JPWO2012157752A1 - Loxoprofen-containing pharmaceutical composition - Google Patents

Abstract

Providing a pharmaceutical composition having improved stability problems between an interactive component such as loxoprofen or a salt thereof and chlorpheniramine or a salt thereof. A pharmaceutical composition comprising an interactive component such as loxoprofen or a salt thereof and chlorpheniramine or a 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), and its excellent antipyretic analgesic action is expected to be incorporated into a general cold medicine, antipyretic analgesic, and the like.

  On the other hand, so far in general cold medicine and antipyretic analgesics, in addition to antipyretic analgesic ingredients, antihistamine ingredients, expectorant ingredients, anti-inflammatory enzyme ingredients, antitussive ingredients, central nervous excitable ingredients, anticholinergic ingredients, antiplasmin ingredients, herbal medicines Various combinations of ingredients such as ingredients are blended.

  Specific examples of the antihistamine component include chlorpheniramine or a salt thereof; clemastine or a salt thereof; carbinoxamine or a salt thereof; diphenylpyraline or a salt thereof, etc. It is used for various pharmaceuticals such as pharmaceuticals (Non-Patent Documents 2 to 5). Of the above, chlorpheniramine has the following formula:

It is a compound represented by these. In addition, clemastine has the following formula:

It is a compound represented by these. Carbinoxamine has the following formula:

It is a compound represented by these. In addition, diphenylpyraline has the following formula:

It is a compound represented by these.

Specific examples of the expectorant component include bromhexine or a salt thereof; ambroxol or a salt thereof; phenol derivative such as guaiacol sulfonic acid or a salt thereof, guaifenesin, cresolsulfonic acid or a salt thereof, or the like.
Of the above, bromhexine has the following formula:

It has a expectorant action based on the viscosity adjustment action that dilutes mucus by promoting secretion of the respiratory tract mucosa, and is approved as a switch OTC drug, used for general cold medicine, and for medical use It is used for expectoration such as acute and chronic bronchitis and pneumoconiosis (Non-patent Document 6).
Ambroxol has the following formula:

Is known as an active metabolite of the above bromhexine, which is an expectorant component, and is also called a mucosal lubricating component. In addition to being approved as a switch OTC drug and used for general cold medicine, it is used for medical treatment for expectoration of acute / chronic bronchitis, pneumoconiosis, etc. (Non-patent Document 7).

  In addition, phenol derivatives such as guaiacol sulfonic acid or a salt thereof, guaifenesin, cresol sulfonic acid or a salt thereof, or a salt thereof are components having an airway secretion promoting action or the like (Non-patent Document 8).

  Specific examples of the anti-inflammatory enzyme component include lysozyme or a salt thereof. These have mucopolysaccharide decomposing action, anti-inflammatory action, etc. In addition to comprehensive cold medicine, antitussive expectorant and rhinitis oral medicine, in anticipation of mucopolysaccharide decomposing action to decompose sputum and nasal pus mucus and anti-inflammatory action (Non-patent document 9).

Specific examples of the antitussive component include codeines; ephedrines; dextromethorphan or a salt thereof.
Among the above, codeines are known to be narcotic antitussive components having an antitussive action by suppressing the function of the cough center. And based on this effect | action, it is a drug used for an antitussive expectorant etc. other than a general cold medicine (nonpatent literature 10).
In addition, ephedrines are known to bring about an antitussive action by bronchodilating action based on sympathomimetic action. In addition to being used as a general cold medicine and antitussive expectorant as an antitussive component, it is a drug that is also used as an internal medicine for rhinitis for the purpose of alleviating nasal congestion due to vasoconstriction (Non-patent Documents 11 and 12).
Moreover, dextromethorphan or a salt thereof is a central non-narcotic antitussive component, and is known to exhibit an antitussive action by directly acting on the cough center and suppressing the cough reflex. And based on this effect | action, it is a drug used also for an antitussive expectorant besides a general cold medicine (nonpatent literature 11).

  Specific examples of the central nervous excitatory component include xanthine derivatives such as caffeine. Caffeine exhibits central excitatory action, cardiotonic / diuretic action, gastric acid secretion enhancing action, smooth muscle relaxing action, etc., and is a drug used for antipyretic analgesics, antitussive expectorants, etc. in addition to general cold medicine (Non-patent Document 13) ). In addition, other xanthine derivatives such as theophylline, paraxanthine, theobromine, aminophylline, diprofylline, and proxyphylline having a structure similar to caffeine have pharmacological effects similar to caffeine. Theophylline exhibits central excitatory action, cardiotonic / diuretic action, smooth muscle relaxing action, etc., and is a drug used for antitussive expectorant, antipruritics and the like. 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 14). Proxyphyrin also shows the same action as theophylline (Non-patent Document 15), and paraxanthine and theobromine show the same action.

  In addition, phenol derivatives such as acetaminophen and etenzamid or salts thereof are components having antipyretic analgesic activity (Non-patent Document 16).

Loxoprofen has been studied for combination with various drugs because of its excellent pharmacological action, and various combinations with the components used in the above-mentioned general cold medicine are also known.
For example, Patent Document 1 includes (1) one or more selected from clemastines, phenylamines, carbinoxamine maleate, ephedrines, codeines, phenylpropanolamine hydrochloride, serrapeptase, lysozyme chloride, and bromhexine hydrochloride. A pharmaceutical composition and (2) a pharmaceutical composition containing loxoprofen as an active ingredient is described, and this document enhances analgesic action by combining with carbinoxamine maleate, chlorpheniramine maleate or phenylpropanolamine hydrochloride Action; potentiation of anti-inflammatory effect by combining with dihydrocodeine phosphate, carbinoxamine maleate or bromhexine hydrochloride; enhancement of antipyretic action by combining with carbinoxamine maleate or lysozyme chloride Use; and potentiation of anti-histamine action it has been disclosed by be combined with clemastine fumarate or d- chlorpheniramine maleate.

Patent Document 2 describes a composition for cold and rhinitis comprising at least one selected from the group consisting of (a) loxoprofen and (b) an antiallergic agent and an antihistamine, An effect of improving nasal congestion by combining with carbinoxamine maleate or chlorpheniramine maleate is disclosed.
Patent Document 3 describes a composition for colds containing an expectorant and loxoprofen or a salt thereof, and enhances the effect on cough symptoms by combining with bromhexine hydrochloride or ambroxol. The effect is disclosed.

Patent Document 4 discloses a pharmaceutical composition for suppressing gonorrhea or goblet cell hyperplasia containing loxoprofen and one or more selected from ambroxol or bromhexine, and hydrochloric acid. It is disclosed that a goblet cell hyperplasia inhibitory action is expressed by combining with ambroxol or bromhexine hydrochloride.
Patent Document 5 describes a pharmaceutical composition for antitussive or expectorant containing loxoprofen, and one or more selected from caffeine, ephedrine and codeine, and contains codeine phosphate or anhydrous Expression of goblet cell hyperplasia inhibitory action by combining with caffeine is disclosed.
Patent Document 6 aims at analgesic / anti-inflammatory / antipyretic containing loxoprofen and one or more selected from caffeine, allylisopropylacetylurea, bromvalerylurea, acetaminophens and etenzaamide. A pharmaceutical composition is described, and analgesic enhancing action by combining with etenzamide is disclosed.
Patent Document 7 discloses that loxoprofen and xanthines interact with each other and affect storage stability.
However, as to whether or not an interaction that affects the storage stability and the like of these compounds occurs between loxoprofen or a salt thereof and the above-mentioned various components in the preparation, Xanthine derivatives are disclosed in Patent Document 7 as follows. It is not disclosed at all except that it is disclosed to cause an interaction.

JP 2000-143505 A JP 2001-199882 A JP 2001-172175 A JP 2008-13542 A JP 2007-314517 A Japanese Patent Laid-Open No. 11-139971 JP 2011-46692 A

Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd. C-4790-4759 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 230 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 231 OTC Handbook 2008-09 Academic Information Distribution Center, Inc., page 232 OTC Handbook 2008-09 Academic Information Distribution Center, Inc., page 365 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 292 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 235 OTC Handbook 2008-09 Academic Information Distribution Center 291-292 OTC Handbook 2008-09 Academic Information Distribution Center, Inc., page 232 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 289 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 290 OTC Handbook 2008-09 Academic Information Distribution Center, page 369 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 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 197

  In order to develop a pharmaceutical composition containing loxoprofen or a salt thereof and certain components, the present inventors prepared and stored various mixtures. Loxoprofen or a salt thereof and the following components (B-1) to One of (B-7):

(B-1) The following general formula (1), including chlorpheniramine or a salt thereof, clemastine or a salt thereof, carbinoxamine or a salt thereof, diphenylpyraline or a salt thereof, and the like

[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R ¹ represents a hydrogen atom, a hydroxyl group or an alkyl group, and R ² may have a substituent. A good cyclic amino group or an aminoalkyl group which may have a substituent, and R ³ represents a hydrogen atom or a halogen atom. Or a salt thereof (B-2) represented by the following general formula (2), including bromhexine or a salt thereof, ambroxol or a salt thereof, and the like:

[In the formula (2), R ⁴ represents a hydrogen atom or a methyl group, and R ⁵ represents a hydrogen atom or a hydroxyl group. Or a salt thereof (B-3), including guaiacol sulfonic acid or a salt thereof, guaifenesin, cresol sulfonic acid or a salt thereof, acetaminophen, etezamide, and the like.

[In the formula (3), R ⁶ represents a hydrogen atom, an alkyl group, a carbamoyl group or an alkoxy group which may have a substituent, and R ⁷ represents a hydrogen atom, an acylamino group or a sulfo group. In addition, the phenolic hydroxyl group in Formula (3) may be etherified. ]
Or a salt thereof (B-4) codeine (B-5) ephedrine (B-6) lysozyme or a salt thereof (B-7) dextromethorphan or a salt thereof

It has been found that when the mixture is mixed and stored, unexpectedly, the mixture undergoes state changes such as wetting, solidification, and discoloration over time, resulting in problems in stability.

  Accordingly, an object of the present invention is to provide a pharmaceutical composition in which the problem of stability between loxoprofen or a salt thereof and one or more selected from the above components (B-1) to (B-7) is improved. That is.

When the present inventors examined in order to solve the above-mentioned stability problem, one or more selected from loxoprofen or a salt thereof and the above components (B-1) to (B-7) (hereinafter referred to as “interaction”). It has become clear that the interaction caused by the contact with the “adhesive component” is the cause of the stability problem.
Therefore, the present inventors have intensively studied the technology for suppressing the interaction between loxoprofen or a salt thereof in the pharmaceutical composition and the interactive component, and in addition to loxoprofen or a salt thereof, and the interactive component, Furthermore, it was found that the interaction can be suppressed unexpectedly by coexisting a xanthine derivative.

That is, this invention provides the pharmaceutical composition containing the following component (A), (B) and (C).
(A) Loxoprofen or a salt thereof;
(B) One or more selected from the group consisting of the following components (B-1) to (B-7) (B-1) The following general formula (1)

[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R ¹ represents a hydrogen atom, a hydroxyl group or an alkyl group, and R ² may have a substituent. A good cyclic amino group or an aminoalkyl group which may have a substituent, and R ³ represents a hydrogen atom or a halogen atom. Or a salt thereof (B-2) represented by the following general formula (2)

[In the formula (2), R ⁴ represents a hydrogen atom or a methyl group, and R ⁵ represents a hydrogen atom or a hydroxyl group. Or a salt thereof (B-3) represented by the following general formula (3)

[In the formula (3), R ⁶ represents a hydrogen atom, an alkyl group, a carbamoyl group or an alkoxy group which may have a substituent, and R ⁷ represents a hydrogen atom, an acylamino group or a sulfo group. In addition, the phenolic hydroxyl group in Formula (3) may be etherified. Or a salt thereof (B-4) codeine (B-5) ephedrine (B-6) lysozyme or a salt thereof (B-7) dextromethorphan or a salt thereof;
(C) Xanthine derivative

According to the present invention, the interaction between an interactive component and loxoprofen or a salt thereof can be suppressed. Accordingly, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and an interactive component, which has excellent storage stability.
In addition, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and an interactive component with suppressed interaction, which is simple and inexpensive, without going through complicated steps.

  The present invention relates to a pharmaceutical composition further comprising (C) a xanthine derivative in addition to (A) loxoprofen or a salt thereof and (B) an interactive component. First, each of these components will be described in detail.

<Component (A)>
In the present invention, “loxoprofen or a salt thereof” includes loxoprofen itself, a pharmaceutically acceptable salt of loxoprofen, and a solvate of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol, or the like. It is. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).

  The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, 10 to 300 mg, more preferably 30 to 240 mg, particularly preferably 60 to 180 mg in terms of loxoprofen sodium anhydride can be contained per day. In the present invention, it is preferable to contain loxoprofen or a salt thereof in an amount of 0.4 to 90% by mass in terms of anhydrous loxoprofen sodium, and 0.4 to 50% by mass with respect to the total mass of the pharmaceutical composition. More preferably, the content is 1.2 to 45% by mass, still more preferably 1.2 to 25% by mass.

<Component (B-1)>
In the present invention, the general formula (1)

[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R ¹ represents a hydrogen atom, a hydroxyl group or an alkyl group, and R ² may have a substituent. A good cyclic amino group or an aminoalkyl group which may have a substituent, and R ³ represents a hydrogen atom or a halogen atom. ]
In addition to the compound itself represented by the general formula (1), a pharmaceutically acceptable salt of the compound represented by the general formula (1) is also included in the compound represented by general formula (1). Specific examples of the compound represented by the general formula (1) or a salt thereof include, for example, a compound represented by the general formula (1), an inorganic acid salt or an organic acid salt of the compound represented by the general formula (1) ( For example, hydrochloride, maleate, fumarate, diphenyl disulfonate, theocrate, salicylate, tannate, besylate, phosphate, etc.). In addition, in the chemical structure of the compound represented by the general formula (1), when an asymmetric carbon exists, it has various optical isomers. Or a mixture of various optical isomers. Further, the compound represented by the general formula (1) or a salt thereof may be in the form of a solvate, and a solvate of the compound represented by the general formula (1) or a salt thereof with water, alcohol or the like. Are also included in the “compound represented by the general formula (1) or a salt thereof”.

In the above R ¹ , the alkyl group is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, and a methyl group is preferable.
Further, as the R ^1, a hydrogen atom, preferably an alkyl group, a hydrogen atom, more preferably a methyl group.

In the above R ² , the “cyclic amino group” in the cyclic amino group which may have a substituent is a 5- to 7-membered fat having at least 1, preferably 1 or 2, nitrogen atoms as ring-constituting atoms. Means a cyclic group.
Specific examples of such cyclic amino groups include pyrrolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, homopiperidinyl group, homopiperazinyl group and the like. Among these, piperidinyl group, piperazinyl group and homopiperazinyl group are preferable, and piperidinyl group and piperazinyl group are more preferable.

Examples of the “substituent” in the cyclic amino group which may have a substituent include, for example, an alkylbenzoyl group, a 1,3-dihydro-2H-benzimidazol-2-one-1-yl group, and a carboxyalkoxy group. And an alkyl group which may be substituted with one or more groups selected from a carboxyl group, a carboxyalkylphenyl group and a hydroxyl group. Among these, an alkyl group, a carboxyalkoxyalkyl group, and a carboxyalkylphenyl (hydroxy) alkyl group are preferable.
Specific examples of the “substituent” include, for example, methyl group, 3- (4-tert-butylbenzoyl) propyl group, 3- (1,3-dihydro-2H-benzimidazol-2-one-1-yl ) Propyl group, 2- (carboxymethoxy) ethyl group, 4- [4- (2-carboxypropan-2-yl) phenyl] -4-hydroxybutyl group, 3-carboxypropyl group and the like.

In the above R ² , the “cyclic amino group optionally having substituent (s)” includes 1-methylpiperidin-4-yl group, 4-methylhomopiperazin-1-yl group, 1- [3- (4- tert-butylbenzoyl) propyl] piperidin-4-yl group, 4- [3- (1,3-dihydro-2H-benzimidazol-2-one-1-yl) propyl] piperazin-1-yl group, 4- [2- (carboxymethoxy) ethyl] piperazin-1-yl group, 1- {4- [4- (2-carboxypropan-2-yl) phenyl] -4-hydroxybutyl} piperidin-4-yl group, 1 A-(3-carboxypropyl) piperidin-4-yl group is preferred.

In the above R ² , the “aminoalkyl group” in the aminoalkyl group which may have a substituent is an amino group, a monoalkylamino group, a dialkylamino group or a cyclic amino group (the “cyclic amino group” is as described above). It means an alkyl group substituted with the same meaning as “cyclic amino group” in “cyclic amino group optionally having substituent (s)”. Among these, an alkyl group substituted with a dialkylamino group or a cyclic amino group is preferable. The cyclic amino group is preferably a pyrrolidinyl group.
Specific examples of such an aminoalkyl group include 2- (dimethylamino) ethyl group, 2- (pyrrolidin-2-yl) ethyl group, 2-[(isopropyl) (methyl) amino] ethyl group, and the like. Is mentioned. Examples of the “substituent” in the aminoalkyl group which may have a substituent include a hydroxyl group, a phenyl group, and an alkyl group.

In the above R ² , the “aminoalkyl group optionally having substituent (s)” is 2- (dimethylamino) ethyl group, 2- (1-methylpyrrolidin-2-yl) ethyl group, 2-[(methyl ) (1-Phenyl-1-hydroxypropan-2-yl) amino] ethyl group is preferred.

In the above R ² , as the alkyl group moiety in the “alkyl group”, “alkylbenzoyl group”, “carboxyalkylphenyl group”, “aminoalkyl group”, “monoalkylamino group”, “dialkylamino group”, A linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
In the above R ² , the alkoxy group moiety in the “carboxyalkoxy group” is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, and a propoxy group. , Butoxy group, pentyloxy group, hexyloxy group and the like.

In the above R ³ , examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the present invention, a chlorine atom is preferable. In the general formula (1), the substitution position on the phenyl group of R ³ is not particularly limited, but substitution at the 4-position is preferable.
Further, X, Y, as the combination of R ^1, R ² and R ^3, the following (i) ~ (iv) are preferred.
(I) X is a single bond, Y is a nitrogen atom, R ¹ is a hydrogen atom, R ² is an aminoalkyl group which may have a substituent, and R ³ is a halogen atom. Combination (ii) X is an oxygen atom, Y is a methine group, R ¹ is an alkyl group, R ² is an optionally substituted aminoalkyl group, and R ³ is a halogen atom A certain combination (iii) X is an oxygen atom, Y is a nitrogen atom, R ¹ is a hydrogen atom, R ² is an optionally substituted aminoalkyl group, and R ³ is a halogen atom (Iv) X is an oxygen atom, Y is a methine group, R ¹ is a hydrogen atom, R ² is an optionally substituted cyclic amino group, and R ³ is hydrogen A combination that is an atom

In the present invention, the compound represented by the general formula (1) or a salt thereof has a diarylmethyl structure as a common skeleton, and specifically includes ebastine or a salt thereof; oxatomide or a salt thereof; Carbinoxamine such as samine diphenyl disulfonate and carbinoxamine maleate or salts thereof; clemastine or salt thereof such as clemastine fumarate; chlor such as d-chlorpheniramine maleate and dl-chlorpheniramine maleate Phenylamine or a salt thereof; Dipheterol or a salt thereof such as dipheterol hydrochloride or dipheterol phosphate; Diphenylpyraline or a salt thereof such as diphenylpyraline hydrochloride or diphenylpyraline theoclurate; Diphenhydramine hydrochloride or diphenhydramine salicylate; Zife Diphenhydramine or a salt thereof such as hydramine tannate; cetirizine or a salt thereof such as cetirizine hydrochloride; fexofenadine or a salt thereof; bepotastine or a salt thereof such as bepotastine besylate; a homochlorcyclidine hydrochloride or the like Examples include homochlorocyclidine or a salt thereof.
The compounds represented by the above general formula (1) and salts thereof, in particular, the above-described compounds and salts thereof are known and can be produced by known methods, and commercially available products can be used.

  The content of the compound represented by the general formula (1) or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. . For example, 0.01 to 400 mg, more preferably 0.03 to 300 mg, particularly preferably 0.1 to 200 mg of the compound represented by the general formula (1) or a salt thereof is contained per day. It can be shown. In addition, although suitable content in the case of using a specific component as a compound represented by General formula (1) or its salt is illustrated below, this invention is not limited to this at all.

In the pharmaceutical composition of the present invention, when ebastine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.1 to 50 mg per day, The amount that can be taken from 0.5 to 30 mg is more preferred, and the amount that can be taken from 1 to 20 mg is more preferred.
In the pharmaceutical composition of the present invention, when oxatomide or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken from 0.3 to 200 mg per day, The amount that can be taken 1 to 100 mg is more preferred, and the amount that can be taken 6 to 60 mg is more preferred.
In the pharmaceutical composition of the present invention, when carbinoxamine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.1 to 60 mg per day, The amount that can be taken from 0.5 to 30 mg is more preferred, and the amount that can be taken from 1 to 16 mg is more preferred.

In the pharmaceutical composition of the present invention, when clemastine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content thereof is 0.01 to The amount that can be taken 5 mg is preferred, the amount that can be taken 0.05 to 3 mg is more preferred, and the amount that can be taken 0.1 to 2 mg is more preferred. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
In the pharmaceutical composition of the present invention, when chlorpheniramine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content thereof is an amount that can be taken 0.1 to 20 mg per day. Preferably, the amount that can be taken 0.6 to 12 mg is more preferable. In addition, when using d-chlorpheniramine maleate as chlorpheniramine or its salt, the quantity which can be taken | dosed 0.1-15 mg per day is preferable, and the quantity which can be taken | dosed 0.6-6 mg is more preferable, 1 An amount that can be taken by -5 mg is more preferred. When dl-chlorpheniramine maleate is used, the amount that can be taken from 0.5 to 20 mg per day is preferred, the amount that can be taken from 1 to 12 mg is more preferred, and the amount that can be taken from 2 to 10 mg is even more preferred.
In the pharmaceutical composition of the present invention, when difeterol or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken from 1 to 300 mg per day, The amount that can be taken 150 mg is more preferred, and the amount that can be taken 10 to 100 mg is more preferred.

In the pharmaceutical composition of the present invention, when diphenylpyrine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is an amount that can be taken 0.1 to 13.5 mg per day. The amount that can be taken 1 to 4.5 mg is more preferable. 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 amount that can be taken 0.1 to 13.5 mg per day is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred.
In the pharmaceutical composition of the present invention, when diphenhydramine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken from 1 to 300 mg per day, The amount that can be taken 200 mg is more preferred, and the amount that can be taken 15 to 150 mg is more preferred.
In the pharmaceutical composition of the present invention, when cetirizine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.1 to 50 mg per day, The amount that can be taken 0.3 to 30 mg is more preferred, and the amount that can be taken 1 to 20 mg is more preferred.

In the pharmaceutical composition of the present invention, when fexofenadine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content thereof can be taken in an amount of 0.3 to 200 mg per day. The amount that can be taken 1 to 100 mg is more preferable, and the amount that can be taken 6 to 60 mg is more preferable.
In the pharmaceutical composition of the present invention, when bepotastine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is preferably an amount that can be taken 0.1 to 40 mg per day, The amount that can be taken from 0.5 to 30 mg is more preferred, and the amount that can be taken from 2 to 20 mg is more preferred.
In the pharmaceutical composition of the present invention, when homochlorocyclidine or a salt thereof is used as the compound represented by the general formula (1) or a salt thereof, the content is an amount that can be taken 0.3 to 180 mg per day. The amount that can be taken 1 to 90 mg is more preferred, and the amount that can be taken 3 to 60 mg is more preferred.

  In the present invention, as the compound represented by the general formula (1) or a salt thereof, “chlorpheniramine or a salt thereof”, “clemastine or a salt thereof”, “carbinoxamine or a salt thereof” or “diphenylpyrine or a salt thereof” Is preferably used.

In the present invention, “chlorpheniramine or a salt thereof” includes not only chlorpheniramine itself but also a pharmaceutically acceptable salt of chlorpheniramine.
Since chlorpheniramine has an asymmetric carbon, it has an optical isomer, but in the present invention, any optical isomer may be included, which may be a single optical isomer or a mixture of various optical isomers. . Among these, in the present invention, d-form and dl-form are preferable. Specific examples of the chlorpheniramine or a salt thereof include chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate and the like. In the present invention, d-chlorpheniramine maleate and dl-chlorpheniramine maleate are preferable, and d-chlorpheniramine maleate is particularly preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of chlorpheniramine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose. It is preferable to contain 0.004-1.5 mass% with respect to the total mass of the pharmaceutical composition, more preferably 0.02-1 mass%, more preferably 0.04-0.8 mass%. Particularly preferred.

  The content ratio of loxoprofen or a salt thereof and chlorpheniramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof contains 0.0001 to 1.5 parts by mass of chlorpheniramine or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, 0.0005 to 0.7 What contains a mass part is more preferable, and what contains 0.001-0.5 mass part is especially preferable.

  In the present invention, “clemastine or a salt thereof” includes not only clemastine itself but also a pharmaceutically acceptable salt of clemastine. Specific examples of clemastine or a salt thereof include, for example, clemastine, clemastine fumarate, etc. In the present invention, clemastine fumarate is preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose, but clemastine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.008-0.4 mass% in conversion of the free body of clemastine with respect to mass, It is more preferable to contain 0.01-0.2 mass%, 0.015-0.15 mass% It is particularly preferable to contain it.

  The content ratio of loxoprofen or a salt thereof and clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the daily dose of each component described above. Alternatively, it is preferable to contain 0.0006 to 0.5 parts by mass of clemastine or a salt thereof in terms of a free form of clemastine with respect to 1 part by mass of loxoprofen sodium anhydride in terms of its salt. More preferably, it contains 0.002 to 0.03 parts by mass.

  In the present invention, “carbinoxamine or a salt thereof” includes not only carbinoxamine itself but also a pharmaceutically acceptable salt of carbinoxamine. Specific examples of carbinoxamine or a salt thereof include carbinoxamine, carbinoxamine maleate, carbinoxamine diphenyl disulfonate, and the like, and carbinoxamine maleate is more preferable in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of carbinoxamine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose. Carbinoxamine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.004-4 mass% with respect to mass, It is more preferable to contain 0.02-3 mass%, It is especially preferable to contain 0.04-2 mass%.

  The content ratio of loxoprofen or a salt thereof and carbinoxamine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, with respect to 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium, one containing 0.0003 to 6 parts by mass of carbinoxamine or a salt thereof is preferable, and one containing 0.002 to 1 parts by mass is more preferable. More preferably, 0.005 to 0.3 parts by mass is contained.

  In the present invention, “diphenylpyrine or a salt thereof” includes not only diphenylpyraline itself but also a pharmaceutically acceptable salt of diphenylpyraline. Specific examples of diphenylpyraline or a salt thereof include, for example, diphenylpyraline, diphenylpyraline hydrochloride, diphenylpyraline theocuroate and the like. In the present invention, diphenylpyraline hydrochloride and diphenylpyraline theocuroate are preferable, Diphenylpyraline hydrochloride is particularly preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of diphenylpyralin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the above-mentioned daily dose. It is usually 0.004 to 3% by mass with respect to the total mass of the product, preferably 0.004 to 2.5% by mass, more preferably 0.04 to 2% by mass, It is more preferable to contain 0.04-1.5 mass%, and it is especially preferable to contain 0.06-1 mass%.

  The content ratio of loxoprofen or a salt thereof and diphenylpyraline or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. Although it is good, what contains 0.0001-3 mass parts of diphenyl pyralin or its salt is preferable with respect to 1 mass part of loxoprofen or its salt in conversion of loxoprofen sodium anhydride, 0.0005-2.5 mass part is contained. More preferable are those containing 0.001 to 1 parts by mass, and particularly preferable are those containing 0.001 to 0.3 parts by mass.

<Component (B-2)>
In the present invention, the general formula (2)

[In the formula (2), R ⁴ represents a hydrogen atom or a methyl group, and R ⁵ represents a hydrogen atom or a hydroxyl group. ]
In addition to the compound itself represented by the general formula (2), a pharmaceutically acceptable salt of the compound represented by the general formula (2) is also included in the compound represented by general formula (2). Specific examples of the compound represented by the general formula (2) or a salt thereof include, for example, an inorganic acid salt such as a compound represented by the general formula (2), a hydrochloride of the compound represented by the general formula (2), and the like. Organic acid salt is mentioned, The hydrochloride of the compound represented by General formula (2) is more preferable.

As the compound represented by the general formula (2) or a salt thereof,
(A) Bromohexine (a compound in which R ⁴ is a methyl group and R ⁵ is a hydrogen atom) or a salt thereof (b) Ambroxol (a compound in which R ⁴ is a hydrogen atom and R ⁵ is a hydroxyl group) or a salt thereof Salt (c) a compound wherein R ⁴ is a methyl group and R ⁵ is a hydroxyl group or a salt thereof (d) a compound wherein R ⁴ and R ⁵ are a hydrogen atom or a salt thereof, (a) bromohexine or a salt thereof Salt, (b) ambroxol or a salt thereof is preferable, and bromohexine hydrochloride or ambroxol hydrochloride is particularly preferable.

In the general formula (2), when R ⁵ is a hydroxyl group, the α carbon of the substituent is an asymmetric center, and there are isomers selected from the S and R isomers. Any of them may be sufficient, and a mixture thereof may be sufficient. In addition, these compounds may be used independently and may mix and use 2 or more types. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of the compound represented by the general formula (2) or the salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. . For example, when the compound represented by the general formula (2) or a salt thereof is bromohexine or a salt thereof, 0.1 to 50 mg, more preferably 0, in terms of bromhexine or a salt thereof converted into bromohexine hydrochloride per day. .5 to 25 mg, particularly preferably 1 to 15 mg can be taken. In addition, when the compound represented by the general formula (2) or a salt thereof is ambroxol or a salt thereof, 0.1 to 150 mg of ambroxol or a salt thereof is converted into ambroxol hydrochloride per day. More preferably, it can be contained in an amount of 0.5 to 100 mg, particularly preferably 1 to 50 mg.

  In this invention, it is preferable to contain 0.001-20 mass% of compounds or its salt represented by General formula (2) with respect to the pharmaceutical composition total mass. In addition, when the compound represented by the general formula (2) or a salt thereof is bromohexine or a salt thereof, it is preferably contained in an amount of 0.004 to 5% by mass in terms of bromohexine hydrochloride with respect to the total mass of the pharmaceutical composition. 0.02 to 4% by mass is more preferable, and 0.04 to 3% by mass is particularly preferable. Furthermore, when the compound represented by the general formula (2) or a salt thereof is ambroxol or a salt thereof, 0.004 to 15% by mass in terms of ambroxol hydrochloride is contained with respect to the total mass of the pharmaceutical composition. It is preferable to contain 0.02 to 12.5% by mass, and 0.04 to 10% by mass is particularly preferable.

  The content ratio of loxoprofen or a salt thereof and the compound represented by the general formula (2) or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and depends on the daily dose of each component described above. However, when the compound represented by the general formula (2) or a salt thereof is bromhexine or a salt thereof, loxoprofen or a salt thereof is added to 1 part by mass in terms of anhydrous loxoprofen sodium, What contains 0.0001-10 mass parts of bromhexine or its salt converted into bromohexine hydrochloride is preferable, what contains 0.0005-2 mass parts is more preferable, and what contains 0.001-1 mass parts. Particularly preferred. In addition, when the compound represented by the general formula (2) or a salt thereof is ambroxol or a salt thereof, loxoprofen or a salt thereof is added to 1 part by mass in terms of loxoprofen sodium anhydride with respect to an ambroxol or a salt thereof. Those containing 0.0001 to 10 parts by mass in terms of ambroxol hydrochloride are preferred, those containing 0.0005 to 5 parts by mass are more preferred, and those containing 0.001 to 3 parts by mass are particularly preferred.

<Component (B-3)>
In the present invention, the following general formula (3)

[In the formula (3), R ⁶ represents a hydrogen atom, an alkyl group, a carbamoyl group or an alkoxy group which may have a substituent, and R ⁷ represents a hydrogen atom, an acylamino group or a sulfo group. In addition, the phenolic hydroxyl group in the formula may be etherified. ]
In addition to the compound itself represented by the general formula (3), a pharmaceutically acceptable salt of the compound represented by the general formula (3) is also included in the compound represented by general formula (3). Specific examples of the compound represented by the general formula (3) or a salt thereof include, for example, a compound represented by the general formula (3), an alkali metal salt of the compound represented by the general formula (3), and the like. As the alkali metal salt of the compound represented by the general formula (3), the potassium salt of the compound represented by the general formula (3) is more preferable.

In the above R ⁶ , the alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Etc. In the present invention, a methyl group is preferred.
The alkoxy group is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, and a hexyloxy group. Is mentioned. In the present invention, a methoxy group is preferred.
Examples of the group that can be substituted on the alkoxy group include a hydroxyl group; a halogen atom such as a bromine atom, a chlorine atom, a fluorine atom, and an iodine atom, and these may have one or more as a substituent.
In the above R ⁷ , the acylamino group is preferably an acylamino group having 2 to 6 carbon atoms, and specific examples thereof include an acetyl group, a propionyl group, a butyryl group, and a valeryl group. In the present invention, an acetyl group is preferred.

  In the general formula (3), examples of the case where the phenolic hydroxyl group is etherified include, for example, those obtained by etherifying the phenolic hydroxyl group with a linear or branched monohydric alcohol having 1 to 3 carbon atoms. Examples thereof include those in which a phenolic hydroxyl group is etherified with a chain or branched polyhydric alcohol having 1 to 3 carbon atoms. Examples of the monohydric alcohol include methanol, ethanol, and propanol. Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, and glycerin. In the present invention, a monohydric alcohol having 1 to 3 carbon atoms having a straight chain or a branched chain is preferably one in which a phenolic hydroxyl group is etherified with ethanol, and having 1 to 3 carbon atoms having a straight chain or a branched chain. As the polyhydric alcohol, those in which a phenolic hydroxyl group is etherified with glycerin are preferable. When the phenolic hydroxyl group is etherified, the etherification reaction is not particularly limited.

Further, the following (v) to (ix) are preferable as the combination of the phenolic hydroxyl group, R ⁶ and R ^{7 in} the formula (3).
(V) A combination in which the phenolic hydroxyl group is an unetherified phenolic hydroxyl group, R ⁶ is an optionally substituted alkoxy group, and R ⁷ is a sulfo group (vi) phenol A combination in which the functional hydroxyl group is a phenolic hydroxyl group that is etherified, R ⁶ is an alkoxy group that may have a substituent, and R ⁷ is a hydrogen atom (vii) a phenolic hydroxyl group which are not etherified, R ⁶ is an alkyl group, R ⁷ is combined a sulfo group (viii) phenolic hydroxyl group, a phenolic hydroxyl group which are not etherified, R ⁶ There is a hydrogen atom, R ⁷ is combined an acylamino group (ix) phenolic hydroxyl group, phenolic hydroxyl acid has been etherified And the combination R ⁶ is a carbamoyl group, R ⁷ is a hydrogen atom

Preferred examples of the compound represented by the general formula (3) of the present invention or a salt thereof include a 2-methoxyphenol derivative (guaiacol derivative) or a salt thereof, a 2-methylphenol derivative (cresol derivative) or a salt thereof. Can be mentioned.
Examples of guaiacol derivatives or salts thereof include guaifenesin (guaiacol glycerin ether; (2RS) -3- (2-methoxyphenoxy) propane-1,2-diol) or salts thereof; guaiacol sulfones such as guaiacol sulfonic acid and potassium guaiacol sulfonate. An acid or a salt thereof is preferred. Moreover, as a cresol derivative or its salt, cresol sulfonic acid or its salts, such as cresol sulfonic acid (2-methylphenol sulfonic acid) and potassium cresol sulfonate, are preferable.

As the compound represented by the general formula (3) or a salt thereof, acetaminophen (N- (4-hydroxyphenyl) acetamide) and ethenzamide (ethoxybenzamide) are also preferable examples.
In the present invention, the compound represented by the general formula (3) or a salt thereof is preferably a guaiacol derivative or a salt thereof, a cresol derivative or a salt thereof, acetaminophen or etenzamide, a guaiacol derivative or a salt thereof, acetaminophen, Ethenzamide is more preferable, guaiacol sulfonic acid or a salt thereof, guaifenesin, acetaminophen, and ethenamide are more preferable, and potassium guaiacol sulfonate, guaifenesin, acetaminophen, and ethenamide are particularly preferable.
These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of the compound represented by the general formula (3) or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. . For example, the compound represented by the general formula (3) or a salt thereof can be contained in an amount of 5 to 2000 mg, more preferably 10 to 1700 mg, and particularly preferably 25 to 1500 mg per day.

  In addition, when a guaiacol derivative or a salt thereof is used as the compound represented by the general formula (3) or a salt thereof, 10 to 600 mg, more preferably 20 to 450 mg, particularly preferably a guaiacol derivative or a salt thereof per day. It is preferable to contain an amount of 30 to 300 mg. When a cresol derivative or a salt thereof is used as the compound represented by the general formula (3) or a salt thereof, the cresol derivative or a salt thereof is preferably 5 to 550 mg, more preferably 10 to 400 mg, particularly preferably per day. It is preferable to contain an amount of 25 to 270 mg that can be taken. When acetaminophen is used as the compound represented by the general formula (3) or a salt thereof, 10 to 1500 mg, more preferably 50 to 1200 mg, particularly preferably 100 to 1000 mg of acetaminophen per day is used. It is preferable to include an amount that can be obtained. When etenzamide is used as the compound represented by the general formula (3) or a salt thereof, it contains 50 to 2000 mg, more preferably 100 to 1700 mg, and particularly preferably 150 to 1500 mg of etezamide per day. Preferably.

  In this invention, it is preferable to contain 0.2-85 mass% of compounds or its salt represented by General formula (3) with respect to the pharmaceutical composition total mass. In addition, when the compound represented by the general formula (3) or a salt thereof is a guaiacol derivative or a salt thereof, it is preferably contained in an amount of 0.4 to 50% by mass relative to the total mass of the pharmaceutical composition, 0.8 to The content is more preferably 40% by mass, and particularly preferably 1.2 to 36% by mass. Furthermore, when the compound represented by the general formula (3) or a salt thereof is a cresol derivative or a salt thereof, it is preferably contained in an amount of 0.2 to 35% by mass relative to the total mass of the pharmaceutical composition, 0.4 to The content is more preferably 25% by mass, and particularly preferably 1 to 20% by mass. When the compound represented by the general formula (3) or a salt thereof is acetaminophen, it is preferably contained in an amount of 0.4 to 65% by mass, more preferably 2 to 50% by mass based on the total mass of the pharmaceutical composition. Is more preferable, and it is especially preferable to contain 4-45 mass%. When the compound represented by the general formula (3) or a salt thereof is etenzamid, it is preferably contained in an amount of 2 to 85% by mass, more preferably 4 to 70% by mass, based on the total mass of the pharmaceutical composition. It is particularly preferable to contain 6 to 65% by mass.

  The content ratio of loxoprofen or a salt thereof and the compound represented by the general formula (3) or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and depends on the daily dose of each component described above. The loxoprofen or a salt thereof is contained in an amount of 0.015 to 200 parts by mass of the compound represented by the general formula (3) or a salt thereof with respect to 1 part by mass of loxoprofen sodium as an anhydride. What contains is preferable, What contains 0.04-60 mass parts is more preferable, What contains 0.13-25 mass parts is further more preferable.

<Component (B-4)>
In the present invention, “codeines” means one or more selected from the group consisting of codeine, dihydrocodeine and 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. Specific examples of codeines include, for example, 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, codeine phosphate water More preferred are Japanese and dihydrocodeine phosphate, and more preferred is dihydrocodeine phosphate. 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 is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, 2-60 mg, more preferably 4 to 48 mg, particularly preferably 6 to 36 mg of codeine can be contained per day. In addition, when using codeine phosphate hydrate as codeines, 4-60 mg of codeine phosphate hydrate is contained per day, more preferably 8 to 48 mg, and particularly preferably 12 to 36 mg. Is preferred. Moreover, when using dihydrocodeine phosphate, it is preferable to contain 2-30 mg of dihydrocodeine phosphate per day, more preferably 4-24 mg, particularly preferably 6-24 mg.
In this invention, it is preferable to contain 0.08-4 mass% of codeines with respect to the pharmaceutical composition total mass. Moreover, when codeine is codeine phosphate hydrate, it is preferable to contain 0.15-4 mass% with respect to the pharmaceutical composition total mass, and it is more preferable to contain 0.3-3 mass%, 0 It is particularly preferable to contain 5 to 2.5% by mass. Furthermore, when the codeine is dihydrocodeine phosphate, it is preferably contained in an amount of 0.08 to 2% by mass, more preferably 0.16 to 1.5% by mass, based on the total mass of the pharmaceutical composition, The content is particularly preferably 0.24 to 1.5% by mass.

  The content ratio of loxoprofen or a salt thereof and codeines contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the daily dose of each component described above. , Loxoprofen or a salt thereof is preferably one containing 0.005 to 4 parts by mass of codeine, more preferably 0.01 to 2 parts by mass based on 1 part by mass in terms of anhydrous loxoprofen sodium. What contains 0.02-1 mass part is especially preferable.

<Component (B-5)>
In the present invention, “ephedrines” means one or more selected from the group consisting of ephedrine, ephedrine derivatives, and salts thereof. Here, examples of derivatives of ephedrine include norephedrine (phenylpropanolamine) and methylephedrine. Examples of the salt include salts of pharmaceutically acceptable inorganic acids and organic acids, and preferred specific examples include hydrochloride, sulfate, and saccharin salt. In addition, since ephedrine has two asymmetric carbons, there are various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used. A mixture of In the present invention, l-form and dl-form are preferable.

  In the present invention, specific examples of ephedrines include, for example, methylephedrine hydrochloride such as l-methylephedrine hydrochloride and dl-methylephedrine hydrochloride; methylephedrine such as l-methylephedrine saccharin salt and dl-methylephedrine saccharin salt In addition to saccharin salts, pseudoephedrine hydrochloride, pseudoephedrine sulfate and the like can be mentioned, and these can be used alone or in combination of two or more. Ephedrine and pseudoephedrine are in an enantiomeric relationship with each other. Of these, dl-methylephedrine hydrochloride is preferred in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.

In the present invention, “ephedrines” can also be used mah (mao) containing these as ingredients.
Maou means the ground stem of Ephedra sinica Stapf, Ephedra intermedia Schrenk et CA Meyer or Ephedra equisetina Bunge (Ephedraceae), as published in the 16th revised Japanese Pharmacopoeia. Maow can be adjusted in shape as needed, and can be cut or crushed into small pieces, lumps, or ground into powder. For example, Maow powder is called “Maow powder”.
In addition, Maou is prepared according to the publicly known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations, etc. It may be “extract” or “tinced”. Examples of leaching agents include lower monohydric alcohols such as methanol, ethanol and n-butanol; lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol and glycerine; ethers such as diethyl ether; acetone and ethyl Ketones such as methyl ketone; esters such as ethyl acetate; halogenoalkanes such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene and toluene; and water. These may be used alone or in combination of two or more. Furthermore, the extract can be dried.

  In the present invention, when maou is used as the ephedrines, maou powder, mao stream extract, mao soft extract, mao dry extract, mao extract and the like are preferable, and these can be used alone or in combination of two or more. Furthermore, when using maou, Chinese herbal prescriptions including maou, kakonto (Kakkonto), shosei ryoutou (Sho Seiryuto), maoutou (maoyuto), etc. can also be used. These may be produced by known methods, or commercially available products may be used.

The content of ephedrines in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, the amount of ephedrine that can be taken per day is 5 to 500 mg, more preferably 10 to 360 mg, and particularly preferably 20 to 240 mg.
In addition, a part or all of ephedrines can be substituted for the above-mentioned maou. When using maou as ephedrines, for example, 0.1 to 25 g (powder equivalent) of maou per day, more preferably 0.25 to 10 g (powder equivalent), particularly preferably 0 .4 to 4 g (concentration in bulk drug substance) can be included.
In this invention, it is preferable to contain 0.1-40 mass% of ephedrine with respect to pharmaceutical composition total mass, It is more preferable to contain 0.5-20 mass%, It contains 1-10 mass%. Is more preferable, and 2 to 10% by mass is particularly preferable. Moreover, when using maou as ephedrine, it is preferable to contain 1 to 98 mass% of maou with respect to the total mass of the pharmaceutical composition, more preferably 2 to 50 mass%, and more preferably 4 to 20 mass%. It is particularly preferred to do this.

  The content ratio of loxoprofen or a salt thereof and ephedrine contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the daily dose of each component described above. , Loxoprofen or a salt thereof is preferably 0.001 to 50 parts by mass, more preferably 0.005 to 50 parts by mass of ephedrine, based on 1 part by mass of loxoprofen sodium anhydride. What contains 0.015-50 mass parts is further more preferable. Among these, what contains 0.05-12 mass parts is more preferable, and what contains 0.1-4 mass parts is especially preferable.

<Component (B-6)>
In the pharmaceutical composition of the present invention, “lysozyme or a salt thereof” includes, in addition to lysozyme itself, a pharmaceutically acceptable salt of lysozyme, and further a solvate with water, alcohol or the like. Specific examples of lysozyme or a salt thereof include, for example, lysozyme, lysozyme inorganic acid salt and the like. Among these, lysozyme inorganic acid salt is preferable, and lysozyme hydrochloride is particularly preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.

The content of lysozyme or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, the amount of lysozyme or a salt thereof that can be taken in an amount of 5 to 450 mg (titer) in terms of lysozyme hydrochloride titer is preferable, more preferably 10 to 360 mg (titer) can be taken, and 15 to 270 mg per day. (Titer) The amount that can be taken is more preferable.
In this invention, it is preferable to contain 0.2-30 mass% (titer) of lysozyme or its salt in conversion of the titer of lysozyme hydrochloride with respect to the pharmaceutical composition total mass, 0.4-25 mass % (Titer) is more preferable, and 0.6 to 20% by mass (titer) is particularly preferable.

  The blending ratio of loxoprofen or a salt thereof and lysozyme or a salt thereof contained in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the daily dose of each component described above. Alternatively, it is preferable that the salt contains 0.01 to 45 parts by mass (titer) of lysozyme or a salt thereof in terms of titer of lysozyme hydrochloride with respect to 1 part by mass of loxoprofen sodium anhydride. What contains 03-30 mass parts (titer) is more preferable, What contains 0.04-12 mass parts (titer) is further more preferable, What contains 0.08-5 mass parts (titer) is more preferable.

<Component (B-7)>
In the present invention, the term “dextromethorphan or a salt thereof” includes dextromethorphan itself, pharmaceutically acceptable salts of dextromethorphan, and pharmaceutically acceptable salts of dextromethorphan and dextromethorphan. Solvates with water or alcohol are also included. Specific examples of dextromethorphan or a salt thereof include, for example, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenol phthaline salt, etc., and dextromethorphan hydrobromide hydrate. Dextromethorphan phenol phthaline salt is preferred, and dextromethorphan hydrobromide hydrate is particularly preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.

The content of dextromethorphan or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, dextromethorphan or a salt thereof can be contained in an amount of 0.1 to 270 mg, more preferably 0.5 to 180 mg, and particularly preferably 1 to 90 mg per day. In addition, when dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate, 6 to 60 mg, more preferably 15 to 60 mg of dextromethorphan hydrobromide hydrate per day, It is particularly preferable to contain an amount that can be taken from 20 to 60 mg. Further, when dextromethorphan or a salt thereof is dextromethorphan phenol phthalin salt, 9 to 90 mg, more preferably 22 to 90 mg, particularly preferably 30 to dextromethorphan phenol phthalin salt per day. It is preferable to contain an amount capable of taking 90 mg.
In the present invention, dextromethorphan or a salt thereof is preferably contained in an amount of 0.004 to 20% by mass, more preferably 0.02 to 15% by mass, more preferably 0.04%, based on the total mass of the pharmaceutical composition. It is especially preferable to contain 10 mass%.

  The content ratio of loxoprofen or a salt thereof and dextromethorphan or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and is determined by appropriate examination according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof contains 0.0001 to 20 parts by mass of dextromethorphan or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 10 masses. Those containing parts are more preferred, and those containing 0.001 to 5 parts by mass are particularly preferred.

<Component (C)>
In the present invention, the “xanthine derivative” is preferably a compound represented by the following general formula (4).

[In Formula (4), R ⁸ and R ⁹ each independently represent a hydrogen atom or a methyl group, and R ¹⁰ represents a hydrogen atom, a methyl group, a monohydroxypropyl group or a dihydroxypropyl group. ]

In formula (4), in R ¹⁰ , the monohydroxypropyl group is preferably a 2-hydroxypropyl group. The dihydroxypropyl group is preferably a 2,3-dihydroxypropyl group.

In the general formula (4),
(1) R ⁸ is a methyl group, R ⁹ is a methyl group, and R ¹⁰ is a methyl group means caffeine.
(2) R ⁸ is a methyl group, R ⁹ is a methyl group, those R ¹⁰ is a hydrogen atom, is intended to mean theophylline.
(3) R ⁸ is a hydrogen atom, R ⁹ is a methyl group, and R ¹⁰ is a methyl group means theobromine.
(4) R ⁸ is a methyl group, R ⁹ is a hydrogen atom, and R ¹⁰ is a methyl group means paraxanthine.
(5) R ⁸ is a methyl group, R ⁹ is a methyl group, those wherein R ¹⁰ is 2-hydroxypropyl group is intended to mean a proxy Villingen.
(6) R ⁸ is a methyl group, R ⁹ is a methyl group, and R ¹⁰ is a 2,3-dihydroxypropyl group, which means diprofylline.

The compounds of the general formula (4), 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 xanthine derivative, in addition to the compound of the general formula (4), a pharmaceutically acceptable salt thereof, a solvate of the compound of the general formula (4) or the salt thereof with water, alcohol, or the like may be used. These are also included in the xanthine derivatives. Here, double salt formed as a salt of the compound of the general formula (4) (sodium benzoate caffeine (double salt of sodium benzoate and caffeine), aminophylline (double salt of theophylline and ethylenediamine)) Etc. can also be used. In the present invention, one or more of these xanthine derivatives can be used.

  In the present invention, as a xanthine derivative, in addition to the effect of inhibiting the interaction between loxoprofen or a salt thereof and an interactive component, from the viewpoint of using the pharmaceutical composition of the present invention as an antipyretic analgesic or a general cold medicine, Caffeine is preferred. Specific examples of the caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. Among these, caffeine hydrate, anhydrous caffeine, benzoate Sodium caffeine acid is particularly preferred.

  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 or a salt thereof and the interactive component. For example, 10 to 1000 mg, more preferably 20 to 800 mg, more preferably 30 to 700 mg, and particularly preferably 40 to 600 mg of xanthine derivative can be contained per day. The content when caffeine hydrate is used as the xanthine derivative is preferably 30 to 300 mg per day, and the content when caffeine anhydride is used is preferably 30 to 300 mg per day, and benzoic acid. The content in the case of using sodium caffeine is preferably 30 to 300 mg per day, and the content in the case of using citrate caffeine is preferably 60 to 300 mg per day. In the present invention, the xanthine derivative is preferably contained in an amount of 0.4 to 65% by mass relative to the total mass of the pharmaceutical composition, more preferably 0.8 to 60% by mass, and 1.6 to 55% by mass. It is particularly preferable to contain it.

  Moreover, the content ratio of the xanthine derivative contained in the pharmaceutical composition of the present invention and loxoprofen or a salt thereof is not particularly limited, and is appropriately determined according to the daily dose and the interaction inhibitory effect of each component described above. What is necessary is just to examine and determine, What contains 0.03-100 mass parts of a xanthine derivative with respect to 1 mass part of loxoprofen or its salt in conversion of a loxoprofen sodium anhydride is preferable, and is 0.08-27 mass. Those containing parts are more preferred, and those containing 0.2 to 10 parts by mass are more preferred.

The pharmaceutical composition of the present invention can be used in various forms such as orally administered preparations, intraoral preparations, and injectable preparations by appropriately using formulation additives according to known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations. The dosage form can be made. Although it should not specifically limit as a dosage form, Oral administration formulation and buccal application formulation are preferable. Specific examples of dosage forms include tablets (orally disintegrating tablets, chewable tablets, dispersible tablets, dissolving tablets; including oral tablets such as troches, sublingual tablets, buccal tablets, adhesive tablets, and gums), capsules Pills, powders, granules, fine granules, dry syrups, oral jelly, oral liquids (elixirs, suspensions, emulsions, limonades, etc.), syrups, etc. Among these, solid preparations Is preferred. In addition, the pharmaceutical composition of the present invention may be coated with a sugar coating or a film coating by a known method.
Further, the pharmaceutical composition of the present invention may contain loxoprofen or a salt thereof and an interactive component so as not to substantially contact each other. With such a configuration, the interaction can be further suppressed.
Here, “containing so as not to substantially contact each other” means containing in a pharmaceutical composition so that loxoprofen or a salt thereof, and an interactive component do not come into contact with each other to the extent that no interaction is exhibited. It is preferable to contain such that loxoprofen or a salt thereof and the interactive component do not come into contact with each other.

  The above solid preparation can be produced and formulated by a known method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparation, etc., but from the viewpoint of suppressing interaction, (A ′) loxoprofen or a salt thereof itself, or Loxoprofen containing a solid composition containing loxoprofen or a salt thereof and (B ′) the interactive component itself or a solid composition containing the interactive component, and the components constituting these solid compositions, Or what is arrange | positioned so that the salt and interactive component may not mutually contact is mentioned as a specific example. These solid compositions are in the form of powder, granules, tablets, and the like.

  Among the solid preparations, the following (I)-(VIII) and the like may be exemplified as specific forms of the loxoprofen or a salt thereof and the interactive component arranged so as not to contact each other. As described above, these can be produced and formulated using appropriate formulation additives by known methods, for example, known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.

(I) One of loxoprofen or a salt thereof and an interactive component is granulated by an appropriate method to form a granule, and the other loxoprofen or a salt thereof or an interactive component is contained without granulation. Powders, granules, etc. that have been prepared, and preparations in which the granules are further coated by an appropriate method. In this case, the xanthine derivative may be contained in the granular material, or may be contained separately from the granular material.
(II) Loxoprofen or a salt thereof and an interactive component are separately granulated by an appropriate method to form granules, and powders and granules produced by containing these, and the granules are further suitable. Formulation coated by the method. In this case, the xanthine derivative may be contained in one of the granular materials, may be contained in both granular materials, or may be contained separately from these granular materials.
(III) A capsule filled with the powder or granule produced in (I) or (II) above.
(IV) A tablet obtained by tableting the granular material produced in the above (I) or (II) by an appropriate method. Tableting can be achieved not only by the compression method but also by molding into a certain shape by an appropriate method.
(V) A multi-layer tablet prepared so that loxoprofen or a salt thereof and an interactive component do not substantially contact each other, and a preparation in which the multi-layer tablet is further coated by an appropriate method. The multi-layer tablet is preferably one in which loxoprofen or a salt thereof and an interactive component are located in different layers, and as a multi-layer tablet having three or more layers, a layer containing loxoprofen or a salt thereof and an interactive component are included. More preferably, the layers included are positioned so as not to contact each other. In addition, the granular material manufactured by said (I) and (II) can be used as a loxoprofen or its salt, and an interactive component. In the case of using these granular materials, a multilayer tablet having two or more layers can be obtained. In the multilayer tablet, the xanthine derivative may be located in either the layer containing loxoprofen or a salt thereof, or the layer containing the interactive component, or may be separately located in both layers. May be located in the intermediate layer of either layer.
(VI) Loxoprofen or a salt thereof and any one of the interactive components are arranged in a core tablet (also referred to as a core tablet or a central tablet), and the loxoprofen or a salt thereof and the interactive component do not substantially contact each other. 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 (II) can be used as a loxoprofen or its salt, and an interactive component. 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.
(VII) In place of the granular material of (I) or (II) above, either or both of loxoprofen or a salt thereof and an interactive component is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, etc. A formulation using an inclusion compound that is clathrated with cyclodextrins or the like, wherein the loxoprofen or a salt thereof and the interactive component are not substantially in contact with each other.
(VIII) Loxoprofen or a salt thereof and any one of the interactive components are contained in a preparation prepared by a usual method, and are provided with a sugar coating layer or a film coating layer, the sugar coating layer or the coating layer And a formulation prepared so that loxoprofen or a salt thereof and an interactive component do not substantially contact each other (when the dosage form is a tablet, it is called a sugar-coated tablet or a film-coated tablet). The xanthine derivative may be located in the preparation, may be located in the sugar-coated layer or the like, or may be separately located in either the preparation or the sugar-coated layer.

  Granules in the above (I) and (II) are known granulations such as extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, crushed granulation, melt granulation, etc. Depending on the method, it may be prepared using appropriate formulation additives. In the present invention, any of the granular material containing loxoprofen or a salt thereof and the granular material containing an interactive component may be produced by the same granulation method, or produced by different granulation methods. May be.

  The granular material containing loxoprofen or a salt thereof can be produced by granulation by an appropriate method based on a known method, but a commercially available product can be used.

Examples of the formulation additive that can be used in producing the pharmaceutical composition of the present invention include a binder, an excipient, a disintegrant, a lubricant, a fluidizing agent, and a coloring agent.
Examples of the binder include methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl Alcohol etc. are mentioned. In addition, when using melt granulation when producing the granular material in the above (I) and (II), etc., a binder having a low melting point (freezing point) that is solid at normal temperature and melts or softens when heated. Is preferably used. The melting point (freezing point) of such a binder is preferably lower than the melting point of the components according to the present invention (such as loxoprofen or a salt thereof and an interactive component). Specifically, a binder having a melting point (freezing point) of 30 to 100 ° C. is preferable, and a binder of 50 to 80 ° C. is more preferable. Examples of such materials include macrogols (for example, macrogol 4000, macrogol 6000, macrogol 20000, etc.); fats and oils (for example, beef tallow oil, hydrogenated oil, hydrogenated vegetable oil, soybean hydrogenated oil, carnauba wax) Hydrocarbons (eg, paraffin, microcrystalline wax, etc.); higher alcohols (eg, cetyl alcohol, stearyl alcohol, etc.); fatty acids (eg, stearic acid); fatty acid esters (For example, acetyl glycerin fatty acid ester, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, glyceryl monostearate, etc.) and the like.

  Examples of excipients include crystalline cellulose, powdered cellulose, lactose hydrate, sucrose, glucose, mannitol, erythritol, xylitol, trehalose, maltitol, lactitol, sorbitol, wheat starch, corn starch, potato starch, and anhydrous phosphate Examples thereof include calcium hydrogen, calcium carbonate, silicon dioxide and the like.

  Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl ethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, hydroxypropyl starch, and the like.

Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, and sodium stearyl fumarate.
Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide and the like.
Examples of the colorant include yellow ferric oxide, ferric oxide, edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible yellow No. 5, edible green No. 3, edible red No. 2, and edible red No. 3 Edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106 and the like.

The pharmaceutical composition of the present invention includes the following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof;
(B) One or more selected from the group consisting of the following components (B-1-1) to (B-7); (B-1-1) chlorpheniramine or a salt thereof, (B-1 -2) clemastine or a salt thereof, (B-1-3) carbinoxamine or a salt thereof, (B-1-4) diphenylpyraline or a salt thereof, (B-2-1) bromhexine or a salt thereof, (B-2- 2) Ambroxol or a salt thereof, (B-3-1) guaiacol derivative or a salt thereof, (B-3-2) a cresol derivative or a salt thereof, (B-3-3) acetaminophen, (B-3) -4) ethenzamide, (B-4) codeines, (B-5) ephedrines, (B-6) lysozyme or salts thereof, (B-7) dextromethorphan or salts thereof;
(C) caffeine;
A pharmaceutical composition containing

The following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof;
(B) One or more selected from the group consisting of the following components (B-1-1) to (B-7); (B-1-1) chlorpheniramine or a salt thereof, (B-1 -2) clemastine or a salt thereof, (B-1-3) carbinoxamine or a salt thereof, (B-1-4) diphenylpyraline or a salt thereof, (B-2-1) bromohexine or a salt thereof, (B-2- 2) Ambroxol or a salt thereof, (B-3-1-1) Guaifenesin or a salt thereof, (B-3-1-2) Guayacol sulfonic acid or a salt thereof, (B-3-2-1) Cresol sulfone Acid or salt thereof, (B-3-3) acetaminophen, (B-3-4) etenzaamide, (B-4) codeine, (B-5) ephedrine, (B-6) lysozyme or a salt thereof (B-7) dextromethorphan or a salt thereof;
(C) caffeine;
The pharmaceutical composition containing is more preferable.

  Examples of the route of administration of the pharmaceutical composition of the present invention include oral and parenteral such as transrectal and vaginal. In the present invention, an oral administration preparation is preferred. In addition, the pharmaceutical composition of the present invention can be taken about 1 to 4 times per day before meals, between meals, after meals, before going to bed.

  The pharmaceutical composition of the present invention includes, as a pharmaceutical ingredient, loxoprofen or a salt thereof, a drug other than an interactive ingredient, such as an antipyretic analgesic, an antihistamine, an antitussive, a noscapine, a bronchodilator, an expectorant, a vitamin, It may contain one or more selected from the group consisting of inflammatory agents, gastric mucosal protective agents, anticholinergic agents, herbal medicines, Kampo prescriptions and the like. These components are preferably blended in the solid preparation.

  Examples of antipyretic analgesics include aspirin, aspirin aluminum, isopropylantipyrine, ibuprofen, 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, ketotifen fumarate, triprolidine hydrochloride, tripelenamine hydrochloride, tondylamine hydrochloride Phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, mequitazine, methodirazine hydrochloride, mebhydroline napadisilate and the like.

  Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, dibutate sodium, dimemorphan phosphate, tipepidine citrate, And tipepidine hibenzate.

Examples of noscapine include noscapine hydrochloride and noscapine.
Examples of the bronchodilator include trimethquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and the like.

Examples of expectorants include ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, methylcysteine hydrochloride, l-menthol and the like.
Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromovalerylurea.

Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, Thiamine nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutiamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavinline Acid ester, riboflavin butyrate, riboflavin sodium phosphate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, 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 gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride 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, akamegasiwa (red buds), asenyaku (asenyaku), inyoukaku (horny gourd), fennel (yuka), engosaku (yenkogyo), ougon (yellow japonicus), seisei (yellow spirit), and oak (yellow candy). , Ohi (cherry bark), Ouren (yellow ream), Onji (distant), Gajutsu (Iso), Kanokosou (Deer herb), Chamomile, Caronin (Karojin), Kyokyo (Kikkyo), Kyonin (Kyojin), Kokushi (Lion), wolfberry (bamboo leaf), Keigai (bamboo leaf), keihi (cinnamon bark), ketsumeishi (Keriko), gentian, Gennoshouko (current evidence), kobushi (Katsukiko), gouo (cow yolk), trash beet (Gomiko), Saishin (Spicy), Salamander, Zion (Zipa), Jikoppi (Skin), Peonies (Glue), Musk, Shajin, Shazenshi, Shazenji Saw (car forerunner), beast gall (including Yutan (bear gall)), gyoza (ginger), ziryu (earth dragon), Xinyi (pepper), sexan (stone wall), Senega, Senkyu (river kyu), Zenko ( Mae-hu, Senburi, Sojutsu (蒼朮), Sohakuhi (mulberry skin), Soyo (Soba), Taisan (Daibu), Chiksetsu carrot (Bamboo ginseng), Clove (clove), Chimpi (Chen), Toki (homecoming), Tokon (napping root), Nantenjitsu (Nan Tenji), Carrot (carrot), Baimo (shellfish mother), Bakumondou (Bakumon winter), Hange (half summer), Bankouka (bancho flower), Hampi ( Herbal medicines such as anti-nasal), peony (white bean), peanut (white moth), bukkuri (pepper), button pi (peony skin), ergot (deer moth), and extracts thereof (extract, tincture, dry extract, etc.) It is done.

  Examples of Kampo prescriptions include Keishito (Katsura-yu), Kousosan (Kousosan), Psycho-keito (Shibako), Bakumondou (Bakumontoyu), Hange Examples include Kokubokuto (half-summer Koboku-yu).

  The pharmaceutical composition of the present invention may be further stored in a container in the presence of a desiccant. Hereinafter, what contains the pharmaceutical composition and desiccant of this invention in a container may be called "pharmaceutical formulation" of this invention.

  In the pharmaceutical preparation of the present invention, the desiccant is not particularly limited as long as the desiccant further suppresses or improves 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.

  Specific 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, magnesium oxide. Etc., and a mixture of these and activated carbon may be used. Among these, at least one selected from the group consisting of silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve), and calcium chloride is more preferable, and among them, synthetic zeolite is more preferable in terms of suppressing interaction. .

  As the desiccant, various commercially available products can be used. Examples of the commercially available products include Siblet, MS-Tablet, MS-Serum W, Tokai Gel, Desiccite 25, Alp Sheet, Yamajin manufactured by Tokai Chemical Industry Co., Ltd. Ydrien (registered trademark) packaged product, Yaridan (registered trademark) tablet, Dryan (registered trademark) sheet, Sekawa, Allosheet, Zeosheet, Shinagawa Kasei Co., Ltd. OZO, an ID sheet manufactured by ID Co., Ltd., an ID packing agent, and the like.

In the pharmaceutical preparation of the present invention, the content of the desiccant may be appropriately determined and determined, but is 0.05 to 35 with respect to 1 part by mass of loxoprofen or a salt thereof contained in the pharmaceutical composition according to the present invention. Mass parts are preferred, and 0.15 to 17 parts by mass are more preferred.
Moreover, 0.001-1 mass part is preferable with respect to 1 mass part of pharmaceutical composition of this invention, and 0.004-0.4 mass part is more preferable.
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, and any of a regular container and an irregular container can be used. It can be sealed and is preferably sealed. 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.

  In order to produce the pharmaceutical preparation of the present invention, the pharmaceutical composition of the present invention and the desiccant may be stored in a container, and the method is not particularly limited. Any of these can be achieved by arranging them by appropriate means such as charging them into the container.

  For example, when the container is a bottle, the desiccant (preferably, a columnar shape (tablet shape)) is placed in the bottle, or stored in the back side (inner cap) of the bottle lid, and stored in the container. This can be achieved by storing the pharmaceutical composition in a bottle or the like. Further, when the container is a bag, it can be achieved by storing the desiccant (preferably, a plate-like or bag-like sheet type) and the pharmaceutical composition of the present invention in the bag.

  Furthermore, the pharmaceutical preparation of the present invention is a pharmaceutical composition of the present invention, which is once packaged by SP (Stripe Package) packaging, PTP (Press Through Package) packaging, stick packaging or bag, etc. The product and the desiccant may be enclosed in a bag or the like. More specifically, there may be mentioned, for example, a form in which the solid preparation of the present invention packaged in SP packaging, PTP packaging or stick packaging is combined with a plate-like or bag-like sheet-type desiccant and pillow-packaged. Further, the pillow packaging form may be stored in a box or the like.

And although the pharmaceutical composition of this invention contains a loxoprofen or its salt, and an interactive component, a pharmaceutical composition is excellent in storage stability. In addition, as shown in the examples described below, the xanthine derivative is quite surprisingly an interaction between loxoprofen or a salt thereof and an interactive component, although it causes an interaction with loxoprofen or a salt thereof. To reduce or reduce
Moreover, since the pharmaceutical composition of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, Stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain, menstrual pain, trauma pain relief, chills, fever during fever, cold symptoms (sore pain, chills, fever, headache, joint pain It is effective as a general cold medicine (cold medicine) or antipyretic analgesic.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[Test Example 1] Examination of interaction (1)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.5 g and anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 0.61 g were mixed, It put into the glass bottle (3K specification bottle), and preserve | saved at 40 degreeC75% RH. Immediately after the start of storage, 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.

[Test Example 4] Examination of interaction (4)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 491.5 mg and d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name: D-chlorpheniramine maleate) 8 .5 mg was mixed, put into a glass bottle (3K standard bottle), and stored at 60 ° C. (Comparative Example 1).
Separately, loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 491.5 mg, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-chlorpheniramine maleate) ) 8.5 mg and anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 601.5 mg were mixed and stored at 60 ° C. as in Comparative Example 1 (Example 1).
In addition, loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 491.5 mg, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-chlorpheniramine maleate) ) 8.5 mg and anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 601.5 mg were mixed, and further synthetic zeolite (made by Shin-Etsu Chemical Co., Ltd .: trade name MS-) as a desiccant in the bottle. W1506) 1 g was added and similarly stored at 60 ° C. (Example 2).
For each of Comparative Example 1 and Examples 1 and 2, the state of the mixture immediately after the start of storage, 1 day, 3 days, and 1 week later, that is, the presence or absence of interaction, was evaluated, and the results are shown in Table 4.

As is apparent from Table 4, the mixture of loxoprofen sodium hydrate and d-chlorpheniramine maleate that had been preserved by mixing was wet, solidified, and further discolored as a result of interaction. Example 1).
In contrast, it was found that the above interaction was suppressed (improved) by further mixing anhydrous caffeine with loxoprofen sodium hydrate and d-chlorpheniramine maleate (Example 1). . Further, it was found that by mixing anhydrous caffeine and further using a desiccant, the same state as at the start was maintained, and the above interaction was further suppressed (improved) compared to Example 1. (Example 2).

In addition, from the results of Test Examples 1 to 4, it has been found that interaction occurs between loxoprofen or a salt thereof and a xanthine derivative, and between loxoprofen or a salt thereof and chlorpheniramine or a salt thereof, respectively.
Therefore, when a xanthine derivative is mixed with loxoprofen or a salt thereof and chlorpheniramine or a salt thereof, the interaction between the three components is expected to increase.
Surprisingly, however, it has been found that the xanthine derivative suppresses the interaction between loxoprofen or a salt thereof and chlorpheniramine or a salt thereof (Example 1).

[Example 3] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D -7 parts by mass of chlorpheniramine maleate), anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: brand name anhydrous caffeine), 80 parts by mass, hydroxypropyl cellulose (manufactured by Nippon Soda: brand name HPC-L) 145.8 parts by mass Parts, carmellose calcium (made by Gotoku Pharmaceutical: trade name ECG505) 486 parts by mass, crystalline cellulose (made by Asahi Kasei Chemicals: trade name Theolas PH-101) 3684 parts by mass, high-speed agitation granulator (manufactured by Paulek: VG-25 type) After mixing and mixing, 1972.6 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 4] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, d-chlorpheniramine maleate (manufactured by Kongo Chemical: trade name D -7 parts by mass of chlorpheniramine maleate), anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: brand name anhydrous caffeine), 80 parts by mass, hydroxypropyl cellulose (manufactured by Nippon Soda: brand name HPC-L) 145.8 parts by mass Part, 486 parts by mass of carmellose calcium (product name: ECG505, manufactured by Gotoku Pharmaceutical Co., Ltd.) and 3684 parts by mass of lactose hydrate (product name: lactose 200M, DMV: product name: VG-25) After charging and mixing, 232 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 5] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, d-chlorpheniramine maleate (manufactured by Kongo Chemical: trade name D -Chlorpheniramine maleate) 7 parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine: trade name anhydrous caffeine) 80 parts by weight, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight, Carmellose calcium (product of Gotoku Pharmaceutical: trade name ECG505) 486 parts by mass, lactose hydrate (product of DMV: trade name lactose 200M) 1842 parts by mass, crystalline cellulose (product name: Theolas PH-101) 1842 parts by mass Is added to a high-speed agitation granulator (Paurek: VG-25 type) and mixed, and then purified water 696 is added. Kneaded with the addition of 2 parts by mass, 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 6] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, d-chlorpheniramine maleate (manufactured by Kongo Chemical: trade name D -Chlorpheniramine maleate) 7 parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine: trade name anhydrous caffeine) 80 parts by weight, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight, Carmellose calcium (manufactured by Gotoku Pharmaceutical: trade name ECG505) 486 parts by mass, lactose hydrate (DMV: trade name: lactose 200M) 1228 parts by mass, crystalline cellulose (product name: Theolas PH-101) 1228 parts by mass , Corn starch (manufactured by Nissho Chemical: trade name corn starch ST-C) 1 28 parts by weight of a high speed stirring granulator: after mixing was poured into (manufactured by Powrex VG-25 type), kneaded with the addition of purified water 928.2 parts by mass, 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[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.

[Example 11] Antipyretic test Using Wistar rats (Std: Wistar / ST, male, 8 weeks old, body weight 202.0 to 252.8 g), a test was conducted as 4 to 8 animals per group.
First, a micro precision thermometer (BAT-12, Physitemp) was inserted into the rectum 4.5 cm, the rectal temperature of the rat was measured, and this was taken as normal body temperature. Next, crushed beer yeast (Ebios tablets, Asahi Food and Health Care) suspended in physiological saline to a concentration of 20% was administered subcutaneously at the back of the rat at 10 mL / kg.
Rats were fasted after yeast administration (water was ad libitum), and about 16 hours after administration, rectal temperature was measured, and this was taken as body temperature during fever. Individuals having a calorific value (temperature during heating-normal temperature) of 1 ° C. or higher were grouped so that the average calorific value was almost equal.
To group (1), loxoprofen sodium hydrate (LX) as a test drug was suspended in 0.5% methylcellulose (MC) solution and orally administered in a predetermined amount (1 mg / kg). Further, in group (2), anhydrous caffeine (Caf) and d-chlorpheniramine maleate (CM) are suspended in a 0.5% MC solution as test drugs, and a predetermined amount (Caf: 0.15 mg / day) is obtained. kg, CM: 3.5 mg / kg). In group (3), LX, Caf and CM were suspended in 0.5% MC solution as test drugs, and predetermined amounts (LX: 1 mg / kg, Caf: 0.15 mg / kg, CM: 3.5 mg / kg) Orally administered. In addition, only the solvent (0.5% MC) was orally administered to the control group. In all groups, the administration volume was 5 mL / kg. One hour after administration of the test drug, the rectal temperature was measured, the calorific value of the test drug administration group and the calorific value of the control administration group were calculated, and the fever suppression rate (%) was calculated based on the following formula. The results are shown in Table 5.
Fever suppression rate (%) = (1−fever amount [test drug administration group] / fever amount [control group]) × 100

As is apparent from Table 5, loxoprofen or a salt thereof exhibited an exothermic suppression, that is, an antipyretic action (group (1)). On the other hand, it was confirmed that the combined administration of a xanthine derivative and chlorpheniramine or a salt thereof tends to promote fever and at least exhibits no antipyretic action (group (2)).
However, when a combination of loxoprofen or a salt thereof showing antipyretic action with a xanthine derivative and chlorpheniramine or a salt thereof not showing antipyretic action is surprisingly, the antipyretic action of loxoprofen or a salt thereof is surprisingly enhanced. As a result, an excellent effect of the present invention was found (group (3)).

[Test Example 5] Examination of interaction (5)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 497mg and clemastine fumarate (Daito: trade name: clemastine fumarate) 3mg are mixed, and glass bottle (3K standard bottle) And stored at 60 ° C. for 1 week (Comparative Example 2).
Separately, loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 497 mg, clemastine fumarate (trade name: clemastine fumarate) 3 mg and anhydrous caffeine 608 mg (Shizuoka Cafe) In Industrial Co., Ltd. product name: anhydrous caffeine) was mixed and stored at 60 ° C. in the same manner as in Comparative Example 2 (Example 12).
In addition, loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 497 mg, clemastine fumarate (trade name: clemastine fumarate made by Daito) and 608 mg of anhydrous caffeine (Shizuoka Cafe) IN Industrial Co., Ltd .: trade name: anhydrous caffeine) was mixed, and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name: MS-W1506) was added as a desiccant in the bottle and stored at 60 ° C. in the same manner Example 13).
For each of Comparative Example 2 and Examples 12 and 13, the state of the mixture immediately after the start of storage, 1 day, 3 days, and 1 week, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 6.

As is apparent from Table 6, in the case where loxoprofen sodium hydrate and clemastine fumarate were mixed and stored, as a result of the interaction, the mixture became wet and further discolored (Comparative Example 2).
On the other hand, it was found that the above interaction was suppressed (improved) by further mixing anhydrous caffeine with loxoprofen sodium hydrate and clemastine fumarate (Example 12). Further, it was found that by mixing anhydrous caffeine and further using a desiccant, the same state as at the start was maintained, and the above interaction was further suppressed (improved) compared to Example 12. (Example 13).

In addition, from the results of Test Examples 1 to 3 and 5, it was found that interaction occurred between loxoprofen or a salt thereof and a xanthine derivative, and between loxoprofen or a salt thereof and clemastine or a salt thereof, respectively.
Therefore, when a xanthine derivative is mixed with loxoprofen or a salt thereof and clemastine or a salt thereof, the interaction between the three components is expected to increase.
However, it was surprisingly found that the xanthine derivative inhibits the interaction between loxoprofen or a salt thereof and clemastine or a salt thereof (Example 12).

[Example 14] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 2 0.7 parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine), 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium ( Made by Gotoku Pharmaceutical: 486 parts by mass of ECG505 (trade name) and 3688.3 parts by mass of crystalline cellulose (manufactured by Asahi Kasei Chemicals: brand name Theolas PH-101) were put into a high-speed agitation granulator (product of Paulek: VG-25). After mixing, 1972.6 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 15] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 2 0.7 parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine), 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium ( Made by Gotoku Pharmaceutical Co., Ltd .: Trade name ECG505) 486 parts by weight, lactose hydrate (DMV: trade name: lactose 200M) 3688.3 parts by weight were charged into a high-speed stirring granulator (Paurek: VG-25 type) and mixed. Thereafter, 232 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 16] Tablet Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, clemastine fumarate (Dite: trade name: clemastine fumarate) 2 0.7 parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine), 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium ( Made by Gotoku Pharmaceutical Co., Ltd .: Trade name ECG505) 486 parts by mass, lactose hydrate (DMV: trade name lactose 200M) 1844.3 parts by mass, crystalline cellulose (produced by Asahi Kasei Chemicals: trade name Theolas PH-101) 1844 parts by mass After stirring and mixing into a stirring granulator (Powrec: VG-25 type), 696.2 mass of purified water Kneading was added to obtain granules. 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 17] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 2 0.7 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine: trade name anhydrous caffeine) 80 parts by mass, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by mass, carmellose calcium (Gotoku Pharmaceutical) Manufactured: Trade name ECG505) 486 parts by mass, lactose hydrate (DMV: trade name: lactose 200M) 1229.5 parts by mass, crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name Theolas PH-101) 1229.4 parts by mass, corn Starch (manufactured by Nippon Star Chemical Co., Ltd .: trade name corn starch ST-C) 1229.4 The amount unit of a high speed stirring granulator: after mixing was poured into (manufactured by Powrex VG-25 type), kneaded with the addition of purified water 928.2 parts by mass, 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 18]
Thirty tablets obtained in Example 14 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 19]
Thirty tablets obtained in Example 15 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 20]
Thirty tablets obtained in Example 16 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 21]
Thirty tablets obtained in Example 17 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 6] Examination of interaction (6)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 483mg and carbinoxamine maleate (trade name: Carbinoxamine maleate) 17mg are mixed and mixed into a glass bottle (3K standard) And stored at 60 ° C. (Comparative Example 3).
Separately, loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 483 mg, carbinoxamine maleate (manufactured by Kongo Chemical: trade name: carbinoxamine maleate) and anhydrous caffeine (Shizuoka) 590 mg of Caffeine Kogyo Kogyo: trade name anhydrous caffeine) was mixed and stored at 60 ° C. in the same manner as in Comparative Example 3 (Example 22).
In addition, loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 483 mg, carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) and anhydrous caffeine (Shizuoka) 590 mg of Caffeine Kogyo Co., Ltd .: trade name anhydrous caffeine) is mixed, and 1 g of synthetic zeolite (made by Shin-Koshi Kasei Kogyo Co., Ltd .: trade name MS-W1506) is added as a desiccant in the bottle and stored at 60 ° C. in the same manner. (Example 23).
For each of Comparative Example 3 and Examples 22 and 23, the state of the mixture immediately after the start of storage, one day later, and three days later, ie, the presence or absence of interaction, was evaluated. The results are shown in Table 7.

As is apparent from Table 7, the mixture of loxoprofen sodium hydrate and carbinoxamine maleate that had been stored was solidified after 1 day of storage and further discolored as a result of interaction. (Comparative Example 3).
On the other hand, it was found that the above interaction was suppressed (improved) by further mixing anhydrous caffeine with loxoprofen sodium hydrate and carbinoxamine maleate (Example 22). Further, it was found that the above interaction was further suppressed (improved) compared to Example 22 by mixing anhydrous caffeine and using a desiccant (Example 23).

In addition, from the results of Test Examples 1 to 3 and 6, it has been found that interaction occurs between loxoprofen or a salt thereof and a xanthine derivative, and between loxoprofen or a salt thereof and carbinoxamine or a salt thereof, respectively. .
Therefore, when a xanthine derivative is mixed with loxoprofen or a salt thereof and carbinoxamine or a salt thereof, the interaction between the three components is expected to increase.
Surprisingly, however, it has been found that the xanthine derivative inhibits the interaction between loxoprofen or a salt thereof and carbinoxamine or a salt thereof (Example 22).

[Example 24] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) ) 15 parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight, carmellose calcium ( Goto Pharmaceutical Co., Ltd .: Trade name ECG505) 486 parts by mass, crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: trade name Theolas PH-101) 3676 parts by mass are charged into a high-speed agitation granulator (Paurek: VG-25 type) and mixed. Then, 1972.6 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 25] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) ) 15 parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight, carmellose calcium ( Made by Gotoku Pharmaceutical Co., Ltd .: Trade name ECG505) 486 parts by weight, lactose hydrate (DMV: trade name: lactose 200M) 3676 parts by weight were charged into a high-speed stirring granulator (Paurek: VG-25 type) and mixed. 232 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 26] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) ) 15 parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight, carmellose calcium ( Made by Gotoku Pharmaceutical Co., Ltd .: Trade name ECG505) 486 parts by mass, lactose hydrate (DMV: trade name: lactose 200M) 1838 parts by mass, crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: trade name Theolas PH-101) 1838 parts by mass Purified water 696. after being put into a granulator (Paurek: VG-25 type) and mixing. Parts by kneading was added 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 27] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) ) 15 parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight, carmellose calcium ( Made by Gotoku Pharmaceutical Co., Ltd .: Trade name ECG505) 486 parts by mass, lactose hydrate (DMV: trade name: lactose 200M) 1226 parts by mass, crystalline cellulose (produced by Asahi Kasei Chemicals: trade name: SEOLUS PH-101) 1225 parts by mass, corn starch ( Nippon Star Chemical Co., Ltd .: Brand name Corn starch ST-C) 12 5 parts by weight of a high speed stirring granulator: after mixing was poured into (manufactured by Powrex VG-25 type), kneaded with the addition of purified water 928.2 parts by mass, 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 28]
Thirty tablets obtained in Example 24 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 29]
Thirty tablets obtained in Example 25 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 30]
Thirty tablets obtained in Example 26 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 31]
Thirty tablets obtained in Example 27 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 7] Examination of interaction (7)
Comparative Example 4: Loxoprofen sodium hydrate (manufactured by Daiwa 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 32: Loxoprofen sodium hydrate (manufactured by Daiwa 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) and anhydrous 600 mg of caffeine (manufactured by Shizuoka Caffeine Kogyo: trade name anhydrous caffeine) was mixed to obtain a mixture.
Each mixture of Comparative Example 4 and Example 32 was placed in a glass bottle (3K standard bottle) and stored at 60 ° C.
In addition, as Example 33, loxoprofen sodium hydrate (manufactured by Daiwa 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 (produced by Shizuoka Caffeine Industry: trade name: anhydrous caffeine), 1 g of synthetic zeolite (produced by Shin-Etsu Chemical Co., Ltd .: trade name: MS-W1506) in a glass bottle (3K standard bottle) And stored at 60 ° C. (Example 33).
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 8.

  As is clear from Table 8, the mixture of loxoprofen sodium hydrate and diphenylpyralin that had been preserved only interacted, and as a result, the mixture solidified 1 day after the start of preservation (Comparative Example 4). On the other hand, in addition to loxoprofen sodium hydrate and diphenylpyralin, it was found that a mixture of caffeine further improved the interaction (Example 32). In addition to caffeine, the addition of a desiccant was found to maintain the same state as immediately after the start of storage even after 1 week and to suppress the interaction (Example 33). .

From the results of Test Examples 1 to 3, surprisingly, when loxoprofen or a salt thereof and a xanthine derivative are mixed, an interaction occurs between these compounds, and surprisingly, loxoprofen or a salt thereof and diphenylpyraline or a salt thereof It was found that the xanthine derivative improves the interaction.
It has also been found that the use of a desiccant in addition to the xanthine derivative further suppresses the interaction between loxoprofen or a salt thereof and diphenylpyralin.

[Example 34] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name: diphenylpyraline hydrochloride) 8 Parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium (Gotoku Pharmaceutical) Product: ECG505) 486 parts by mass, crystalline cellulose (manufactured by Asahi Kasei Chemicals: product name Theorus PH-101) 3683 parts by mass are charged into a high-speed agitation granulator (Paulec: VG-25 type), mixed and purified. 1972.6 parts by mass of 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 35] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 8 Parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium (Gotoku Pharmaceutical) Product: ECG505) 486 parts by weight, lactose hydrate (DMV: trade name: lactose 200M) 3683 parts by weight are charged into a high-speed stirring granulator (Paurek: model VG-25), mixed, and purified water 232 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 36] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 8 Parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium (Gotoku Pharmaceutical) Product: ECG505) 486 parts by weight, lactose hydrate (DMV: trade name: lactose 200M) 1842 parts by mass, crystalline cellulose (product name: Theolas PH-101) 1841 parts by mass, high-speed agitation granulator (Powrec: VG-25 type), and after mixing, 696.2 parts by mass of purified water was added. Pressurized to kneading, 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 37] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 8 Parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium (Gotoku Pharmaceutical) Manufactured: Trade name ECG505) 486 parts by weight, lactose hydrate (DMV: trade name: lactose 200M) 1228 parts by weight, crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name Theolas PH-101) 1228 parts by weight, corn starch (Nissho) Chemical: Brand name Corn starch ST-C) 1227 parts by mass High-speed stirring granulator: after mixing was poured into (manufactured by Powrex VG-25 type), kneaded with the addition of purified water 928.2 parts by mass, 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 38]
Thirty tablets obtained in Example 34 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 39]
Thirty tablets obtained in Example 35 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 40]
Thirty tablets obtained in Example 36 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 41]
Thirty tablets obtained in Example 37 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 8] Investigation of interaction (8)
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 1.7 g and bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) 0.1 g are mixed together and mixed with a glass bottle ( 3K standard bottle) and stored at 60 ° C. Immediately after the start of storage, the state of the mixture after 1 day, 2 days, and 1 week was evaluated, that is, the presence or absence of interaction, and the results are shown in Table 9.

  As is clear from Table 9, when loxoprofen sodium hydrate and bromhexine hydrochloride were mixed and stored, the interaction resulted in the mixture solidifying after 1 day and discoloring after 3 days.

[Test Example 9] Examination of interaction (9)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 0.5g and Ambroxol hydrochloride (Shizuoka Caffeine Industry: trade name: Ambroxol hydrochloride) 0.5g It mixed, put into the glass bottle (3K specification bottle), and preserve | saved at 60 degreeC. Immediately after the start of storage, the state of the mixture after 1 day, 3 days, and 1 week was evaluated, that is, the presence or absence of interaction, and the results are shown in Table 10.

  As is apparent from Table 10, when loxoprofen sodium hydrate and ambroxol hydrochloride were mixed and stored, the interaction resulted in the mixture solidifying after 1 day and discoloring after 3 days. .

[Test Example 10] Examination of interaction (10)
Comparative Example 5: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 945 mg and bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) 55 mg were mixed together. Obtained.
Example 42: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 945 mg, bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) and anhydrous caffeine (Shizuoka) 1156 mg of Caffeine Kogyosho, trade name: anhydrous caffeine) was mixed to obtain a mixture.
Each mixture of Comparative Example 5 and Example 42 was placed in a glass bottle (3K standard bottle) and stored at 60 ° C. As Example 43, in addition to the mixture of Example 42, 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) was placed in a glass bottle (3K standard bottle) and stored at 60 ° C. For each, the state of the mixture immediately after the start of storage, 1 day, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 11.

As is apparent from Table 11, the mixture of loxoprofen sodium hydrate and bromhexine hydrochloride that had been stored was solidified after 1 day from the start of storage as a result of the interaction, and the mixture solidified after 3 days. The color changed (Comparative Example 5).
On the other hand, in addition to loxoprofen sodium hydrate and bromhexine hydrochloride, it was found that a mixture obtained by further mixing and storing caffeine can suppress discoloration (Example 42). It was also found that the addition of a desiccant in addition to the mixing of caffeine maintained the same state as at the start even after 1 week had passed and could suppress the interaction (Example 43).

  From the results of Test Examples 1-3 and 10, it was found that when loxoprofen or a salt thereof and a xanthine derivative, or loxoprofen or a salt thereof and bromhexine or a salt thereof were mixed, an interaction occurred between these compounds (Test Example). 1-3) Surprisingly, it was found that the xanthine derivative inhibits the interaction between loxoprofen or a salt thereof and bromohexine or a salt thereof (Test Example 10).

[Test Example 11] Investigation of interaction (11)
Comparative Example 6: Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 819 mg and ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: ambroxol hydrochloride) Mix to obtain a mixture.
Example 44: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 819 mg, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: ambroxol hydrochloride) 181 mg and 1002 mg of anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyo: trade name anhydrous caffeine) was mixed to obtain a mixture.
Each mixture of Comparative Example 6 and Example 44 was placed in a glass bottle (3K standard bottle) and stored at 60 ° C. As Example 45, in addition to the mixture of Example 3, 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) was put in a glass bottle (3K standard bottle) and stored at 60 ° C. For each, the presence or absence of discoloration of the mixture immediately after the start of storage, 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 12.

As can be seen from Table 12, the mixture of loxoprofen sodium hydrate and ambroxol hydrochloride which had been preserved only changed its color to slightly yellow after 1 day of the preservation as a result of interaction. After 3 days, the color changed more strongly to slightly yellowish brown (Comparative Example 6).
On the other hand, in addition to loxoprofen sodium hydrate and bromhexine hydrochloride, caffeine further mixed and stored (Example 44) was found to be capable of suppressing discoloration. In addition to the mixing of caffeine, it was also found that the desiccant added (Example 45) can suppress discoloration.

  From the results of Test Examples 1 to 3 and 11, when loxoprofen or a salt thereof and a xanthine derivative, or loxoprofen or a salt thereof and ambroxol or a salt thereof are mixed with each other, an interaction occurs between these compounds ( Test Examples 1-3) Surprisingly, it was found that the xanthine derivative inhibits the interaction between loxoprofen or a salt thereof and ambroxol or a salt thereof (Test Example 11).

[Example 46] Tablets Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 24 Parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium (Gotoku Pharmaceutical) Manufactured: Trade name ECG505) 486 parts by mass, crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd .: trade name Theolas PH-101) 3667 parts by mass are charged into a high-speed agitation granulator (Paulec: VG-25 type), mixed and purified. 1972.6 parts by mass of 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 47] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 24 Parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium (Gotoku Pharmaceutical) Made: Trade name ECG505) 486 parts by weight, lactose hydrate (DMV: trade name: lactose 200M) 3667 parts by weight are added to a high-speed stirring granulator (Paurek: model VG-25), mixed and purified water 232 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 48] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 24 Parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium (Gotoku Pharmaceutical) Product: ECG505) 486 parts by weight, lactose hydrate (DMV: trade name: lactose 200M) 1834 parts by mass, crystalline cellulose (product name: Theolas PH-101) 1833 parts by mass, high-speed agitation granulator (Powrec: VG-25 type), mixed and mixed with 696.2 parts by mass of purified water Kneaded Te to obtain granules. 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 49] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride) 24 Parts by weight, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 145.8 parts by weight, carmellose calcium (Gotoku Pharmaceutical) Product name: ECG505) 486 parts by mass, lactose hydrate (DMV product name: lactose 200M) 1223 parts by mass, crystalline cellulose (Asahi Kasei Chemicals product name: Theolas PH-101) 1222 parts by mass, corn starch (Nissho) Chemical: Brand name Corn starch ST-C) 1222 parts by mass high Mixing granulator: after mixing was poured into (manufactured by Powrex VG-25 type), kneaded with the addition of purified water 928.2 parts by mass, 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 50] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: hydrochloric acid 90 parts by weight of ambroxol), anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name: anhydrous caffeine), 80 parts by weight, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name: HPC-L), 145.8 parts by weight, carme 486 parts by weight of roast calcium (manufactured by Gotoku Yakuhin: trade name ECG505) and 3601 parts by weight of crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name Theolas PH-101) were charged into a high-speed agitation granulator (manufactured by Paulek: VG-25). After mixing, 1972.6 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 51] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: hydrochloric acid 90 parts by weight of ambroxol), anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name: anhydrous caffeine), 80 parts by weight, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name: HPC-L), 145.8 parts by weight, carme 486 parts by weight of roast calcium (product name: ECG505) and lactose hydrate (DMV: product name: lactose 200M) 3601 parts by weight were charged into a high-speed stirring granulator (manufactured by Paulec: model VG-25). After mixing, 232 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 52] Tablets Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry Co., Ltd .: trade name, hydrochloric acid) 90 parts by weight of ambroxol), anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name: anhydrous caffeine), 80 parts by weight, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name: HPC-L), 145.8 parts by weight, carme Loose calcium (product name: ECG505: 486 parts by mass, lactose hydrate (DMV: product name: lactose 200M) 1801 parts by mass, crystalline cellulose (Asahi Kasei Chemicals: product name: Theolas PH-101) 1800 parts by mass Purified water 696. after being put into a high speed agitation granulator (Paurek: VG-25 type) and mixing. Parts by kneading was added 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 53] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry, trade name: hydrochloric acid 90 parts by weight of ambroxol), anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name: anhydrous caffeine), 80 parts by weight, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name: HPC-L), 145.8 parts by weight, carme Loose calcium (product name: ECG505) 486 parts by mass, lactose hydrate (product name: DMV: product name lactose 200M) 1201 parts by mass, crystalline cellulose (product name: Asola Kasei Chemicals: product name Theorus PH-101) 1200 parts by mass, Corn starch (manufactured by Nippon Star Chemical Co., Ltd .: Brand name Corn starch ST-C) 12 0 parts by weight of a high speed stirring granulator: after mixing was poured into (manufactured by Powrex VG-25 type), kneaded with the addition of purified water 928.2 parts by mass, 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 54]
Thirty tablets obtained in Example 46 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 55]
Thirty tablets obtained in Example 47 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 56]
Thirty tablets obtained in Example 48 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 57]
30 tablets obtained in Example 49 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 58]
30 tablets obtained in Example 50 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 59]
Thirty tablets obtained in Example 51 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 60]
Thirty tablets obtained in Example 52 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 61]
Thirty tablets obtained in Example 53 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 11] Investigation of interaction (11)
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.5g and guaifenesin (manufactured by Alps Pharmaceutical Co., Ltd .: trade name guaifenesin) were mixed and mixed in a glass bottle (3K standard bottle). And stored at 60 ° C. for 1 week. Immediately after the start of storage, the state of the mixture after 1 day, 3 days, and 1 week was evaluated, that is, the presence or absence of interaction, and the results are shown in Table 12.

  As is apparent from Table 12, the mixture of loxoprofen sodium hydrate and guaifenesin that had been preserved by mixing had changed to a clear liquid after 1 day as a result of the interaction.

[Test Example 12] Examination of interaction (12)
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.5g and potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: potassium guaiacol sulfonate) mixed And stored in a glass bottle (3K standard bottle) at 60 ° C. for 1 week. Immediately after the start of storage, the state of the mixture after 1 day, 3 days, and 1 week was evaluated, ie, the presence or absence of interaction, and the results are shown in Table 13.

  As is apparent from Table 13, the mixture of loxoprofen sodium hydrate and potassium guaiacol sulfonate stored as a result of the interaction changed the wet state after 3 days.

[Test Example 13] Investigation of interaction (13)
Comparative Example 7: Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) (225 mg) and guaifenesin (manufactured by Alps: trade name: guaifenesin) were mixed to obtain a mixture.
Example 62: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 225 mg, guaifenesin (manufactured by Alps: trade name: guaifenesin) 275 mg and anhydrous caffeine (manufactured by Shizuoka Caffeine Industries) : Trade name Anhydrous caffeine) 275 mg was mixed to obtain a mixture.
About each mixture of the said comparative example 7 and Example 62, it put into the glass bottle (3K specification bottle), and preserve | saved at 60 degreeC. For each, the state of the mixture immediately after the start of storage, 1 day, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 14.

As is apparent from Table 14, the mixture of loxoprofen sodium hydrate and guaifenesin that had been preserved was changed to a clear liquid one day after the start of preservation as a result of interaction (Comparative Example 7). . On the other hand, in addition to loxoprofen sodium hydrate and guaifenesin, it was found that the interaction could be suppressed when caffeine was further mixed and stored (Example 62).
From the results of Test Examples 1-3 and 13, surprisingly, when loxoprofen or a salt thereof and a xanthine derivative are mixed, an interaction occurs between these compounds, but surprisingly, an interaction between loxoprofen or a salt thereof and guaifenesin. It was found that xanthine derivatives improved.

[Test Example 14] Investigation of interaction (14)
Comparative Example 8: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) (225 mg) and potassium guaiacol sulfonate (trade name: Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: guaiacol potassium sulfonate) were mixed. To obtain a mixture.
Example 63: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 225 mg, potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name, potassium guaiacol sulfonate) and anhydrous 275 mg of caffeine (product name: anhydrous caffeine, manufactured by Shizuoka Caffeine Industry) was mixed to obtain a mixture.
Each mixture of Comparative Example 8 and Example 63 was put in a glass bottle (3K standard bottle) and stored at 60 ° C. Further, as Example 64, loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 225 mg, potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name, guaiacol potassium sulfonate) In addition to a mixture of 275 mg and anhydrous caffeine (Shizuoka Caffeine Industry: trade name anhydrous caffeine) 275 mg, 1 g of synthetic zeolite (made by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) in a glass bottle (3K standard bottle) And stored at 60 ° C.
For each, the state of the mixture immediately after the start of storage, 1 day, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 15.

As can be seen from Table 15, the mixture of loxoprofen sodium hydrate and potassium guaiacol sulfonate stored as a result of the interaction changed to a wet state 3 days after the start of storage (comparison) Example 8). On the other hand, in addition to loxoprofen sodium hydrate and potassium guaiacol sulfonate, further mixing of caffeine was found to improve the interaction (Example 63). In addition to caffeine, the addition of a desiccant was found to maintain the same state as immediately after the start of storage even after 1 week and to suppress the interaction (Example 64). .
From the results of Test Examples 1-3 and 14, surprisingly, when loxoprofen or a salt thereof and a xanthine derivative are mixed, an interaction occurs between these compounds, but surprisingly, loxoprofen or a salt thereof and guaiacol sulfonic acid It was found that the xanthine derivative improves the interaction.
In addition to the xanthine derivative, it has been found that further use of a desiccant further suppresses the interaction between loxoprofen or a salt thereof and guaiacol sulfonic acid.

[Example 65] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, guaifenesin (manufactured by Alps Pharmaceuticals: trade name: guaifenesin) 500 parts by weight, anhydrous cafe 80 parts by mass of in (Shizuoka Caffeine Kogyo Co., Ltd .: trade name anhydrous caffeine), 145.8 parts by mass of hydroxypropyl cellulose (trade name: HPC-L, manufactured by Nippon Soda), carmellose calcium (trade name: ECG505, manufactured by Gotoku Pharmaceutical) 486 parts by mass, 3191 parts by mass of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd .: trade name Theorus PH-101) was added to a high-speed agitation granulator (manufactured by Paulek: model VG-25), mixed, and purified water 1972.6 parts by mass Part 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 66] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name guaiacol sulfone) Potassium acid) 500 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 parts by weight, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight, carmellose 486 parts by mass of calcium (product name: ECG505, manufactured by Gotoku Pharmaceutical Co., Ltd.) and 3191 parts by mass of crystalline cellulose (product name: Theolas PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.) are charged into a high-speed agitation granulator (manufactured by Paulek: Model VG-25). After mixing, 1972.6 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass of magnesium stearate (manufactured by Taihei Kagaku Kogyo Co., Ltd .: trade name magnesium stearate (vegetable)) were added to a mixer (manufactured by Kotobuki: PM50 type) and mixed. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 67]
Thirty tablets obtained in Example 65 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 68]
Thirty tablets obtained in Example 66 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 14] Investigation of interaction (14)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 500 mg and dihydrocodeine phosphate (manufactured by Shionogi Seiyaku: trade name: dihydrocodeine phosphate “Shionogi”) were mixed and mixed in a glass bottle ( 3K standard bottle) and stored at 60 ° C. 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 15.

  As is apparent from Table 15, 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 15] Examination of interaction (15)
Comparative Example 9: Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 495 mg and dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name dihydrocodeine phosphate “Shionogi”) 5 mg To obtain a mixture.
Example 69: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 495 mg, dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi”) 5 mg and anhydrous 500 mg of caffeine (manufactured by Shizuoka Caffeine Kogyo: trade name anhydrous caffeine) was mixed to obtain a mixture.
The mixtures of Comparative Example 9 and Example 69 were each placed in a glass bottle (3K standard bottle) and stored at 60 ° C. As Example 70, in addition to the mixture of Example 69, 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) was placed in a glass bottle (3K standard bottle) and stored at 60 ° C.
For each, the state of the mixture immediately after the start of storage, 1 day, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated. The results are shown in Table 16.

As is apparent from Table 16, the mixture of loxoprofen sodium hydrate and dihydrocodeine phosphate that had been stored alone solidified as a result of the interaction, and the mixture solidified one day after the start of storage (Comparative Example 9). ).
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 69). It was also found that the addition of desiccant in addition to the mixing of anhydrous caffeine maintained the same state as at the start even after 1 week, and the above interaction was suppressed (Example 70). .

  From the results of Test Examples 1 to 3 and 15, when loxoprofen or a salt thereof and a xanthine derivative, or loxoprofen or a salt thereof and codeine are mixed with each other, an interaction occurs between these compounds ( Test Examples 1 to 3) Surprisingly, it was found that the interaction between loxoprofen and codeines was suppressed by the xanthine derivative (Test Example 15).

[Example 71] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate) Shionogi ") 48 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by mass, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by mass, carmellose 486 parts by mass of calcium (product name: ECG505, manufactured by Gotoku Pharmaceutical Co., Ltd.) and 3643 parts by mass of crystalline cellulose (product name: Theolas PH-101, manufactured by Asahi Kasei Chemicals Co., Ltd.) were charged into a high-speed agitation granulator (manufactured by Paulek: VG-25 type). Next, 1972.6 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 72] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate) Shionogi ") 48 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by mass, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by mass, carmellose 486 parts by mass of calcium (product name: ECG505, manufactured by Gotoku Pharmaceutical Co., Ltd.) and 3643 parts by weight of lactose hydrate (product name: DMV: product name: lactose 200M) are charged into a high-speed agitation granulator (manufactured by Paulek: model VG-25) and mixed. Then, 232 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 73] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate) Shionogi ") 48 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by mass, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by mass, carmellose 486 parts by mass of calcium (product name: ECG505), 1822 parts by weight of lactose hydrate (product name: DMV: product name: lactose 200M) and 1821 parts by mass of crystalline cellulose (product name: Theolas PH-101) by high-speed Stirring and granulating (Powrec: VG-25 type), mixing, then The mixture was formed into granules kneaded with the addition of purified water 696.2 parts by mass. 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 74] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name dihydrocodeine phosphate) Shionogi ") 48 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 80 parts by mass, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by mass, carmellose 486 parts by mass of calcium (product name: ECG505), lactose hydrate (DMV: product name: lactose 200M), 1215 parts by mass, crystalline cellulose (product name: Theolas PH-101), 1214 parts by mass and corn Starch (Nippon Chemical Co., Ltd .: Brand name Corn starch ST- ) 1214 parts by weight of a high speed stirring granulator (manufactured by Powrex were mixed was poured into VG-25 type), then the mixture was formed into granules kneaded with the addition of purified water 928.2 parts by mass. 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 75]
Thirty tablets obtained in Example 71 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 76]
Thirty tablets obtained in Example 72 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 77]
Thirty tablets obtained in Example 73 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 78]
Thirty tablets obtained in Example 74 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 15] Examination of interaction (15)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.9 g and dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 0.1 g was mixed, put into 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, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 16.

  As is clear from Table 16, when loxoprofen sodium hydrate and dl-methylephedrine hydrochloride were mixed and stored, an interaction occurred, resulting in the mixture solidifying after 1 day and discoloring after 1 week.

  From this result, it became clear that when loxoprofen or a salt thereof and ephedrine are mixed, an interaction occurs between these compounds.

[Test Example 16] Examination of interaction (16)
Comparative Example 10: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.9 g and dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Industries: trade name: Japanese Pharmacopoeia dl-hydrochloric acid 0.1 g of methyl ephedrine powder) was mixed to obtain a mixture.
Example 79: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.9 g, dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia dl-hydrochloric acid 0.1 g of methyl ephedrine powder) and 1.0 g of anhydrous caffeine (manufactured by Shizuoka Caffeine Industries, trade name: anhydrous caffeine) were mixed to obtain a mixture.
Example 80 A mixture was obtained in the same manner as in Example 79 except that the content of anhydrous caffeine was changed from 1.0 g to 2.0 g.
Example 81 A mixture was obtained in the same manner as in Example 79 except that the content of anhydrous caffeine was changed from 1.0 g to 4.0 g.
The mixtures of Comparative Example 10 and Examples 79 to 81 were put in glass bottles (3K standard bottles) and stored at 50 ° C. Immediately after the start of storage, the state of the mixture after 1 day, 4 days, and 1 week was evaluated, that is, the presence or absence of interaction, and the results are shown in Table 17.

  As is apparent from Table 17, the mixture of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride was solidified 1 day after the start of storage as a result of the interaction (Comparative Example 10). On the other hand, in addition to loxoprofen sodium hydrate and dl-methylephedrine hydrochloride, the mixture of Examples 79 to 81 containing anhydrous caffeine was a white powder even after 1 week.

  From the results of Test Examples 1 to 3 and 16, when loxoprofen or a salt thereof and a xanthine derivative, or loxoprofen or a salt thereof and an ephedrine were mixed, the interaction occurred between these compounds (Test Examples 1 to 1). 3) Surprisingly, it was found that the xanthine derivative inhibits the interaction between loxoprofen and ephedrines (Test Example 16).

[Example 82] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japan Pharmacy) Dl-methyl ephedrine hydrochloride powder) 120 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine Industries: trade name anhydrous caffeine) 150 parts by mass, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 Mass part, Carmellose calcium (product name: ECG505, manufactured by Gotoku Pharmaceutical Co., Ltd.) 486 parts by mass, crystalline cellulose (product name: Asahi Kasei Chemicals Co., Ltd .: product name Theorus PH-101) 3501 parts by mass are mixed with a high-speed agitation granulator (product of Paulek: VG-25 type). ), And after mixing, add 1972.6 parts by mass of purified water. To obtain things. 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 83] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacy) Dl-methyl ephedrine hydrochloride powder) 120 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine: trade name anhydrous caffeine) 150 parts by weight, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight , 486 parts by mass of carmellose calcium (product name: ECG505) and lactose hydrate (DMV: product name: lactose 200M) 3501 parts by mass in a high-speed agitation granulator (manufactured by Paulec: model VG-25) After charging and mixing, 232 parts by mass of purified water was added and kneaded to obtain a granulated product. This was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then sized using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 4811.4 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 84] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japan Pharmacy) Dl-methyl ephedrine hydrochloride powder) 120 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine: trade name anhydrous caffeine) 150 parts by weight, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight , 486 parts by mass of carmellose calcium (product name: ECG505), lactose hydrate (product name: DMV: product name: lactose 200M), 1751 parts by mass, and crystalline cellulose (product name: Theolas PH-101) 1750 The mass part is put into a high-speed agitation granulator (Powrec: VG-25 type). After mixing, 696.2 parts by mass of purified water was added and kneaded to obtain a granulated product. This was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then sized using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 4811.4 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 85] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japan Pharmacy) Dl-methyl ephedrine hydrochloride powder) 120 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine: trade name anhydrous caffeine) 150 parts by weight, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by weight , 486 parts by mass of carmellose calcium (product name: ECG505), lactose hydrate (product name: DMV: product name: lactose 200M), 1167 parts by mass, crystalline cellulose (product name: Theolas PH-101), 1167 parts by mass And corn starch (manufactured by Nissho Chemical Co., Ltd. Sistarch ST-C) 1167 parts by mass into a high-speed agitation granulator (manufactured by Paulek: VG-25 type) is mixed and then mixed with 928.2 parts by mass of purified water to obtain a granulated product. It was. This was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then sized using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 4811.4 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 86]
Thirty tablets obtained in Example 82 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 87]
Thirty tablets obtained in Example 83 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 88]
Thirty tablets obtained in Example 84 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 89]
Thirty tablets obtained in Example 85 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 17] Examination of interaction (17)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 347.1 mg and lysozyme hydrochloride (product name: Eisai: trade name: lysozyme chloride) 152.9 mg were mixed and mixed 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, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated. The results are shown in Table 18.

  As can be seen from Table 18, when loxoprofen sodium hydrate and lysozyme hydrochloride were mixed and stored, the interaction resulted in the mixture becoming wet after 1 day and changing to a solidified state after 3 days. .

  From this result, it became clear that when loxoprofen or a salt thereof and lysozyme or a salt thereof are mixed, an interaction occurs between these compounds.

[Test Example 18] Examination of interaction (18)
Comparative Example 11: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg and lysozyme hydrochloride (manufactured by Eisai: trade name: lysozyme chloride) were mixed to obtain a mixture. It was.
Example 90: Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, lysozyme hydrochloride (manufactured by Eisai: trade name: lysozyme chloride) and anhydrous caffeine (Shizuoka Cafe) IN INDUSTRIAL CO., LTD .: Trade name anhydrous caffeine) 250 mg was mixed to obtain a mixture.
Each mixture of Comparative Example 11 and Example 90 was placed in a glass bottle (3K standard bottle) and stored at 50 ° C. Immediately after the start of storage, 1 day, 3 days, 4 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 19.

  As is clear from Table 19, the mixture of Comparative Example 1 in which loxoprofen sodium hydrate and lysozyme hydrochloride were mixed resulted in an interaction. As a result, the mixture became wet after 3 days from the start of storage. In contrast, the mixture of Example 90 containing caffeine in addition to loxoprofen sodium hydrate and lysozyme hydrochloride was a white powder even after one week.

  From the results of Test Examples 1 to 3 and 18, when loxoprofen or a salt thereof and a xanthine derivative, or loxoprofen or a salt thereof and lysozyme or a salt thereof are mixed with each other, an interaction occurs between these compounds (Test Example). 1-3) Surprisingly, it was found that the xanthine derivative suppresses the interaction between loxoprofen or a salt thereof and lysozyme or a salt thereof (Test Example 18).

[Example 91] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, lysozyme hydrochloride (manufactured by Eisai: trade name: lysozyme chloride) 180 parts by mass, anhydrous 150 parts by weight of caffeine (made by Shizuoka Caffeine Kogyo: trade name anhydrous caffeine), 145.8 parts by weight of hydroxypropylcellulose (made by Nippon Soda: trade name HPC-L), carmellose calcium (made by Gotoku Pharmaceutical: trade name) ECG505) 486 parts by mass and 3441 parts by mass of crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name Theorus PH-101) were charged into a high-speed agitation granulator (manufactured by Paulek: model VG-25) and mixed, and then purified water 1972. 6 parts by mass was added and kneaded to obtain a granulated product. This was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then sized using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 4811.4 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 92] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, lysozyme hydrochloride (manufactured by Eisai: trade name: lysozyme chloride) 180 parts by mass, 150 parts by weight of anhydrous caffeine (made by Shizuoka caffeine: trade name anhydrous caffeine), 145.8 parts by weight of hydroxypropyl cellulose (made by Nippon Soda: trade name HPC-L), carmellose calcium (product name: ECG505) ) 486 parts by mass and lactose hydrate (manufactured by DMV: trade name: lactose 200M) 3441 parts by mass are charged into a high-speed stirring granulator (manufactured by POWREC: V part by mass-25 type) and mixed, and then purified water 232 parts by mass Part was added and kneaded to obtain a granulated product. This was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then sized using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 4811.4 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 93] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, lysozyme hydrochloride (manufactured by Eisai: trade name: lysozyme chloride) 180 parts by mass, 150 parts by weight of anhydrous caffeine (made by Shizuoka caffeine: trade name anhydrous caffeine), 145.8 parts by weight of hydroxypropyl cellulose (made by Nippon Soda: trade name HPC-L), carmellose calcium (product name: ECG505) ) 486 parts by weight, lactose hydrate (DMV: trade name: lactose 200M) 1721 parts by weight, and crystalline cellulose (Asahi Kasei Chemicals: trade name: Seolus PH-101) 1720 parts by weight are mixed with a high-speed agitation granulator (Powrec: VG-25 type) and mixing, and then add 696.2 parts by mass of purified water and knead. To obtain a granulated product. This was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then sized using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 4811.4 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 94] Tablets Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, lysozyme hydrochloride (manufactured by Eisai: trade name: lysozyme chloride) 180 parts by mass, 150 parts by weight of anhydrous caffeine (made by Shizuoka caffeine: trade name anhydrous caffeine), 145.8 parts by weight of hydroxypropyl cellulose (made by Nippon Soda: trade name HPC-L), carmellose calcium (product name: ECG505) 486 parts by weight, lactose hydrate (DMV: trade name: lactose 200M), 1147 parts by weight, crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name: Seolus PH-101), 1147 parts by weight, and corn starch (manufactured by Nissho Chemical: product) Name Corn starch ST-C) 1147 parts by mass Machine: After mixing was poured into (manufactured by Powrex VG-25 type), kneaded with the addition of purified water 928.2 parts by mass, to obtain a granulated product. This was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then sized using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 4811.4 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.

[Example 95]
Thirty tablets obtained in Example 91 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 96]
Thirty tablets obtained in Example 92 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 97]
Thirty tablets obtained in Example 93 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 98]
Thirty tablets obtained in Example 94 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 19] Analgesic test The pain threshold value of the right hind leg of a 5-6 week old Wistar male rat (body weight 102.7-120.5 g) was measured and designated as "pain threshold before inflammation".
After measurement of the pain threshold before inducing inflammation, 100 μL of 20% yeast solution was subcutaneously administered to the right hind footpad to induce inflammation. The pain threshold was measured 3 hours after the onset of inflammation and was defined as “pain threshold before drug administration”.
Immediately after the measurement of the pain threshold before drug administration, the test drug was orally administered, and the pain threshold was measured with 1 hour after the drug administration as a measurement point, and was defined as “pain threshold after drug administration”.
In addition, the pain threshold value was measured using the Randall Cerit type analgesic effect measuring apparatus (MK-201D: Muromachi Kikai Co., Ltd. product). Each test drug of the following group constitution (the 1st group-the 5th group) was administered.

Group 1: Loxoprofen sodium hydrate Single administration group (hereinafter referred to as “LX alone”) Loxoprofen sodium hydrate was dissolved or suspended in a 0.5% methylcellulose solution at a dose of 0.1 mg / kg body weight. Administered in turbidity.
Group 2: Cremastine fumarate 3 mg / kg alone administration group (hereinafter referred to as “CF alone (3 mg / kg)”)
Cremastine fumarate was administered at a dose of 3 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
Group 3: Two-component administration group of loxoprofen sodium hydrate and clemastine fumarate 3 mg / kg (hereinafter referred to as “LX + CF (3 mg / kg)”)
Loxoprofen sodium hydrate was dissolved or suspended in a 0.5% methylcellulose solution at a dose of 0.1 mg / kg body weight and clemastine fumarate at a dose of 3 mg / kg body weight and administered simultaneously.

Group 4: Cremastine fumarate 30 mg / kg single administration group (hereinafter referred to as “CF alone (30 mg / kg)”)
Cremastine fumarate was administered at a dose of 30 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
Group 5: Loxoprofen sodium hydrate and clemastine fumarate 30 mg / kg two-component combination administration group (hereinafter referred to as “LX + CF (30 mg / kg)”)
Loxoprofen sodium hydrate was dissolved or suspended in a 0.5% methylcellulose solution at a dose of 0.1 mg / kg body weight and clemastine fumarate at a dose of 30 mg / kg body weight and administered simultaneously. From the pain threshold obtained in the above test, the pain improvement rate was calculated according to the following formula.

Pain improvement rate (%) = (pain threshold after drug administration−pain threshold before drug administration) / (pain threshold before inflammation induction−pain threshold before drug administration) × 100
Four rats were used for each test drug administration group.
The results are shown in Table 20. The pain improvement rate was expressed as an average value ± standard error for each group.

As is apparent from Table 20, the combination of loxoprofen sodium hydrate and clemastine fumarate was found to have an excellent analgesic action (group 3 pain improvement rate: about 41%, group 5). Pain improvement rate: about 68%).
Therefore, it was revealed that the combination of loxoprofen sodium hydrate and clemastine fumarate showed excellent analgesic action, and clemastine enhanced the analgesic action of loxoprofen.

[Test Example 20] Examination of interaction (19)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 404.9mg and dextromethorphan hydrobromide hydrate (Daiichi Fine Chemical: trade name: dextromethorphan HBR) 95 .1 mg was mixed, put into 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, 3 days, and 1 week, ie, the presence or absence of interaction, was evaluated. The results are shown in Table 21.

  As is apparent from Table 21, when loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate were simply stored and stored, the interaction resulted in the mixture becoming wet after one day.

  From this result, it was revealed that when loxoprofen or a salt thereof and dextromethorphan or a salt thereof are mixed, an interaction occurs between these compounds.

[Test Example 21] Examination of interaction (20)
Example 99: Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.81 g, dextromethorphan hydrobromide hydrate (manufactured by Daiichi Fine Chemical: trade name, dextrome Toluphan HBR) 0.19 g and anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 1.0 g were mixed to obtain a mixture.
Example 100: A mixture was obtained in the same manner as in Example 99 except that the content of anhydrous caffeine was changed from 1.0 g to 2.0 g.
Example 101: A mixture was obtained in the same manner as in Example 99 except that the content of anhydrous caffeine was changed from 1.0 g to 4.0 g.
The mixtures of Comparative Example 12 and Examples 99 to 101 were each placed in glass bottles (3K standard bottles) and stored at 60 ° C. Immediately after the start of storage, the condition of the mixture after 1 day, 3 days and 1 week, ie, the presence or absence of interaction, was evaluated. The results are shown in Table 22.

As is apparent from Table 22, the mixture of Examples 99 to 101 containing anhydrous caffeine in addition to loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate was white even after 1 week. It was a powder.
On the other hand, as apparent from Table 21 of Test Example 20, the mixture of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate solidified after 1 day from the start of storage as a result of interaction. did.

  From the results of Test Examples 1 to 3 and 20, when loxoprofen or a salt thereof and a xanthine derivative, or loxoprofen or a salt thereof and dextromethorphan or a salt thereof are mixed, the interaction occurs between these compounds ( Test Examples 1-3 and 20) Surprisingly, it was found that the xanthine derivative inhibits the interaction between loxoprofen and dextromethorphan (Test Example 21).

[Example 102] Tablet Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 parts by mass, dextromethorphan hydrobromide hydrate (manufactured by Daiichi Fine Chemical: Product name Dextromethorphan HBR) 48 parts by mass, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name anhydrous caffeine) 80 parts by mass, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 parts by mass Part, Carmellose calcium (product name: ECG505, manufactured by Gotoku Pharmaceutical Co., Ltd.) 486 parts by mass and crystalline cellulose (product name: Asahi Kasei Chemicals: product name: SEOLUS PH-101) 3643 parts by mass are mixed with a high-speed agitation granulator (manufactured by POWREC: VG-25 type). And then add 1972.6 parts by mass 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 parts by mass of this sized product and 48.6 parts by mass 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. Then, tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg.
[Example 103]
Thirty tablets obtained in Example 102 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

  According to the present invention, the interaction between loxoprofen or a salt thereof and an interactive component can be suppressed. Therefore, it is possible to provide a pharmaceutical composition comprising loxoprofen or a salt thereof and an interactive component, which has excellent storage stability.

Claims (25)

A pharmaceutical composition comprising the following components (A), (B) and (C).
(A) Loxoprofen or a salt thereof;
(B) One type or two or more types selected from the group consisting of the following components (B-1) to (B-7) (B-1) The following general formula (1)

[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R ¹ represents a hydrogen atom, a hydroxyl group or an alkyl group, and R ² may have a substituent. A good cyclic amino group or an aminoalkyl group which may have a substituent, and R ³ represents a hydrogen atom or a halogen atom. Or a salt thereof (B-2) the following general formula (2)

[In the formula (2), R ⁴ represents a hydrogen atom or a methyl group, and R ⁵ represents a hydrogen atom or a hydroxyl group. Or a salt thereof (B-3) the following general formula (3)

[In the formula (3), R ⁶ represents a hydrogen atom, an alkyl group, a carbamoyl group or an alkoxy group which may have a substituent, and R ⁷ represents a hydrogen atom, an acylamino group or a sulfo group. In addition, the phenolic hydroxyl group in Formula (3) may be etherified. Or a salt thereof (B-4) codeines (B-5) ephedrines (B-6) lysozyme or a salt thereof (B-7) dextromethorphan or a salt thereof;
(C) Xanthine derivative   The pharmaceutical composition according to claim 1, wherein component (A) is loxoprofen sodium hydrate.   The pharmaceutical composition according to claim 1 or 2, wherein the component (A) contains 10 to 300 mg as a daily dose in terms of loxoprofen sodium anhydride.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the component (C) is caffeine.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the component (C) 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 5, comprising 10 to 1000 mg of component (C) as a daily dose.   The component (B) is a compound represented by the general formula (1) or a salt thereof, The pharmaceutical composition according to any one of claims 1 to 6.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is chlorpheniramine or a salt thereof, clemastine or a salt thereof, carbinoxamine or a salt thereof, or diphenylpyraline or a salt thereof.   The component (B) is a compound represented by the general formula (2) or a salt thereof, The pharmaceutical composition according to any one of claims 1 to 6.   The pharmaceutical composition according to any one of claims 1 to 6, wherein component (B) is bromhexine or a salt thereof, or ambroxol or a salt thereof.   The component (B) is a compound represented by the general formula (3) or a salt thereof, The pharmaceutical composition according to any one of claims 1 to 6.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is a guaiacol derivative or a salt thereof, a cresol derivative or a salt thereof, acetaminophen, or ethenamide.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is guaifenesin or potassium guaiacol sulfonate.   A component (B) is codeine, The pharmaceutical composition of any one of Claims 1-6.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is one or more selected from the group consisting of codeine, dihydrocodeine and salts thereof, and solvates thereof.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is codeine phosphate hydrate or dihydrocodeine phosphate.   Component (B) is ephedrines, The pharmaceutical composition of any one of Claims 1-6.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is one or more selected from the group consisting of ephedrine and derivatives thereof and salts thereof.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is methylephedrine hydrochloride or methylephedrine saccharin salt.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is lysozyme or a salt thereof.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is lysozyme hydrochloride.   The pharmaceutical composition according to any one of claims 1 to 6, wherein component (B) is dextromethorphan or a salt thereof.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (B) is dextromethorphan, dextromethorphan hydrobromide hydrate, or dextromethorphan phenolphthaline salt.   The pharmaceutical composition according to any one of claims 1 to 23, wherein the dosage form is a solid preparation. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 24 and a desiccant in a container.