JP2011116751A - Loxoprofen-containing pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable pharmaceutical composition containing loxoprofen or a salt thereof and a compound represented by formula (I) or a salt thereof. <P>SOLUTION: The pharmaceutical composition contains loxoprofen or a salt thereof, the compound represented by formula (I) (wherein R<SP>1</SP>is hydrogen atom or methyl group; and R<SP>2</SP>is hydrogen atom or hydroxyl group) or a salt thereof and a xanthine derivative. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition comprising 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).

  Loxoprofen has been studied for combining with various drugs because of its excellent pharmacological action. Examples of the action obtained by the combination include, for example, an anti-inflammatory / analgesic / antipyretic effect-enhancing action (Patent Document 1), carbinoxamine maleate, chlorpheniramine maleate, Examples include nasal congestion ameliorating action by combining with ketotifen fumarate, mequitazine and epinastine hydrochloride (Patent Document 2), goblet cell hyperplasia suppressing action by combining with azelastine hydrochloride and mequitazine (Patent Document 3), etc. .

  Further, it is known that loxoprofen enhances the antihistamine action of chlorpheniramine maleate and clemastine fumarate (Patent Document 4).

  On the other hand, bromhexine has the following formula (II)

Bromhexine hydrochloride has an expectorant action based on the viscosity-adjusting action of diluting mucus by promoting secretion of the respiratory tract mucosa. For medical use, acute and chronic bronchitis, pneumoconiosis, etc. It is used for the expectoration. In addition, bromhexine hydrochloride is approved as a switch OTC drug, and is a drug used for general cold medicine and antitussive expectorant (Non-patent Document 2).

  Ambroxol has the following formula (III)

Is known as an active metabolite of the above bromhexine, which is an expectorant component, and is also called a mucosal lubricating component. For medical use, it is used for expectoration such as acute and chronic bronchitis and pneumoconiosis. Ambroxol hydrochloride is a drug that is approved as a switch OTC drug and is also used for general cold medicine (Non-patent Document 3).

  Further, by combining loxoprofen with bromhexine hydrochloride or ambroxol hydrochloride, an effect of enhancing the effect on cough symptoms (Patent Document 5) and an inhibitory effect on goblet cell hyperplasia (Patent Document 6), and loxoprofen with bromhexine hydrochloride There are known anti-inflammatory, analgesic, antipyretic effects, and the like (Patent Document 4).

  In the said patent document, the combination of a loxoprofen and various drugs is examined, and the formulation example which combined the loxoprofen and various drugs is described. However, it is not known whether or not an interaction that affects the storage stability of these compounds occurs between loxoprofen or a salt thereof and bromhexine or a salt thereof or ambroxol or a salt thereof.

  Further, as xanthine derivatives, caffeine, theophylline, paraxanthine, theobromine, aminophylline, diprofylline, proxyphylline, etc. are known. It is a drug used for antipyretic analgesics, general cold medicines, antitussive expectorants and the like (Non-patent Document 4). Theophylline exhibits smooth muscle relaxing action, central excitatory action, cardiotonic / diuretic action, and the like, and is a drug used for antitussive expectorant and antipruritic drug. 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 5). Proxyphyrin also shows the same action as theophylline (Non-patent Document 6), and paraxanthine and theobromine show the same action.

In addition, tablets containing caffeine or aminophylline and loxoprofen are known (Patent Documents 7, 8, and 9).
However, there is no known pharmaceutical composition containing loxoprofen or a salt thereof, bromhexine or a salt thereof and / or ambroxol or a salt thereof, and a xanthine derivative.

Japanese Patent Laid-Open No. 11-139971 JP 2001-199882 A JP 2008-169193 A JP 2000-143505 A JP 2001-172175 A JP 2008-13542 A JP 2006-52210 A International Publication No. 2004/050110 JP 2007-314517 A

OTC Handbook 2008-09 Academic Information Distribution Center 505-506 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 292 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 235 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. pp. 198-199 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Pages 292-294 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 688

The present inventors first examined the storage stability when loxoprofen or a salt thereof and bromhexine or a salt thereof, or loxoprofen or a salt thereof and ambroxol or a salt thereof were combined, respectively. When loxoprofen or a salt thereof and bromhexine or a salt thereof or ambroxol or a salt thereof are mixed and stored, surprisingly, an interaction occurs between these compounds, and this interaction causes discoloration, solidification, etc. And found that there is a problem with stability.
Accordingly, an object of the present invention is to provide loxoprofen or a salt thereof and the following general formula (I):

[In Formula (I), R ¹ represents a hydrogen atom or a methyl group, and R ² represents a hydrogen atom or a hydroxyl group. ]
It is providing the stable pharmaceutical composition containing the compound (henceforth a compound (I)) represented by these, or its salt.

By the way, the present inventors separately examined the storage stability of a solid preparation containing loxoprofen or a salt thereof and a xanthine derivative. As a result, when loxoprofen or a salt thereof and a xanthine derivative were mixed and stored, an interaction occurred between these compounds, and the mixture solidified by this interaction, resulting in a problem in stability.
However, the inventors of the present invention further studied to solve the above-mentioned problem. As a result, the xanthine derivative that produces an interaction with loxoprofen or a salt thereof as described above was converted into loxoprofen or a salt thereof and compound (I) or When coexisting with the salt, it was surprisingly found that the interaction between loxoprofen or a salt thereof and compound (I) or the salt thereof was suppressed, and a pharmaceutical composition excellent in stability was obtained.

  That is, the present invention relates to loxoprofen or a salt thereof, general formula (I)

[In Formula (I), R ¹ represents a hydrogen atom or a methyl group, and R ² represents a hydrogen atom or a hydroxyl group. ]
Or a salt thereof, and a pharmaceutical composition containing a xanthine derivative.
Moreover, this invention provides the pharmaceutical formulation which contains the said pharmaceutical composition and desiccant in a container.

  The xanthine derivative can improve the interaction between loxoprofen or a salt thereof and compound (I) or a salt thereof. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition such as loxoprofen or a salt thereof and a solid preparation containing compound (I) or a salt thereof having improved storage stability.

<Pharmaceutical composition>
First, the pharmaceutical composition of the present invention will be described.
The pharmaceutical composition of the present invention comprises loxoprofen or a salt thereof, a compound represented by the general formula (I) or a salt thereof and a xanthine derivative.
Loxoprofen or a salt thereof used in the pharmaceutical composition of the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate with water, alcohol or the like. 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).

  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, per day, The amount that can be taken 10 to 300 mg in terms of loxoprofen sodium anhydride is preferred, the amount that can be taken 30 to 240 mg is more preferred, and the amount that can be taken 60 to 180 mg is more preferred.

  General formula (I) used in the pharmaceutical composition of the present invention

[In Formula (I), R ¹ represents a hydrogen atom or a methyl group, and R ² represents a hydrogen atom or a hydroxyl group. ]
In addition to the compound itself represented by the general formula (I), a pharmaceutically acceptable salt of the compound represented by the general formula (I) is included.
Preferred specific examples of the compound represented by the general formula (I) or a salt thereof include inorganic acids such as a compound represented by the general formula (I) and a hydrochloride of the compound represented by the general formula (I). Examples thereof include salts and organic acid salts, and hydrochlorides of the compounds represented by the general formula (I) are more preferable.
Examples of the compound represented by the general formula (I) or a salt thereof include the following (a) to (d).
(A) Bromohexine (a compound in which R ¹ is a methyl group and R ² is a hydrogen atom) or a salt thereof,
(B) Ambroxol (a compound represented by R ¹ is a hydrogen atom and R ² is a hydroxyl group)) or a salt thereof,
(C) a compound in which R ¹ is a methyl group and R ² is a hydroxyl group,
(D) Compounds in which R ¹ and R ² are hydrogen atoms Among these, (a) bromohexine or a salt thereof and (b) ambroxol or a salt thereof are preferable.

In the general formula (I), when R ² 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 these may be sufficient and a racemate 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 (I) or the salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. When the compound represented by the general formula (I) is bromhexine, the amount that can be taken as bromhexine hydrochloride per day is preferably 0.1 to 50 mg, more preferably 0.5 to 25 mg, more preferably 1 to 15 mg. The amount that can be taken is more preferred. Moreover, when the compound represented by the general formula (I) is ambroxol, an amount that can be taken as 0.1 to 150 mg of ambroxol hydrochloride per day is preferable, and an amount that can be taken as 0.5 to 100 mg is preferable. More preferably, the amount that can be taken 1-50 mg is even more preferable.

  As a xanthine derivative used for the pharmaceutical composition of the present invention, a compound represented by the following general formula (X) is preferable.

[In Formula (X), R ³ and R ⁴ each independently represent a hydrogen atom or a methyl group, and R ⁵ represents a hydrogen atom, a methyl group, a monohydroxypropyl group or a dihydroxypropyl group. ]

In R ⁵ described above, the monohydroxypropyl group is preferably a 2-hydroxypropyl group. The dihydroxypropyl group is preferably a 2,3-dihydroxypropyl group.

In the general formula (X),
(1) R ³ is a methyl group, R ⁴ is a methyl group, and R ⁵ is a methyl group means caffeine.
(2) R ³ is a methyl group, R ⁴ is a methyl group, and R ⁵ is a hydrogen atom means theophylline.
(3) R ³ is a hydrogen atom, R ⁴ is a methyl group, and R ⁵ is a methyl group means theobromine.
(4) R ³ is a methyl group, R ⁴ is a hydrogen atom, and R ⁵ is a methyl group means paraxanthine.
(5) R ³ is a methyl group, R ⁴ is a methyl group, and R ⁵ is a 2-hydroxypropyl group means proxyphylline.
(6) R ³ is a methyl group, R ⁴ is a methyl group, and R ⁵ is a 2,3-dihydroxypropyl group means diprofylline.
The compounds of the general formula (X), especially the above-mentioned compounds are known, and in the present invention, commercially available products can be used in addition to those produced by known methods.

  As the caffeine and theophylline, those in which a double salt is formed (sodium benzoate caffeine (double salt of sodium benzoate and caffeine), aminophylline (double salt of theophylline and ethylenediamine)) and the like can also be used.

  As the xanthine derivative in the pharmaceutical composition of the present invention, caffeine is preferable from the viewpoint of the use of the pharmaceutical composition of the present invention as an antipyretic analgesic, a general cold medicine, etc., and interaction suppression. Specific examples of the caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. Among these, caffeine hydrate, anhydrous caffeine, sodium benzoate Caffeine is particularly preferred.

  The content of the xanthine derivative in the pharmaceutical composition of the present invention is appropriately examined according to the interaction inhibitory effect of the compound represented by loxoprofen and the general formula (I) or a salt thereof, the sex, age, and symptom of the user. The amount that can be taken 10 to 1000 mg per day is preferable, the amount that can be taken 20 to 800 mg is more preferable, and the amount that can be taken 40 to 600 mg is more preferable.

  The compounding ratio of loxoprofen or a salt thereof and the compound represented by the general formula (I) or a salt thereof contained in the pharmaceutical composition of the present invention is appropriately examined according to the daily dose of each component described above. However, when the compound represented by the general formula (I) is bromohexine, loxoprofen or a salt thereof is 0.0001 to 1 part by mass in terms of loxoprofen sodium anhydride as bromhexine hydrochloride. What contains 10 mass parts is preferable, and what contains 0.0005-2 mass parts is more preferable. Further, when the compound represented by the general formula (I) is ambroxol, 0.0001 to 10 masses of loxoprofen or a salt thereof as ambroxol hydrochloride with respect to 1 mass part in terms of anhydrous loxoprofen sodium. Those containing parts are preferred, and those containing 0.0005 to 5 parts by mass are more preferred.

  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. Or it is preferable that the salt 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 in terms of loxoprofen sodium anhydride. What contains 2-10 mass parts is further more preferable.

The pharmaceutical composition of the present invention can be produced and formulated by a known method described in, for example, the 15th revised Japanese Pharmacopoeia General Rules for Preparations. In addition, the dosage form is not particularly limited, and examples thereof include oral administration preparations such as capsules, pills, granules, fine granules, powders, tablets, liquids, syrups, jellies, and troches. Examples include parenteral preparations such as external preparations, ointments, creams, gel creams, poultices, transdermal preparations, patches, liniments, lotions and suppositories. Among these, in the present invention, solid preparations are preferable, and examples of solid preparations include oral solid preparations such as capsules, pills, granules, fine granules, powders, tablets, troches, and suppositories. Examples include parenteral solid preparations, and oral solid preparations are preferred.
The pharmaceutical composition of the present invention may be coated with a sugar coating or a film coating by a known method.
Loxoprofen or a salt thereof, a compound represented by the general formula (I) or a salt thereof, and a xanthine derivative included in the pharmaceutical composition of the present invention are loxoprofen or a salt in terms of convenience of administration and management of a drug dose. It is preferably a solid preparation containing the salt and the compound represented by formula (I) or the salt and xanthine derivative.
The pharmaceutical composition of the present invention contains loxoprofen or a salt thereof in the pharmaceutical composition and a compound represented by the general formula (I) or a salt thereof so that they do not substantially come into contact with each other in terms of inhibition of interaction. , Manufactured and formulated. 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 (a) to (f) can be exemplified, and these can be produced and formulated by a known method.

(I) Either loxoprofen or a salt thereof and a compound represented by the general formula (I) or a salt thereof are granulated by an appropriate method to form a granular material, and the other is not granulated. Preparations prepared by coating powders, granules, etc., as well as the granules with appropriate methods. In addition, the xanthine derivative used by this invention may be contained in the said granular material, and may be contained separately from a granular material.
(B) Loxoprofen or a salt thereof, and a compound represented by the general formula (I) or a salt thereof are granulated by an appropriate method to form a granular material, and a powder or a granule prepared by containing them, and A preparation in which the granular material is further coated by an appropriate method. In addition, the xanthine derivative used in the present invention may be contained in any one of the granular materials, may be contained in both granular materials, or may be contained separately from these granular materials. Good.
(C) A capsule filled with the powder or granule prepared in (i) or (b) above. (D) Tablets obtained by tableting the granular material produced in (b) or (b) above.

(E) Loxoprofen or a salt thereof, and a multilayer tablet prepared so that the compound represented by formula (I) or a salt thereof does not come into contact with each other, and a preparation in which the multilayer tablet is further coated by an appropriate method. As the multilayer tablet, loxoprofen or a salt thereof and a compound represented by the general formula (I) or a salt thereof are preferably located in different layers, and as a multilayer tablet having three or more layers, loxoprofen or a salt thereof More preferably, the layer containing the compound and the layer containing the compound represented by formula (I) or a salt thereof are positioned so as not to contact each other. Incidentally, as the loxoprofen or a salt thereof and the compound represented by the general formula (I) or the salt thereof, the granular material produced in the above (i) or (b) can be used. In the multilayer tablet, the xanthine derivative may be located in either the layer containing loxoprofen or a salt thereof, or the layer containing the compound represented by the general formula (I) or a salt thereof, or separately in both layers. May be located. Furthermore, you may locate in the intermediate | middle layer of either layer.
(F) Loxoprofen or a salt thereof, a dry-coated tablet in which any one of the compound represented by the general formula (I) or a salt thereof is arranged in a nuclear tablet, and a preparation in which the dry-coated tablet is further coated by an appropriate method . Incidentally, as the loxoprofen or a salt thereof and the compound represented by the general formula (I) or the salt thereof, the granular material produced in the above (i) or (b) can be used. In the dry-coated tablet, the xanthine derivative may be positioned in the core tablet, may be positioned in the outer shell, or may be separately positioned in either the core tablet or the outer shell.

The route of administration of the pharmaceutical composition of the present invention includes oral; parenteral such as transrectal and vaginal, and oral administration is preferred. In addition, when the pharmaceutical composition of the present invention is orally administered, it can be divided into about 1 to 4 times per day and taken before meals, between meals, after meals, before going to bed.
The pharmaceutical composition of the present invention may be further stored in the presence of a desiccant from the viewpoint of interaction inhibition. Hereinafter, what contains the pharmaceutical composition and desiccant of this invention in a container may be called "pharmaceutical formulation" of this invention.

<Pharmaceutical formulation>
Next, the pharmaceutical preparation of the present invention will be described in detail.
In the present invention, the desiccant is not particularly limited as long as it can further suppress or improve the interaction when stored together with the pharmaceutical composition of the present invention. Also, the shape is not limited, and examples thereof include a plate-shaped or bag-shaped sheet mold, a cylinder (tablet mold), etc., and a cylinder with paper wrapping or film coating. But you can.

  The desiccant is selected from, for example, silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride, magnesium oxide. 1 type or 2 types or more can be mentioned, and these and activated carbon may be mixed. Among these, one or more selected from silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve) and calcium chloride are more preferable, and synthetic zeolite is particularly preferable in terms of interaction suppression.

  Various desiccants are commercially available. For example, Shiblet, MS-Tablet, MS-Serum W, Tokai Gel, Decite Kite 25, Alp sheet, Toray Chemical Co., Ltd. ) Packaged items, Dryan (registered trademark) tablets, Dryan (registered trademark) sheets, Sekawa, Allosheet, Zeosheet, Shinzo Kasei Co., Ltd., OZO Co., Ltd. OZO, IDi Co., Ltd. IDi-packing desiccant and the like.

The content of the desiccant may be determined as appropriate, but is preferably 0.05 to 35 parts by mass, more preferably 0.15 to 17 parts by mass with respect to 1 part by mass of loxoprofen or a salt thereof.
Moreover, 0.001-1 mass part is preferable with respect to 1 mass part of solid preparation containing a loxoprofen or its salt, the compound or its salt represented with general formula (I), and a xanthine derivative, 0.004 -0.4 mass part is more preferable.

  The pharmaceutical composition of the present invention includes, as a pharmaceutical ingredient, a drug other than a compound represented by loxoprofen or a salt thereof and the general formula (I) or a salt thereof and a xanthine derivative, such as an antipyretic analgesic, an antihistamine, an antitussive, noscapine Including one or more selected from the group consisting of: bronchodilators, expectorants, hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosal protective agents, anticholinergics, herbal medicines, Kampo prescriptions, etc. Also good. These components are preferably blended in the solid preparation.

  Examples of antipyretic analgesics 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, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, clemastine fumarate. Acid salt, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, dipheterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine Hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethad Methylene two salicylates, mequitazine, methdilazine hydrochloride, main blanking hydro Linna Paji sill acid salts.

  Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, codeine phosphate, dihydrocodeine phosphate, dibutarate sodium, dimemorphan Examples thereof include phosphate, dextromethorphan hydrobromide, dextromethorphan / phenol phthaline salt, tipepidine citrate, and tipepidine hibenzate.

Examples of noscapine include noscapine hydrochloride and noscapine.
Examples of bronchodilators include trimethquinol hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, dl-methylephedrine saccharin. Salt, methoxyphenamine hydrochloride and the like.

  Examples of expectorants include ammonia fennel spirit, ethyl cysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacol sulfonate, potassium cresol sulfonate, methyl cysteine hydrochloride, l-menthol and the like.

Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromovalerylurea.
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 nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavinline Acid ester, riboflavin butyrate, sodium riboflavin phosphate, panthenol, pantethine, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecoba Lamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

  Examples of anti-inflammatory agents include lysozyme chloride, glycyrrhizic acid and derivatives thereof, and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, Bromelain etc. are mentioned.

  Examples of the gastric mucosa protective agent include aminoacetic acid, aldioxa, magnesium silicate, gefarnate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product , Sucralfate, cetraxate hydrochloride, sofalcone, magnesium carbonate, teprenone, copper chlorophyllin potassium, copper chlorophyllin sodium, magnesium metasilicate aluminate, methylmethionine sulfate Niumukurorido, and the like.

  Anticholinergic agents include, for example, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, chipepidium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl- 1-hyostiamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodopropamide iodide, diphenylpiperidinomethyldioxolane, funnel extract, funnel root, funnel Examples include root total alkaloid citrate.

  Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyoukaku (horny sheep), fennel (yuka), engosaku (yenko), ougon (yellow), seisei (yellow spirit), and oak (yellow candy). , Ohi (cherry bark), Ouren (yellow ream), Onji (distant), Gajutsu (Iso), Kanokosou (Deer herb), Chamomile, Caronin (Karojin), Kyokyo (Kikkyo), Kyonin (Kyojin), Kokushi (枸杞 子), KOKOYO (枸杞 枸杞), keigai (荊芥), keihi (cinnamon), Ketsumeishi (Keiko), gentian, gennoshouko (current evidence), kobushi (Katsukiko), gooh (oxen), trash Saishin (Spicy), Salamander, Zion (Zipa), Jikoppi (Skin Bark), Peonies (Shakuyaku), Musk (Shako), Shajin, Shazenshi, Shazenshi Saw (car forerunner), beast gall (including Yutan (bear gall)), gyoza (ginger), ziryu (earth dragon), Xinyi (pepper), sexan (stone wall), Senega, Senkyu (river kyu), Zenko ( Mae-hu, Senburi, Sojutsu (蒼朮), Sohakuhi (mulberry skin), Soyo (Soba), Taisan (Daibu), Chiksetsu carrot (Bamboo ginseng), Clove (clove), Chimpi (Chen), Toki (homecoming), Tokon (napping root), Nantenjitsu (Nan Tenji), Carrot (carrot), Baimo (shellfish mother), Bakumondou (Bakumon winter), Hange (half summer), Bankouka (bancho flower), Hampi ( Herbal medicines such as anti-nasal), peony (white), peanut (white cocoon), bukkuri (茯苓), button pi (peony skin), borei (oyster), mao (mao), rossou (deer moth) and their extracts (extracts) , Tincture, dried extract, etc.) .

  The Kampo prescription includes, for example, Kakkon-to, Katsue-yu, Koso-san, Saiko-Kei-to, Sho-saiko-to, Shosei-ryu, Mumon-tou-yu, Hanka-kopaku-to, Mao-to, etc.

  The container used for storing the pharmaceutical composition and the desiccant of the present invention is not particularly limited as long as it can be used as a container for food, supplements, pharmaceuticals, health foods, etc. Any of them can be used, and those that can be sealed are 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, a resin or a resin film, or a member such as a metal or a metal film, and a composite structure or a 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 of storing loxoprofen or a salt thereof, a compound represented by the general formula (I) or a salt thereof, a xanthine derivative, and a desiccant in a container used in the present invention is not particularly limited. Can also be achieved by placing the container into the container by an appropriate means such as charging.

  For example, when the container is a bottle, a desiccant (preferably a cylindrical shape (tablet shape)) is placed in the bottle or stored in the back side (inner cap) of the bottle lid, and loxoprofen or This can be achieved by storing the salt, the compound represented by the general formula (I) or the salt thereof, and the xanthine derivative in a bottle. When storing in a bottle, loxoprofen or a salt thereof, a compound represented by the general formula (I) or a salt thereof, and a xanthine derivative are preferably solid preparations containing these.

  In the case where the container is a bag, a desiccant (preferably a plate or bag-shaped sheet type), loxoprofen or a salt thereof, a compound represented by the general formula (I) or a salt thereof, and a xanthine derivative are contained in the bag. This can be achieved by storing it in the storage. When storing in a bag, loxoprofen or a salt thereof, a compound represented by formula (I) or a salt thereof, and a xanthine derivative are preferably solid preparations containing them.

  Further, the solid preparation of the present invention may be once packaged by SP packaging, PTP packaging or a bag, and then the packaged solid preparation and desiccant may be enclosed in a bag. More specifically, the form etc. which carry out pillow packaging of the solid formulation which carried out SP packaging or PTP packaging, and a plate-shaped or bag-shaped sheet type desiccant etc. are mentioned. Further, the pillow packaging form may be stored in a box or the like.

  The pharmaceutical composition of the present invention includes loxoprofen which is a kind of NSAID or a salt thereof, a compound represented by the general formula (I) having expectorant action or a salt thereof (for example, bromhexine or a salt thereof, ambroxol or a salt thereof) And xanthine derivatives with central excitability, cardiotonic / diuretic activity, gastric acid secretion enhancing activity, smooth muscle relaxation activity, etc., so headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia・ Back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain), pain relief, chills, antipyretic fever, symptoms of cold (sore pain, tan, chills) , Fever, headache, joint pain, muscle pain, etc., and is useful as a cold medicine. In addition, when loxoprofen or a salt thereof is combined with a compound represented by the general formula (I) or a salt thereof (for example, bromhexine or a salt thereof or ambroxol or a salt thereof), the effect on cough symptoms is enhanced. The pharmaceutical composition of the invention is useful.

EXAMPLES The present invention will be described in detail below with reference to examples and the like, but the present invention is not limited to these examples.
[Test Example 1] Examination of interaction (1)
Example 1: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.5 g and anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 0.61 g Mix to obtain a mixture.
Example 2: Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.5 g and sodium benzoate caffeine (manufactured by Shizuoka Caffeine Industry: trade name: sodium benzoate caffeine) 0.74 g was mixed to obtain a mixture.
The mixtures of Examples 1 and 2 were each placed in a glass bottle (3K standard bottle) and stored at 40 ° C. and 75% RH. Immediately after the start of storage, the state of the mixture after 1 week, 1 month, and 2 months, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 1.

  As is apparent from Table 1, when loxoprofen sodium hydrate was mixed with anhydrous caffeine or sodium caffeine benzoate, an interaction occurred and the mixture changed to a solidified state after one week. .

[Test Example 2] Examination of interaction (2)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 202.6 mg and sodium benzoate caffeine (Shizuoka Caffeine Industry: trade name: sodium benzoate caffeine) 297.4 mg Were put in a glass bottle (3K standard bottle) and stored at 60 ° C. Immediately after the start of storage, the state of the mixture after 1 day, 2 days and 1 week, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 2.

  As is apparent from Table 2, when loxoprofen sodium hydrate and sodium caffeine benzoate were mixed and stored, an interaction occurred, resulting in the mixture changing to a solidified state after 1 day. Similar results were obtained.

  From the results of Test Examples 1 and 2, it was revealed that when loxoprofen or a salt thereof and a xanthine derivative were mixed, an interaction occurred between these compounds.

[Test Example 3] Examination of interaction (3)
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 1.7 g and bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) 0.1 g are mixed together and mixed with a glass bottle ( 3K standard bottle) and stored at 60 ° C. Immediately after the start of storage, the state of the mixture after 1 day, 2 days, and 1 week was evaluated, that is, the presence or absence of interaction, and the results are shown in Table 3.

  As is clear from Table 3, when loxoprofen sodium hydrate and bromhexine hydrochloride were mixed and stored, the interaction resulted in the mixture solidifying after 1 day and discoloring after another 3 days.

[Test Example 4] Examination of interaction (4)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 0.5g and Ambroxol hydrochloride (Shizuoka Caffeine Industry: trade name: Ambroxol hydrochloride) 0.5g It mixed, put into the glass bottle (3K specification bottle), and preserve | saved at 60 degreeC. Immediately after the start of storage, 1 day, 3 days, and 1 week later, the state of the mixture, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 4.

  As can be seen from Table 4, when loxoprofen sodium hydrate and ambroxol hydrochloride were mixed and stored, the interaction resulted in the mixture solidifying after 1 day and discoloring after 3 days. .

[Test Example 5] Examination of interaction (5)
Comparative Example 1: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 945 mg and bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) 55 mg were mixed together. Obtained.
Example 1: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 945 mg, bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) 55 mg and anhydrous caffeine (Shizuoka) 1156 mg of Caffeine Kogyosho, trade name: anhydrous caffeine) was mixed to obtain a mixture.
Each mixture of Comparative Example 1 and Example 1 was placed in a glass bottle (3K standard bottle) and stored at 60 ° C. As Example 2, in addition to the mixture of Example 1, 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) was placed in a glass bottle (3K standard bottle) and stored at 60 ° C. For each, the state of the mixture immediately after the start of storage, 1 day, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated. The results are shown in Table 5.

As is apparent from Table 5, the mixture of loxoprofen sodium hydrate and bromhexine hydrochloride that had been stored was solidified after 1 day from the start of storage as a result of the interaction. The color changed (Comparative Example 1).
On the other hand, in addition to loxoprofen sodium hydrate and bromhexine hydrochloride, it was found that a mixture obtained by further mixing and storing caffeine can suppress discoloration (Example 1). Further, it was found that the addition of a desiccant in addition to the mixing of caffeine maintained the same state as at the start even after one week had passed and could suppress the interaction (Example 2).

  From the results of Test Examples 1 to 3 and 5, when loxoprofen or a salt thereof and a xanthine derivative, or loxoprofen or a salt thereof and bromhexine or a salt thereof are mixed, an interaction occurs between these compounds (Test Example). 1-3) Surprisingly, it was found that the xanthine derivative inhibits the interaction between loxoprofen or a salt thereof and bromohexine or a salt thereof (Test Example 5).

[Test Example 6] Examination of interaction (6)
Comparative Example 2: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 819 mg and ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: ambroxol hydrochloride) Mix to obtain a mixture.
Example 3: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 819 mg, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: ambroxol hydrochloride) 181 mg and 1002 mg of anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyo: trade name anhydrous caffeine) was mixed to obtain a mixture.
Each mixture of Comparative Example 2 and Example 3 was placed in a glass bottle (3K standard bottle) and stored at 60 ° C. Moreover, as Example 4, in addition to the mixture of Example 3, 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) was put in a glass bottle (3K standard bottle) and stored at 60 ° C. For each, the presence or absence of discoloration of the mixture immediately after the start of storage, 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 6.

As can be seen from Table 6, the mixture of loxoprofen sodium hydrate and ambroxol hydrochloride that had been preserved was changed to a slightly yellow color after 1 day from the start of preservation as a result of interaction. After 3 days, the color changed more strongly (Comparative Example 2).
On the other hand, in addition to loxoprofen sodium hydrate and bromhexine hydrochloride, it was proved that the color which was further mixed and stored (Example 3) can suppress discoloration. In addition to the mixture of caffeine, it was also found that the desiccant added (Example 4) can suppress discoloration.

  From the results of Test Examples 1, 2, 4 and 6, when loxoprofen or a salt thereof and a xanthine derivative, or loxoprofen or a salt thereof and ambroxol or a salt thereof are mixed, an interaction occurs between these compounds. (Test Examples 1, 2 and 4), surprisingly, it was found that the xanthine derivative inhibits the interaction between loxoprofen or a salt thereof and ambroxol or a salt thereof (Test Example 6).

[Example 5] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 24 g, anhydrous Caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 g, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g, carmellose calcium (product name: ECG505) 486 g, Crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd .: trade name: Theolas PH-101) 3667 g 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. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: 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: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 6] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, bromhexine hydrochloride (Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 24 g, anhydrous Caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g, carmellose calcium (product name: ECG505) 486 g, Lactose hydrate (manufactured by DMV: trade name: lactose 200M) 3667 g is put into a high-speed agitation granulator (manufactured by Paulek: VG-25 type) and mixed, and then 232 g of purified water is added and kneaded, and the granulated product Got. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: 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: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 7] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 24 g, anhydrous Caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g, carmellose calcium (product name: ECG505) 486 g, Lactose hydrate (manufactured by DMV: trade name: lactose 200M) 1834 g and crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name: Theolas PH-101) 1833 g are charged into a high-speed agitation granulator (manufactured by Paulek: model VG-25) and mixed. Thereafter, 696.2 g of purified water was added and kneaded to obtain a granulated product. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: 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: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 8] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 24 g, anhydrous Caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g, carmellose calcium (product name: ECG505) 486 g, Lactose hydrate (manufactured by DMV: trade name: lactose 200M) 1223 g, crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name: Theolas PH-101) 1222 g, corn starch (manufactured by Nippon Star Chemical Co., Ltd .: trade name: corn starch ST-C) 1222 g at high speed Agitation granulator (Powrec: VG- After mixing was charged into type 5), kneaded with the addition of purified water 928.2G, to obtain a granulated product. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: 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: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 9] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry Co., Ltd .: trade name, ambrox hydrochloride) Sole) 90 g, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g, carmellose calcium (manufactured by Gotoku Pharmaceutical: product) Name ECG505) 486g, crystalline cellulose (Asahi Kasei Chemicals: brand name Theolas PH-101) 3601g was put into a high-speed stirring granulator (Paurek: VG-25 type) and mixed, and then 1972.6g of purified water was added. And kneaded to obtain a granulated product. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: 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: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 10] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry Co., Ltd .: trade name, ambrox hydrochloride) Sole) 90 g, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 g, carmellose calcium (manufactured by Gotoku Pharmaceutical: product) Name ECG505) 486g, lactose hydrate (DMV: trade name: lactose 200M) 3601g was put into a high-speed stirring granulator (Paurek: VG-25 type) and mixed, then purified water 232g was added and kneaded. To obtain a granulated product. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: 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 put into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 11] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry Co., Ltd .: trade name: ambrox hydrochloride) Sole) 90 g, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g, carmellose calcium (manufactured by Gotoku Pharmaceutical: product) Name ECG505) 486 g, lactose hydrate (manufactured by DMV: trade name: lactose 200M) 1801 g, crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name: SEOLUS PH-101) 1800 g high-speed agitation granulator (manufactured by POWREC: VG-25 type) After mixing and mixing, 696.2 g of purified water is added and kneaded. Obtained. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: 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: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 12] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry Co., Ltd .: trade name, ambrox hydrochloride) Sole) 90 g, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g, carmellose calcium (manufactured by Gotoku Pharmaceutical: product) Name ECG505) 486 g, lactose hydrate (manufactured by DMV: trade name: lactose 200M) 1201 g, crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name: SEOLUS PH-101), corn starch (manufactured by Nissho Chemical Co., Ltd .: trade name corn starch ST- C) 1200 g of high speed agitation granulator (Pow Click Ltd. After mixing was poured into VG-25 type), kneaded with the addition of purified water 928.2G, to obtain a granulated product. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: 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: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 13]
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 14]
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 15]
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 16]
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 17]
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 18]
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 19]
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 20]
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.

  According to the present invention, the interaction between loxoprofen or a salt thereof and the compound represented by formula (I) or a salt thereof can be suppressed. Therefore, it is possible to provide a pharmaceutical composition comprising loxoprofen or a salt thereof, and a compound represented by the general formula (I) or a salt thereof, which has excellent storage stability.

Claims (11)

Loxoprofen or a salt thereof, general formula (I)

[In Formula (I), R ¹ represents a hydrogen atom or a methyl group, and R ² represents a hydrogen atom or a hydroxyl group. ]
Or a salt thereof, and a pharmaceutical composition comprising a xanthine derivative. The combination of R ¹ and R ^{2 in} formula (I) is a combination in which R ¹ is a methyl group and R ² is a hydrogen atom, or a combination in which R ¹ is a hydrogen atom and R ² is a hydroxyl group. The pharmaceutical composition according to claim 1.   The pharmaceutical composition according to claim 1 or 2, wherein the loxoprofen or a salt thereof is loxoprofen sodium hydrate.   The pharmaceutical composition according to claim 3, comprising loxoprofen sodium hydrate in an amount of 10 to 300 mg per day in terms of anhydrous loxoprofen sodium.   The pharmaceutical composition according to any one of claims 2 to 4, wherein the compound represented by the general formula (I) or a salt thereof is bromohexine hydrochloride, and contains 0.1 to 50 mg of bromohexine hydrochloride as a daily dose. object.   The compound represented by the general formula (I) or a salt thereof is ambroxol hydrochloride, and contains 0.1 to 150 mg of ambroxol hydrochloride as a daily dose. A pharmaceutical composition according to Item.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the xanthine derivative is caffeine.   The pharmaceutical composition according to claim 7, wherein the caffeine is at least one selected from caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine and caffeine citrate.   The pharmaceutical composition according to any one of claims 1 to 8, comprising 10 to 1000 mg of a xanthine derivative as a daily dose.   The pharmaceutical composition according to any one of claims 1 to 9, wherein the dosage form is a solid preparation.   A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 10 and a desiccant in a container.