JP2016014063A - Loxoprofen-containing pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a stable pharmaceutical composition comprising loxoprofen or salt thereof and diphenylpyraline or salt thereof.SOLUTION: A pharmaceutical composition comprises loxoprofen or salt thereof, diphenylpyraline or salt thereof and a xanthine derivative.

Description

  The present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof.

  Loxoprofen is a type of non-steroidal anti-inflammatory analgesic (NSAID), including rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, cervical-shoulder arm syndrome, toothache, acute upper respiratory inflammation, post-surgical / post-traumatic It is known as effective for anti-inflammatory, analgesic and antipyretic after tooth extraction (Non-patent Document 1).

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, diphenylpyraline or a salt thereof is a drug that has an antihistaminic action and is used as a general cold medicine, a rhinitis medicine, etc. as an antihistamine component (Non-patent Document 2).

  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 7, 8, and 9).
However, a pharmaceutical composition containing loxoprofen and diphenylpyraline is not known, and it may affect the storage stability of these compounds between loxoprofen or a salt thereof and diphenylpyraline or a salt thereof in the preparation. It is not known whether or not an interaction occurs. Naturally, there is no known pharmaceutical composition containing three components of loxoprofen or a salt thereof, diphenylpyraline 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 365 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 studied the storage stability of a mixture containing these two components in order to develop a solid preparation containing loxoprofen or a salt thereof and diphenylpyraline or a salt thereof. It was found that an interaction occurs between these compounds, and this interaction causes solidification and the like, which causes a 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 diphenylpyrine or a salt thereof.

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 an interaction with loxoprofen or a salt thereof as described above is selected from loxoprofen or a salt thereof, and diphenylpyraline or a salt thereof. It has been surprisingly found that the interaction between loxoprofen or a salt thereof and diphenylpyraline 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, diphenylpyraline 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.

According to the present invention, the interaction between loxoprofen or a salt thereof and diphenylpyraline or a salt thereof can be improved. Accordingly, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof, and diphenylpyrine or a salt thereof having excellent storage stability.
Moreover, the pharmaceutical composition which improved the interaction containing loxoprofen or its salt, and diphenyl pyralin or its salt can be provided easily and cheaply without passing through a complicated process.
On the other hand, the present inventors have found that diphenylpyraline or a salt thereof reduces or suppresses gastrointestinal disorders caused by loxoprofen.
Therefore, according to the present invention, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and diphenylpyraline or a salt thereof, which has excellent storage stability and reduces or suppresses gastrointestinal disorders caused by loxoprofen. .

The pharmaceutical composition of the present invention comprises loxoprofen or a salt thereof, diphenylpyrine or a salt thereof and a xanthine derivative. First, among the three components, 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, 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.

Next, diphenylpyrine or a salt thereof will be described in detail.
The diphenyl pyralin or a salt thereof used in the pharmaceutical composition of the present invention includes not only diphenyl pyralin itself but also a pharmaceutically acceptable salt of diphenyl pyralin. Preferable specific examples of the diphenyl pyralin or a salt thereof include diphenyl pyralin, diphenyl pyralin hydrochloride, diphenyl pyralin theocuroate and the like, and these may be used alone or in combination of two or more. Among these, diphenylpyraline hydrochloride and diphenylpyraline theoculoate are preferable. These are known compounds and can be produced by a known method or commercially available.

  The content of diphenylpyralin 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, but 0.1-13. The amount that can be taken 5 mg is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred. In addition, when using a diphenyl pyraline hydrochloride as diphenyl pyraline or its salt, the quantity which can be taken | dosed 0.1-12 mg per day is preferable, and the quantity which can be taken | dosed 1-4 mg is more preferable. When using diphenylpyraline theocuroate, the quantity which can be taken | dosed 0.1-13.5 mg per day is preferable, and the quantity which can be taken | dosed 1-4.5 mg is more preferable.

Next, the xanthine derivative will be described in detail.
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 represent a hydrogen atom or a methyl group, and R ³ represents 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 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 between loxoprofen and diphenylpyraline, the sex, age, symptom, etc. of the user. The amount that can be taken is preferably 10 to 1000 mg, more preferably 20 to 800 mg, and still more preferably 40 to 600 mg.

  The content ratio of loxoprofen or a salt thereof and diphenylpyraline 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 one containing 0.0001 to 1 part by mass of diphenylpyraline or a salt thereof per 1 part by mass in terms of loxoprofen sodium anhydride, and one containing 0.0005 to 0.5 parts by mass. 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.

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.
The dosage form is not particularly limited. For example, oral dosage formulations such as capsules, pills, granules, fine granules, powders, tablets, solutions, syrups, jellies, troches, external preparations, ointments, etc. Preparations, creams, gel creams, cataplasms, transdermal preparations, patches, liniments, lotions, suppositories and the like. Among these, solid preparations are preferable from the viewpoint of convenience of administration and management of drug doses. Examples of the solid preparation include oral solid preparations such as capsules, pills, granules, fine granules, powders, tablets and troches, and parenteral solid preparations such as suppositories. Among these, an oral solid preparation is preferable.
The pharmaceutical composition of the present invention may be coated with a sugar coating or a film coating by a known method.

  The pharmaceutical composition of the present invention may be prepared and formulated by containing loxoprofen or a salt thereof and diphenylpyrine or a salt thereof in the pharmaceutical composition so that they do not substantially contact each other in terms of inhibition of interaction. Good. 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. 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 produced by granulating any one of loxoprofen or a salt thereof and diphenylpyrine or a salt thereof into a granular material, 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 diphenylpyraline or a salt thereof are separately granulated by an appropriate method to form granules, and powders and granules produced 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) Multi-layer tablets prepared so that loxoprofen or a salt thereof and diphenylpyraline or a salt thereof do not contact each other, and a preparation in which the multi-layer tablet is further coated by an appropriate method. The multi-layered tablet is preferably one in which loxoprofen or a salt thereof and diphenylpyraline or a salt thereof are positioned in different layers, and as a multi-layered tablet having three or more layers, a layer containing loxoprofen or a salt thereof and diphenylpyraline or a salt thereof More preferably, the salt-containing layers are positioned so as not to contact each other. In addition, the granular material manufactured by said (i) and (b) can be used as a loxoprofen or its salt, and diphenyl pyralin or its salt. In the multilayer tablet, the xanthine derivative may be located in either the layer containing loxoprofen or a salt thereof, or the layer containing diphenylpyraline 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 either one of loxoprofen or a salt thereof and diphenylpyralin 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 a loxoprofen or its salt, and diphenyl pyralin 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 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, diphenyl pyralin 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 further suppress or improve the interaction when stored together with the pharmaceutical composition of the present invention. Also, the shape is not limited, and examples thereof include a plate-shaped or bag-shaped sheet mold, a cylinder (tablet mold), etc., and a cylinder with paper wrapping or film coating. But you can.

  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.
In addition, the content of the desiccant is preferably 0.001 to 1 part by mass with respect to 1 part by mass of the solid preparation of the present invention containing loxoprofen or a salt thereof, diphenylpyralin or a salt thereof, and a xanthine derivative. 0.004-0.4 mass part is more preferable.

  In the pharmaceutical composition of the present invention, as a pharmaceutical ingredient, a drug other than loxoprofen or a salt thereof, diphenylpyraline or a salt thereof and a xanthine derivative, such as an antipyretic analgesic, an antihistamine, an antitussive, a noscapine, a bronchodilator, an expectorant, It may contain one or more selected from the group consisting of hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosa protective agents, anticholinergic agents, herbal medicines, Chinese herbal 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, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, dipheterol phosphate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, Triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, mequitazine, methodirazine hydrochloride, Bed 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 (Ishizuchi), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Oiso), Chixetsu Carrot (Takebushi Ginseng), Clove (Chiko), Chimp (Chan), Toki (Toki), Tokon (Nanten), Carrot (Ginseng), Baimo (Shell), 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 (Oysters), maou (mao), rokjo (deer) ) And the like of crude drugs and extracts thereof (extract, tincture, dry extract, 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, and the like.

  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 metal film. 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, diphenylpyraline 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 may be appropriately charged into the container. This can be achieved by arranging by various 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 It can be achieved by storing the salt, diphenylpyralin or a salt thereof, and a xanthine derivative in a bottle. When storing in a bottle, loxoprofen or a salt thereof, diphenylpyraline or a salt thereof, and a xanthine derivative are preferably solid preparations containing these.

  Further, when the container is a bag, it can be achieved by storing a desiccant (preferably, a plate-type or bag-shaped sheet type), loxoprofen or a salt thereof, and a xanthine derivative in the bag. When storing in a bag, loxoprofen or a salt thereof, diphenylpyraline 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 or a salt thereof, which is a kind of NSAID, diphenylpyraline or a salt thereof having an antihistamine action, and central excitatory action, cardiotonic / diuretic action, gastric acid secretion enhancing action, smooth muscle relaxing action, etc. Because it contains xanthine derivatives, it has 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 (physiology) Pain) / traumatic pain relief, chills / antipyretic fever, cold symptoms (nasal discharge, stuffy nose, sneezing, sore throat, chills, fever, headache, joint pain, muscle pain), acute rhinitis, Efficacy or effects on allergic rhinitis or sinusitis symptoms (sneezing, runny nose (excessive nasal discharge), stuffy nose, sore eyes, sore throat, headache), etc., for cold medicine, antipyretic analgesics, rhinitis Internal medicine As useful.
Moreover, the diphenyl pyralin which concerns on the pharmaceutical composition of this invention, or its salt can suppress the digestive tract disorder | damage | failure resulting from a loxoprofen as evident from a postscript test example. Accordingly, gastrointestinal disorders caused by loxoprofen are suppressed, and patients suffering from peptic ulcer and patients with a history of history can also take the pharmaceutical composition of the present invention.

  Hereinafter, the present invention will be described in detail 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, the state of the mixture after 1 week, 1 month, and 2 months, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 1.

  As is apparent from Table 1, when loxoprofen sodium hydrate 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 (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, the state of the mixture after 1 week, 1 month, and 2 months, ie, the presence or absence of interaction, was evaluated. 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 (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 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)
Comparative Example 1: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 490.5 mg and diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name: diphenylpyraline hydrochloride) mixed To obtain a mixture.
Example 1: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 490.5 mg, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name: diphenylpyralin hydrochloride) and anhydrous 600 mg of caffeine (manufactured by Shizuoka Caffeine Kogyo: trade name anhydrous caffeine) 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.

In addition, as Example 2, loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 490.5 mg, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name, diphenylpyraline hydrochloride) 9. In addition to a mixture of 5 mg and anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 600 mg, 1 g of synthetic zeolite (made by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) is added to a glass bottle (3K standard bottle). And stored at 60 ° C. (Example 2).
For each, the state of the mixture immediately after the start of storage, 1 day, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated. The results are shown in Table 4.

  As is apparent from Table 4, the mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochloride that had been stored was solidified after 1 day from the start of storage as a result of interaction (Comparative Example 1). . On the other hand, in addition to loxoprofen sodium hydrate and diphenylpyraline hydrochloride, the mixture further mixed with anhydrous caffeine inhibited the interaction as compared with the formulation of Comparative Example 1 (Example 1). Moreover, it turned out that what added the desiccant to the prescription of Example 1 maintains the same state as immediately after a storage start, even if 1 week passes (Example 2).

  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 4, It has been found that xanthine derivatives improve the interaction between loxoprofen or a salt thereof and diphenylpyraline or a salt thereof. It was also found that the interaction between loxoprofen or a salt thereof and diphenylpyrine or a salt thereof is further suppressed by using a desiccant in addition to the above three components.

[Example 3] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride), 8 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, Crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd .: trade name: Theolas PH-101) was charged into a high-speed agitation granulator (manufactured by Paulek: model VG-25) and mixed, and then 1972.6 g of purified water was added and kneaded. A granulated product was obtained. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 4] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 8 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) 3683 g is put into a high speed stirring granulator (Paurek: model VG-25) and mixed, and then 232 g of purified water is added and kneaded to form a granulated product. Got. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 5] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name: diphenylpyraline hydrochloride), 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 (DMV: trade name: lactose 200M) 1842g and crystalline cellulose (Asahi Kasei Chemicals: trade name: Theolas PH-101) 1841g are charged into a high-speed stirring granulator (Paurek: VG-25 type) and mixed. Thereafter, 696.2 g of purified water was added and kneaded to obtain a granulated product. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 6] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 8 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) 1228 g, crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name: Theolas PH-101) 1228 g, corn starch (manufactured by Nippon Star Chemical Co., Ltd .: trade name: corn starch ST-C) 1227 g at high speed Agitation granulator (Powrec: V After mixing it was charged to -25 inch), kneaded with the addition of purified water 928.2G, to obtain a granulated product. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 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.

[Test Example 5] Loxoprofen-induced gastrointestinal tract disorder inhibitory effect Wistar rats (Std: Wistar / ST, male, 8 weeks old, body weight 198.5 to 216.6 g) were used, and the test was carried out as 4 animals per group. 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, diphenylpyraline hydrochloride (PP) was suspended in a 0.5% methylcellulose (MC) solution, and a predetermined amount (3, 10 mg / 5 mL / kg) was orally administered. 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. The ulcer suppression rate (%) in the test drug was calculated according to the following formula.
Ulcer inhibition rate (%) = {1− (ulcer index of test drug / ulcer index of control group)} × 100
The results are shown in Table 5.

  As can be seen from Table 5, diphenylpyralin reduced gastric mucosal damage caused by loxoprofen.

The xanthine derivative suppresses the interaction between loxoprofen or a salt thereof and diphenylpyraline or a salt thereof. In addition, diphenylpyralin or a salt thereof reduces or suppresses gastrointestinal disorders caused by loxoprofen.
Therefore, according to the present invention, not only the effects and effects of loxoprofen or a salt thereof and diphenylpyraline or a salt thereof are exhibited, but also storage stability is excellent, and gastrointestinal disorders caused by loxoprofen are reduced or suppressed. Can be provided. According to the present invention, patients suffering from peptic ulcers and patients with a history of history can also take loxoprofen or a salt thereof without fear of gastrointestinal disorders caused by loxoprofen.
According to the present invention, it is possible to provide a very useful pharmaceutical composition containing loxoprofen or a salt thereof and diphenylpyraline or a salt thereof.

Claims (10)

  A pharmaceutical composition comprising loxoprofen or a salt thereof, diphenylpyraline 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 the diphenylpyraline or a salt thereof is diphenylpyraline hydrochloride or diphenylpyraline theocrate.   The pharmaceutical composition according to any one of claims 1 to 4, comprising 0.1 to 13.5 mg of diphenylpyralin or a salt thereof 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.   The pharmaceutical composition according to any one of claims 1 to 8, which is a solid preparation.   The pharmaceutical formulation which contains the pharmaceutical composition and desiccant of any one of Claims 1-9 in a container.