JP2011173861A - 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 clemastine or a salt thereof. <P>SOLUTION: The pharmaceutical composition contains loxoprofen or a salt thereof, clemastine 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 enhancement of anti-inflammatory, analgesic and antipyretic effects by combining with caffeine, ethenamide and acetaminophen (Patent Document 1), carbinoxamine maleate, chlorpheniramine malee Of nasal congestion by combining with acid salt, ketotifen fumarate, mequitazine and epinastine hydrochloride (Patent Document 2), inhibitory effect on goblet cell hyperplasia by combining with azelastine hydrochloride and mequitazine (Patent Document 3), etc. Is mentioned.
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 this patent document, combinations of loxoprofen with various drugs are studied. In addition, formulation examples in which loxoprofen and various drugs are combined are 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, clemastine or a salt thereof has an antihistamine action, and is a drug used as a general cold medicine, a rhinitis drug, an allergy drug, etc. as an antihistamine component (Non-patent Document 2). And as above-mentioned, as an effect | action obtained by combining a clemastine fumarate salt and a loxoprofen, the enhancement effect | action (patent document 6) of an antihistamine action is known.

  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.

Further, tablets containing caffeine or aminophylline and loxoprofen are known (Patent Documents 7, 8, and 9).
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 clemastine or a salt thereof in the preparation. There is no known pharmaceutical composition containing loxoprofen or a salt thereof, clemastine or a salt thereof, and a xanthine derivative.

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 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, Inc. Page 231 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 solid preparation containing loxoprofen or a salt thereof and clemastine or a salt thereof, and as a result, mixed loxoprofen or a salt thereof and clemastine or a salt thereof. Surprisingly, it has been found that there is an interaction between these compounds when stored, and this interaction causes wetting, discoloration and the like, resulting in problems with stability.
Accordingly, an object of the present invention is to provide a stable pharmaceutical composition containing loxoprofen or a salt thereof and clemastine or a salt thereof.

By the way, the inventors separately stored loxoprofen or a salt thereof and a xanthine derivative in order to examine the storage stability of a solid preparation containing loxoprofen or a salt thereof and a xanthine derivative. An interaction occurred between the compounds, and this interaction solidified the mixture, causing a problem in the storage stability of the mixture.
However, the present inventors have further studied to solve the above-mentioned problems. Surprisingly, despite the fact that the xanthine derivative causes the interaction as described above, surprisingly, the xanthine derivative is converted into loxoprofen or a salt thereof, And coexistence with clemastine or a salt thereof, it was found that the interaction between loxoprofen or a salt thereof and clemastine or a salt thereof was suppressed, and a pharmaceutical composition excellent in stability was obtained.

That is, the present invention provides a pharmaceutical composition containing loxoprofen or a salt thereof, clemastine or a salt thereof and 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 suppress the interaction between loxoprofen or a salt thereof and clemastine or a salt thereof. Therefore, according to the pharmaceutical composition of the present invention, a solid preparation containing loxoprofen or a salt thereof and clemastine or a salt thereof having excellent storage stability can be provided.

The pharmaceutical composition of the present invention comprises loxoprofen or a salt thereof, clemastine 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 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, the amount that can be taken 30-240 mg is more preferred, and the amount that can be taken 60-180 mg is even more preferred.

Clemastine or a salt thereof used in the pharmaceutical composition of the present invention includes clemastine itself and pharmaceutically acceptable salts of clemastine. Specific examples of the clemastine or a salt thereof include clemastine and clemastine fumarate, and clemastine fumarate is more preferable.
These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of clemastine or a salt thereof in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the sex, age, symptom, etc. of the user. The amount that can be taken 5 mg is preferred, the amount that can be taken 0.3 to 3 mg is more preferred, and the amount that can be taken 0.4 to 2 mg is more preferred. In addition, clemastine fumarate 1.34 mg is equivalent to 1 mg as clemastine.

  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 ¹ and R ² each independently represents a hydrogen atom or a methyl group. R ³ means a hydrogen atom, a methyl group, a monohydroxypropyl group or a dihydroxypropyl group. ]

In R ³ 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 ¹ is a methyl group, R ² is a methyl group, and R ³ is a methyl group means caffeine.
(2) R ¹ is a methyl group, R ² is a methyl group, and R ³ is a hydrogen atom means theophylline.
(3) R ¹ is a hydrogen atom, R ² is a methyl group, and R ³ is a methyl group means theobromine.
(4) R ¹ is a methyl group, R ² is a hydrogen atom, and R ³ is a methyl group means paraxanthine.
(5) A compound in which R ¹ is a methyl group, R ² is a methyl group, and R ³ is a 2-hydroxypropyl group means proxyphylline.
(6) The case where R ¹ is a methyl group, R ² is a methyl group, and R ³ 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 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, anhydrous caffeine, and sodium benzoate caffeine are preferable. Particularly preferred.

  The content of the xanthine derivative in the pharmaceutical composition of the present invention may be determined by appropriately examining, depending on the interaction inhibitory effect of loxoprofen and clemastine, the sex, age, symptoms, etc. of the user, per day, The amount that can be taken 10 to 1000 mg 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.

  The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose, but with respect to the total mass of the pharmaceutical composition, Loxoprofen or a salt thereof is preferably contained in an amount of 0.4 to 80% by mass in terms of loxoprofen sodium anhydride, more preferably 0.4 to 50% by mass, and 1.2 to 40% by mass. More preferred.

  The content of clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose, but clemastine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.008-0.4 mass% in conversion of the free body of clemastine with respect to mass, It is more preferable to contain 0.01-0.3 mass%, 0.015-0.25 mass% It is particularly preferable to contain it.

  The content ratio of loxoprofen or a salt thereof and clemastine or a salt thereof 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 the salt thereof is preferably one containing 0.0006 to 0.5 parts by mass of clemastine or a salt thereof, and 0.0012 to 0.1 parts by mass in terms of 1 part by mass in terms of loxoprofen sodium anhydride. More preferably, what contains 0.002-0.03 mass part is further more preferable.

  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.

The pharmaceutical composition of the present invention can be produced and formulated based on a known method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations. Examples of the dosage form of the pharmaceutical composition include solid preparations such as tablets, powders, granules, fine granules, pills, capsules and the like.
The pharmaceutical composition of the present invention is preferably a solid preparation containing three components of loxoprofen or a salt thereof and clemastine or a salt thereof and a xanthine derivative from the viewpoint of ease of administration and management of a drug dose.

  The solid preparation contains loxoprofen or a salt thereof, clemastine or a salt thereof and a xanthine derivative, but contains loxoprofen or a salt thereof and clemastine or a salt thereof in the solid preparation so as not to substantially contact each other. It may be 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) One of loxoprofen or a salt thereof, and clemastine or a salt thereof is granulated by an appropriate method to form a granular material, and a powder or a granule prepared by incorporating 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 clemastine or a salt thereof are separately granulated by an appropriate method to form a granular material, and a powder or a granule prepared by containing them, and the granular material are further suitable. Formulation coated by the 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) A multilayer tablet prepared so that loxoprofen or a salt thereof and clemastine or a salt thereof do not contact each other, and a preparation in which the multilayer tablet is further coated by an appropriate method. As the multi-layered tablet, as a multi-layered tablet having three or more layers, loxoprofen or a salt thereof, and clemastine or a layer containing loxoprofen or a salt thereof and a layer containing clemastine or a salt thereof are positioned so as not to contact each other. Examples thereof include those in which the salts are located in different layers. In addition, the granular material manufactured by said (i) and (b) can be used as loxoprofen or its salt, and clemastine or its salt. In the case of using these granular materials, a multilayer tablet having two or more layers can be obtained. In the multilayer tablet, the xanthine derivative may be located in either the layer containing loxoprofen or a salt thereof, the layer containing clemastine 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 clemastine 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, the granular material manufactured by said (i) and (b) can be used as loxoprofen or its salt, and clemastine or its salt. 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, and the pharmaceutical composition of the present invention is preferably a solid preparation and more preferably an oral administration preparation. In addition, the pharmaceutical composition of the present invention can be taken orally, divided into about 1 to 4 times per day, before meals, between meals, after meals, before going to bed.
In the present invention, a pharmaceutical composition containing loxoprofen or a salt thereof, clemastine or a salt thereof, and a xanthine derivative 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.

  In the present invention, the desiccant is not particularly limited as long as it can further suppress (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. It's okay.

  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 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 in the pharmaceutical preparation of the present invention may be determined by appropriate examination, but is preferably 0.05 to 35 parts by weight, and 0.15 to 17 parts by weight with respect to 1 part by weight of loxoprofen or a salt thereof. Part is more preferred.
The content of the desiccant is preferably 0.001 to 1.5 parts by mass with respect to 1 part by mass of the solid preparation of the present invention containing loxoprofen or a salt thereof, clemastine or a salt thereof, and a xanthine derivative. 0.001-1 mass part is more preferable, and 0.004-0.4 mass part is still more preferable.

  In the pharmaceutical composition of the present invention, as a pharmaceutical ingredient, a drug other than loxoprofen or a salt thereof, clemastine or a salt thereof and a xanthine derivative, such as an antipyretic analgesic, an antihistamine, an antitussive, a noscapine, a bronchodilator, an expectorant, hypnosis It may contain one or more selected from the group consisting of sedatives, vitamins, anti-inflammatory agents, gastric mucosa protective agents, anticholinergic agents, herbal medicines, Kampo prescriptions and the like. 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 diphenyldisulfonate, carbinoxamine maleate, d- Chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, dipheterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theoclurate, diphenhydramine hydrochloride, diphenhydramine salicylic acid Salt, diphenhydramine tannate, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate 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, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, dl. -Methylephedrine saccharin salt, methoxyphenamine hydrochloride, etc. are mentioned.

  As an expectorant, for example, ambroxol hydrochloride, ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, methylcysteine hydrochloride, Examples thereof include l-menthol and lysozyme hydrochloride.

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, tipidium 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 lamb), fennel (yuka), turmeric (depressed gold), engosaku (yenkogyo), enmaiso (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Owaku (yellow twilight), Spruce (cherry bark), Auren (yellow ream), Onji (distant), Gajutsu (weather), valerian (deer grass), chamomile, caronin (karojin), Licorice, licorice, bellflowers, kokushi (coconut), cucumber (cucumber leaves), keigai (cocoon), keihi (cinnamon), ketsumeishi (actual child), gentian, 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 (Sekiyu), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Otsuchi) Chiku Ginseng (bamboo ginseng), clove (clove), chimpi (Chen), Toki (to home), Tokon (root), Nantenjitsu (southern), carrot (carrot), baimo (shellfish mother), Bakumondou (baramon) Winter), mint (thin load), Hange (half-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 herbal medicines such as these and extracts thereof (extracts, tinctures, dry extracts, 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, and the like.

  The container used for the pharmaceutical preparation of the present invention is not particularly limited as long as it can be used as a container for foods, supplements, pharmaceuticals, health foods, and the like, but any of a fixed container and an amorphous container can be used and sealed. What is possible is preferred. Examples of the fixed container include bottles, cans, and boxes. Examples of the amorphous container include bags (pillow packaging, stick packaging, PTP packaging, SP packaging, etc.) and the like. Of these containers, specifically, bottles and bags are preferable.

The forming member of the container is not particularly limited, and examples thereof include paper, glass, 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 a loxoprofen or a salt thereof, clemastine or a salt thereof, and a xanthine derivative, and a desiccant in the container used in the present invention is not particularly limited. This can be achieved by arranging by an appropriate means such as charging in.

  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 It can be achieved by storing the salt, clemastine or a salt thereof, and a pharmaceutical composition containing a xanthine derivative in a bottle. When storing in a bottle, the pharmaceutical composition containing loxoprofen or a salt thereof, clemastine or a salt thereof, and a xanthine derivative is preferably a solid preparation containing these.

  In the case where the container is a bag, a pharmaceutical composition containing a desiccant (preferably a plate or bag-shaped sheet type), loxoprofen or a salt thereof, clemastine or a salt thereof, and a xanthine derivative is stored in the bag. Etc. can be achieved. When storing in a bag, the pharmaceutical composition containing loxoprofen or a salt thereof, clemastine or a salt thereof, and a xanthine derivative is preferably a solid preparation containing these.

  Furthermore, the pharmaceutical composition of the present invention can be once packaged by SP packaging, PTP packaging, a bag or the like, and then the packaged pharmaceutical composition and desiccant can 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, clemastine or an salt thereof having an antihistamine action, and a central excitatory action, a cardiotonic / diuretic action, a gastric acid secretion enhancing action, a smooth muscle relaxing action, etc. It contains xanthine derivatives, and the combination of loxoprofen or a salt thereof and clemastine or a salt thereof has an enhanced antihistamine action, so that headache, toothache, post-extraction pain, sore throat, ear pain, joint pain・ Neural pain, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain), pain relief, chills, antipyretic during fever, cold symptoms (nasal discharge, stuffy nose, Symptoms of sneezing, sore throat, chills, fever, headache, joint pain, muscle pain, acute rhinitis, allergic rhinitis or sinusitis (sneezing, runny nose (nasal discharge) Multi), nasal congestion, watery eyes, sore throat, Zuomo) etc. have the potency or effect, cold remedies, antipyretic analgesics, is useful as rhinitis for oral medicine or the like.
Moreover, the pharmaceutical composition of the present invention contains clemastine or a salt thereof. As will be apparent from the following test examples, clemastine or a salt thereof contained in the pharmaceutical composition of the present invention suppresses or reduces gastrointestinal disorders caused by loxoprofen. Therefore, patients suffering from peptic ulcer and patients with a past history can also take loxoprofen or a salt thereof without fear of gastrointestinal disorders caused by loxoprofen, and the pharmaceutical composition of the present invention is excellent. .

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 (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 0.5g and anhydrous caffeine (Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 0.61g are 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, after 1 month, and after 2 months, the state of the mixture, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 1.

  As is clear from Table 1, when loxoprofen and anhydrous caffeine were mixed and stored, the interaction occurred, and as a result, the mixture changed to a solidified state after one week.

[Test Example 2] Examination of interaction (2)
Loxoprofen sodium hydrate (manufactured by Yamato 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 Were put in a glass bottle (3K standard bottle) and stored at 40 ° C. and 75% 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 2.

  As is apparent from Table 2, when loxoprofen and sodium benzoate caffeine 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 (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 202.6 mg and sodium benzoate caffeine (manufactured by 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 3.

As is apparent from Table 3, when loxoprofen and sodium caffeine benzoate were mixed and stored, an interaction occurred, and as a result, the mixture changed to a solidified state after 1 day. became.
Moreover, it became clear from the result of the said Test Examples 1-3 that when loxoprofen or its salt, and a xanthine derivative are mixed, interaction will arise between these compounds (Tables 1-3).

[Test Example 4] Examination of interaction (4)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 497mg and clemastine fumarate (Daito: trade name: clemastine fumarate) 3mg are mixed, and glass bottle (3K standard bottle) And stored at 60 ° C. for 1 week (Comparative Example 1).
Separately, loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 497 mg, clemastine fumarate (trade name: clemastine fumarate) 3 mg and anhydrous caffeine 608 mg (Shizuoka Cafe) In Industrial Co., Ltd. product name: anhydrous caffeine) was mixed and stored at 60 ° C. as in Comparative Example 1 (Example 1).
In addition, loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 497 mg, clemastine fumarate (trade name: clemastine fumarate made by Daito) and 608 mg of anhydrous caffeine (Shizuoka Cafe) IN Industrial Co., Ltd .: trade name: anhydrous caffeine) was mixed, and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name: MS-W1506) was added as a desiccant in the bottle and stored at 60 ° C. in the same manner ( Example 2).
For each of Comparative Example 1 and Examples 1 and 2, the state of the mixture immediately after the start of storage, after 1 day, after 3 days, and after 1 week, that is, the presence or absence of interaction, was evaluated.

As is apparent from Table 4, in the case where loxoprofen sodium hydrate and clemastine fumarate were mixed and stored, as a result of interaction, the mixture became wet and further discolored (Comparative Example 1).
On the other hand, it was found that the above interaction was suppressed (improved) by further mixing anhydrous caffeine with loxoprofen sodium hydrate and clemastine fumarate (Example 1). Further, it was found that by mixing anhydrous caffeine and further using a desiccant, the same state as at the start was maintained, and the above interaction was further suppressed (improved) compared to Example 1. (Example 2).

In addition, from the results of Test Examples 1 to 4, it has been found that interaction occurs between loxoprofen or a salt thereof and a xanthine derivative, and between loxoprofen or a salt thereof and clemastine or a salt thereof (Test Example 1). ~ 4).
Therefore, when a xanthine derivative is mixed with loxoprofen or a salt thereof and clemastine or a salt thereof, the interaction between the three components is expected to increase.
However, it was surprisingly found that the xanthine derivative inhibits the interaction between loxoprofen or a salt thereof and clemastine or a salt thereof (Example 1).

[Test Example 5] Loxoprofen-induced gastrointestinal tract disorder inhibitory effect Using Wistar rats (Std: Wistar / ST, male, 8 weeks old, body weight 198.5-234.2 g), a test was conducted with 4 to 8 animals per group did. Rats were fasted from the day before the test (16 hours or longer). Water intake was free up to 1 hour before the start of the test, and then water was stopped.
As a test drug, clemastine fumarate (CF) was suspended in a 0.5% methylcellulose (MC) solution and orally administered in a predetermined amount (1 mg / 5 mL / kg). In the control group, only the solvent (0.5% MC) was orally administered in the same volume (5 mL / kg).
One hour after administration of the test drug, loxoprofen sodium hydrate 120 mg / 2 mL saline / kg was orally administered to each group of rats to induce gastric mucosal damage. Five hours after administration of loxoprofen sodium hydrate, the rats were euthanized by cervical dislocation, the cardia was ligated, and the stomach was removed. After injecting 10 mL of 1% formalin solution into the stomach from the pyloric region and ligating the pyloric region, the entire stomach was immersed in the formalin solution for about 20 minutes and fixed lightly.
Evaluation of the degree of gastric mucosal damage is performed by measuring the length (mm) of individual damage (erosion) occurring in the glandular stomach portion under a stereomicroscope after incising the stomach along the large curvature. The total damage per rat was calculated as the ulcer index. According to the following formula, the ulcer suppression rate (%) in the test drug was calculated, and the results are shown in Table 5.
Ulcer inhibition rate (%) = {1− (ulcer index of test drug / ulcer index of control group)} × 100

  As is apparent from Table 5, clemastine or a salt thereof reduced gastric mucosal damage caused by loxoprofen or a salt thereof.

[Example 3] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 2.7 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) 486g, crystalline cellulose (product name: Theolas PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.) 3688.3g was charged into a high-speed stirring granulator (manufactured by Paulek: model VG-25) and mixed, and then 1972.6g of purified water was added. Kneaded. 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 4] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical: Brand name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 2.7 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) 486g, lactose hydrate (DMV: trade name: lactose 200M) 3688.3g was put into a high-speed stirring granulator (Paurek: VG-25 type) and mixed, and then purified water 232g was added and kneaded. . 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 5] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical: Brand name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 2.7 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) 1844.3 g, crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name: Theolas PH-101) in a high-speed stirring granulator (manufactured by Paulek: VG-25) After charging and mixing, 696.2 g of purified water was added and kneaded. 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: Brand name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 2.7 g , Anhydrous caffeine (Shizuoka Caffeine: trade name anhydrous caffeine) 80 g, hydroxypropyl cellulose (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) 1229.5 g, crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name: Theolas PH-101), 1229.4 g, corn starch (manufactured by Nissho Chemical Co., Ltd .: trade name, corn starch ST-C ) 129.4g of high-speed stirring granulator (Paurek) : After mixing was poured into VG-25 type), it was kneaded with the addition of purified water 928.2G. 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]
Thirty tablets obtained in Example 3 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 8]
Thirty tablets obtained in Example 4 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 9]
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 10]
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.

  According to the present invention, the xanthine derivative suppresses the interaction between loxoprofen or a salt thereof and clemastine or a salt thereof. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition comprising loxoprofen or a salt thereof, and clemastine or a salt thereof having excellent storage stability.

Claims (9)

  A pharmaceutical composition comprising loxoprofen or a salt thereof, clemastine 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 2, comprising loxoprofen sodium hydrate as a daily dose of 10 to 300 mg in terms of loxoprofen sodium anhydride.   The pharmaceutical composition according to any one of claims 1 to 3, wherein clemastine or a salt thereof is clemastine fumarate.   The pharmaceutical composition according to any one of claims 1 to 4, comprising clemastine or a salt thereof as clemastine and 0.2 to 5 mg as a daily dose.   The pharmaceutical composition according to any one of claims 1 to 5, wherein the xanthine derivative is caffeine.   The pharmaceutical composition according to claim 6, 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 7, 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 8 and a desiccant in a container.