JP2011116750A - Loxoprofen-containing pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that is excellent in shelf stability and contains loxoprofen or a salt thereof and codeines. <P>SOLUTION: The pharmaceutical composition contains loxoprofen or a salt thereof, codeines 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, codeines are known to be narcotic antitussive components having an antitussive action by suppressing the function of the cough center. And based on this action, it is a drug used as a general cold medicine and antitussive expectorant as an antitussive component (Non-patent Document 2).
Several combinations of loxoprofen and codeines are known. For example, the combination of loxoprofen and dihydrocodeine hydrochloride enhances the anti-inflammatory effect (Patent Document 6), and the combination of loxoprofen and codeine phosphate exhibits an airway goblet cell hyperplasia inhibitory effect (Patent Document 8). Are known.
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 codeines in the preparation.

  As xanthine derivatives, caffeine, theophylline, paraxanthine, theobromine, aminophylline, diprofylline, proxyphylline, etc. are known. Of these, caffeine is a central excitatory action, cardiac / diuretic action, gastric acid secretion enhancing action, smooth muscle relaxation. It is a drug that shows action and the like, and is used for antipyretic analgesics, general cold medicines, antitussive expectorants 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.

  Incidentally, tablets containing caffeine or aminophylline and loxoprofen are known (Patent Documents 7, 9 and 10).

In addition, tablets and solutions containing loxoprofen or a salt thereof, codeines, and a xanthine derivative are known (Patent Documents 2 and 4).
Patent Document 2 discloses a tablet (one tablet 200 mg) prepared based on a conventional method such as mixing 90 g of loxoprofen sodium, 24 g of dihydrocodeine phosphate, 150 g of theophylline, 75 g of anhydrous caffeine, etc., and Patent Document 4 discloses loxoprofen sodium. Tablets (one tablet 200 mg) prepared by mixing directly with 150 g, dihydrocodeine phosphate 24 g, theophylline 150 g, anhydrous caffeine 75 g, etc. are described specifically.
However, as described above, it is not known whether codeine and loxoprofen interact with each other. Furthermore, it is not known at all that the xanthine derivative improves the interaction.

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 JP 2007-314517 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 289 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 pharmaceutical composition containing loxoprofen or a salt thereof and codeine, and found that loxoprofen or a salt thereof and codeine were mixed and stored. Surprisingly, it has been found that an interaction occurs between these compounds, and this interaction causes solidification, discoloration and the like, resulting in a problem in stability.
Accordingly, an object of the present invention is to provide a stable pharmaceutical composition containing loxoprofen or a salt thereof and codeine.

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 problems, and as a result, a xanthine derivative that causes an interaction with loxoprofen or a salt thereof as described above,
When coexisting with loxoprofen or a salt thereof and codeine, it was surprisingly found that the interaction between loxoprofen or a salt thereof and codeine is suppressed, and a pharmaceutical composition excellent in stability can be obtained.

1) That is, the present invention provides a pharmaceutical composition containing loxoprofen or a salt thereof, codeines and a xanthine derivative.
2) Moreover, this invention provides the pharmaceutical composition which contains the pharmaceutical composition of said 1), and a desiccant in a container.

  The xanthine derivative suppresses the interaction between loxoprofen or a salt thereof and codeine. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition such as a solid preparation containing loxoprofen or a salt thereof and codeine having excellent storage stability.

<Pharmaceutical composition>
First, the pharmaceutical composition of the present invention will be described.
The pharmaceutical composition of the present invention contains loxoprofen or a salt thereof, codeines 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. For example, per day, in terms of loxoprofen sodium anhydride equivalent The amount that can be taken 10 to 300 mg is preferred, the amount that can be taken 30 to 240 mg is more preferred, and the amount that can be taken 60 to 180 mg is more preferred.

  The codeines used in the pharmaceutical composition of the present invention mean one or more selected from the group consisting of codeine, dihydrocodeine, salts thereof and solvates thereof. This group includes codeine and dihydrocodeine itself, as well as pharmaceutically acceptable salts of codeine and dihydrocodeine and solvates thereof. Preferred specific examples in this group include codeine, dihydrocodeine, codeine phosphate hydrate, dihydrocodeine phosphate and the like from the viewpoint of using the pharmaceutical composition of the present invention as a general cold medicine. Salt hydrate and dihydrocodeine phosphate are more preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of codeine in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the gender, age, symptom of the user, and the effect of reducing or suppressing the gastrointestinal tract disorder caused by the observed loxoprofen, For example, the amount that can be taken 2 to 60 mg per day is preferable, the amount that can be taken 4 to 48 mg is more preferable, and the amount that can be taken 6 to 36 mg is more preferable. In addition, when using codeine phosphate hydrate as codeine, the quantity which can be taken | dosed 4-60 mg per day is preferable, the quantity which can be taken | dosed 8-48 mg is more preferable, and the quantity which can be taken | dosed 12-36 mg is further more preferable. Moreover, when using dihydrocodeine phosphate, the quantity which can be taken | dosed 2-30 mg per day is preferable, the quantity which can be taken | dosed 4-24 mg is more preferable, and the quantity which can be taken | dosed 6-24 mg is further more preferable.

  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. In the present invention, one or more of these xanthine derivatives can be used.

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

  The content of the xanthine derivative in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the sex, age, symptom, and observed interaction improvement effect of the user. The amount that can be taken 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 blending ratio of loxoprofen or a salt thereof and codeine 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. What contains 0.005-4 mass parts codeine is preferable with respect to 1 mass part of loxoprofen sodium anhydride conversion, The thing containing 0.01-2 mass parts is more preferable, 0.02-1 What contains a mass part is especially preferable.

  In addition, the blending ratio of loxoprofen or a salt thereof and xanthine derivative contained in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the daily dose of each component described above. From the standpoint of action suppression and the like, it is preferable that loxoprofen or a salt thereof contains 0.03 to 100 parts by mass of a xanthine derivative with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and contains 0.08 to 27 parts by mass. More preferred are those containing 0.2 to 10 parts by mass.

The pharmaceutical composition of the present invention can be produced and formulated by a known method described in, for example, the 15th revised Japanese Pharmacopoeia General Rules for Preparations. In addition, the dosage form is not particularly limited, and for example, oral dosage formulations such as capsules, pills, granules, fine granules, powders, tablets, liquids, syrups, jellies, lozenges, etc. Examples include parenteral preparations such as external preparations, ointments, creams, gel creams, poultices, transdermal preparations, patches, liniments, lotions and suppositories. Among these, in the present invention, solid preparations are preferable. Examples of solid preparations include oral solid preparations such as capsules, pills, granules, fine granules, powders, tablets, and troches, and suppositories. Examples include parenteral solid preparations, and oral solid preparations are preferred.
The pharmaceutical composition of the present invention may be coated with a sugar coating or a film coating by a known method.

The pharmaceutical composition of the present invention preferably does not contain the following (a) to (d).
(A) Loxoprofen sodium hydrate 90 g, noscapine 48 g, dihydrocodeine phosphate 24 g, ketotifen fumarate 4 g, ambroxol hydrochloride 45 g, phenylpropanolamine 60 g, theophylline 150 g, lysozyme hydrochloride 90 g (potency), anhydrous Tablets (1 tablet 200 mg) prepared by mixing 75 g of caffeine, 8 g of vitamin B ₁ nitrate, 4 g of vitamin B ₂ , 350 g of lactose, 320 g of microcrystalline cellulose, 16 g of magnesium stearate and 16 g of hardened castor oil,
(B) Loxoprofen sodium hydrate 150 g, noscapine 48 g, dihydrocodeine phosphate 24 g, ketotifen fumarate 2 g, ambroxol hydrochloride 45 g, phenylpropanolamine 60 g, theophylline 150 g, lysozyme hydrochloride 90 g (potency), anhydrous Tablets (1 tablet 200 mg) made by mixing 75 g of caffeine, 8 g of vitamin B ₁ nitrate, 4 g of vitamin B ₂ , 150 g of lactose, 150 g of microcrystalline cellulose, 22 g of magnesium stearate and 22 g of hardened castor oil,
(C) Loxoprofen sodium hydrate 120 g, dihydrocodeine phosphate 24 g, epinastine hydrochloride 20 g, dl-methylephedrine hydrochloride 60 g, ambroxol hydrochloride 45 g, anhydrous caffeine 75 g, vitamin B ₁ nitrate 8 g, vitamin B ₂ 4 g, sucrose fatty acid ester 15 g, mannitol 15 g, stevia 10 g, ethyl aminobenzoate 5 g and orange flavor 0.8 g, and (d) loxoprofen sodium hydrate 100 g, dihydrocodeine phosphate 24 g, epinastine hydrochloride 20 g, dl-methylephedrine hydrochloride 60 g, ambroxol hydrochloride 45 g, anhydrous caffeine 75 g, vitamin B ₁ nitrate 8 g, vitamin B ₂ 4g, sucrose fatty acid ester 1 g, sweeteners qs, solutions containing a preservative qs and Perfume qs (1000 ml).

Moreover, as a pharmaceutical composition of this invention, what does not contain the following (a-2), (c-2), and (d-2) is more preferable.
(A-2) Loxoprofen sodium hydrate, noscapine, dihydrocodeine phosphate, ketotifen fumarate, ambroxol hydrochloride, phenylpropanolamine, theophylline, lysozyme hydrochloride, anhydrous caffeine, vitamin B ₁ nitrate, vitamin B ₂ , tablets (one tablet 200 mg) made by mixing lactose, microcrystalline cellulose, magnesium stearate and hydrogenated castor oil,
(C-2) Loxoprofen sodium hydrate, dihydrocodeine phosphate, epinastine hydrochloride, dl-methylephedrine hydrochloride, ambroxol hydrochloride, anhydrous caffeine, vitamin B ₁ nitrate, vitamin B ₂ , sucrose fatty acid ester , Liquid containing mannitol, stevia, ethyl aminobenzoate and orange flavor (1000 ml), and (d-2) loxoprofen sodium hydrate, dihydrocodeine phosphate, epinastine hydrochloride, dl-methylephedrine hydrochloride, ambroxy A solution (1000 ml) containing sole hydrochloride, anhydrous caffeine, vitamin B ₁ nitrate, vitamin B ₂ , sucrose fatty acid ester, sweetener, preservative and flavor.

Moreover, as a pharmaceutical composition of this invention, what does not contain the following (a-3)-(d-3) is more preferable.
(A-3) Loxoprofen sodium hydrate, dihydrocodeine phosphate, ketotifen fumarate, theophylline and anhydrous caffeine mixed tablets,
(B-3) tablets prepared by mixing loxoprofen sodium hydrate, dihydrocodeine phosphate, ambroxol hydrochloride, theophylline and anhydrous caffeine,
(C-3) Loxoprofen sodium hydrate, dihydrocodeine phosphate, epinastine hydrochloride, dl-methylephedrine hydrochloride and a solution containing anhydrous caffeine, and (d-3) loxoprofen sodium hydrate, dihydrocodeine phosphate A solution containing a salt, dl-methylephedrine hydrochloride, ambroxol hydrochloride and anhydrous caffeine.

  Moreover, when the pharmaceutical composition of the present invention is a solid preparation, those not containing the tablets of (a) and (b) are preferred, those not containing (a-2) are more preferred, and (a- Those not containing 3) and (b-3) are more preferred.

  As the pharmaceutical composition of the present invention, in view of interaction inhibition, it is more preferable that loxoprofen or a salt thereof and codeine in the pharmaceutical composition are contained, manufactured and formulated so as not to contact each other substantially. 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. When the pharmaceutical composition of the present invention is a solid preparation, examples of the form thereof include (a) to (f) below, and these can be produced and formulated by a known method.

(I) One of loxoprofen or a salt thereof, and codeine is granulated by an appropriate method to form a granular material, and the other is not granulated. 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 codeine are separately granulated by an appropriate method to form granules, and powders and granules produced by containing these, and the granules are further processed by an appropriate method. Coated formulation. 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 multi-layer tablet prepared so that loxoprofen or a salt thereof and codeine 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 codeine are located in different layers, and as a multi-layered tablet having three or more layers, a layer containing loxoprofen or a salt thereof and a layer containing codeine are mutually attached. What was located so that it may not contact | connect is more preferable. In addition, as the loxoprofen or a salt thereof and codeine, the granular material produced in the above (i) or (b) can be used. In the multilayer tablet, the xanthine derivative may be located in either the layer containing loxoprofen or a salt thereof or the layer containing codeines, or may be separately located 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 codeine is arranged in a nuclear tablet, and a preparation in which the dry-coated tablet is further coated by an appropriate method. In addition, as the loxoprofen or a salt thereof and codeine, the granular material produced in the above (i) or (b) can be used. In the dry-coated tablet, the xanthine derivative may be positioned in the core tablet, may be positioned in the outer shell, or may be separately positioned in either the core tablet or the outer shell.

Examples of the route of administration of the pharmaceutical composition of the present invention include oral and parenteral such as rectal and vaginal routes. The route of administration of the pharmaceutical composition of the present invention is preferably oral administration. 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.
The pharmaceutical composition of the present invention may be further stored in the presence of a desiccant from the viewpoint of interaction inhibition. Hereinafter, what contains the pharmaceutical composition and desiccant of this invention in a container may be called "pharmaceutical formulation" of this invention.

<Pharmaceutical formulation>
Next, the pharmaceutical preparation of the present invention will be described in detail.
In the present invention, the desiccant is not particularly limited. 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 are mentioned, What mixed these and activated carbon may be sufficient. 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.
In addition, the shape of the desiccant is not particularly limited, and examples thereof include a plate-shaped or bag-shaped sheet mold, a cylinder-shaped (tablet mold), and the like. A film-coated one may also be used.

  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, OZO, 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 part by mass with respect to 1 part by mass of the solid preparation of the present invention containing loxoprofen or a salt thereof, codeines, and a xanthine derivative. 0.4 parts by mass is more preferable.

  In the pharmaceutical composition of the present invention, as a pharmaceutical ingredient, a drug other than loxoprofen or a salt thereof, codeines and xanthine derivatives, such as antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotic sedatives In addition, one or more selected from the group consisting of vitamins, anti-inflammatory agents, gastric mucosa protective agents, anticholinergic agents, herbal medicines, Kampo prescriptions and the like may be included.

  Examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, sazapyrine, salicylamide, sodium salicylate, thiaramide hydrochloride, lactylphenetidine, and the like.

  Antihistamines include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, clemastine fumarate. Acid salt, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, dipheterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine Hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethad Methylene two salicylates, mequitazine, methdilazine hydrochloride, main blanking hydro Linna Paji sill acid salts.

  Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, dibutate sodium, dimemorphan phosphate, dextromethorphan bromide Examples thereof include hydroacid salts, dextromethorphan / phenolphthalin salts, 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 (bamboo ginseng), clove (clove), chimpi (chonse), touki (to home), tokong (napping root), Nantenjitsu (southern), carrot (carrot), baimo (shellfish), bacmond (wheat) Gate winter), mint (light load), Hange (semi-summer), bankouka (banka), hampi (anti-nose), juniper (white bean), juniper (white moth), bukkuri (茯苓), button pi (peony skin), volley (Oyster), maou (mao), rokjo (deer moth) ) And their extracts (extracts, tinctures, dried extracts, etc.) and the like.

  Examples of Kampo prescriptions include Keishi-yu, Kosou-san, Saiko-Kei-do, Sho-saiko-yu, Bakumon-fu-to, Hanka-koboku-yu, 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 for storing the pharmaceutical composition containing loxoprofen or a salt thereof, codeine and xanthine derivative, and the desiccant used in the present invention in the container is not particularly limited, and both are put into the container. It can be achieved by arranging by appropriate means such as.

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

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

  Further, the pharmaceutical composition of the present invention may be once packaged by SP packaging, PTP packaging or a bag, and then the packaged pharmaceutical composition and desiccant may be enclosed in a bag. More specifically, the form 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 comprises loxoprofen, which is a kind of NSAID, or a salt thereof, antitussive activity, codeines having an inhibitory / reducing effect on gastrointestinal disorders caused by loxoprofen, and central excitatory activity, cardiac / diuretic activity, gastric acid secretion Contains xanthine derivatives that have an enhancing action, smooth muscle relaxation action, etc., so headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, shoulder pain, bruise pain, fracture Pain, cramps, menstrual pain, menstrual pain, trauma pain relief, chills, fever during fever, cold symptoms (sore throat, cough, tan, chills, fever, headache, joint pain, muscle pain Pain), cough, sputum, etc., and is useful as a cold medicine, antipyretic analgesic and the like.
Moreover, the present inventors have found that codeine suppresses / reduces gastrointestinal disorders caused by loxoprofen, as will be apparent from the test examples described later. Therefore, patients suffering from peptic ulcer and patients with a history of history can also take loxoprofen or a salt thereof without fear of gastrointestinal disorders caused by loxoprofen.
That is, according to the present invention, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and codeine, which is excellent in storage stability and has reduced or suppressed gastrointestinal disorders caused by loxoprofen.

  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 Example 1: 0.5 g of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) and 0.61 g of anhydrous caffeine (Shizuoka Caffeine Industry) (Product name: Anhydrous caffeine) was mixed to obtain a mixture.
Example 2: Loxoprofen sodium hydrate 0.5 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and sodium benzoate caffeine 0.74 g (manufactured by Shizuoka Caffeine Industry: trade name: sodium benzoate) Caffeine) was mixed to obtain a mixture.
The mixtures of Examples 1 and 2 were each placed in a glass bottle (3K standard bottle) and stored at 40 ° C. and 75% RH. Immediately after the start of storage, the state of the mixture after 1 week, 1 month, and 2 months, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 1.

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

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

As is apparent from Table 2, when loxoprofen sodium hydrate and sodium caffeine benzoate were mixed and stored, an interaction occurred, resulting in the mixture changing to a solidified state after 1 day. Similar results were obtained.
From the results of Test Examples 1 and 2, it was revealed that when loxoprofen or a salt thereof and a xanthine derivative were mixed, an interaction occurred between these compounds.

[Test Example 3] Examination of interaction (3)
Loxoprofen sodium hydrate 0.5 g (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and dihydrocodeine phosphate 60 mg (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi”) It put into the glass bottle (3K specification bottle), and preserve | saved at 60 degreeC. Immediately after the start of storage, 1 day, 3 days, and 1 week later, the state of the mixture, that is, the presence or absence of interaction was evaluated, and the results are shown in Table 3.

  As is clear from Table 3, the mixture of loxoprofen sodium hydrate and dihydrocodeine phosphate that had been preserved only solidified after one day and changed color after one week as a result of the interaction. did.

[Test Example 4] Examination of interaction (4)
Comparative Example 1: Loxoprofen sodium hydrate 495 mg (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and dihydrocodeine phosphate 5 mg (Shiono Yoshimi: trade name: dihydrocodeine phosphate “Shionogi”) To obtain a mixture.
Example 1: Loxoprofen sodium hydrate 495 mg (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), dihydrocodeine phosphate 5 mg (manufactured by Shionogi Pharmaceutical: trade name dihydrocodeine phosphate “Shionogi”) and anhydrous Caffeine 500 mg (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) was mixed to obtain a mixture.
The mixtures of Comparative Example 1 and Example 1 were put in glass bottles (3K standard bottles) and stored at 60 ° C. As Example 2, in addition to the mixture of Example 1, 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) was put in a glass bottle (3K standard bottle) and stored at 60 ° C.
For each, the state of the mixture immediately after the start of storage, 1 day, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated. The results are shown in Table 4.

As is clear from Table 4, the mixture of loxoprofen sodium hydrate and dihydrocodeine phosphate that had been preserved only solidified after 1 day from the start of preservation as a result of the interaction (Comparative Example 1). ).
On the other hand, in addition to loxoprofen sodium hydrate and dihydrocodeine phosphate, anhydrous caffeine further mixed and stored maintained the same state as at the beginning after one week, and the above interaction was suppressed. (Example 1). Further, it was found that the addition of a desiccant in addition to the mixing of anhydrous caffeine also maintained the same state as at the start even after 1 week, and the above interaction was suppressed (Example 2). .

  From the results of Test Examples 1 to 4, when loxoprofen or a salt thereof and a xanthine derivative, or loxoprofen or a salt thereof and codeine were mixed, respectively, despite the interaction between these compounds (Test Example) 1-3) Surprisingly, it was found that the interaction between loxoprofen and codeines was suppressed by the xanthine derivative (Test Example 4).

[Example 3] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi” ) 48 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 (manufactured by Gotoku Pharmaceutical: trade name) 486 g of ECG505) and 3643 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name Theolas PH-101) are put into a high-speed agitation granulator (manufactured by Paulek: model VG-25) and mixed, and then 1972.6 g of purified water is 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 4] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi” ) 48 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 (manufactured by Gotoku Pharmaceutical: trade name) ECG505) 486 g and lactose hydrate (DMV: trade name: lactose 200M) 3643 g were put in a high-speed agitation granulator (Paurek: VG-25 type) and mixed, then purified water 232 g was added and kneaded. Combined 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 5] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, dihydrocodeine phosphate (manufactured by Shionogi & Co .: trade name: dihydrocodeine phosphate “Shionogi” ) 48 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 (manufactured by Gotoku Pharmaceutical: trade name) ECG505) 486 g, lactose hydrate (DMV: trade name: lactose 200M) 1822 g and crystalline cellulose (Asahi Kasei Chemicals: trade name: Theolas PH-101) 1821 g were added to a high-speed agitation granulator (Paurek: VG-25 type). Add and mix, then add 696.2 g of purified water To obtain granules engaged. 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 Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi” ) 48 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 (manufactured by Gotoku Pharmaceutical: trade name) ECG505) 486 g, lactose hydrate (DMV: trade name: lactose 200M) 1215 g, crystalline cellulose (Asahi Kasei Chemicals: trade name Theolas PH-101) 1214 g and corn starch (manufactured by Nissho Chemical: trade name: corn starch ST-C ) 1214g high speed stirring granulator Manufactured by Powrex was mixed was poured into VG-25 type), then the mixture was formed into granules 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.

[Test Example 5] Loxoprofen-induced gastrointestinal tract disorder inhibitory effect Wistar rats (Std: Wistar / ST, male, 8 weeks old, body weight 188.9 to 227.9 g) were used, and the test was carried out as 6 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, dihydrocodeine phosphate (DP) was suspended in a 0.5% methylcellulose (MC) solution and orally administered in predetermined amounts (8, 24, 72 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, dihydrocodeine phosphate reduced gastric mucosal damage caused by loxoprofen.

According to the present invention, the xanthine derivative suppresses the interaction between loxoprofen or a salt thereof and codeine. Codeine also 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 codeine, which is excellent in storage stability and reduces or suppresses gastrointestinal disorders caused by loxoprofen.

Claims (14)

  A pharmaceutical composition comprising loxoprofen or a salt thereof, codeines and a xanthine derivative. Pharmaceutical composition containing loxoprofen or a salt thereof, codeine and xanthine derivative (however, the following (a) to (d)
(A) Loxoprofen sodium hydrate 90 g, noscapine 48 g, dihydrocodeine phosphate 24 g, ketotifen fumarate 4 g, ambroxol hydrochloride 45 g, phenylpropanolamine 60 g, theophylline 150 g, lysozyme hydrochloride 90 g (potency), anhydrous Tablets (1 tablet 200 mg) prepared by mixing 75 g of caffeine, 8 g of vitamin B ₁ nitrate, 4 g of vitamin B ₂ , 350 g of lactose, 320 g of microcrystalline cellulose, 16 g of magnesium stearate and 16 g of hardened castor oil,
(B) Loxoprofen sodium hydrate 150 g, noscapine 48 g, dihydrocodeine phosphate 24 g, ketotifen fumarate 2 g, ambroxol hydrochloride 45 g, phenylpropanolamine 60 g, theophylline 150 g, lysozyme hydrochloride 90 g (potency), anhydrous Tablets (1 tablet 200 mg) made by mixing 75 g of caffeine, 8 g of vitamin B ₁ nitrate, 4 g of vitamin B ₂ , 150 g of lactose, 150 g of microcrystalline cellulose, 22 g of magnesium stearate and 22 g of hardened castor oil,
(C) Loxoprofen sodium hydrate 120 g, dihydrocodeine phosphate 24 g, epinastine hydrochloride 20 g, dl-methylephedrine hydrochloride 60 g, ambroxol hydrochloride 45 g, anhydrous caffeine 75 g, vitamin B ₁ nitrate 8 g, vitamin B ₂ 4 g, sucrose fatty acid ester 15 g, mannitol 15 g, stevia 10 g, ethyl aminobenzoate 5 g and orange flavor 0.8 g, and (d) loxoprofen sodium hydrate 100 g, dihydrocodeine phosphate 24 g, epinastine hydrochloride 20 g, dl-methylephedrine hydrochloride 60 g, ambroxol hydrochloride 45 g, anhydrous caffeine 75 g, vitamin B ₁ nitrate 8 g, vitamin B ₂ 4g, sucrose fatty acid ester 1 g, sweetening agents, solutions containing a preservative and fragrance (1000 ml)
except for. ).   The pharmaceutical composition according to claim 1 or 2, wherein the loxoprofen or a salt thereof is loxoprofen sodium hydrate.   The pharmaceutical composition according to any one of claims 1 to 3, comprising loxoprofen sodium hydrate in an amount of 10 to 300 mg per day in terms of loxoprofen sodium anhydride.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the codeines are at least one selected from codeine phosphate hydrate and dihydrocodeine phosphate.   The pharmaceutical composition according to claim 5, comprising 4-60 mg of codeine phosphate hydrate as a daily dose.   The pharmaceutical composition according to claim 5, comprising 2 to 30 mg of dihydrocodeine phosphate as a daily dose.   The pharmaceutical composition according to any one of claims 1 to 7, wherein the xanthine derivative is caffeine.   The pharmaceutical composition according to claim 8, wherein the caffeine is one or more selected from caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine and caffeine citrate.   The pharmaceutical composition according to any one of claims 1 to 9, 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 10 and a desiccant in a container.   A pharmaceutical preparation comprising a pharmaceutical composition according to any one of claims 1 to 10, which is packaged in stick packaging, PTP packaging or SP, and a desiccant in pillow packaging or stick packaging.   One or two desiccants selected from 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 The pharmaceutical preparation according to claim 11 or 12, which is a species or more. Solid preparation containing loxoprofen or a salt thereof, codeine and xanthine derivative (however, the following (a) to (b)
(A) Loxoprofen sodium hydrate 90 g, noscapine 48 g, dihydrocodeine phosphate 24 g, ketotifen fumarate 4 g, ambroxol hydrochloride 45 g, phenylpropanolamine 60 g, theophylline 150 g, lysozyme hydrochloride 90 g (potency), anhydrous Tablets (1 tablet 200 mg) prepared by mixing 75 g of caffeine, 8 g of vitamin B ₁ nitrate, 4 g of vitamin B ₂ , 350 g of lactose, 320 g of microcrystalline cellulose, 16 g of magnesium stearate and 16 g of hardened castor oil, and (b) loxoprofen Sodium hydrate 150 g, noscapine 48 g, dihydrocodeine phosphate 24 g, ketotifen fumarate 2 g, ambroxol hydrochloride 45 g, phenylpropanolamine 60 g, theophylline 150 , Lysozyme hydrochloride 90 g (potency), anhydrous caffeine 75 g, Vitamin B ₁ nitrate 8 g, vitamin B ₂ 4g, lactose 150 g, microcrystalline cellulose 150 g, tablets papermaking by mixing magnesium stearate 22g and hardened castor oil 22g (1 tablet 200mg)
except for. ).