.
[Mixture 6-B]
Loxoprofen sodium hydrate (trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 409.8 mg, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name ambroxol hydrochloride) 90.2 mg 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate manufactured by Tomita Pharmaceutical Co., Ltd.) was mixed to obtain a mixture 6-B.
[Mixture 6-C]
A mixture 6-C was obtained in the same manner as the mixture 6-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium aluminate silicate.
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
　表６に示す試験結果から、ロキソプロフェンナトリウム水和物とアンブロキソール塩酸塩のみを混合した混合物６－Ａにおいては、相互作用が生じ、混合物が強度に湿潤し、その後変色することが判明した。
　一方、ロキソプロフェンナトリウム水和物、アンブロキソール塩酸塩に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物６－Ｂ及び６－Ｃにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、６－Ｂ及び６－Ｃで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩と、アンブロキソール又はその塩を包含する一般式（２）で表される化合物又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 6, it was found that in the mixture 6-A in which only loxoprofen sodium hydrate and ambroxol hydrochloride were mixed, an interaction occurred, and the mixture was strongly wetted and then discolored.
On the other hand, in the mixtures 6-B and 6-C, in which loxoprofen sodium hydrate and ambroxol hydrochloride were further mixed with a basic compound having an acid neutralizing ability and mixed, Similarly, it was found that the white powder state was maintained.
From the above test results, the basic compound having acid neutralizing ability used in 6-B and 6-C is represented by the general formula (2) including loxoprofen or a salt thereof and ambroxol or a salt thereof. It became clear that it has the effect | action which suppresses interaction with a compound or its salt.
［試験例７］ロキソプロフェンナトリウム水和物とグアヤコールスルホン酸カリウムの相互作用の検討
　以下に示す混合物７－Ａ～７－Ｅをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて６０℃で１週間保存し、保存開始直後、１日後、３日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表７に示す。 [Test Example 7] Examination of interaction between loxoprofen sodium hydrate and potassium guaiacol sulfonate After preparing the following mixtures 7-A to 7-E, each was put in a glass bottle (3K standard bottle) at 60 ° C for 1 week. The state of the mixture was evaluated immediately after the start of storage, one day later, three days later and one week later, and the presence or absence of interaction was confirmed. The results are shown in Table 7.
〔混合物７－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２２４．９ｍｇ及びグアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）２７５．１ｍｇを混合し、混合物７－Ａを得た。
〔混合物７－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２２４．９ｍｇ、グアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）２７５．１ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物７－Ｂを得た。 [Mixture 7-A]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 224.9 mg and potassium guaiacol sulfonate (trade name: Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: guaiacol potassium sulfonate) mixed with 275.1 mg Thus, a mixture 7-A was obtained.
[Mixture 7-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 224.9 mg, potassium guaiacol sulfonate (trade name: Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: potassium guaiacol sulfonate) 275.1 mg and water Magnesium oxide (Kyowa Chemical Industry, trade name: Kyowasui Mug) (500 mg) was mixed to obtain a mixture 7-B.
〔混合物７－Ｃ〕
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物７－Ｂと同様の方法により、混合物７－Ｃを得た。
〔混合物７－Ｄ〕
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物７－Ｂと同様の方法により、混合物７－Ｄを得た。
〔混合物７－Ｅ〕
　水酸化マグネシウムの代わりに沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）５００ｍｇを用いたほかは混合物７－Ｂと同様の方法により、混合物７－Ｅを得た。 [Mixture 7-C]
A mixture 7-C was obtained in the same manner as the mixture 7-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
[Mixture 7-D]
A mixture 7-D was obtained in the same manner as the mixture 7-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
[Mixture 7-E]
A mixture 7-E was obtained in the same manner as the mixture 7-B, except that 500 mg of precipitated calcium carbonate (manufactured by Sankyo Seimitsu Co., Ltd., trade name: precipitated carbonic acid CA) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
　表７に示す試験結果から、ロキソプロフェンナトリウム水和物とグアヤコールスルホン酸カリウムのみを混合した混合物７－Ａにおいては、相互作用が生じ、混合物が湿潤することが判明した。
　一方、ロキソプロフェンナトリウム水和物、グアヤコールスルホン酸カリウムに、さらに酸中和能を有する塩基性化合物を加えて混合した混合物７－Ｂ、７－Ｃ、７－Ｄ及び７－Ｅにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、７－Ｂ～７－Ｅで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩と、グアヤコールスルホン酸又はその塩を包含する一般式（３）で表される化合物又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 7, it was found that in the mixture 7-A in which only loxoprofen sodium hydrate and potassium guaiacol sulfonate were mixed, an interaction occurred and the mixture became wet.
On the other hand, in the mixtures 7-B, 7-C, 7-D and 7-E, in which loxoprofen sodium hydrate and guaiacol potassium sulfonate were further mixed with a basic compound having acid neutralizing ability, It was found that the state of the white powder was maintained after storage as well as immediately after the start of storage.
From the above test results, the basic compound having acid neutralizing ability used in 7-B to 7-E is represented by the general formula (3) including loxoprofen or a salt thereof and guaiacol sulfonic acid or a salt thereof. It became clear that it has the effect | action which suppresses interaction with a compound or its salt.
［試験例８］ロキソプロフェンナトリウム水和物とリゾチーム塩酸塩の相互作用の検討
　以下に示す混合物８－Ａ～８－Ｆをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて６０℃で１週間保存し、保存開始直後、１日後、３日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表８に示す。 [Test Example 8] Examination of interaction between loxoprofen sodium hydrate and lysozyme hydrochloride After preparing each of the following mixtures 8-A to 8-F, each mixture was put in a glass bottle (3K standard bottle) and stored at 60 ° C for 1 week. Then, immediately after the start of storage, the state of the mixture after 1 day, 3 days and 1 week was evaluated, and the presence or absence of interaction was confirmed. The results are shown in Table 8.
〔混合物８－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）３４７．１ｍｇ及びリゾチーム塩酸塩（エーザイ製：商品名　塩化リゾチーム）１５２．９ｍｇを混合し、混合物８－Ａを得た。
〔混合物８－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）３４７．１ｍｇ、リゾチーム塩酸塩（エーザイ製：商品名　塩化リゾチーム）１５２．９ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物８－Ｂを得た。
〔混合物８－Ｃ〕
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物８－Ｂと同様の方法により、混合物８－Ｃを得た。 [Mixture 8-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 347.1 mg and lysozyme hydrochloride (product name: Eisai: trade name lysozyme chloride) 152.9 mg were mixed, and the mixture 8-A was mixed. Obtained.
[Mixture 8-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: Japan Pharmacopoeia Loxoprofen sodium hydrate) 347.1 mg, lysozyme hydrochloride (manufactured by Eisai: trade name lysozyme chloride) 152.9 mg and magnesium hydroxide (manufactured by Kyowa Chemical Industry) : Product name Kyowasui Mug) 500 mg was mixed to obtain a mixture 8-B.
[Mixture 8-C]
A mixture 8-C was obtained in the same manner as the mixture 8-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
〔混合物８－Ｄ〕
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物８－Ｂと同様の方法により、混合物８－Ｄを得た。
〔混合物８－Ｅ〕
　水酸化マグネシウムの代わりに沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）５００ｍｇを用いたほかは混合物８－Ｂと同様の方法により、混合物８－Ｅを得た。
〔混合物８－Ｆ〕
　水酸化マグネシウムの代わりにケイ酸マグネシウム（富田製薬製：商品名　ケイ酸マグネシウム（軽質））５００ｍｇを用いたほかは混合物８－Ｂと同様の方法により、混合物８－Ｆを得た。 [Mixture 8-D]
A mixture 8-D was obtained in the same manner as the mixture 8-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
[Mixture 8-E]
A mixture 8-E was obtained in the same manner as the mixture 8-B, except that 500 mg of precipitated calcium carbonate (manufactured by Sankyo Seimitsu Co., Ltd., trade name: precipitated carbonated CA) was used instead of magnesium hydroxide.
[Mixture 8-F]
A mixture 8-F was obtained in the same manner as the mixture 8-B, except that 500 mg of magnesium silicate (trade name: magnesium silicate (light)) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
　表８に示す試験結果から、ロキソプロフェンナトリウム水和物とリゾチーム塩酸塩のみを混合した混合物８－Ａにおいては、相互作用が生じ、混合物が湿潤し、その後固化することが判明した。
　一方、ロキソプロフェンナトリウム水和物、リゾチーム塩酸塩に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物８－Ｂ、８－Ｃ、８－Ｄ、８－Ｅ及び８－Ｆにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、８－Ｂ～８－Ｆで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩とリゾチーム又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 8, it was found that in the mixture 8-A in which only loxoprofen sodium hydrate and lysozyme hydrochloride were mixed, an interaction occurred and the mixture became wet and then solidified.
On the other hand, in the mixtures 8-B, 8-C, 8-D, 8-E and 8-F in which loxoprofen sodium hydrate and lysozyme hydrochloride are further mixed with a basic compound having acid neutralizing ability, It was found that the state of the white powder was maintained after storage for 1 week as well as immediately after the start of storage.
From the above test results, it is clear that the basic compound having acid neutralizing ability used in 8-B to 8-F has an action of suppressing the interaction between loxoprofen or a salt thereof and lysozyme or a salt thereof. became.
［試験例９］ロキソプロフェンナトリウム水和物とジヒドロコデインリン酸塩の相互作用の検討
　以下に示す混合物９－Ａ～９－Ｃをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて６０℃で１週間保存し、保存開始直後、１日後、２日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表９に示す。 [Test Example 9] Examination of interaction between loxoprofen sodium hydrate and dihydrocodeine phosphate After preparing the following mixtures 9-A to 9-C, each was put in a glass bottle (3K standard bottle) at 60 ° C for 1 week. The state of the mixture was evaluated immediately after the start of storage, 1 day later, 2 days later and 1 week later, and the presence or absence of interaction was confirmed. The results are shown in Table 9.
〔混合物９－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４４７．４ｍｇ及びジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）５２．６ｍｇを混合し、混合物９－Ａを得た。
〔混合物９－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４４７．４ｍｇ、ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）５２．６ｍｇ及びケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを混合し、混合物９－Ｂを得た。
〔混合物９－Ｃ〕
　ケイ酸アルミン酸マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物９－Ｂと同様の方法により、混合物９－Ｃを得た。 [Mixture 9-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 447.4 mg and dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi”) 52.6 mg Thus, a mixture 9-A was obtained.
[Mixture 9-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 447.4 mg, dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name dihydrocodeine phosphate “Shionogi”) 52.6 mg and Kei 500 mg of magnesium aluminate (trade name: magnesium aluminate manufactured by Tomita Pharmaceutical Co., Ltd.) was mixed to obtain a mixture 9-B.
[Mixture 9-C]
A mixture 9-C was obtained in the same manner as the mixture 9-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium aluminate silicate.
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
　表９に示す試験結果から、ロキソプロフェンナトリウム水和物とジヒドロコデインリン酸塩のみを混合した混合物９－Ａにおいては、相互作用が生じ、混合物が固化し、その後変色することが判明した。
　一方、ロキソプロフェンナトリウム水和物、ジヒドロコデインリン酸塩に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物９－Ｂ及び９－Ｃにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、９－Ｂ及び９－Ｃで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩とコデイン類との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 9, it was found that in the mixture 9-A in which only loxoprofen sodium hydrate and dihydrocodeine phosphate were mixed, an interaction occurred and the mixture solidified and then changed color.
On the other hand, in the mixtures 9-B and 9-C in which loxoprofen sodium hydrate and dihydrocodeine phosphate were further added and mixed with a basic compound having acid neutralizing ability, after storage for 1 week, the same as immediately after the start of storage It was found that the white powder state was maintained.
From the above test results, it was clarified that the basic compound having acid neutralizing ability used in 9-B and 9-C has an action of suppressing the interaction between loxoprofen or a salt thereof and codeines. .
［試験例１０］ロキソプロフェンナトリウム水和物とｄｌ－メチルエフェドリン塩酸塩の相互作用の検討
　以下に示すサンプル１０－Ａ～１０－Ｇをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて５０℃で６日間保存し、保存開始直後、１日後、２日後及び６日後の混合物の状態を評価し、相互作用の有無を確認した。結果を表１０に示す。 [Test Example 10] Examination of interaction between loxoprofen sodium hydrate and dl-methylephedrine hydrochloride Samples 10-A to 10-G shown below were prepared and placed in glass bottles (3K standard bottles) at 50 ° C. The mixture was stored for 6 days, immediately after the start of storage, 1 day, 2 days and 6 days later, the state of the mixture was evaluated to confirm the presence or absence of interaction. The results are shown in Table 10.
〔混合物１０－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２２５ｍｇ及びｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）２５ｍｇを混合し、混合物１０－Ａを得た。
〔混合物１０－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２２５ｍｇ、ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）２５ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物１０－Ｂを得た。
〔混合物１０－Ｃ〕
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物１０－Ｂと同様の方法により、混合物１０－Ｃを得た。 [Mixture 10-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 225 mg and dl-methylephedrine hydrochloride (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 25 mg Mixing to obtain a mixture 10-A.
[Mixture 10-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 225 mg, dl-methylephedrine hydrochloride (trade name: Alpine Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 25 mg and Magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd., trade name: Kyowasui Mug) 500 mg was mixed to obtain a mixture 10-B.
[Mixture 10-C]
A mixture 10-C was obtained in the same manner as the mixture 10-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
〔混合物１０－Ｄ〕
　水酸化マグネシウムの代わりに無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）５００ｍｇを用いたほかは混合物１０－Ｂと同様の方法により、混合物１０－Ｄを得た。
〔混合物１０－Ｅ〕
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物１０－Ｂと同様の方法により、混合物１０－Ｅを得た。
〔混合物１０－Ｆ〕
　水酸化マグネシウムの代わりに沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）５００ｍｇを用いたほかは混合物１０－Ｂと同様の方法により、混合物１０－Ｆを得た。
〔混合物１０－Ｇ〕
　水酸化マグネシウムの代わりにメタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）５００ｍｇを用いたほかは混合物１０－Ｂと同様の方法により、混合物１０－Ｇを得た。 [Mixture 10-D]
A mixture 10-D was obtained in the same manner as the mixture 10-B except that 500 mg of anhydrous calcium hydrogen phosphate (trade name: anhydrous calcium hydrogen phosphate GS-H) was used instead of magnesium hydroxide. It was.
[Mixture 10-E]
A mixture 10-E was obtained in the same manner as the mixture 10-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
[Mixture 10-F]
A mixture 10-F was obtained in the same manner as the mixture 10-B, except that 500 mg of precipitated calcium carbonate (manufactured by Sankyo Seimitsu Co., Ltd .: trade name precipitated carbonated CA) was used instead of magnesium hydroxide.
[Mixture 10-G]
A mixture 10-G was obtained in the same manner as the mixture 10-B, except that 500 mg of magnesium aluminate metasilicate (product name: Neusilin UFL2) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
　表１０に示す試験結果から、ロキソプロフェンナトリウム水和物とｄｌ－メチルエフェドリン塩酸塩のみを混合した混合物１０－Ａにおいては、相互作用が生じ、混合物が固化することが判明した。
　一方、ロキソプロフェンナトリウム水和物、ｄｌ－メチルエフェドリン塩酸塩に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物１０－Ｂ、１０－Ｃ、１０－Ｄ、１０－Ｅ、１０－Ｆ及び１０－Ｇにおいては、６日間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、１０－Ｂ～１０－Ｇで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩と、エフェドリン類との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 10, it was found that in the mixture 10-A in which only loxoprofen sodium hydrate and dl-methylephedrine hydrochloride were mixed, an interaction occurred and the mixture solidified.
On the other hand, a mixture 10-B, 10-C, 10-D, 10-E, 10-, in which loxoprofen sodium hydrate and dl-methylephedrine hydrochloride were further mixed with a basic compound having acid neutralizing ability. In F and 10-G, it was found that the white powder state was maintained even after 6 days of storage, just after the start of storage.
From the above test results, it is clear that the basic compound having acid neutralizing ability used in 10-B to 10-G has an action of suppressing the interaction between loxoprofen or a salt thereof and ephedrines. It was.
［試験例１１］ロキソプロフェンナトリウム水和物とデキストロメトルファン臭化水素酸塩水和物の相互作用の検討
　以下に示す混合物１１－Ａ～１１－Ｅをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れて６０℃で１週間保存し、保存開始直後、１日後、３日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表１１に示す。 [Test Example 11] Examination of interaction between loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate Mixtures 11-A to 11-E shown below were prepared and placed in glass bottles (3K standard bottles). The mixture was stored at 60 ° C. for 1 week, and immediately after the start of storage, the state of the mixture was evaluated after 1 day, 3 days, and 1 week, and the presence or absence of interaction was confirmed. The results are shown in Table 11.
〔混合物１１－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４０４．９ｍｇ及びデキストロメトルファン臭化水素酸塩水和物（第一ファインケミカル製：商品名　デキストロメトルファン　ＨＢＲ）９５．１ｍｇを混合し、混合物１１－Ａを得た。
〔混合物１１－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４０４．９ｍｇ、デキストロメトルファン臭化水素酸塩水和物（第一ファインケミカル製：商品名　デキストロメトルファン　ＨＢＲ）９５．１ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物１１－Ｂを得た。
〔混合物１１－Ｃ〕
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物１１－Ｂと同様の方法により、混合物１１－Ｃを得た。 [Mixture 11-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 404.9mg and dextromethorphan hydrobromide hydrate (Daiichi Fine Chemical: trade name: dextromethorphan HBR) 95 .1 mg was mixed to obtain a mixture 11-A.
[Mixture 11-B]
Loxoprofen sodium hydrate (trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 404.9 mg, dextromethorphan hydrobromide hydrate (Daiichi Fine Chemical: trade name dextromethorphan HBR) 95 .1 mg and magnesium hydroxide (trade name: Kyowasui Mug) 500 mg were mixed to obtain a mixture 11-B.
[Mixture 11-C]
A mixture 11-C was obtained in the same manner as the mixture 11-B except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
〔混合物１１－Ｄ〕
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物１１－Ｂと同様の方法により、混合物１１－Ｄを得た。
〔混合物１１－Ｅ〕
　水酸化マグネシウムの代わりに沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）５００ｍｇを用いたほかは混合物１１－Ｂと同様の方法により、混合物１１－Ｅを得た。 [Mixture 11-D]
A mixture 11-D was obtained in the same manner as the mixture 11-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
[Mixture 11-E]
A mixture 11-E was obtained in the same manner as the mixture 11-B, except that 500 mg of precipitated calcium carbonate (trade name: precipitated carbon dioxide CA, manufactured by Sankyo Seimitsu) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
　表１１に示す試験結果から、ロキソプロフェンナトリウム水和物とデキストロメトルファン臭化水素酸塩水和物のみを混合した混合物１１－Ａにおいては、相互作用が生じ、混合物が湿潤することが判明した。
　一方、ロキソプロフェンナトリウム水和物、デキストロメトルファン臭化水素酸塩水和物に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物１１－Ｂ、１１－Ｃ、１１－Ｄ及び１１－Ｅにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、１１－Ｂ～１１－Ｅで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩とデキストロメトルファン又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 11, it was found that in the mixture 11-A in which only loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate were mixed, an interaction occurred and the mixture became wet.
On the other hand, mixtures 11-B, 11-C, 11-D and 11- in which loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate were further mixed with a basic compound having acid neutralization ability were mixed. In E, it was found that the state of the white powder was maintained after storage for 1 week as well as immediately after the start of storage.
From the above test results, it is found that the basic compound having acid neutralizing ability used in 11-B to 11-E has an action of suppressing the interaction between loxoprofen or a salt thereof and dextromethorphan or a salt thereof. It became clear.
［試験例１２］ロキソプロフェンナトリウム水和物と安息香酸ナトリウムカフェインの相互作用の検討
　以下に示す混合物１２－Ａ～１２－Ｆをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れ６０℃で１週間保存し、保存開始直後、１日後、３日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表１２に示す。 [Test Example 12] Examination of interaction between loxoprofen sodium hydrate and sodium benzoate caffeine Each of the following mixtures 12-A to 12-F was prepared and then placed in a glass bottle (3K standard bottle) at 60 ° C for 1 week. The state of the mixture was evaluated immediately after the start of storage, one day later, three days later and one week later, and the presence or absence of interaction was confirmed. The results are shown in Table 12.
［混合物１２－Ａ］
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２０２．６ｍｇ及び安息香酸ナトリウムカフェイン（静岡カフェイン製：商品名　安息香酸ナトリウムカフェイン）２９７．４ｍｇを混合し、混合物１２－Ａを得た。
［混合物１２－Ｂ］
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２０２．６ｍｇ、安息香酸ナトリウムカフェイン（静岡カフェイン製：商品名　安息香酸ナトリウムカフェイン）２９７．４ｍｇ及び水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）５００ｍｇを混合し、混合物１２－Ｂを得た。
［混合物１２－Ｃ］
　水酸化マグネシウムの代わりにケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを用いたほかは混合物１２－Ｂと同様の方法により、混合物１２－Ｃを得た。 [Mixture 12-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 202.6 mg and sodium benzoate caffeine (Shizuoka caffeine: trade name: sodium benzoate caffeine) 297.4 mg are mixed. Thus, a mixture 12-A was obtained.
[Mixture 12-B]
Loxoprofen sodium hydrate (trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 202.6 mg, sodium benzoate caffeine (product name: sodium benzoate caffeine, trade name: 297.4 mg) and water Magnesium oxide (Kyowa Chemical Industry, trade name: Kyowasui Mug) (500 mg) was mixed to obtain a mixture 12-B.
[Mixture 12-C]
A mixture 12-C was obtained in the same manner as the mixture 12-B, except that 500 mg of magnesium aluminate silicate (trade name: magnesium aluminate silicate) was used instead of magnesium hydroxide.
［混合物１２－Ｄ］
　水酸化マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）５００ｍｇを用いたほかは混合物１２－Ｂと同様の方法により、混合物１２－Ｄを得た。
［混合物１２－Ｅ］
　水酸化マグネシウムの代わりにメタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）５００ｍｇを用いたほかは混合物１２－Ｂと同様の方法により、混合物１２－Ｅを得た。
［混合物１２－Ｆ］
　水酸化マグネシウムの代わりに沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）５００ｍｇを用いたほかは混合物１２－Ｂと同様の方法により、混合物１２－Ｆを得た。 [Mixture 12-D]
A mixture 12-D was obtained in the same manner as the mixture 12-B, except that 500 mg of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium hydroxide.
[Mixture 12-E]
A mixture 12-E was obtained in the same manner as the mixture 12-B, except that 500 mg of magnesium aluminate metasilicate (product name: Neusilin UFL2) was used instead of magnesium hydroxide.
[Mixture 12-F]
A mixture 12-F was obtained in the same manner as the mixture 12-B, except that 500 mg of precipitated calcium carbonate (trade name: precipitated carbon dioxide CA manufactured by Sankyo Seimitsu) was used instead of magnesium hydroxide.
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
　表１２に示す試験結果から、ロキソプロフェンナトリウム水和物と安息香酸ナトリウムカフェインのみを混合した混合物１２－Ａにおいては、相互作用が生じ、混合物が固化することが判明した。
　一方、ロキソプロフェンナトリウム、安息香酸ナトリウムカフェインに、さらに酸中和能を有する塩基性化合物を加えて混合した混合物１２－Ｂ、１２－Ｃ、１２－Ｄ、１２－Ｅ及び１２－Ｆにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、１２－Ｂ～１２－Ｆで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩とキサンチン誘導体との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 12, it was found that in the mixture 12-A in which only loxoprofen sodium hydrate and sodium caffeine benzoate were mixed, an interaction occurred and the mixture solidified.
On the other hand, in the mixtures 12-B, 12-C, 12-D, 12-E and 12-F, in which loxoprofen sodium and sodium benzoate caffeine were further mixed with a basic compound having acid neutralizing ability, It was found that the state of the white powder was maintained after the storage for one week as well as immediately after the start of the storage.
From the above test results, it was clarified that the basic compound having acid neutralizing ability used in 12-B to 12-F has an action of suppressing the interaction between loxoprofen or a salt thereof and a xanthine derivative. .
［試験例１３］ロキソプロフェンナトリウム水和物とブロムワレリル尿素の相互作用の検討
　以下に示す混合物１３－Ａ～１３－Ｄをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れ６０℃で１週間保存し、保存開始直後、１日後、３日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表１３に示す。 [Test Example 13] Examination of interaction between loxoprofen sodium hydrate and bromvaleryl urea Each of the following mixtures 13-A to 13-D was prepared, placed in a glass bottle (3K standard bottle), and stored at 60 ° C for 1 week. Immediately after the start of storage, the state of the mixture after 1 day, 3 days and 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 13.
〔混合物１３－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）１２７ｍｇ及びブロムワレリル尿素（八代製薬製：商品名　日本薬局方　ブロモバレリル尿素Ｐ）３７３ｍｇを混合し、混合物１３－Ａを得た。
〔混合物１３－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）１２７ｍｇ、ブロムワレリル尿素（八代製薬製：商品名　日本薬局方　ブロモバレリル尿素Ｐ）３７３ｍｇ及びケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）５００ｍｇを混合し、混合物１３－Ｂを得た。
〔混合物１３－Ｃ〕
　ケイ酸アルミン酸マグネシウムの代わりにメタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）５００ｍｇを用いたほかは混合物１３－Ｂと同様の方法により、混合物１３－Ｃを得た。
〔混合物１３－Ｄ〕
　ケイ酸アルミン酸マグネシウムの代わりにケイ酸マグネシウム（富田製薬製：商品名　ケイ酸マグネシウム（軽質））５００ｍｇを用いたほかは混合物１３－Ｂと同様の方法により、混合物１３－Ｄを得た。 [Mixture 13-A]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 127 mg and bromovaleryl urea (manufactured by Yatsushiro Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Bromovalerylurea P) were mixed together, and the mixture 13-A was mixed. Obtained.
[Mixture 13-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 127 mg, bromvaleryl urea (manufactured by Yatsushiro Pharmaceutical Co., Ltd .: trade name: Japanese pharmacopoeia bromovaleryl urea P) and magnesium aluminate silicate (Tonda Pharmaceutical) (Product name: magnesium aluminate silicate) 500 mg was mixed to obtain a mixture 13-B.
[Mixture 13-C]
A mixture 13-C was obtained in the same manner as the mixture 13-B except that 500 mg of magnesium aluminate metasilicate (product name: Neusilin UFL2) was used instead of magnesium aluminate silicate.
[Mixture 13-D]
A mixture 13-D was obtained in the same manner as the mixture 13-B, except that 500 mg of magnesium silicate (trade name: magnesium silicate (light)) was used in place of the magnesium aluminate silicate.
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
　表１３に示す試験結果から、ロキソプロフェンナトリウム水和物とブロムワレリル尿素のみを混合した混合物１３－Ａにおいては、相互作用が生じ、混合物が固化することが判明した。
　一方、ロキソプロフェンナトリウム水和物、ブロムワレリル尿素に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物１３－Ｂ、１３－Ｃ及び１３－Ｄにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、１３－Ｂ～１３－Ｄで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩とイソバレリル尿素誘導体との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 13, it was found that in the mixture 13-A in which only loxoprofen sodium hydrate and bromvalerylurea were mixed, an interaction occurred and the mixture solidified.
On the other hand, in the mixtures 13-B, 13-C and 13-D in which loxoprofen sodium hydrate and bromvaleryl urea were further added with a basic compound having acid neutralizing ability and mixed, the storage immediately after the start of storage after 1 week It was found that the white powder was maintained in the same manner as in FIG.
From the above test results, it is clear that the basic compound having acid neutralizing ability used in 13-B to 13-D has an action of suppressing the interaction between loxoprofen or a salt thereof and an isovaleryl urea derivative. It was.
［試験例１４］ロキソプロフェンナトリウム水和物とブチルスコポラミン臭化物の相互作用の検討
　以下に示す混合物１４－Ａ～１４－Ｈをそれぞれ調製後、ガラス瓶（３Ｋ規格瓶）に入れ６０℃で１週間保存し、保存開始直後、１日後、２日後及び１週間後の混合物の状態を評価し、相互作用の有無を確認した。結果を表１４に示す。 [Test Example 14] Examination of interaction between loxoprofen sodium hydrate and butyl scopolamine bromide After preparing each of the mixtures 14-A to 14-H shown below, they were placed in glass bottles (3K standard bottles) and stored at 60 ° C for 1 week. Immediately after the start of storage, the state of the mixture after 1 day, 2 days and 1 week was evaluated, and the presence or absence of interaction was confirmed. The results are shown in Table 14.
〔混合物１４－Ａ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２０４．３質量部及びブチルスコポラミン臭化物（アルプス薬品工業製：商品名　日本薬局方　ブチルスコポラミン臭化物）３０質量部を混合し、混合物１４－Ａを得た。
〔混合物１４－Ｂ〕
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２０４．３質量部、ブチルスコポラミン臭化物（アルプス薬品工業製：商品名　日本薬局方　ブチルスコポラミン臭化物）３０質量部及びケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）２３４．３質量部を混合し、混合物１４－Ｂを得た。
〔混合物１４－Ｃ〕
　ケイ酸アルミン酸マグネシウムの代わりにメタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）２３４．３質量部を用いたほかは混合物１４－Ｂと同様の方法により、混合物１４－Ｃを得た。
〔混合物１４－Ｄ〕
　ケイ酸アルミン酸マグネシウムの代わりにケイ酸カルシウム（トクヤマ製：商品名　フローライトＲＥ）２３４．３質量部を用いたほかは混合物１４－Ｂと同様の方法により、混合物１４－Ｄを得た。 [Mixture 14-A]
204.3 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and 30 parts by mass of butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia butyl scopolamine bromide) Mixing to give mixture 14-A.
[Mixture 14-B]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 parts by mass, butylscopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia butylscopolamine bromide) 30 parts by mass and 234.3 parts by mass of magnesium aluminate silicate (trade name: magnesium aluminate manufactured by Tomita Pharmaceutical Co., Ltd.) was mixed to obtain a mixture 14-B.
[Mixture 14-C]
A mixture 14-C was obtained in the same manner as the mixture 14-B except that 234.3 parts by mass of magnesium aluminate metasilicate (product name: Neusilin UFL2) was used instead of magnesium aluminate silicate. It was.
[Mixture 14-D]
A mixture 14-D was obtained in the same manner as the mixture 14-B, except that 234.3 parts by mass of calcium silicate (trade name: FLORITE RE) manufactured by Tokuyama instead of magnesium aluminate silicate was used.
〔混合物１４－Ｅ〕
　ケイ酸アルミン酸マグネシウムの代わりに沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）２３４．３質量部を用いたほかは混合物１４－Ｂと同様の方法により、混合物１４－Ｅを得た。
〔混合物１４－Ｆ〕
　ケイ酸アルミン酸マグネシウムの代わりに無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）２３４．３質量部を用いたほかは混合物１４－Ｂと同様の方法により、混合物１４－Ｆを得た。
〔混合物１４－Ｇ〕
　ケイ酸アルミン酸マグネシウムの代わりに水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）２３４．３質量部を用いたほかは混合物１４－Ｂと同様の方法により、混合物１４－Ｇを得た。
〔混合物１４－Ｈ〕
　ケイ酸アルミン酸マグネシウムの代わりに酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）２３４．３質量部を用いたほかは混合物１４－Ｂと同様の方法により、混合物１４－Ｈを得た。 [Mixture 14-E]
A mixture 14-E was obtained in the same manner as the mixture 14-B, except that 234.3 parts by mass of precipitated calcium carbonate (trade name: precipitated carbon dioxide CA, manufactured by Sankyo Seimitsu) was used instead of magnesium aluminate silicate. .
[Mixture 14-F]
In the same manner as in the mixture 14-B, except that 234.3 parts by mass of anhydrous calcium hydrogen phosphate (trade name: anhydrous calcium hydrogen phosphate GS-H) was used instead of magnesium aluminate silicate, Mixture 14-F was obtained.
[Mixture 14-G]
A mixture 14-G was obtained in the same manner as the mixture 14-B, except that 234.3 parts by mass of magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd., trade name: Kyowasui Mug) was used instead of magnesium aluminate silicate.
[Mixture 14-H]
A mixture 14-H was obtained in the same manner as the mixture 14-B, except that 234.3 parts by mass of magnesium oxide (trade name: heavy magnesium oxide, manufactured by Tomita Pharmaceutical Co., Ltd.) was used instead of magnesium aluminate silicate.
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
　表１４に示す試験結果から、ロキソプロフェンナトリウム水和物とブチルスコポラミン臭化物のみを混合した混合物１４－Ａにおいては、相互作用が生じ、混合物が固化することが判明した。
　一方、ロキソプロフェンナトリウム水和物、ブチルスコポラミン臭化物に、さらに酸中和能を有する塩基性化合物を加えて混合した混合物１４－Ｂ、１４－Ｃ、１４－Ｄ、１４－Ｅ、１４－Ｆ、１４－Ｇ及び１４－Ｈにおいては、１週間保存後も保存開始直後と同様に白色粉体の状態が保たれることが判明した。
　以上の試験結果から、１４－Ｂ～１４－Ｈで用いた酸中和能を有する塩基性化合物が、ロキソプロフェン又はその塩と、ブチルスコポラミン又はその塩との相互作用を抑制する作用を有することが明らかとなった。 From the test results shown in Table 14, it was found that in the mixture 14-A in which only loxoprofen sodium hydrate and butyl scopolamine bromide were mixed, an interaction occurred and the mixture solidified.
On the other hand, mixtures 14-B, 14-C, 14-D, 14-E, 14-F, 14 in which loxoprofen sodium hydrate and butyl scopolamine bromide were further mixed with a basic compound having acid neutralizing ability. In the cases of -G and 14-H, it was found that the state of the white powder was maintained after storage for 1 week as well as immediately after the start of storage.
From the above test results, it is found that the basic compound having acid neutralizing ability used in 14-B to 14-H has an action of suppressing the interaction between loxoprofen or a salt thereof and butyl scopolamine or a salt thereof. It became clear.
［試験例１５］ロキソプロフェンナトリウム水和物と相互作用性成分を含有する錠剤の膨張の検討
　試験例１～１４で確認されたロキソプロフェン又はその塩と相互作用性成分との間の相互作用（固化、湿潤等の状態変化）が固形製剤に与える影響を確認するため、ロキソプロフェンナトリウム水和物と相互作用性成分を含有する錠剤を製造し、その経時的な膨張の有無を確認した。
　具体的には、以下に示す錠剤１５－Ａ～１５－Ｃをそれぞれ調製後、６０℃で１ヶ月間保存し、調製直後及び１ヶ月保存後の錠剤の厚みを測定し、さらに下記式に従って膨張率（％）を算出した。結果（各種錠剤当たり３錠の膨張率の平均値）を表１５に示す。 [Test Example 15] Examination of swelling of tablets containing loxoprofen sodium hydrate and an interactive component Interaction between loxoprofen or a salt thereof confirmed in Test Examples 1 to 14 and an interactive component (solidification, In order to confirm the influence of a change in state such as wetting) on the solid preparation, a tablet containing loxoprofen sodium hydrate and an interactive component was produced, and the presence or absence of swelling over time was confirmed.
Specifically, after preparing tablets 15-A to 15-C shown below, each tablet was stored at 60 ° C. for 1 month, the thickness of the tablet immediately after preparation and after storage for 1 month was measured, and further expanded according to the following formula The rate (%) was calculated. The results (average value of the expansion rate of 3 tablets per various tablets) are shown in Table 15.
　膨張率（％）＝｛（１ヶ月保存後の錠剤の厚み）－（調製直後の錠剤の厚み）｝／（調製直後の錠剤の厚み）×１００ Expansion rate (%) = {(tablet thickness after 1 month storage) − (thickness of tablet immediately after preparation)} / (thickness of tablet immediately after preparation) × 100
［錠剤１５－Ａ］
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）３４０．５ｇ、ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）５．８ｇ、ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）１００．０ｇ、グアイフェネシン（アルプス薬品工業製：商品名　日本薬局方　グアイフェネシン）４１６．７ｇ、無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）６６．７ｇ、ヒドロキシプロピルセルロース（日本曹達製：商品名　ＨＰＣ－Ｌ）１２１．５ｇ、カルメロースカルシウム（五徳薬品製：商品名　ＥＣＧ５０５）４０５ｇ、乳糖水和物（ＤＭＶ製：商品名　乳糖２００Ｍ）４９４．３ｇ、及び結晶セルロース（旭化成ケミカルズ製：商品名　セオラスＰＨ－１０１）１９１７．０ｇを高速攪拌造粒機（パウレック製：ＶＧ－２５型）に投入して混合後、精製水２３０ｇを添加して練合し、造粒物を得た。この造粒物を流動層乾燥機（フロイント産業製：ＦＬＯ－５型）に投入して乾燥後、整粒機（岡田精工製：ＮＤ－１０型）を用いて整粒した。この整粒物３８６７．５ｇ及びステアリン酸マグネシウム（太平化学工業製：商品名　ステアリン酸マグネシウム（植物性））１８２．５ｇを混合機（コトブキ製：ＰＭ５０型）に投入して混合した後、直径８．５ｍｍの杵を取り付けた打錠機（畑鉄工所製：ＨＴ－ＡＰ１８ＳＳ型）を用いて打錠し、１錠の質量が２７０ｍｇの錠剤を得た。 [Tablet 15-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 340.5 g, d-chlorpheniramine maleate (manufactured by Kongo Chemicals: trade name D-chlorpheniramine maleate) 5 .8 g, dl-methylephedrine hydrochloride (Alps Yakuhin Kogyo Co., Ltd .: trade name: Japanese Pharmacopoeia dl-Methylephedrine hydrochloride powder) 100.0 g, Guayphenesine (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia Guayphenesine) 416.7 g, anhydrous Caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 66.7 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 121.5 g, carmellose calcium (product name: ECG505) 405 g, lactose hydrate (DMV: trade name: lactose 00M) 494.3 g and crystalline cellulose (Asahi Kasei Chemicals: trade name: Theolas PH-101) 1917.0 g were put into a high-speed agitating granulator (Paulec: model VG-25), mixed, and then purified water 230 g The mixture was added and kneaded to obtain a granulated product. This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 3.87.5 g of this sized product and 182.5 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a blender (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 5 mm punch, and tablets with a weight of 270 mg were obtained.
［錠剤１５－Ｂ］
　結晶セルロースの代わりに酸中和能を有する塩基性化合物である無水リン酸水素カルシウムを用いたほかは錠剤１５－Ａと同様の方法により、錠剤１５－Ｂを得た。
　具体的には、ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）３４０．５ｇ、ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）５．８ｇ、ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）１００．０ｇ、グアイフェネシン（アルプス薬品工業製：商品名　日本薬局方　グアイフェネシン）４１６．７ｇ、無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）６６．７ｇ、ヒドロキシプロピルセルロース（日本曹達製：商品名　ＨＰＣ－Ｌ）１２１．５ｇ、カルメロースカルシウム（五徳薬品製：商品名　ＥＣＧ５０５）４０５ｇ、乳糖水和物（ＤＭＶ製：商品名　乳糖２００Ｍ）４９４．３ｇ、及び無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）１９１７．０ｇを高速攪拌造粒機（パウレック製：ＶＧ－２５型）に投入して混合後、精製水３００ｇを添加して練合し、造粒物を得た。この造粒物を流動層乾燥機（フロイント産業製：ＦＬＯ－５型）に投入して乾燥後、整粒機（岡田精工製：ＮＤ－１０型）を用いて整粒した。この整粒物３８６７．５ｇ及びステアリン酸マグネシウム（太平化学工業製：商品名　ステアリン酸マグネシウム（植物性））１８２．５ｇを混合機（コトブキ製：ＰＭ５０型）に投入して混合した後、直径８．５ｍｍの杵を取り付けた打錠機（畑鉄工所製：ＨＴ－ＡＰ１８ＳＳ型）を用いて打錠し、１錠の質量が２７０ｍｇの錠剤を得た。 [Tablet 15-B]
Tablet 15-B was obtained in the same manner as Tablet 15-A, except that anhydrous calcium hydrogen phosphate, which is a basic compound having acid neutralizing ability, was used instead of crystalline cellulose.
Specifically, loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 340.5 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-maleic acid) Chlorpheniramine) 5.8 g, dl-methylephedrine hydrochloride (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia dl-methyl ephedrine hydrochloride powder) 100.0 g, guaifenesin (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia Guayphenesin) 416.7 g, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 66.7 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 121.5 g, carmellose calcium (manufactured by Gotoku Pharmaceutical) : Product name ECG505) 405 g, lactose hydrate (manufactured by DMV: 494.3 g of trade name lactose 200M) and 1917.0 g of anhydrous calcium hydrogen phosphate (Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) (high-speed agitation granulator (made by Paulek: VG-25 type)) After adding and mixing, 300 g of purified water was added and kneaded to obtain a granulated product. This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 3.87.5 g of this sized product and 182.5 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a blender (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 5 mm punch, and tablets with a weight of 270 mg were obtained.
［錠剤１５－Ｃ］
　結晶セルロースの代わりに酸中和能を有する塩基性化合物である無水リン酸水素カルシウムとメタケイ酸アルミン酸マグネシウムの組み合わせを用いたほかは錠剤１５－Ａと同様の方法により、錠剤１５－Ｃを得た。
　具体的には、ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）３４０．５ｇ、ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）５．８ｇ、ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）１００．０ｇ、グアイフェネシン（アルプス薬品工業製：商品名　日本薬局方　グアイフェネシン）４１６．７ｇ、無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）６６．７ｇ、ヒドロキシプロピルセルロース（日本曹達製：商品名　ＨＰＣ－Ｌ）１２１．５ｇ、カルメロースカルシウム（五徳薬品製：商品名　ＥＣＧ５０５）４０５ｇ、乳糖水和物（ＤＭＶ製：商品名　乳糖２００Ｍ）４９４．３ｇ、無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）１４３３．７ｇ、及びメタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）４８３．３ｇを高速攪拌造粒機（パウレック製：ＶＧ－２５型）に投入して混合後、精製水１５００ｇを添加して練合し、造粒物を得た。この造粒物を流動層乾燥機（フロイント産業製：ＦＬＯ－５型）に投入して乾燥後、整粒機（岡田精工製：ＮＤ－１０型）を用いて整粒した。この整粒物３８６７．５ｇ及びステアリン酸マグネシウム（太平化学工業製：商品名　ステアリン酸マグネシウム（植物性））１８２．５ｇを混合機（コトブキ製：ＰＭ５０型）に投入して混合した後、直径８．５ｍｍの杵を取り付けた打錠機（畑鉄工所製：ＨＴ－ＡＰ１８ＳＳ型）を用いて打錠し、１錠の質量が２７０ｍｇの錠剤を得た。 [Tablet 15-C]
Tablet 15-C is obtained in the same manner as Tablet 15-A except that a combination of anhydrous calcium hydrogen phosphate and magnesium aluminate metasilicate, which is a basic compound having acid neutralizing ability, is used instead of crystalline cellulose. It was.
Specifically, loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 340.5 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-maleic acid) Chlorpheniramine) 5.8 g, dl-methylephedrine hydrochloride (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia dl-methyl ephedrine hydrochloride powder) 100.0 g, guaifenesin (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia Guayphenesin) 416.7 g, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 66.7 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 121.5 g, carmellose calcium (manufactured by Gotoku Pharmaceutical) : Product name ECG505) 405 g, lactose hydrate (manufactured by DMV: Trade name: Lactose (200M) 494.3 g, anhydrous calcium hydrogen phosphate (Kyowa Chemical Industry: trade name: anhydrous calcium hydrogen phosphate GS-H) 1433.7 g, and magnesium metasilicate aluminate (Fuji Chemical Industry: trade name: Neusilin 483.3 g of UFL2) was added to a high-speed agitation granulator (manufactured by POWREC: VG-25 type) and mixed, and then 1500 g of purified water was added and kneaded to obtain a granulated product. This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 3.87.5 g of this sized product and 182.5 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a blender (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 5 mm punch, and tablets with a weight of 270 mg were obtained.
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
　表１５に示す試験結果から、ロキソプロフェンナトリウム水和物と相互作用性成分を含有するが、酸中和能を有する塩基性化合物を含有しない錠剤１５－Ａにおいては、時間の経過に伴い錠剤が膨張することが明らかとなった。
　一方、ロキソプロフェンナトリウム水和物、相互作用性成分及び酸中和能を有する塩基性化合物を含有する錠剤１５－Ｂ、１５－Ｃにおいては、錠剤の膨張が抑制されることが明らかとなった。
　以上の試験結果から、ロキソプロフェン又はその塩、相互作用性成分及び酸中和能を有する塩基性化合物を含有する固形製剤は、経時的な膨張が抑制された、安定性に優れたものであることが明らかとなった。 From the test results shown in Table 15, in Tablet 15-A containing loxoprofen sodium hydrate and an interactive component but not containing a basic compound having acid neutralizing ability, the tablet expands over time. It became clear to do.
On the other hand, in tablets 15-B and 15-C containing loxoprofen sodium hydrate, an interactive component, and a basic compound having acid neutralizing ability, it was revealed that tablet expansion was suppressed.
From the above test results, the solid preparation containing loxoprofen or a salt thereof, an interactive component and a basic compound having an acid neutralizing ability is excellent in stability with suppressed swelling over time. Became clear.
［実施例１］
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）４０８．６ｇ、ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）７ｇ、水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）４００ｇ、ヒドロキシプロピルセルロース（日本曹達製：商品名　ＨＰＣ－Ｌ）１４５．８ｇ、カルメロースカルシウム（五徳薬品製：商品名　ＥＣＧ５０５）４８６ｇ、及び結晶セルロース（旭化成ケミカルズ製：商品名　セオラスＰＨ－１０１）３３６４ｇを高速攪拌造粒機（パウレック製：ＶＧ－２５型）に投入して混合後、精製水１９７２．６ｇを添加して練合し、造粒物を得た。この造粒物を流動層乾燥機（フロイント産業製：ＦＬＯ－５型）に投入して乾燥後、整粒機（岡田精工製：ＮＤ－１０型）を用いて整粒した。この整粒物４８１１．４ｇ及びステアリン酸マグネシウム（太平化学工業製：商品名　ステアリン酸マグネシウム（植物性））４８．６ｇを混合機（コトブキ製：ＰＭ５０型）に投入して混合した後、直径８．５ｍｍの杵を取り付けた打錠機（畑鉄工所製：ＨＴ－ＡＰ１８ＳＳ型）を用いて打錠し、１錠の質量が２７０ｍｇの錠剤１８０００錠を得た。 [Example 1]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical: trade name: D-chlorpheniramine maleate) 7 g , 400 g of magnesium hydroxide (Kyowa Chemical Industry, trade name: Kyowasui Mug), 145.8 g of hydroxypropyl cellulose (trade name: HPC-L, manufactured by Nippon Soda), 486 g of carmellose calcium (trade name: ECG505), and Crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd .: trade name: Theolas PH-101) was charged into a high-speed stirring granulator (manufactured by Paulek: model VG-25) and mixed, and then 1972.6 g of purified water was added and kneaded. A granulated product was obtained. This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.
［実施例２］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）　３．５ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６８２ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 2]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 3.5 mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1682mg
Magnesium stearate 24.3mg
［実施例３］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）　３．５ｍｇ
　沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６８２ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 3]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 3.5 mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1682mg
Magnesium stearate 24.3mg
［実施例４］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）　３．５ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　乳糖水和物　１６８２ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 4]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 3.5 mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1682mg
Magnesium stearate 24.3mg
［実施例５］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　クレマスチンフマル酸塩（ダイト製：商品名　クレマスチンフマル酸塩）　１．３４ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６８４．１６ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 5]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 1.34 mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1684.16mg
Magnesium stearate 24.3mg
［実施例６］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　カルビノキサミンマレイン酸塩（金剛化学製：商品名　マレイン酸カルビノキサミン）　７．５ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６７８ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 6]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1678mg
Magnesium stearate 24.3mg
［実施例７］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　カルビノキサミンマレイン酸塩（金剛化学製：商品名　マレイン酸カルビノキサミン）　７．５ｍｇ
　沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６７８ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 7]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1678mg
Magnesium stearate 24.3mg
［実施例８］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例４と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　カルビノキサミンマレイン酸塩（金剛化学製：商品名　マレイン酸カルビノキサミン）　７．５ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　乳糖水和物　１６７８ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 8]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 4.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1678mg
Magnesium stearate 24.3mg
［実施例９］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ジフェニルピラリン塩酸塩（金剛化学製：商品名　塩酸ジフェニルピラリン）４ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６８１．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 9]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Diphenylpyraline hydrochloride (product of Kongo Chemicals: trade name diphenylpyraline hydrochloride) 4mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1681.5mg
Magnesium stearate 24.3mg
［実施例１０］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ジフェニルピラリン塩酸塩（金剛化学製：商品名　塩酸ジフェニルピラリン）４ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６８１．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 10]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Diphenylpyraline hydrochloride (product of Kongo Chemicals: trade name diphenylpyraline hydrochloride) 4mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1681.5mg
Magnesium stearate 24.3mg
［実施例１１］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ブロムヘキシン塩酸塩（山洋化学製：商品名　ブロムヘキシン塩酸塩）１２ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６７３．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 11]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromhexine hydrochloride (trade name: Bromhexine hydrochloride, manufactured by Sanyo Chemical) 12 mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1673.5mg
Magnesium stearate 24.3mg
［実施例１２］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ブロムヘキシン塩酸塩（山洋化学製：商品名　ブロムヘキシン塩酸塩）　１２ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２） ２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６７３．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 12]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 12mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1673.5mg
Magnesium stearate 24.3mg
［実施例１３］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ブロムヘキシン塩酸塩（山洋化学製：商品名　ブロムヘキシン塩酸塩）　１２ｍｇ
　沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６７３．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 13]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 12mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1673.5mg
Magnesium stearate 24.3mg
［実施例１４］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アンブロキソール塩酸塩（静岡カフェイン工業所製：商品名　塩酸アンブロキソール）　４５ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６４０．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 14]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1640.5mg
Magnesium stearate 24.3mg
［実施例１５］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アンブロキソール塩酸塩（静岡カフェイン工業所製：商品名　塩酸アンブロキソール）　４５ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６４０．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 15]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1640.5mg
Magnesium stearate 24.3mg
［実施例１６］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アンブロキソール塩酸塩（静岡カフェイン工業所製：商品名　塩酸アンブロキソール）　４５ｍｇ
　沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６４０．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 16]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1640.5mg
Magnesium stearate 24.3mg
［実施例１７］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアイフェネシン（アルプス薬品製：商品名　グアイフェネシン）２５０ｍｇ
　水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 17]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Guaifenesin (product name: Guaifenesin) 250 mg
Magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例１８］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアイフェネシン（アルプス薬品製：商品名　グアイフェネシン）２５０ｍｇ
　ケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 18]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Guaifenesin (product name: Guaifenesin) 250 mg
Magnesium aluminate silicate (Tonda Pharmaceutical: Brand name Magnesium aluminate) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例１９］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアイフェネシン（アルプス薬品製：商品名　グアイフェネシン）２５０ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 19]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Guaifenesin (product name: Guaifenesin) 250 mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２０］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアイフェネシン（アルプス薬品製：商品名　グアイフェネシン）２５０ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 20]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Guaifenesin (product name: Guaifenesin) 250 mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２１］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアイフェネシン（アルプス薬品製：商品名　グアイフェネシン）２５０ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 21]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Guaifenesin (product name: Guaifenesin) 250 mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２２］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアイフェネシン（アルプス薬品製：商品名　グアイフェネシン）　２５０ｍｇ
　沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 22]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Guaifenesin (product name: Guaifenesin) 250 mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２３］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）２５０ｍｇ
　水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 23]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Potassium guaiacol sulfonate (trade name: Potassium guaiacol sulfonate manufactured by Yonezawa Hamari Chemical Co., Ltd.) 250mg
Magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２４］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）　２５０ｍｇ
　ケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 24]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate) 250mg
Magnesium aluminate silicate (Tonda Pharmaceutical: Brand name Magnesium aluminate) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２５］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）　２５０ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 25]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate)
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２６］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）　２５０ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 26]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate) 250mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２７］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）　２５０ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 27]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate)
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２８］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　グアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）　２５０ｍｇ
　沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１４３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 28]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate)
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1435.5mg
Magnesium stearate 24.3mg
［実施例２９］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
　水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６６１．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 29]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1661.5mg
Magnesium stearate 24.3mg
［実施例３０］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６６１．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 30]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1661.5mg
Magnesium stearate 24.3mg
［実施例３１］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６６１．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 31]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”) 24mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1661.5mg
Magnesium stearate 24.3mg
［実施例３２］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
　沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６６１．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 32]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”) 24mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1661.5mg
Magnesium stearate 24.3mg
［実施例３３］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例４と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）２４ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　乳糖水和物　１６６１．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 33]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 4.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1661.5mg
Magnesium stearate 24.3mg
［実施例３４］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）　６０ｍｇ
　水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６２５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 34]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
Magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1625.5mg
Magnesium stearate 24.3mg
［実施例３５］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）　６０ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６２５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 35]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1625.5mg
Magnesium stearate 24.3mg
［実施例３６］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）　６０ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６２５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 36]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1625.5mg
Magnesium stearate 24.3mg
［実施例３７］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）　６０ｍｇ
　沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１６２５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 37]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1625.5mg
Magnesium stearate 24.3mg
［実施例３８］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例４と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）　６０ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　乳糖水和物　１６２５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 38]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 4.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1625.5mg
Magnesium stearate 24.3mg
［実施例３９］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）　１５０ｍｇ
　水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 39]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Anhydrous caffeine (product name: anhydrous caffeine, manufactured by Shizuoka Caffeine Industry) 150mg
Magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1535.5mg
Magnesium stearate 24.3mg
［実施例４０］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）　１５０ｍｇ
　ケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 40]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Anhydrous caffeine (product name: anhydrous caffeine, manufactured by Shizuoka Caffeine Industry) 150mg
Magnesium aluminate silicate (Tonda Pharmaceutical: Brand name Magnesium aluminate) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1535.5mg
Magnesium stearate 24.3mg
［実施例４１］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）　１５０ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 41]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Anhydrous caffeine (product name: anhydrous caffeine, manufactured by Shizuoka Caffeine Industry) 150mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1535.5mg
Magnesium stearate 24.3mg
［実施例４２］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）１５０ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 42]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1535.5mg
Magnesium stearate 24.3mg
［実施例４３］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）１５０ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 43]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1535.5mg
Magnesium stearate 24.3mg
［実施例４４］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）１５０ｍｇ
　沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 44]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1535.5mg
Magnesium stearate 24.3mg
［実施例４５］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）１５０ｍｇ
　乾燥水酸化アルミニウムゲル（協和化学工業製：商品名　乾燥水酸化アルミニウムゲル）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 45]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg
Dry aluminum hydroxide gel (Kyowa Chemical Industry: trade name Dry aluminum hydroxide gel) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1535.5mg
Magnesium stearate 24.3mg
［実施例４６］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）１５０ｍｇ
　合成ヒドロタルサイト（富田製薬製：商品名　合成ヒドロタルサイト）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５３５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 46]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg
Synthetic hydrotalcite (trade name: Synthetic hydrotalcite, manufactured by Tomita Pharmaceutical) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1535.5mg
Magnesium stearate 24.3mg
［実施例４７］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ブロムワレリル尿素（八代製薬製：商品名　日本薬局方　ブロモバレリル尿素Ｐ）　６００ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１０８５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 47]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromvalerylurea (product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P) 600mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1085.5mg
Magnesium stearate 24.3mg
［実施例４８］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ブロムワレリル尿素（八代製薬製：商品名　日本薬局方　ブロモバレリル尿素Ｐ）　６００ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１０８５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 48]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromvalerylurea (product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P) 600mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1085.5mg
Magnesium stearate 24.3mg
［実施例４９］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ブロムワレリル尿素（八代製薬製：商品名　日本薬局方　ブロモバレリル尿素Ｐ）　６００ｍｇ
　乾燥水酸化アルミニウムゲル（協和化学工業製：商品名　乾燥水酸化アルミニウムゲル）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１０８５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 49]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromvalerylurea (product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P) 600mg
Dry aluminum hydroxide gel (Kyowa Chemical Industry: trade name Dry aluminum hydroxide gel) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1085.5mg
Magnesium stearate 24.3mg
［実施例５０］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ブロムワレリル尿素（八代製薬製：商品名　日本薬局方　ブロモバレリル尿素Ｐ）　６００ｍｇ
　合成ヒドロタルサイト（富田製薬製：商品名　合成ヒドロタルサイト）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１０８５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 50]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromvalerylurea (product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P) 600mg
Synthetic hydrotalcite (trade name: Synthetic hydrotalcite, manufactured by Tomita Pharmaceutical) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1085.5mg
Magnesium stearate 24.3mg
［実施例５１］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アリルイソプロピルアセチル尿素（金剛化学製：商品名　アリプロナール「コンゴー」）　１８０ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５０５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 51]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Allyl isopropyl acetyl urea (product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”) 180 mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1505.5mg
Magnesium stearate 24.3mg
［実施例５２］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アリルイソプロピルアセチル尿素（金剛化学製：商品名　アリプロナール「コンゴー」）　１８０ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５０５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 52]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Allyl isopropyl acetyl urea (product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”) 180 mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1505.5mg
Magnesium stearate 24.3mg
［実施例５３］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アリルイソプロピルアセチル尿素（金剛化学製：商品名　アリプロナール「コンゴー」）　１８０ｍｇ
　乾燥水酸化アルミニウムゲル（協和化学工業製：商品名　乾燥水酸化アルミニウムゲル）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５０５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 53]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Allyl isopropyl acetyl urea (product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”) 180 mg
Dry aluminum hydroxide gel (Kyowa Chemical Industry: trade name Dry aluminum hydroxide gel) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1505.5mg
Magnesium stearate 24.3mg
［実施例５４］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アリルイソプロピルアセチル尿素（金剛化学製：商品名　アリプロナール「コンゴー」）　１８０ｍｇ
　合成ヒドロタルサイト（富田製薬製：商品名　合成ヒドロタルサイト）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１５０５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 54]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Allyl isopropyl acetyl urea (product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”) 180 mg
Synthetic hydrotalcite (trade name: Synthetic hydrotalcite, manufactured by Tomita Pharmaceutical) 200 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1505.5mg
Magnesium stearate 24.3mg
［実施例５５］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　クレマスチンフマル酸塩（ダイト製：商品名　クレマスチンフマル酸塩）　１．３４ｍｇ
　リゾチーム塩酸塩（エーザイ製：商品名　塩化リゾチーム）　９０ｍｇ
　ベラドンナ総アルカロイド　０．３ｍｇ
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
　ノスカピン　４８ｍｇ
　ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）　６０ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）７５ｍｇ
　ベンフォチアミン（ビタミンＢ１誘導体）　２４ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１３６２．８６ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 55]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 1.34 mg
Lysozyme hydrochloride (product of Eisai: trade name lysozyme chloride) 90mg
Belladonna Total Alkaloid 0.3mg
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Noscapine 48mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 75mg
Benfotiamine (vitamin B1 derivative) 24mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1362.86mg
Magnesium stearate 24.3mg
［実施例５６］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アンブロキソール塩酸塩（静岡カフェイン工業所製：商品名　塩酸アンブロキソール）　４５ｍｇ
　ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
　ｄｌ－メチルエフェドリン塩酸塩（アルプス薬品工業製：商品名　日本薬局方　ｄｌ－塩酸メチルエフェドリン末）　６０ｍｇ
　ｄｌ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　マレイン酸クロルフェニラミン）　７．５ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）　７５ｍｇ
　チアミン硝化物（ビタミンＢ１硝酸塩）　２４ｍｇ
　リボフラビン（ビタミンＢ２）　１２ｍｇ
　アスコルビン酸（ビタミンＣ）　５００ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　９３８ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 56]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
dl-chlorpheniramine maleate (manufactured by Kongo Chemicals: trade name chlorpheniramine maleate) 7.5mg
Anhydrous caffeine (Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 75mg
Thiamine nitrate (vitamin B1 nitrate) 24mg
Riboflavin (vitamin B2) 12mg
Ascorbic acid (vitamin C) 500mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 938mg
Magnesium stearate 24.3mg
［実施例５７］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　エテンザミド　２５２ｍｇ
　ブロムワレリル尿素（八代製薬製：商品名　日本薬局方　ブロモバレリル尿素Ｐ）　６００ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）１５０ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　８８３．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 57]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Ethenzamid 252mg
Bromvalerylurea (product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P) 600mg
Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 150mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 883.5mg
Magnesium stearate 24.3mg
［実施例５８］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アリルイソプロピルアセチル尿素（金剛化学製：商品名　アリプロナール「コンゴー」）　１８０ｍｇ
　無水カフェイン（静岡カフェイン工業所製：商品名　無水カフェイン）　２４０ｍｇ
　酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　３００ｍｇ
　ヒドロキシプロピルセルロース　７２．９ｍｇ
　カルメロースカルシウム　２４３ｍｇ
　結晶セルロース　１１６５．５ｍｇ
　ステアリン酸マグネシウム　２４．３ｍｇ [Example 58]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Allyl isopropyl acetyl urea (product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”) 180 mg
Anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 240mg
Magnesium oxide (trade name: Heavy magnesium oxide, manufactured by Tomita Pharmaceutical) 300 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1165.5mg
Magnesium stearate 24.3mg
［実施例５９］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　アリルイソプロピルアセチル尿素（金剛化学製：商品名　アリプロナール「コンゴー」）　１８０ｍｇ
　ブチルスコポラミン臭化物（アルプス薬品工業製：商品名　日本薬局方　ブチルスコポラミン臭化物）　３０ｍｇ
　ケイ酸カルシウム（トクヤマ製：商品名　フローライトＲＥ）　８．１ｍｇ
　トラネキサム酸　４２０ｍｇ
　結晶セルロース　２５．２ｍｇ
　乳糖水和物　２５．２ｍｇ
　ヒドロキシプロピルセルロース　３２．４ｍｇ
　カルメロースカルシウム　２４．３ｍｇ
　クロスポビドン　２４．３ｍｇ
　ステアリン酸マグネシウム　１６．２ｍｇ [Example 59]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Allyl isopropyl acetyl urea (product of Kongo Chemical Co., Ltd., trade name: Alipronal “Congo”) 180 mg
Butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Butyl scopolamine bromide) 30mg
Calcium silicate (product of Tokuyama: trade name FLORITE RE) 8.1mg
Tranexamic acid 420mg
Crystalline cellulose 25.2mg
Lactose hydrate 25.2mg
Hydroxypropylcellulose 32.4mg
Carmellose calcium 24.3mg
Crospovidone 24.3mg
Magnesium stearate 16.2mg
［実施例６０］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ブチルスコポラミン臭化物（アルプス薬品工業製：商品名　日本薬局方　ブチルスコポラミン臭化物）　３０ｍｇ
　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　１００ｍｇ
　結晶セルロース　１９４．７ｍｇ
　乳糖水和物　２００ｍｇ
　ヒドロキシプロピルセルロース　３２．４ｍｇ
　クロスカルメロースナトリウム　２４．３ｍｇ
　含水二酸化ケイ素　８．１ｍｇ
　ステアリン酸マグネシウム　１６．２ｍｇ [Example 60]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Butyl scopolamine bromide) 30mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 100mg
Crystalline cellulose 194.7mg
Lactose hydrate 200mg
Hydroxypropylcellulose 32.4mg
Croscarmellose sodium 24.3mg
Hydrous silicon dioxide 8.1mg
Magnesium stearate 16.2mg
［実施例６１］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ブチルスコポラミン臭化物（アルプス薬品工業製：商品名　日本薬局方　ブチルスコポラミン臭化物）　３０ｍｇ
　ケイ酸カルシウム（トクヤマ製：商品名　フローライトＲＥ）　８．１ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　１００ｍｇ
　結晶セルロース　１７０．４ｍｇ
　乳糖水和物　２００ｍｇ
　ヒドロキシプロピルセルロース　３２．４ｍｇ
　低置換度ヒドロキシプロピルセルロース　２４．３ｍｇ
　クロスポビドン　２４．３ｍｇ
　ステアリン酸マグネシウム　１６．２ｍｇ [Example 61]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Butyl scopolamine bromide) 30mg
Calcium silicate (product of Tokuyama: trade name FLORITE RE) 8.1mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 100 mg
Crystalline cellulose 170.4mg
Lactose hydrate 200mg
Hydroxypropylcellulose 32.4mg
Low substituted hydroxypropylcellulose 24.3mg
Crospovidone 24.3mg
Magnesium stearate 16.2mg
［実施例６２］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ベラドンナエキス（アルプス薬品工業製：商品名　日本薬局方　ベラドンナエキス）　３０ｍｇ
　ケイ酸カルシウム（トクヤマ製：商品名　フローライトＲＥ）　８．１ｍｇ
　無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　１００ｍｇ
　結晶セルロース　１７０．４ｍｇ
　乳糖水和物　２００ｍｇ
　ヒドロキシプロピルセルロース　３２．４ｍｇ
　低置換度ヒドロキシプロピルセルロース　２４．３ｍｇ
　クロスポビドン　２４．３ｍｇ
　ステアリン酸マグネシウム　１６．２ｍｇ [Example 62]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Belladonna extract (trade name: Japanese Pharmacopoeia Belladonna Extract) 30mg
Calcium silicate (product of Tokuyama: trade name FLORITE RE) 8.1mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 100 mg
Crystalline cellulose 170.4mg
Lactose hydrate 200mg
Hydroxypropylcellulose 32.4mg
Low substituted hydroxypropylcellulose 24.3mg
Crospovidone 24.3mg
Magnesium stearate 16.2mg
［実施例６３］
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１と同様の方法により製造した。
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
　ロートエキス（アルプス薬品工業製：商品名　日本薬局方　ロートエキス）　３０ｍｇ　メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　１００ｍｇ
　結晶セルロース　１９４．７ｍｇ
　乳糖水和物　２００ｍｇ
　ヒドロキシプロピルセルロース　３２．４ｍｇ
　クロスカルメロースナトリウム　２４．３ｍｇ
　含水二酸化ケイ素　８．１ｍｇ
　ステアリン酸マグネシウム　１６．２ｍｇ [Example 63]
Tablets containing the following components in 9 tablets (daily dose) were produced in the same manner as in Example 1.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Rohto extract (Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia Roto Extract) 30 mg Magnesium aluminate metasilicate (Fuji Kagaku Kogyo: trade name Neusilin UFL2) 100 mg
Crystalline cellulose 194.7mg
Lactose hydrate 200mg
Hydroxypropylcellulose 32.4mg
Croscarmellose sodium 24.3mg
Hydrous silicon dioxide 8.1mg
Magnesium stearate 16.2mg
［実施例６４］
　実施例１で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 64]
Thirty tablets obtained in Example 1 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例６５］
　実施例２で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 65]
Thirty tablets obtained in Example 2 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例６６］
　実施例３で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 66]
Thirty tablets obtained in Example 3 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例６７］
　実施例４で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 67]
Thirty tablets obtained in Example 4 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例６８］
　実施例５で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 68]
Thirty tablets obtained in Example 5 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例６９］
　実施例６で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 69]
Thirty tablets obtained in Example 6 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７０］
　実施例７で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 70]
Thirty tablets obtained in Example 7 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７１］
　実施例８で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 71]
Thirty tablets obtained in Example 8 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７２］
　実施例９で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 72]
Thirty tablets obtained in Example 9 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７３］
　実施例１０で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 73]
Thirty tablets obtained in Example 10 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７４］
　実施例１１で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 74]
Thirty tablets obtained in Example 11 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７５］
　実施例１２で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 75]
Thirty tablets obtained in Example 12 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７６］
　実施例１３で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 76]
Thirty tablets obtained in Example 13 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７７］
　実施例１４で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 77]
Thirty tablets obtained in Example 14 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７８］
　実施例１５で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 78]
Thirty tablets obtained in Example 15 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例７９］
　実施例１６で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 79]
Thirty tablets obtained in Example 16 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８０］
　実施例１７で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 80]
Thirty tablets obtained in Example 17 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８１］
　実施例１８で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 81]
Thirty tablets obtained in Example 18 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８２］
　実施例１９で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 82]
Thirty tablets obtained in Example 19 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８３］
　実施例２０で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 83]
Thirty tablets obtained in Example 20 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８４］
　実施例２１で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 84]
Thirty tablets obtained in Example 21 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８５］
　実施例２２で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 85]
Thirty tablets obtained in Example 22 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８６］
　実施例２３で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 86]
Thirty tablets obtained in Example 23 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８７］
　実施例２４で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 87]
Thirty tablets obtained in Example 24 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８８］
　実施例２５で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 88]
Thirty tablets obtained in Example 25 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例８９］
　実施例２６で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 89]
Thirty tablets obtained in Example 26 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９０］
　実施例２７で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 90]
Thirty tablets obtained in Example 27 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９１］
　実施例２８で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 91]
Thirty tablets obtained in Example 28 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９２］
　実施例２９で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 92]
Thirty tablets obtained in Example 29 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９３］
　実施例３０で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 93]
Thirty tablets obtained in Example 30 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９４］
　実施例３１で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 94]
Thirty tablets obtained in Example 31 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９５］
　実施例３２で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 95]
30 tablets obtained in Example 32 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９６］
　実施例３３で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 96]
Thirty tablets obtained in Example 33 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９７］
　実施例３４で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 97]
Thirty tablets obtained in Example 34 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９８］
　実施例３５で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 98]
Thirty tablets obtained in Example 35 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例９９］
　実施例３６で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 Example 99
Thirty tablets obtained in Example 36 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１００］
　実施例３７で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 100]
Thirty tablets obtained in Example 37 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１０１］
　実施例３８で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 101]
Thirty tablets obtained in Example 38 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１０２］
　実施例３９で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 102]
Thirty tablets obtained in Example 39 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１０３］
　実施例４０で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 103]
Thirty tablets obtained in Example 40 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１０４］
　実施例４１で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 104]
Thirty tablets obtained in Example 41 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１０５］
　実施例４２で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 105]
Thirty tablets obtained in Example 42 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１０６］
　実施例４３で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 106]
Thirty tablets obtained in Example 43 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１０７］
　実施例４４で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 107]
Thirty tablets obtained in Example 44 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１０８］
　実施例４５で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 108]
Thirty tablets obtained in Example 45 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１０９］
　実施例４６で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 109]
Thirty tablets obtained in Example 46 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１０］
　実施例４７で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 110]
Thirty tablets obtained in Example 47 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１１］
　実施例４８で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 111]
30 tablets obtained in Example 48 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１２］
　実施例４９で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 112]
Thirty tablets obtained in Example 49 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１３］
　実施例５０で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 113]
Thirty tablets obtained in Example 50 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１４］
　実施例５１で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 114]
Thirty tablets obtained in Example 51 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１５］
　実施例５２で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 115]
Thirty tablets obtained in Example 52 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１６］
　実施例５３で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 116]
Thirty tablets obtained in Example 53 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１７］
　実施例５４で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 117]
Thirty tablets obtained in Example 54 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１８］
　実施例５５で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 118]
Thirty tablets obtained in Example 55 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１１９］
　実施例５６で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 119]
Thirty tablets obtained in Example 56 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１２０］
　実施例５７で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 120]
Thirty tablets obtained in Example 57 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１２１］
　実施例５８で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 121]
Thirty tablets obtained in Example 58 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１２２］
　実施例５９で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 122]
Thirty tablets obtained in Example 59 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１２３］
　実施例６０で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 123]
Thirty tablets obtained in Example 60 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１２４］
　実施例６１で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 124]
Thirty tablets obtained in Example 61 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１２５］
　実施例６２で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 125]
Thirty tablets obtained in Example 62 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１２６］
　実施例６３で得た錠剤３０錠及び合成ゼオライト１ｇ（新越化成工業製：商品名　ＭＳ－Ｗ１５０６）をガラス瓶（３Ｋ規格瓶）に入れ、医薬製剤を製した。 [Example 126]
Thirty tablets obtained in Example 63 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.
［実施例１２７］ロキソプロフェンナトリウム水和物とジヒドロコデインリン酸塩とが実質的に接しない製剤
　ロキソプロフェンナトリウム水和物６８．１ｇ（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）、２９．２ｇのマクロゴール６０００（日本油脂製：商品名　マクロゴール６０００Ｐ）及びトウモロコシデンプン２４．３ｇ（日澱化学製：商品名　トウモロコシデンプンＳＴ－Ｃ）を６５℃湯浴上のガラスビーカー中にて撹拌し、次いで冷却した後、１８号篩で篩過して、造粒物を得た。得られた造粒物にジヒドロコデインリン酸塩８ｇ（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）、カルメロースカルシウム８１ｇ（五徳薬品製：商品名　ＥＣＧ５０５）、乳糖水和物５２４．６ｇ（ＤＭＶ製：商品名　乳糖２００Ｍ）、水酸化マグネシウム６６．７ｇ（協和化学工業製：商品名　キョーワスイマグ）及びステアリン酸マグネシウム８．１ｇ（太平化学工業製：商品名　ステアリン酸マグネシウム（植物性））を混合した後、直径８．５ｍｍの杵を取り付けた打錠機（畑鉄工所製：ＨＴ－ＡＰ１８ＳＳ型）を用いて打錠し、１錠の質量が２７０ｍｇの錠剤を得た。 [Example 127] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact with each other Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29 Stir 2 g of macrogol 6000 (manufactured by NOF Corporation: trade name Macrogol 6000P) and 24.3 g of corn starch (manufactured by Nissho Chemical Co., Ltd .: trade name corn starch ST-C) in a glass beaker on a 65 ° C. water bath. Then, after cooling, it was sieved with No. 18 sieve to obtain a granulated product. To the resulting granulated product, dihydrocodeine phosphate 8 g (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”), carmellose calcium 81 g (manufactured by Gotoku Pharmaceutical: trade name ECG505), lactose hydrate 524.6 g ( Made by DMV: Trade name Lactose 200M), Magnesium hydroxide 66.7 g (Kyowa Chemical Industry: trade name Kyowasui Mug) and Magnesium stearate 8.1 g (Taihei Chemical Industry: trade name Magnesium stearate (vegetable)) After mixing, tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a punch with a diameter of 8.5 mm to obtain a tablet having a mass of 270 mg.
［実施例１２８］ロキソプロフェンナトリウム水和物とジヒドロコデインリン酸塩とが実質的に接しない製剤
　９錠中に以下の成分・分量を有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５７３．９ｍｇ
メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 128] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact Tablets having the following ingredients and amounts in 9 tablets were produced in the same manner as in Example 117.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg
［実施例１２９］ロキソプロフェンナトリウム水和物とジヒドロコデインリン酸塩とが実質的に接しない製剤
　９錠中に以下の成分・分量を有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
硬化油（川研ファインケミカル製：商品名　Ｋ－３ワックス－２００）　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５７３．９ｍｇ
無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 129] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate do not substantially contact each other 9 tablets in 9 tablets were produced in the same manner as in Example 117.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Hardened oil (manufactured by Kawaken Fine Chemicals: Trade name K-3 Wax-200) 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg
［実施例１３０］ロキソプロフェンナトリウム水和物とジヒドロコデインリン酸塩とが実質的に接しない製剤
　９錠中に以下の成分・分量を有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５７３．９ｍｇ
沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 130] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact Nine tablets were produced in the same manner as in Example 117, but with the following ingredients and amounts.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Magnesium stearate 24.3mg
［実施例１３１］ロキソプロフェンナトリウム水和物とジヒドロコデインリン酸塩とが実質的に接しない製剤
　９錠中に以下の成分・分量を有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５７３．９ｍｇ
酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 131] Preparation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact Nine tablets were prepared in the same manner as in Example 117, with the following ingredients and amounts.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg
［実施例１３２］ロキソプロフェンナトリウム水和物とジヒドロコデインリン酸塩とが実質的に接しない製剤
　９錠中に以下の成分・分量を有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ジヒドロコデインリン酸塩（塩野義製薬製：商品名　リン酸ジヒドロコデイン「シオノギ」）　２４ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５７３．９ｍｇ
酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 132] Preparation in which loxoprofen sodium hydrate and dihydrocodeine phosphate do not substantially come into contact Tablets having the following components and amounts in 9 tablets were produced in the same manner as in Example 117.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg
［実施例１３３］ロキソプロフェンナトリウム水和物とｄ－クロルフェニラミンマレイン酸塩とが実質的に接しない製剤
　９錠中に以下の成分・分量を有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）　３．５ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５９４．４ｍｇ
メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 133] Formulation in which loxoprofen sodium hydrate and d-chlorpheniramine maleate are not substantially in contact with each other Nine tablets were prepared by the same method as in Example 117. did.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 3.5 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1594.4mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg
［実施例１３４］ロキソプロフェンナトリウム水和物とｄ－クロルフェニラミンマレイン酸塩とが実質的に接しない製剤
　９錠中に以下の成分・分量を有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ｄ－クロルフェニラミンマレイン酸塩（金剛化学製：商品名　Ｄ－マレイン酸クロルフェニラミン）　３．５ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５９４．４ｍｇ
酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 134] Formulation in which loxoprofen sodium hydrate and d-chlorpheniramine maleate are not substantially in contact with each other Nine tablets were prepared by the same method as in Example 117. did.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
d-Chlorpheniramine maleate (trade name: D-chlorpheniramine maleate) 3.5 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1594.4mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg
［実施例１３５］ロキソプロフェンナトリウム水和物とクレマスチンフマル酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
クレマスチンフマル酸塩（ダイト製：商品名　クレマスチンフマル酸塩）　１．３４ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５９６．６ｍｇ
無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 135] Preparation in which loxoprofen sodium hydrate and clemastine fumarate are not substantially in contact Nine tablets (daily dose) containing the following ingredients were produced in the same manner as in Example 117 did.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 1.34 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1596.6mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg
［実施例１３６］ロキソプロフェンナトリウム水和物とカルビノキサミンマレイン酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
カルビノキサミンマレイン酸塩（金剛化学製：商品名　マレイン酸カルビノキサミン）　　７．５ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５９０．４ｍｇ
無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 136] Preparation in which loxoprofen sodium hydrate and carbinoxamine maleate are not substantially in contact with each other Nine tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured by.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1590.4mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg
［実施例１３７］ロキソプロフェンナトリウム水和物とカルビノキサミンマレイン酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
カルビノキサミンマレイン酸塩（金剛化学製：商品名　マレイン酸カルビノキサミン）　　７．５ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５９０．４ｍｇ
沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 137] Formulation in which loxoprofen sodium hydrate and carbinoxamine maleate are not substantially in contact 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured by.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1590.4mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Magnesium stearate 24.3mg
［実施例１３８］ロキソプロフェンナトリウム水和物とカルビノキサミンマレイン酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
カルビノキサミンマレイン酸塩（金剛化学製：商品名　マレイン酸カルビノキサミン）　　７．５ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５９０．４ｍｇ
酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 138] Formulation in which loxoprofen sodium hydrate and carbinoxamine maleate are not substantially in contact 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured by.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1590.4mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg
［実施例１３９］ロキソプロフェンナトリウム水和物とジフェニルピラリン塩酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ジフェニルピラリン塩酸塩（金剛化学製：商品名　塩酸ジフェニルピラリン）　４ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５９３．９ｍｇ
無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 139] Preparation in which loxoprofen sodium hydrate and diphenylpyraline hydrochloride are not substantially in contact with each other Nine tablets (daily dose) containing the following ingredients were prepared in the same manner as in Example 117 did.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Diphenylpyraline hydrochloride (product of Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 4mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1593.9mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg
［実施例１４０］ロキソプロフェンナトリウム水和物とジフェニルピラリン塩酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ジフェニルピラリン塩酸塩（金剛化学製：商品名　塩酸ジフェニルピラリン）　４ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５９３．９ｍｇ
メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 140] Preparation in which loxoprofen sodium hydrate and diphenylpyraline hydrochloride are not substantially in contact with each other 9 tablets (daily dose) containing the following ingredients were prepared in the same manner as in Example 117 did.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Diphenylpyraline hydrochloride (product of Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 4mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1593.9mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg
［実施例１４１］ロキソプロフェンナトリウム水和物とブロムヘキシン塩酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ブロムヘキシン塩酸塩（山洋化学製：商品名　ブロムヘキシン塩酸塩）　１２ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５８５．９ｍｇ
無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 141] Preparation in which loxoprofen sodium hydrate and bromhexine hydrochloride are not substantially in contact Nine tablets (daily dose) were prepared in the same manner as in Example 117. .
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 12mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1585.9mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg
［実施例１４２］ロキソプロフェンナトリウム水和物とブロムヘキシン塩酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ブロムヘキシン塩酸塩（山洋化学製：商品名　ブロムヘキシン塩酸塩）　１２ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５８５．９ｍｇ
メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 142] Preparation in which loxoprofen sodium hydrate and bromhexine hydrochloride are not substantially in contact Nine tablets (daily dose) containing the following ingredients were produced in the same manner as in Example 117. .
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 12mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1585.9mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg
［実施例１４３］ロキソプロフェンナトリウム水和物とブロムヘキシン塩酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ブロムヘキシン塩酸塩（山洋化学製：商品名　ブロムヘキシン塩酸塩）　１２ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５８５．９ｍｇ
沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 143] Formulation in which loxoprofen sodium hydrate and bromhexine hydrochloride are not substantially in contact Nine tablets (daily dose) were prepared in the same manner as in Example 117. .
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 12mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1585.9mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Magnesium stearate 24.3mg
［実施例１４４］ロキソプロフェンナトリウム水和物とアンブロキソール塩酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
アンブロキソール塩酸塩（静岡カフェイン工業所製：商品名　塩酸アンブロキソール）　４５ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５５２．９ｍｇ
無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム）　　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 144] Formulation in which loxoprofen sodium hydrate and ambroxol hydrochloride do not substantially contact each other 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1552.9mg
Anhydrous calcium hydrogen phosphate (Kyowa Chemical Industry, trade name: anhydrous calcium hydrogen phosphate) 200mg
Magnesium stearate 24.3mg
［実施例１４５］ロキソプロフェンナトリウム水和物とアンブロキソール塩酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
アンブロキソール塩酸塩（静岡カフェイン工業所製：商品名　塩酸アンブロキソール）　４５ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５５２．９ｍｇ
メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 145] Formulation in which loxoprofen sodium hydrate and ambroxol hydrochloride do not substantially contact each other 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1552.9mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg
［実施例１４６］ロキソプロフェンナトリウム水和物とアンブロキソール塩酸塩とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
アンブロキソール塩酸塩（静岡カフェイン工業所製：商品名　塩酸アンブロキソール）　４５ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１５５２．９ｍｇ
沈降炭酸カルシウム（三共精粉製：商品名　沈降炭酸ＣＡ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 146] Formulation in which loxoprofen sodium hydrate and ambroxol hydrochloride do not substantially contact each other 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1552.9mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Magnesium stearate 24.3mg
［実施例１４７］ロキソプロフェンナトリウム水和物とグアヤコールスルホン酸カリウムとが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
グアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）　２５０ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１３４７．９ｍｇ
水酸化マグネシウム（協和化学工業製：商品名　キョーワスイマグ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 147] Formulation in which loxoprofen sodium hydrate and potassium guaiacol sulfonate are not substantially in contact Nine tablets (daily dose) containing the following ingredients were produced in the same manner as in Example 117 did.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate)
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1347.9mg
Magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg
Magnesium stearate 24.3mg
［実施例１４８］ロキソプロフェンナトリウム水和物とグアヤコールスルホン酸カリウムとが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
グアヤコールスルホン酸カリウム（米沢浜理薬品工業製：商品名　グアヤコールスルホン酸カリウム）　２５０ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１３４７．９ｍｇ
ケイ酸アルミン酸マグネシウム（富田製薬製：商品名　ケイ酸アルミン酸マグネシウム）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 148] Formulation in which loxoprofen sodium hydrate and potassium guaiacol sulfonate are not substantially in contact Nine tablets (daily dose) are prepared in the same manner as in Example 117. did.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Chemical Co., Ltd .: trade name potassium guaiacol sulfonate)
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1347.9mg
Magnesium aluminate silicate (Tonda Pharmaceutical: Brand name Magnesium aluminate) 200mg
Magnesium stearate 24.3mg
［実施例１４９］ロキソプロフェンナトリウム水和物と安息香酸ナトリウムカフェインとが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
安息香酸ナトリウムカフェイン（静岡カフェイン製：商品名　安息香酸ナトリウムカフェイン）　３００ｍｇ
マクロゴール６０００　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　１２９７．９ｍｇ
無水リン酸水素カルシウム（協和化学工業製：商品名　無水リン酸水素カルシウム　ＧＳ－Ｈ）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 149] Formulation in which loxoprofen sodium hydrate and sodium caffeine benzoate do not substantially contact each other 9 tablets (daily dose) containing the following ingredients in the same manner as in Example 117 Manufactured.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Sodium benzoate caffeine (manufactured by Shizuoka Caffeine: trade name sodium benzoate caffeine) 300mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1297.9mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg
［実施例１５０］ロキソプロフェンナトリウム水和物とブロムワレリル尿素とが実質的に接しない製剤
　９錠（１日量）中に以下の成分を含有する錠剤を、実施例１１７と同様の方法により製造した。
ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）　２０４．３ｍｇ
ブロムワレリル尿素（八代製薬製：商品名　日本薬局方　ブロモバレリル尿素Ｐ）　６００ｍｇ
硬化油　８７．６ｍｇ
トウモロコシデンプン　７２．９ｍｇ
カルメロースカルシウム　２４３ｍｇ
乳糖水和物　９９７．９ｍｇ
酸化マグネシウム（富田製薬製：商品名　重質酸化マグネシウム）　２００ｍｇ
ステアリン酸マグネシウム　２４．３ｍｇ [Example 150] Preparation in which loxoprofen sodium hydrate and bromvaleryl urea do not substantially contact each other In 9 tablets (daily dose), tablets containing the following components were produced in the same manner as in Example 117.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Bromvalerylurea (product of Yatsushiro Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Bromovaleryl Urea P) 600mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 997.9mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg
［実施例１５１］ロキソプロフェンナトリウム水和物とブチルスコポラミン臭化物とが実質的に接しない製剤
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２０４．３質量部、ケイ酸カルシウム（トクヤマ製：商品名　フローライトＲＥ）８．１質量部、ヒドロキシプロピルセルロース１６．２質量部、カルボキシメチルスターチナトリウム２４．３質量部及び結晶セルロース５０．４質量部を混合し、精製水を用いて練合し、造粒した後、整粒して造粒物を得た。一方、ブチルスコポラミン臭化物（アルプス薬品工業製：商品名　日本薬局方　ブチルスコポラミン臭化物）３０質量部、トラネキサム酸７５０質量部、ヒドロキシプロピルセルロース１６．２質量部、カルメロースカルシウム２４．３質量部及び乳糖水和物６０質量部を混合し、エタノールを用いて練合し、造粒した後、整粒して造粒物を得た。得られた２種類の造粒物にステアリン酸マグネシウム１６．２質量部を加えて混合し、打錠用顆粒を得た。
　得られた打錠用顆粒を打錠し、ロキソプロフェンナトリウム水和物とブチルスコポラミン臭化物とが実質的に接しない錠剤を得た。 [Example 151] Formulation in which loxoprofen sodium hydrate and butylscopolamine bromide are not substantially in contact with each other Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 parts by mass, Calcium silicate (manufactured by Tokuyama: trade name FLORITE RE) 8.1 parts by mass, 16.2 parts by mass of hydroxypropylcellulose, 24.3 parts by mass of sodium carboxymethyl starch and 50.4 parts by mass of crystalline cellulose are mixed and purified After kneading and granulating with water, the granules were sized to obtain a granulated product. On the other hand, butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia butyl scopolamine bromide) 30 parts by mass, tranexamic acid 750 parts by mass, hydroxypropylcellulose 16.2 parts by mass, carmellose calcium 24.3 parts by mass and lactose water 60 parts by mass of a Japanese product 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 granule for tableting was tableted to obtain a tablet in which loxoprofen sodium hydrate and butyl scopolamine bromide were not substantially in contact with each other.
［実施例１５２］ロキソプロフェンナトリウム水和物とブチルスコポラミン臭化物とが実質的に接しない製剤
　ロキソプロフェンナトリウム水和物（大和薬品工業製：商品名　日本薬局方　ロキソプロフェンナトリウム水和物）２０４．３質量部、ヒドロキシプロピルセルロース１６．２質量部、クロスカルメロースナトリウム２４．３質量部、軽質無水ケイ酸８．１質量部及び結晶セルロース６５．２質量部を混合し、精製水を用いて練合し、造粒した後、整粒して造粒物を得た。一方、ブチルスコポラミン臭化物（アルプス薬品工業製：商品名　日本薬局方　ブチルスコポラミン臭化物）３０質量部、メタケイ酸アルミン酸マグネシウム（富士化学工業製：商品名　ノイシリンＵＦＬ２）１００質量部、トラネキサム酸７５０質量部、ヒドロキシプロピルセルロース１６．２質量部、クロスカルメロースナトリウム２４．３質量部及び乳糖水和物６質量部を混合し、エタノールを用いて練合し、造粒した後、整粒して造粒物を得た。得られた２種類の造粒物にステアリン酸マグネシウム１６．２質量部を加えて混合し、打錠用顆粒を得た。
　得られた打錠用顆粒を打錠し、ロキソプロフェンナトリウム水和物とブチルスコポラミン臭化物とが実質的に接しない錠剤を得た。 [Example 152] Formulation in which loxoprofen sodium hydrate and butyl scopolamine bromide are not substantially in contact with each other Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 parts by mass, 16.2 parts by mass of hydroxypropylcellulose, 24.3 parts by mass of croscarmellose sodium, 8.1 parts by mass of light anhydrous silicic acid and 65.2 parts by mass of crystalline cellulose were mixed and kneaded using purified water. After granulation, the granules were sized to obtain a granulated product. On the other hand, butyl scopolamine bromide (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia butyl scopolamine bromide) 30 parts by mass, magnesium metasilicate aluminate (trade name: Neusilin UFL2) 100 parts by mass, tranexamic acid 750 parts by mass, 16.2 parts by mass of hydroxypropylcellulose, 24.3 parts by mass of croscarmellose sodium and 6 parts by mass of lactose hydrate are mixed, kneaded using ethanol, granulated, and then granulated and granulated. Got. 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 granule for tableting was tableted to obtain a tablet in which loxoprofen sodium hydrate and butyl scopolamine bromide were not substantially in contact with each other.
　本発明によれば、ロキソプロフェン又はその塩と相互作用性成分との相互作用を抑制できる。従って、保存安定性が優れた、ロキソプロフェン又はその塩、及び相互作用性成分を含む医薬組成物を提供することができる。 According to the present invention, the interaction between loxoprofen or a salt thereof and an interactive component can be suppressed. Therefore, it is possible to provide a pharmaceutical composition comprising loxoprofen or a salt thereof and an interactive component, which has excellent storage stability.

Claims (10)

  1. 　次の成分（Ａ）、（Ｂ）及び（Ｃ）：
    （Ａ）ロキソプロフェン又はその塩
    （Ｂ）次の成分（Ｂ－１）～（Ｂ－１０）からなる群より選ばれる１種又は２種以上
    　（Ｂ－１）下記一般式（１）
    Figure JPOXMLDOC01-appb-C000001
     ［式（１）中、Ｘは単結合又は酸素原子を示し、Ｙはメチン基又は窒素原子を示し、Ｒ１は水素原子、水酸基又はアルキル基を示し、Ｒ２は置換基を有していてもよい環状アミノ基、又は置換基を有していてもよいアミノアルキル基を示し、Ｒ３は水素原子又はハロゲン原子を示す。］
    で表される化合物又はその塩
    　　　（Ｂ－２）下記一般式（２）
    Figure JPOXMLDOC01-appb-C000002
     ［式（２）中、Ｒ４は水素原子又はメチル基を示し、Ｒ５は水素原子又は水酸基を示す。］
    で表される化合物又はその塩
    　　　（Ｂ－３）下記一般式（３）
    Figure JPOXMLDOC01-appb-C000003
     ［式（３）中、Ｒ６はアルキル基又は置換基を有していてもよいアルコキシ基を示し、Ｒ７は水素原子又はスルホ基を示す。なお、式（３）中のフェノール性水酸基はエーテル化されていてもよい。］
    で表される化合物又はその塩
    　（Ｂ－４）リゾチーム又はその塩
    　（Ｂ－５）コデイン類
    　（Ｂ－６）エフェドリン類
    　（Ｂ－７）デキストロメトルファン又はその塩
    　（Ｂ－８）キサンチン誘導体
    　（Ｂ－９）イソバレリル尿素誘導体
    　（Ｂ－１０）トロパンアルカロイド類
    （Ｃ）酸中和能を有する塩基性化合物
    を含有する医薬組成物。     The following components (A), (B) and (C):
    (A) Loxoprofen or a salt thereof (B) One or more selected from the group consisting of the following components (B-1) to (B-10) (B-1) The following general formula (1)
    Figure JPOXMLDOC01-appb-C000001
     [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group, and R 2 has a substituent. A cyclic amino group which may be substituted, or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom. ]
    (B-2) The following general formula (2)
    Figure JPOXMLDOC01-appb-C000002
     [In the formula (2), R 4 represents a hydrogen atom or a methyl group, and R 5 represents a hydrogen atom or a hydroxyl group. ]
    (B-3) The following general formula (3)
    Figure JPOXMLDOC01-appb-C000003
     [In Formula (3), R 6 represents an alkyl group or an alkoxy group which may have a substituent, and R 7 represents a hydrogen atom or a sulfo group. In addition, the phenolic hydroxyl group in Formula (3) may be etherified. ]
    (B-4) Lysozyme or a salt thereof (B-5) Codeine (B-6) Ephedrine (B-7) Dextromethorphan or a salt thereof (B-8) Xanthine derivative B-9) Isovaleryl urea derivative (B-10) A pharmaceutical composition comprising a tropane alkaloid (C) a basic compound having acid neutralizing ability.
  2. 　成分（Ｂ）が、次の成分からなる群より選ばれる１種又は２種以上
    （Ｂ－１－１）クロルフェニラミン又はその塩、（Ｂ－１－２）クレマスチン又はその塩、（Ｂ－１－３）カルビノキサミン又はその塩、（Ｂ－１－４）ジフェニルピラリン又はその塩、（Ｂ－２－１）ブロムヘキシン又はその塩、（Ｂ－２－２）アンブロキソール又はその塩、（Ｂ－３－１）グアヤコール誘導体又はその塩、（Ｂ－３－２）クレゾール誘導体又はその塩、（Ｂ－４）リゾチーム又はその塩、（Ｂ－５）コデイン類、（Ｂ－６－１）エフェドリン、ノルエフェドリン及びメチルエフェドリン並びにこれらの塩からなる群より選ばれる１種以上、（Ｂ－７）デキストロメトルファン又はその塩、（Ｂ－８－１）カフェイン、（Ｂ－９－１）ブロムワレリル尿素及びアリルイソプロピルアセチル尿素からなる群より選ばれる１種以上、（Ｂ－１０－１）ダツラエキス、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ベラドンナエキス、ロートコン総アルカロイドクエン酸塩、ロートエキス及びブチルスコポラミン臭化物からなる群より選ばれる１種以上
    である、請求項１記載の医薬組成物。     Component (B) is one or more selected from the group consisting of the following components (B-1-1) chlorpheniramine or a salt thereof, (B-1-2) clemastine or a salt thereof, (B- 1-3) Carbinoxamine or a salt thereof, (B-1-4) Diphenylpyraline or a salt thereof, (B-2-1) Bromhexine or a salt thereof, (B-2-2) Ambroxol or a salt thereof, (B 3-1) Guayacol derivative or salt thereof, (B-3-2) Cresol derivative or salt thereof, (B-4) Lysozyme or salt thereof, (B-5) Codeine, (B-6-1) Ephedrine , Norephedrine and methylephedrine and one or more selected from the group consisting of these salts, (B-7) dextromethorphan or a salt thereof, (B-8-1) caffeine, (B-9-1) bromovaleryl urea One or more selected from the group consisting of allyl isopropylacetylurea, (B-10-1) duck extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, rotcon total alkaloid citrate, funnel extract and butyl scopolamine bromide The pharmaceutical composition according to claim 1, which is at least one selected from the group consisting of more than one.
  3. 　成分（Ｂ）が、次の成分からなる群より選ばれる１種又は２種以上
    （Ｂ－１－１）クロルフェニラミン又はその塩、（Ｂ－１－２）クレマスチン又はその塩、（Ｂ－１－４）ジフェニルピラリン又はその塩、（Ｂ－２－１）ブロムヘキシン又はその塩、（Ｂ－２－２）アンブロキソール又はその塩、（Ｂ－３－１）グアヤコール誘導体又はその塩、（Ｂ－３－２）クレゾール誘導体又はその塩、（Ｂ－４）リゾチーム又はその塩、（Ｂ－５）コデイン類、（Ｂ－７）デキストロメトルファン又はその塩、（Ｂ－９－１）ブロムワレリル尿素及びアリルイソプロピルアセチル尿素からなる群より選ばれる１種以上、（Ｂ－１０－１－１）ブチルスコポラミン臭化物
    である、請求項１又は２記載の医薬組成物。     Component (B) is one or more selected from the group consisting of the following components (B-1-1) chlorpheniramine or a salt thereof, (B-1-2) clemastine or a salt thereof, (B- 1-4) diphenylpyrine or a salt thereof, (B-2-1) bromohexine or a salt thereof, (B-2-2) ambroxol or a salt thereof, (B-3-1) a guaiacol derivative or a salt thereof, B-3-2) Cresol derivative or salt thereof, (B-4) lysozyme or salt thereof, (B-5) codeine, (B-7) dextromethorphan or salt thereof, (B-9-1) bromovaleryl The pharmaceutical composition according to claim 1 or 2, which is one or more selected from the group consisting of urea and allylisopropylacetylurea, (B-10-1-1) butyl scopolamine bromide.
  4. 　成分（Ｂ）が、コデイン類である、請求項１～３のいずれか１項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3, wherein the component (B) is a codeine.
  5. 　成分（Ｃ）が、アルカリ土類金属及び／又は土類金属系塩基性無機化合物、アルカリ金属系塩基性無機化合物、アミン系塩基性無機化合物、アルカリ土類金属及び／又は土類金属系塩基性有機化合物、アルカリ金属系塩基性有機化合物並びにアミン系塩基性有機化合物からなる群より選ばれる１種又は２種以上である、請求項１～４のいずれか１項記載の医薬組成物。 Component (C) is alkaline earth metal and / or earth metal basic inorganic compound, alkali metal basic inorganic compound, amine basic inorganic compound, alkaline earth metal and / or earth metal basic The pharmaceutical composition according to any one of claims 1 to 4, which is one or more selected from the group consisting of organic compounds, alkali metal basic organic compounds, and amine basic organic compounds.
  6. 　成分（Ｃ）が、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウムアルミニウム、酸化マグネシウム、水酸化マグネシウム、水酸化マグネシウム・硫酸アルミニウムカリウムの共沈生成物、炭酸マグネシウム、合成ヒドロタルサイト、メタケイ酸アルミン酸マグネシウム、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、合成ケイ酸アルミニウム・ヒドロキシプロピルスターチ・結晶セルロース、水酸化アルミナマグネシウム、水酸化アルミニウムゲル、水酸化アルミニウム・炭酸水素ナトリウム共沈生成物、水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲル、水酸化アルミニウム・炭酸マグネシウム・炭酸カルシウム共沈生成物、ベントナイト、ケイ酸カルシウム、炭酸カルシウム、沈降炭酸カルシウム、リン酸水素カルシウム、無水リン酸水素カルシウム、炭酸水素ナトリウム、アルジオキサ、ジヒドロキシアルミニウムアミノアセテート、スクラルファート水和物、烏賊骨、石決明及びボレイからなる群より選ばれる１種又は２種以上である、請求項１～５のいずれか１項記載の医薬組成物。 Ingredient (C) is magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide and potassium aluminum sulfate coprecipitation product, magnesium carbonate, synthetic hydrotalcite, metasilica Magnesium aluminate, dry aluminum hydroxide gel, synthetic aluminum silicate, synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose, magnesium hydroxide alumina, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate 1 or more selected from the group consisting of bismuth, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sodium hydrogen carbonate, aldioxa, dihydroxyaluminum aminoacetate, sucralfate hydrate, bandit bone, stone decision and borei The pharmaceutical composition according to any one of claims 1 to 5.
  7. 　成分（Ｃ）が、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、ケイ酸カルシウム、酸化マグネシウム、水酸化マグネシウム、沈降炭酸カルシウム、無水リン酸水素カルシウム及びメタケイ酸アルミン酸マグネシウムからなる群より選ばれる１種又は２種以上である、請求項１～６のいずれか１項記載の医薬組成物。 Component (C) is selected from the group consisting of magnesium aluminate silicate, magnesium silicate, calcium silicate, magnesium oxide, magnesium hydroxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate and magnesium aluminate metasilicate Alternatively, the pharmaceutical composition according to any one of claims 1 to 6, wherein there are two or more kinds.
  8. 　次の成分（Ａ）、（Ｂ）及び（Ｃ）：
    （Ａ）ロキソプロフェン又はその塩
    （Ｂ）コデイン、ジヒドロコデイン及びこれらの塩並びにこれらの溶媒和物からなる群より選ばれる１種以上
    （Ｃ）ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、ケイ酸カルシウム、酸化マグネシウム、水酸化マグネシウム、沈降炭酸カルシウム、無水リン酸水素カルシウム及びメタケイ酸アルミン酸マグネシウムからなる群より選ばれる１種又は２種以上
    を含有する医薬組成物。     The following components (A), (B) and (C):
    (A) loxoprofen or a salt thereof (B) one or more selected from the group consisting of codeine, dihydrocodeine and salts thereof and solvates thereof (C) magnesium aluminate silicate, magnesium silicate, calcium silicate, oxidation A pharmaceutical composition comprising one or more selected from the group consisting of magnesium, magnesium hydroxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate and magnesium aluminate metasilicate.
  9. 　固形製剤である、請求項１～８のいずれか１項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 8, which is a solid preparation.
  10. 　剤形が、錠剤、カプセル剤、丸剤、顆粒剤、散剤又は細粒剤である、請求項１～９のいずれか１項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, wherein the dosage form is a tablet, capsule, pill, granule, powder or fine granule.
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