JP2011132226A - Loxoprofen-containing medicinal composition and medicinal preparation containing the composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable medicinal composition containing loxoprofen or a salt thereof, and a phenol derivative or a salt thereof. <P>SOLUTION: The medicinal composition contains the loxoprofen or the salt thereof, the phenol derivative or the salt thereof, and a xanthine derivative. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof, and a pharmaceutical preparation containing the composition.

  Loxoprofen is a non-steroidal anti-inflammatory analgesic (NSAID), rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, neck-shoulder arm syndrome, toothache, acute upper respiratory tract, 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, combining loxoprofen with bromhexine hydrochloride or ambroxol hydrochloride enhances the effect on cough symptoms (Patent Document 4) and suppresses goblet cell hyperplasia (Patent Document 5), and combines loxoprofen with bromhexine hydrochloride. There are known anti-inflammatory, analgesic and antipyretic effects (Patent Document 6).

  It is also known that loxoprofen enhances the antihistamine action of chlorpheniramine maleate and clemastine fumarate (Patent Document 6). 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. Furthermore, a gastric mucosal disorder inhibiting action caused by loxoprofen by combining with an antacid and a xanthine derivative is known (Patent Document 7). In this document, formulation examples in which loxoprofen is combined with caffeine or theophylline as a xanthine derivative are described.

  On the other hand, phenol derivatives such as guaifenesin, potassium guaiacol sulfonate, potassium cresol sulfonate, and the like thereof have airway secretion promoting action and the like, and are used as a general cold medicine, antitussive expectorant, etc. Patent Document 2).

  A tablet containing guaifenesin and loxoprofen is already known (Patent Document 7). However, a pharmaceutical composition containing potassium guaiacol sulfonate and loxoprofen, and a pharmaceutical composition containing potassium cresolsulfonate and loxoprofen have been disclosed so far. unknown. It is not known whether these phenol derivatives interact with loxoprofen. Naturally, there is no known method for solving the interaction.

  Further, as xanthine derivatives, caffeine, theophylline, paraxanthine, theobromine, aminophylline, diprofylline, proxyphylline, etc. are known, and caffeine has central excitatory action, cardiotonic / diuretic action, gastric acid secretion enhancing action, smooth muscle relaxing action, etc. It is a drug used for antipyretic analgesics, general cold medicine, antitussive expectorant and the like (Non-patent Document 3). 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 4). Proxyphyrin also exhibits the same action as theophylline (Non-patent Document 5), and paraxanthine and theobromine also exhibit the same action.

By the way, tablets containing caffeine or aminophylline and loxoprofen are known (Patent Documents 8, 9, and 10).
A tablet containing loxoprofen, guaifenesin, and theophylline is known. However, it is not known whether or not an interaction occurs between loxoprofen or a salt thereof and guaifenesin in a tablet, and the exact reason for theophylline is unknown.
Further, as described above, a pharmaceutical composition containing guaiacol sulfonic acid or cresol sulfonic acid and loxoprofen is not known, and this also applies to a pharmaceutical composition containing guaiacol sulfonic acid or cresol sulfonic acid, loxoprofen and a xanthine derivative. Not known until.

Japanese Patent Laid-Open No. 11-139971 JP 2001-199882 A JP 2008-169193 A JP 2001-172175 A JP 2008-13542 A JP 2000-143505 A JP 2002-316927 A JP 2006-52210 A International Publication No. 2004/050110 JP 2007-314517 A

Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd. C-4790-4759 OTC Handbook 2008-09 Academic Information Distribution Center 291-292 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 of a mixture containing these two components in order to develop a solid preparation containing loxoprofen or a salt thereof and a phenol derivative or a salt thereof. It was found that an interaction occurs between these compounds, and this interaction causes liquefaction and the like, which causes a very serious problem in storage stability.
Accordingly, an object of the present invention is to provide a stable pharmaceutical composition containing loxoprofen or a salt thereof and a phenol derivative or a salt thereof, and a pharmaceutical preparation containing the pharmaceutical composition.

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 present inventors have further studied to solve the above-mentioned problems. As a result, the xanthine derivative that causes interaction with loxoprofen or a salt thereof as described above is converted into a loxoprofen or a salt thereof, and a phenol derivative or a salt thereof. It has been surprisingly found that the interaction between loxoprofen or a salt thereof and a phenol derivative or a salt thereof can be improved by coexisting with the salt.

That is, the present invention provides a pharmaceutical composition containing loxoprofen or a salt thereof, a phenol derivative or a salt thereof, and a xanthine derivative.
Moreover, this invention provides the pharmaceutical formulation which contains the said pharmaceutical composition and a desiccant in a container.
The present invention also provides an agent for improving the interaction between loxoprofen or a salt thereof and a phenol derivative or a salt thereof in a pharmaceutical composition, comprising a xanthine derivative as an active ingredient.

According to the present invention, the interaction between loxoprofen or a salt thereof and a phenol derivative or a salt thereof can be improved. Therefore, a pharmaceutical composition containing loxoprofen or a salt thereof and a phenol derivative or a salt thereof having excellent storage stability can be provided.
Moreover, the pharmaceutical composition in which the interaction containing loxoprofen or its salt, and the phenol derivative or its salt was suppressed can be provided easily and cheaply without passing through a complicated process.

The pharmaceutical composition of the present invention comprises loxoprofen or a salt thereof, a phenol derivative or a salt thereof and a xanthine derivative. First, the loxoprofen or a salt thereof will be described.
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 may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but 10 per day in terms of loxoprofen sodium anhydride. The amount that can be taken -300 mg is preferred, and the amount that can be taken 30-240 mg is more preferred. The amount that can be taken 60 to 180 mg is more preferable.

Next, a phenol derivative or its salt is demonstrated in detail.
As a phenol derivative or its salt used for the pharmaceutical composition of this invention, the compound represented by following General formula (1) or its salt is preferable.

[Wherein, R ¹ represents an alkyl group or an alkoxy group which may have a substituent, and R ² represents a hydrogen atom or a sulfo group. In addition, the phenolic hydroxyl group in the formula may be etherified. ]

In R ¹ , the alkyl group is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group, and a butyl group. . In the present invention, a methyl group is preferred.
The alkoxy group is preferably a linear or branched alkoxy group having 1 to 5 carbon atoms, and specific examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, and the like. It is done. 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, and a fluorine atom, and may have one or more of these.

  In the above general formula, when the phenolic hydroxyl group is etherified, for example, a linear or branched monohydric alcohol having 1 to 3 carbon atoms, the phenolic hydroxyl group being etherified, a polyhydric alcohol And those having a phenolic hydroxyl group etherified. Examples of the monohydric alcohol include methanol, ethanol, propanol and the like. Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, and glycerin. In the present invention, a polyhydric alcohol is preferable for etherification, and glycerin is more preferable. When the phenolic hydroxyl group is etherified, the etherification reaction is not particularly limited.

Specific examples of suitable phenol derivatives in the pharmaceutical composition of the present invention include 2-methoxyphenol derivatives (guaiacol derivatives) and 2-methylphenol derivatives (cresol derivatives). Examples of such 2-methoxyphenol derivatives or salts thereof include guaifenesin (guaiacol glycerin ether; (2RS) -3- (2-methoxyphenoxy) propane-1,2-diol); guaiacol such as guaiacol sulfonic acid and potassium guaiacol sulfonate. A sulfonic acid or a salt thereof is preferred. Moreover, as a cresol derivative or its salt, cresol sulfonic acid or its salts, such as cresol sulfonic acid (2-methylphenol sulfonic acid) and potassium cresol sulfonate, are preferable.
These are known compounds, and can be produced by known methods, or commercially available products can be used.

The content of the phenol derivative or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptom, etc. of the user, but can be taken in an amount of 5 to 600 mg per day. Is preferable, more preferably 10 to 450 mg, more preferably 25 to 300 mg.
In addition, when using a guaiacol derivative or its salt as a phenol derivative or its salt, the quantity which can be taken | dosed 10-600 mg per day is preferable, the quantity which can be taken | dosed 20-450 mg is more preferable, and the quantity which can be taken | dosed 30-300 mg is further more preferable. . Moreover, when using a cresol derivative or its salt as a phenol derivative or its salt, the quantity which can be taken | dosed 5-550 mg per day is preferable, the quantity which can be taken | dosed 10-400 mg is more preferable, and the quantity which can be taken | dosed 25-270 mg is further more preferable. .

  The content ratio of loxoprofen or a salt thereof and a phenol derivative or a salt thereof contained in the pharmaceutical composition of the present invention may be determined by appropriately examining according to the daily dose of each component described above, Loxoprofen or a salt thereof is preferably contained in an amount of 0.015 to 60 parts by mass, more preferably 0.04 to 15 parts by mass, with respect to 1 part by mass in terms of loxoprofen sodium anhydride. What contains 0.13-5 mass parts is more preferable.

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

[Wherein, 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 (I),
(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 (I), especially the above-mentioned compounds are known, and in the present invention, commercially available products can be used in addition to those produced by known methods.

  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 using the pharmaceutical composition of the present invention as an antipyretic analgesic, a general cold medicine or the like. Specific examples of the caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine and caffeine citrate. Among these, caffeine hydrate, anhydrous caffeine, and sodium benzoate caffeine are particularly preferable.

  The content of the xanthine derivative in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the interaction inhibitory effect of the loxoprofen and the phenol derivative or a salt thereof, the gender of the user, age, symptoms, The amount that can be taken 10 to 1000 mg per day is preferred, the amount that can be taken 20 to 800 mg is more preferred, and the amount that can be taken 40 to 600 mg is more preferred.

  In addition, the content ratio of loxoprofen or a salt thereof and xanthine derivative contained in the pharmaceutical composition of the present invention may be determined by appropriate examination 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.

In the pharmaceutical composition of the present invention, the following combinations are preferred.
A pharmaceutical composition containing loxoprofen or a salt thereof, the compound represented by the formula (1), and a xanthine derivative (provided that the compound represented by the formula (1) is guaifenesin and the xanthine derivative is theophylline. except.).

Next, the dosage form of the pharmaceutical composition of the present invention will be described in detail.
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 phenol derivative or a salt thereof, and a xanthine derivative, which are included in the pharmaceutical composition of the present invention, are loxoprofen or a salt thereof and a phenol derivative or a salt thereof in terms of convenience of administration and management of a drug dose. And a solid preparation containing three components of xanthine derivative.

  As the pharmaceutical composition of the present invention, in terms of interaction inhibition, loxoprofen or a salt thereof and a phenol derivative or a salt thereof in the pharmaceutical composition are contained so as not to substantially contact each other, manufactured and formulated. Good. The preparations prepared so as to be substantially in contact with each other can be easily understood by a general pharmaceutical technology researcher, using appropriate formulation additives based on known methods. Can be manufactured and formulated. Examples of the form of the solid preparation of the present invention include the following (A) to (F), and these can be produced and formulated by known methods.

(I) Powders or granules, etc. produced by granulating any one of loxoprofen or a salt thereof and phenol derivative or a salt thereof by an appropriate method and containing the other without granulation In addition, a preparation in which the granular material is further coated by an appropriate method. 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 phenol derivative or a salt thereof are separately granulated by an appropriate method to form granules, and powders or granules made by containing them, and the granules are further suitable. Coated by various methods. 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) A multilayer tablet prepared so that loxoprofen or a salt thereof, and a phenol derivative or a salt thereof do not contact 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 a phenol derivative or salt thereof 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 a phenol derivative or a salt thereof More preferably, the salt-containing layers are positioned so as not to contact each other. In addition, as the loxoprofen or a salt thereof and the phenol derivative 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 a phenol derivative or a salt thereof, or may be located separately in both layers. Furthermore, you may locate in the intermediate | middle layer of either layer.
(F) A dry-coated tablet in which any one of loxoprofen or a salt thereof and a phenol derivative 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. In addition, as the loxoprofen or a salt thereof and the phenol derivative 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.

  Examples of the route of administration of the pharmaceutical composition of the present invention include oral and parenteral such as rectal and vaginal administration. When the pharmaceutical composition of the present invention is orally administered, it is divided into about 1 to 4 times per day. It can be taken before meals, between meals, after meals, before going to bed.

Next, the pharmaceutical preparation of the present invention will be described.
In this invention, you may preserve | save the pharmaceutical composition containing a loxoprofen or its salt, a phenol derivative or its salt, and a xanthine derivative in the presence of a desiccant from the point of interaction suppression. Hereinafter, what contains the pharmaceutical composition and desiccant of this invention in a container may be called "pharmaceutical formulation" of this invention.

  In the present invention, the desiccant is not particularly limited as long as it can 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.

  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 and 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 from the viewpoint 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.
The content of the desiccant is preferably 0.001 to 1 part by mass with respect to 1 part by mass of the pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, a phenol derivative or a salt thereof 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 loxoprofen or a salt thereof and a phenol derivative of an expectorant ingredient or a salt thereof and a xanthine derivative, such as an antipyretic analgesic, an antihistamine, an antitussive, noscapine, a bronchodilator, It may contain one or more selected from the group consisting of expectorants, hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosal protective agents, anticholinergic agents, herbal medicines, Kampo prescriptions and the like. These components are preferably contained 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 sills salts include emetine Das Chin fumarate salt.

  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, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, dl -Methylephedrine saccharin salt, methoxyphenamine hydrochloride, etc. are mentioned.

  Examples of expectorants include ambroxol hydrochloride, ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, bromohexine hydrochloride, methylcysteine hydrochloride, l-menthol, lysozyme hydrochloride, 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 the anti-inflammatory agent include glycyrrhizic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, bromelain and the like. Can be 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), inyokaku (horny sheep), fennel (mushrooms), turmeric (depressed gold), engosaku (yenkogong), enmeisou (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Oubak (yellow twilight), Spruce (cherry skin), Auren (yellow ream), Onji (distant), Gajutsu (we), Ganoderma (deer herb), Chamomile, Caronin (Karojin), Licorice (licorice), Kyo-kyo (kikyo), Kyo-nin (Kyojin), Kukoshi (coconut), Kuko-yo (Kashiwa), Keihi (Kinko), Ketsumeishi (Katsumeko), Gentiana, Gennoshouko (current evidence), Koubushi (Kosuke), Gooh (Gyuhuang), Goshi (Gomiko), Saishin (Spicy), Salamander (Sambu), Zion (Purple), Zykopi (Peel), Peonies (Glue), Ji Jakkou, Shajin, Shazenshi (car forerunner), Shazenso (car forerunner), Beast gall (including yutan (gum gal)), Shakyo (ginger), Giryu (land dragon), Xinyi ), Sexan (Ishizuchi), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Oiso), Chixetsu carrot (bamboo ginseng), clove (clove), chimpi (chonse), touki (to home), tokong (napping root), Nantenjitsu (southern), carrot (carrot), baimo (shellfish), bacmond (wheat) Gate winter), mint (light load), Hange (semi-summer), bankouka (banka), hampi (anti-nose), juniper (white bean), juniper (white moth), bukkuri (茯苓), button pi (peony skin), volley (Oyster), maou (mao), rokjo (deer moth) ) And their extracts (extracts, tinctures, dried extracts, etc.) and the like.

  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 phenol derivative or a salt thereof, a xanthine derivative and a desiccant used in the present invention in the container is not particularly limited, and any of them is suitable for charging into the container. This can be achieved by arranging by means.

  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 The salt, the phenol derivative or the salt thereof, and the xanthine derivative can be achieved by storing in a bottle. In storing in a bottle, loxoprofen or a salt thereof, a phenol derivative or a salt thereof, and a xanthine derivative are preferably solid preparations containing these.

  In the case where the container is a bag, it can be achieved by storing a desiccant (preferably, a plate-like or bag-like sheet type), loxoprofen or a salt thereof, and a phenol derivative or a salt thereof in the bag. When storing in a bag, loxoprofen or a salt thereof, a phenol derivative or a salt thereof, and a xanthine derivative are preferably solid preparations containing these.

  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 has loxoprofen which is a kind of NSAID or a salt thereof, a phenol derivative or a salt thereof having an expectorant action, and a central excitatory action, a cardiotonic / diuretic action, a gastric acid secretion enhancing action, a smooth muscle relaxing action, etc. Containing xanthine derivative, 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 ) ・ Efficacy or effect on pain relief, pain relief, chills / fever, fever, cold symptoms (sore throat, chills, chills, fever, headache, joint pain, muscle pain) It is useful as a cold medicine.

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 (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 were mixed, It put into the glass bottle (3K specification bottle), and preserve | saved at 40 degreeC75% RH. Immediately after the start of storage, after 1 week, 1 month, and 2 months, the state of the mixture, that is, 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 and anhydrous caffeine were mixed and stored, the interaction occurred, resulting in the mixture changing to a solid 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) 0.5g and sodium benzoate caffeine (Shizuoka Caffeine Industry: trade name: sodium benzoate caffeine) 0.74g Were put 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 was evaluated, that is, the presence or absence of interaction, 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 solid state after one month.

[Test Example 3] Examination of interaction (3)
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 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 sodium caffeine benzoate were mixed and stored, an interaction occurred, resulting in the mixture changing to a solid state after one day.

  From the results of Test Examples 1 to 3, it was found that when loxoprofen or a salt thereof and a xanthine derivative were mixed, an interaction occurred between these compounds.

[Test Example 4] Examination of interaction (4)
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.5g and guaifenesin (manufactured by Alps Pharmaceutical Co., Ltd .: trade name guaifenesin) were mixed and mixed in a glass bottle (3K standard bottle). And stored at 60 ° C. for 1 week. 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 is apparent from Table 4, the mixture of loxoprofen sodium hydrate and guaifenesin that had been stored was changed to a clear liquid after one day as a result of the interaction.

[Test Example 5] Examination of interaction (5)
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.5g and potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: potassium guaiacol sulfonate) mixed And stored in a glass bottle (3K standard bottle) 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, that is, the presence or absence of interaction, and the results are shown in Table 5.

  As can be seen from Table 5, the mixture of loxoprofen sodium hydrate and potassium guaiacol sulfonate, which had been stored, changed to a wet state after 3 days as a result of the interaction.

[Test Example 6] Examination of interaction (6)
Comparative Example 1: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) (225 mg) and guaifenesin (manufactured by Alps: trade name: guaifenesin) were mixed to obtain a mixture.
Example 1: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 225 mg, guaifenesin (manufactured by Alps: trade name: guaifenesin) 275 mg and anhydrous caffeine (manufactured by Shizuoka Caffeine Industries) : Trade name Anhydrous caffeine) 275 mg was mixed to obtain a mixture.
The mixtures of Comparative Example 1 and Example 1 were each placed in a glass bottle (3K standard bottle) and stored at 60 ° C. About these, the state of the mixture immediately after the start of storage, 1 day, 3 days, and 1 week later, that is, the presence or absence of interaction was evaluated, and the results are shown in Table 6.

As can be seen from Table 6, the mixture of loxoprofen sodium hydrate and guaifenesin that had been stored was changed to a clear liquid one day after the start of storage as a result of interaction (Comparative Example 1). . On the other hand, in addition to loxoprofen sodium hydrate and guaifenesin, the mixture which was further mixed and stored with anhydrous caffeine was suppressed in interaction as compared with Comparative Example 1 (Example 1).
When loxoprofen or a salt thereof and a xanthine derivative are mixed, an interaction occurs between these compounds, and the mixture solidifies (Test Examples 1 to 3). Surprisingly, from the results of Test Example 6, It has been found that xanthine derivatives improve the interaction between loxoprofen or a salt thereof and guaifenesin.

[Test Example 7] Examination of interaction (7)
Comparative Example 2: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) (225 mg) and potassium guaiacol sulfonate (trade name: Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: guaiacol potassium sulfonate) To obtain a mixture.
Example 2: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 225 mg, potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: potassium guaiacol sulfonate) and anhydrous 275 mg of caffeine (product name: anhydrous caffeine, manufactured by Shizuoka Caffeine Industry) was mixed to obtain a mixture.
The mixtures of Comparative Example 2 and Example 2 were each placed in a glass bottle (3K standard bottle) and stored at 60 ° C.
In addition, as Example 3, loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 225 mg, potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name, potassium guaiacol sulfonate) In addition to 275 mg of a mixture of 275 mg and anhydrous caffeine (Shizuoka Caffeine Kogyo: trade name anhydrous caffeine) 275 mg, 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) 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, and the results are shown in Table 7.

As is apparent from Table 7, the mixture of loxoprofen sodium hydrate and potassium guaiacol sulfonate stored in the mixture was changed to a wet state 3 days after the start of storage as a result of the interaction (comparison) Example 2). On the other hand, in addition to loxoprofen sodium hydrate and potassium guaiacol sulfonate, the mixture further mixed with anhydrous caffeine was suppressed in interaction as compared with Comparative Example 2 (Example 2). Further, it was found that, in addition to the formulation of Example 2, a further addition of a desiccant maintained the same state as immediately after the start of storage even after 1 week (Example 3).
When loxoprofen or a salt thereof and a xanthine derivative are mixed, an interaction occurs between these compounds, and the mixture solidifies (Test Examples 1 to 3). Surprisingly, from the results of Test Example 7, It has been found that xanthine derivatives improve the interaction between loxoprofen or a salt thereof and guaiacol sulfonic acid or a salt thereof. Further, it has been found that, in addition to the above three components, a further use of a desiccant further suppresses the interaction between loxoprofen or a salt thereof and guaiacol sulfonic acid or a salt thereof.

[Production Example 1]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 408.6g, Guaifenesin (Alps Pharmaceuticals: trade name Guaifenesin) 500g, Anhydrous caffeine (Shizuoka Caffeine Industry: Commodity) Name Anhydrous caffeine) 80 g, Hydroxypropyl cellulose (Nippon Soda: trade name HPC-L) 145.8 g, Carmellose calcium (product name: ECG505), 486 g, Crystalline cellulose (Asahi Kasei Chemicals: trade name Theolas PH -101) 3191 g was put into a high-speed stirring granulator (manufactured by Paulec: VG-25 type) and mixed, and then 1972.6 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.

[Production Example 2]
Loxoprofen sodium hydrate (trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, potassium guaiacol sulfonate (product name: Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name potassium guaiacol sulfonate), anhydrous caffeine (Shizuoka Caffeine Kogyo Kogyo Co., Ltd .: trade name anhydrous caffeine) 80 g, hydroxypropyl cellulose (Nippon Soda Co., Ltd .: trade name HPC-L) 145.8 g, carmellose calcium (manufactured by Gotoku Pharmaceutical: trade name ECG505) 486 g, crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: trade name: Theolas PH-101) 3191 g was put into a high-speed agitation granulator (Paurek: VG-25 type) and mixed, and then purified water 1972.6 g was added and kneaded, and granulated. I got a thing. 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). This granulated product 4811.4 g and magnesium stearate 48.6 g (manufactured by Taihei Chemical Industry: trade name magnesium stearate (vegetable)) were put into a mixer (manufactured by Kotobuki: PM50 type) and mixed, and then the diameter 8 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.

[Production Example 3]
Thirty tablets obtained in Production 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.

[Production Example 4]
Thirty tablets obtained in Production 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.

  According to the present invention, the interaction between loxoprofen or a salt thereof and a phenol derivative or a salt thereof can be suppressed. Therefore, a solid preparation containing loxoprofen or a salt thereof and a phenol derivative or a salt thereof having excellent storage stability can be provided.

Claims (9)

  A pharmaceutical composition comprising loxoprofen or a salt thereof, a phenol derivative or a salt thereof, and a xanthine derivative.   The pharmaceutical composition according to claim 1, wherein the loxoprofen or a salt thereof is loxoprofen sodium hydrate.   The pharmaceutical composition according to claim 1 or 2, comprising loxoprofen sodium hydrate in an amount of 10 to 300 mg per day in terms of anhydrous loxoprofen sodium. A phenol derivative or a salt thereof is represented by the following formula (1):

[Wherein, R ¹ represents an alkyl group or an alkoxy group which may have a substituent, and R ² represents a hydrogen atom or a sulfo group. ]
The compound or its salt represented by these, and the phenolic hydroxyl group of the compound represented by Formula (1) are 1 or more types chosen from the etherified compound or its salt, The any one of Claims 1-3 The pharmaceutical composition as described.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the phenol derivative or a salt thereof is one or more selected from guaifenesin, guaiacol sulfonic acid or a salt thereof, and cresol sulfonic acid or a salt thereof.   The pharmaceutical composition according to any one of claims 1 to 5, comprising 5 to 600 mg of a phenol derivative or a salt thereof as a daily dose.   The pharmaceutical composition according to any one of claims 1 to 6, comprising 10 to 1000 mg of a xanthine derivative as a daily dose.   A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 7 and a desiccant in a container.   An agent for improving the interaction between loxoprofen or a salt thereof and a phenol derivative or a salt thereof in a pharmaceutical composition, comprising a xanthine derivative as an active ingredient.