JP2012097002A - Pharmaceutical preparation containing loxoprofen - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical preparation suppressed in interaction of loxoprofen or a salt thereof with an interactive ingredient.SOLUTION: The pharmaceutical preparation containing loxoprofen or a salt thereof and an interactive ingredient includes a pharmaceutical composition containing loxoprofen or a salt thereof and the interactive ingredient packaged in an airtightly preservable package.

Description

  The present invention relates to a pharmaceutical preparation 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 analgesics, antihistamine, expectorant, anti-inflammatory enzyme, antitussive, central nervous excitable, hypnotic sedative, anticholinergic, anticholinergic Various combinations of ingredients such as plasmin ingredients and herbal medicine 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, guaiacol sulfonic acid or a salt thereof, a phenol derivative such as guaifenesin, cresol sulfonic acid or a salt thereof, or a salt thereof is a component having an airway secretion promoting action or the like (Non-patent Document 8).
In addition, cysteine derivatives such as carbocysteine or a salt thereof, methylcysteine or a salt thereof, and ethylcysteine or a salt thereof are expectorants that reduce the viscosity of sputum (Non-patent Documents 6 and 9).

  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 10).

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 11).
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 in oral medicine for rhinitis for the purpose of alleviating nasal congestion due to vasoconstriction (Non-patent Documents 12 and 13).
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 for an antitussive expectorant besides a general cold medicine (nonpatent literature 12).

  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 14) ). 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 15). Proxyphylline also exhibits the same action as theophylline (Non-patent Document 16), and paraxanthine and theobromine also exhibit the same action.

Specific examples of the hypnotic sedative component include isovaleryl urea derivatives such as bromovalerylurea and allylisopropylacetylurea.
Of the above, bromvalerylurea is represented by the following formula:

It is a compound represented by these.
Allyl isopropyl acetyl urea is represented by the following formula:

It is a compound represented by these. All of these isovaleryl urea derivatives have a sedative effect and are components that are blended in antipyretic analgesics and the like (Non-patent Document 17).
In addition, phenol derivatives such as acetaminophen and etenzamid or salts thereof are components having antipyretic analgesic activity (Non-patent Document 18).

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 one or more selected from loxoprofen and 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 a combination of cycloalkane derivatives is used to suppress gastric mucosal damage caused by loxoprofen.
Patent Documents 1 to 6 disclose a solid preparation containing loxoprofen and the above-described various components. However, it is not disclosed whether or not an interaction that affects the storage stability of these compounds occurs between loxoprofen or a salt thereof and the above-described various components in the preparation.
Patent Documents 8 to 10 disclose soft capsules filled with a liquid containing loxoprofen and one kind of cycloalkane derivative. However, it is not disclosed whether loxoprofen interacts with a cycloalkane derivative. As a matter of course, the solution is not disclosed at all, and further, a solid preparation containing loxoprofen and a cycloalkane derivative has not been known so far.

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 2010-83882 A JP 2009-242360 A JP 2009-242365 A JP 2009-242366 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 234 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. Pages 199-200 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 other components, the present inventor prepared and stored various mixtures, and either loxoprofen or a salt thereof and any of the following components 1 to 11 When the heels are mixed and stored, unexpectedly, although the components are in a solid state, the mixture undergoes state changes such as wetting, solidification, and discoloration over time, resulting in problems in stability. I found it.

1 including 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

[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 2 represented by the following general formula (2), including bromhexine or a salt thereof, ambroxol or a salt thereof

[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 guaiacolsulfonic acid or a salt thereof, guaifenesin, cresolsulfonic acid or a salt thereof, acetaminophen, etenzaamide, or 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 4 cysteine derivative 5 lysozyme or salt 6 codeine 7 ephedrine 8 dextromethorphan or salt 9 xanthine derivative 10 isovaleryl urea derivative 11 3- {4- [trans-4- (aminomethyl) ) Cyclohexylcarbonyloxy] phenyl} propanoic acid monohydrochloride, trans-4- (aminomethyl) cyclohexanecarboxylic acid and other cycloalkane derivatives represented by the following general formula (4) or salts thereof

[In Formula (4), A shows a C5-C8 cycloalkylene group, Q shows a carboxyalkylphenyl group or a hydrogen atom. ]

  Accordingly, an object of the present invention is to provide a pharmaceutical preparation in which the stability problem between loxoprofen or a salt thereof and at least one of the components selected from 1 to 11 is improved.

The present inventor has intensively studied to solve the above-described stability problem, and as a result, the cause of the above-described stability is one or more components selected from loxoprofen or a salt thereof and 1 to 11 above (hereinafter referred to as “mutually” It was clarified that the interaction was caused by contact with “active ingredient”.
Therefore, the present inventor examined a technique for suppressing the interaction between loxoprofen or a salt thereof in the pharmaceutical composition and the interactive component, and surprisingly, the loxoprofen or a salt thereof and the interactive component were added. It has been found that the interaction is suppressed by preserving the contained pharmaceutical composition in an airtight manner.

That is, this invention provides the pharmaceutical formulation which packaged the pharmaceutical composition containing the following component (A) and (B) with the package which can be airtight-preserved.
(A) Loxoprofen or a salt thereof,
(B) One or more selected from the group consisting of the following components (B-1) to (B-11) (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. ]
(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. ]
(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. ]
(B-4) Cysteine derivatives (B-5) Lysozyme or salts thereof (B-6) Codeines (B-7) Ephedrines (B-8) Dextromethorphan or salts thereof B-9) xanthine derivative (B-10) isovaleryl urea derivative, and (B-11) a compound represented by the following general formula (4) or a salt thereof

[In Formula (4), A shows a C5-C8 cycloalkylene group, Q shows a carboxyalkylphenyl group or a hydrogen atom. ]

According to the present invention, the interaction between loxoprofen or a salt thereof and the interactive component can be suppressed. Accordingly, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and an interactive component that is excellent in 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 is characterized by hermetically preserving a pharmaceutical composition containing loxoprofen or a salt thereof and an interactive component, and the pharmaceutical preparation of the present invention comprises loxoprofen or a salt thereof and an interactive component Is packaged in a hermetically storable packaging.

First, component (A) and components (B-1) to (B-11) in the pharmaceutical composition of the present invention will be described.
<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 30% 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 , examples of the “optionally substituted aminoalkyl group” include 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 quantity which can be taken | dosed 0.1-13.5 mg per day is preferable, and the quantity which can take 1-4.5 mg is more preferable.
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 pharmaceutical composition total mass, it is more preferable to contain 0.02-0.8 mass%, and 0.04-0.7 mass% is contained. Is 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 0.02-2 mass%, It is especially preferable to contain 0.04-1 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 preferable to contain 0.004-1.5 mass% with respect to the total mass of a thing, and it is more preferable to contain 0.004-1 mass%. Among these, it is preferable to contain 0.04-0.5 mass%, it is more preferable to contain 0.04-0.3 mass%, and it is especially preferable to contain 0.06-0.25 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 4% by mass in terms of bromohexine hydrochloride with respect to the total mass of the pharmaceutical composition. 0.02 to 2% by mass is more preferable, and 0.04 to 1% 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 10% by mass in terms of ambroxol hydrochloride is contained relative to the total mass of the pharmaceutical composition. It is preferable to contain 0.02-7 mass%, and it is especially preferable to contain 0.04-5 mass%.

  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, an alkali metal salt such as a compound represented by the general formula (3) and a potassium 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 with 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 may have one or more of these.
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, acetaminophen or ethenamide, more preferably a guaiacol sulfonic acid or a salt thereof, guaifenesin, acetaminophen or ethenamide. Among them, potassium guaiacol sulfonate, guaifenesin, acetaminophen, and etenzamide 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. Further, 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 40% by mass based on the total mass of the pharmaceutical composition, 0.8 to The content is more preferably 30% by mass, and particularly preferably 1.2 to 25% 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, the “cysteine derivative” is preferably a compound represented by the following general formula (5) or a salt thereof.

[In Formula (5), R ⁸ represents a hydrogen atom or an alkyl group, and R ⁹ represents a hydrogen atom or a carboxyalkyl group. ]

In the above R ⁸ , 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. Of these, a methyl group and an ethyl group are preferable.
In the above R ⁹ , the carboxyalkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms substituted by a carboxy group, and specific examples include a carboxymethyl group, a carboxyethyl group, a carboxypropyl group. Carboxybutyl group, carboxypentyl group, carboxyhexyl group and the like. In the present invention, a carboxymethyl group is preferred.
In the general formula (5), R ⁸ is preferably a hydrogen atom, and R ⁹ is preferably a carboxyalkyl group, particularly a carboxymethyl group.

The compound represented by the general formula (5) or a salt thereof includes not only the compound itself represented by the general formula (5) but also a pharmaceutically acceptable salt thereof. Specific examples of the compound represented by the general formula (5) or a salt thereof include, for example, an inorganic acid salt such as a compound represented by the general formula (5), a hydrochloride of the compound represented by the general formula (5), and the like. Organic acid salt is mentioned, The hydrochloride of the compound represented by General formula (5) is more preferable.
Further, since the compound represented by the general formula (5) has an asymmetric carbon, it has an optical isomer, but in the present invention, any optical isomer may be included, and a single optical isomer may be used. A mixture of various optical isomers may be used. Among these, in the present invention, it is preferable that the configuration of cysteine constituting the basic skeleton according to the general formula (5) is L-type.

In the above general formula (5),
(1) The case where R ⁸ is a hydrogen atom and R ⁹ is a carboxymethyl group means carbocysteine.
(2) The case where R ⁸ is a methyl group and R ⁹ is a hydrogen atom means methylcysteine.
(3) R ⁸ is an ethyl group, R ⁹ is hydrogen atom is intended to mean ethyl cysteine.
The compounds represented by the general formula (5) and salts thereof, particularly the above-mentioned compounds and salts thereof are known, and in the present invention, commercially available products can be used in addition to those produced by known methods.

  In the present invention, the cysteine derivative is preferably one or more selected from the group consisting of carbocysteine or a salt thereof, methylcysteine or a salt thereof, and ethylcysteine or a salt thereof. L-carbocysteine, L-methylcysteine or a salt thereof And at least one selected from the group consisting of L-ethylcysteine or a salt thereof is more preferable, and at least one selected from the group consisting of L-carbocysteine, L-methylcysteine hydrochloride and L-ethylcysteine hydrochloride is more preferable. L-carbocysteine is particularly preferred.

  The content of the cysteine derivative 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 cysteine derivative that can be taken is 50 to 3000 mg, more preferably 100 to 2000 mg, and particularly preferably 150 to 1500 mg per day. In this invention, it is preferable to contain 1-90 mass% of cysteine derivatives with respect to the pharmaceutical composition total mass, it is more preferable to contain 1-80 mass%, and it is further more preferable to contain 1-75 mass%. . Among these, it is preferable to contain 5-70 mass%, it is preferable to contain 6-60 mass%, and it is especially preferable to contain 7-50 mass%.

  Further, the content ratio of loxoprofen or a salt thereof and a cysteine derivative 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, it is preferable to contain 0.1 to 25 parts by mass of cysteine derivative with respect to 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium, more preferably 0.2 to 15 parts by mass. Those containing 3 to 10 parts by mass are particularly preferable.

<Component (B-5)>
In the present invention, “lysozyme or a salt thereof” includes not only lysozyme itself but also a pharmaceutically acceptable salt of lysozyme. Specific examples of the lysozyme or a salt thereof include lysozyme and lysozyme hydrochloride, and lysozyme hydrochloride is 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, per day, lysozyme or a salt thereof in terms of titration of lysozyme hydrochloride is 5 to 450 mg (titer), more preferably 10 to 360 mg (titer), particularly preferably 15 to 270 mg (titer). ) Can be taken in an amount that can be taken. When lysozyme hydrochloride is used as lysozyme or a salt thereof, 5-450 mg (titer) of lysozyme hydrochloride per day, more preferably 10-360 mg (titer), particularly preferably 15-270 mg. (Titer) It is preferable to include an amount that can be taken.
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 content ratio of loxoprofen or a salt thereof and lysozyme 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, it is preferable that loxoprofen or a salt thereof 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 0.04-12 mass parts (titer) is more preferable, and what contains 0.08-5 mass parts (titer) is further more preferable.

<Component (B-6)>
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-7)>
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 1-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, 1-methylephedrine saccharin salt, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, pseudoephedrine sulfate and the like. These may 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 15th Amendment 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 a liquid obtained by adding an appropriate leaching agent and concentrating the leaching liquid after being appropriately sized based on a known method described in the 15th revision of the 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 the ephedrines, for example, 0.1 to 25 g of maou per day (powder equivalent), 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 preferable 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-8)>
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 (B-9)>
In the present invention, the “xanthine derivative” is preferably a compound represented by the following general formula (6).

[In Formula (6), R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or a methyl group, and R ¹² represents a hydrogen atom, a methyl group, a monohydroxypropyl group, or a dihydroxypropyl group. ]

In formula (6), in R ¹² , the monohydroxypropyl group is preferably a 2-hydroxypropyl group. The dihydroxypropyl group is preferably a 2,3-dihydroxypropyl group.

In the general formula (6),
(1) R ¹⁰ is a methyl group, R ¹¹ is a methyl group, and R ¹² is a methyl group means caffeine.
(2) R ¹⁰ is a methyl group, R ¹¹ is a methyl group, and R ¹² is a hydrogen atom means theophylline.
(3) The case where R ¹⁰ is a hydrogen atom, R ¹¹ is a methyl group, and R ¹² is a methyl group means theobromine.
(4) R ¹⁰ is a methyl group, an R ¹¹ is a hydrogen atom and R ¹² is a methyl group is intended to mean a paraxanthine.
(5) R ¹⁰ is a methyl group, R ¹¹ is a methyl group, those wherein R ¹² is 2-hydroxypropyl group is intended to mean a proxy Villingen.
(6) R ¹⁰ is a methyl group, R ¹¹ is a methyl group, and R ¹² is a 2,3-dihydroxypropyl group, which means diprofylline.

The compounds of the general formula (6), particularly the above-mentioned compounds, are known, and in the present invention, commercially available products can be used in addition to those produced by known methods.
As the caffeine and theophylline, those formed in a double salt (sodium benzoate caffeine (double salt of sodium benzoate and caffeine), aminophylline (double salt of theophylline and ethylenediamine)) and the like can also be used. In the present invention, one or more of these xanthine derivatives can be used.

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

  The content of the xanthine derivative in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. 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 50% by mass, and 1.6 to 40% by mass. It is particularly preferable to contain it.

  In addition, the blending ratio of loxoprofen or a salt thereof and xanthine derivative contained in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the daily dose of each component described above. Or it is preferable that the salt contains 0.03 to 100 parts by mass, more preferably 0.08 to 27 parts by mass of xanthine derivative with respect to 1 part by mass in terms of loxoprofen sodium anhydride. What contains 2-10 mass parts is further more preferable.

<Component (B-10)>
In the present invention, the “isovaleryl urea derivative” means one or more selected from the group consisting of bromovalerylurea and allylisopropylacetylurea. Since there are asymmetric carbons in isovaleryl urea derivatives, there are various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used, or a mixture of various optical isomers. But you can.

  The content of the isovaleryl urea derivative 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, when the isovaleryl urea derivative is bromvaleryl urea or a salt thereof, 10 to 1000 mg, more preferably 30 to 800 mg, particularly preferably 60 to 600 mg of bromvaleryl urea can be taken per day. It can be shown. Further, when the isovaleryl urea derivative is allyl isopropyl acetyl urea or a salt thereof, 1 to 500 mg, more preferably 10 to 300 mg, particularly preferably 20 to 180 mg of allyl isopropyl acetyl urea is converted to free form per day. An amount that can be contained can be included.

  In this invention, it is preferable to contain 0.1-95 mass% of isovaleryl urea derivatives with respect to the pharmaceutical composition total mass. In particular, when the isovaleryl urea derivative is bromvaleryl urea or a salt thereof, it is preferable to contain 1 to 95% by mass of bromvaleryl urea in terms of free form, and preferably 4 to 90% by mass with respect to the total mass of the pharmaceutical composition. More preferably, it is particularly preferably 8 to 80% by mass. Further, when the isovaleryl urea derivative is allyl isopropyl acetyl urea or a salt thereof, it is preferable to contain 0.1 to 70% by mass of allyl isopropyl acetyl urea in terms of a free form with respect to the total mass of the pharmaceutical composition. More preferably, it is contained in an amount of 2 to 24% by mass.

  The content ratio of loxoprofen or a salt thereof and isovaleryl urea derivative 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. When the isovaleryl urea derivative is bromvaleryl urea or a salt thereof, loxoprofen or a salt thereof is contained in an amount of 0.03 to 100 parts by mass in terms of a free form relative to 1 part by mass in terms of anhydrous loxoprofen sodium. What contains 0.1-30 mass parts is more preferable, What contains 0.3-10 mass parts is especially preferable. In addition, when the isovaleryl urea derivative is allyl isopropyl acetyl urea or a salt thereof, 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium, and 0.003 to 0.003 in terms of a free form of allyl isopropyl acetyl urea or a salt thereof. Those containing 50 parts by mass are preferred, those containing 0.04 to 10 parts by mass are more preferred, and those containing 0.1 to 3 parts by mass are particularly preferred.

<Component (B-11)>
In the present invention, the following general formula (4)

[In Formula (4), A shows a C5-C8 cycloalkylene group, Q shows a carboxyalkylphenyl group or a hydrogen atom. ]
In addition to the compound itself represented by the general formula (4), a pharmaceutically acceptable salt of the compound represented by the general formula (4) is also included in the cycloalkane derivative represented by general formula (4). Specific examples of the compound represented by the general formula (4) or a salt thereof include, for example, a compound represented by the general formula (4), an alkali such as a sodium salt or a potassium salt of the compound represented by the general formula (4). Metal salts; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and carbonate; tartrate, maleate, tosylate and mesylate And organic acid salts such as In the chemical structure of the compound represented by the general formula (4), when an asymmetric carbon atom is present, the compound has various optical isomers. However, in the present invention, any optical isomer is included. One optical isomer or a mixture of various optical isomers may be used. Furthermore, the compound represented by the general formula (4) or a salt thereof may be in the form of a solvate, and the solvation of the compound represented by the general formula (4) or a salt thereof with water, alcohol or the like. The product is also included in the “compound represented by the general formula (4) or a salt thereof”.
In General Formula (4), the cycloalkylene group having 5 to 8 carbon atoms in A is preferably a cyclohexylene group. The binding site in the cycloalkylene group is not particularly limited, but the 1 and 4 positions are preferred.
Q is a hydrogen atom or a carboxyalkylphenyl group, and the alkyl group in the carboxyalkylphenyl group is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably an ethyl group.

In the present invention, the compound represented by the general formula (4) or a salt thereof includes 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] phenyl} propanoic acid hydrochloride, trans-4- (Aminomethyl) cyclohexanecarboxylic acid is preferred.
The cycloalkane derivative represented by the general formula (4) or a salt thereof is a known one described in JP-B-47-23535, JP-B-59-134758, JP-B-60-6353, or the like. In addition to production by known methods, commercially available products can be used.

The content of the compound represented by the general formula (4) 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, 10 to 2000 mg, preferably 50 to 1000 mg, more preferably 100 to 800 mg of the compound represented by the general formula (4) or a salt thereof can be contained per day.
In the pharmaceutical composition of the present invention, 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] -phenyl} propanoic acid monohydrochloride is used as the compound represented by the general formula (4) or a salt thereof. In this case, the content is preferably an amount that can be taken 10 to 1500 mg per day, more preferably an amount that can be taken 50 to 1000 mg, and even more preferably an amount that can be taken 100 to 800 mg. In addition, when trans-4- (aminomethyl) cyclohexanecarboxylic acid or a salt thereof is used as the compound represented by the general formula (4) or a salt thereof, the content thereof per day in terms of a free form of the compound. The amount that can be taken 50 to 2000 mg is preferred, the amount that can be taken 70 to 750 mg is more preferred, and the amount that can be taken 400 to 750 mg is more preferred.

  In the present invention, the compound represented by the general formula (4) or a salt thereof is preferably contained in an amount of 0.4 to 90% by mass, more preferably 2 to 70% by mass, based on the total mass of the pharmaceutical composition. Is more preferable, 3 to 60% by mass is more preferable, and 4 to 50% by mass is particularly preferable.

  The content ratio of loxoprofen or a salt thereof and the cycloalkane derivative represented by the general formula (4) or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and the daily dose of each component described above The amount of loxoprofen or a salt thereof is 0.03 to 200 parts by mass of a cycloalkane derivative or a salt thereof relative to 1 part by mass in terms of loxoprofen sodium anhydride. Are preferable, those containing 0.2 to 40 parts by mass are more preferable, and those containing 0.5 to 20 parts by mass are more preferable.

Next, the pharmaceutical preparation of the present invention will be described in detail.
In the present invention, “airtightly storable package” means a package that can prevent liquid or solid foreign matter from entering under normal handling or storage conditions, and is either regular or irregular. Can also be used. Examples of the package include bottle packaging with a cap or lid, SP (Stripe Package) packaging, PTP (Press Through Package) packaging, stick packaging, and the like. In the present invention, as will be apparent from the examples, SP packaging, PTP packaging, stick packaging, and the like, which can be stored air-tightly by one or one dosage unit as a solid preparation preferable as the dosage form of the pharmaceutical composition of the present invention described later, One or two or more solid preparations, or a bottle package with a cap or lid capable of hermetically storing one dosage unit or two or more dosage units is preferable. Hereinafter, what carried out the bottle packaging, SP packaging, PTP packaging, and stick packaging of the pharmaceutical composition which concerns on this invention may be called a bottle packaging body, SP packaging body, PTP packaging body, and stick packaging body.

The material of the bottle used for the bottle packaging is not particularly limited, and examples thereof include glass, plastic (polyester, polyethylene, polycarbonate, polystyrene, polypropylene, etc.), metal, and the like. Examples thereof include metals and plastics (polyethylene, polypropylene, etc.). These can use a commercial item. When packaging in a bottle, for example, an appropriate amount of the solid preparation according to the present invention may be stored in a commercially available bottle and then sealed with an appropriate stopper or lid. In addition, what is necessary is just to select the bottle of the magnitude | size according to the quantity of the solid formulation to store, As a capacity | capacitance of a bottle, it is 10-250 ml normally, 14-206 ml is preferable and 24-134 ml is more preferable. .
In addition, the packaging material used for the airtight storage packaging such as SP packaging, PTP packaging, and stick packaging is not particularly limited. For example, biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET) ), Glycol-modified PET (PET-G), biaxially stretched nylon (ONy, PA), cellophane, paper, low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer Copolymer (EVA), unstretched polypropylene (CPP, IPP), ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially stretched polyvinylidene chloride (PVDC), ethylene-vinyl Alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic polyolefin Fin (COC), unstretched nylon (CNY), polycarbonate (PC), polystyrene (PS), a metal foil such as hard vinyl chloride (VSC) such as resin or aluminum foil (AL) and the like.

  When carrying out SP packaging, PTP packaging, stick packaging, etc., it may be produced by a known method using a sheet using one or more of the above packaging materials, and the packaging materials may have a multilayer structure appropriately combined. it can. Examples of a method for forming a multilayer structure using two or more kinds of packaging materials as a sheet include a method of laminating the packaging materials to produce a laminated sheet. The laminated sheet can be produced by a known method such as extrusion lamination, dry lamination, coextrusion lamination, thermal lamination, wet lamination, non-solvent lamination, heat lamination and the like. Moreover, a well-known commercial item can also be used for the sheet | seat for SP packaging, PTP packaging, and stick packaging.

  In the said sheet | seat, as a single layer sheet using 1 type of packaging materials, a PVC sheet, a CPP sheet, etc. are mentioned, Moreover, as a laminated sheet using 2 or more types of packaging materials, the sheet | seat structure is, for example, Laminated PVC and PVDC (PVC / PVDC; hereinafter abbreviated), PVC / PVDC / PE / PVC, PVC / PVDC / PE / PVDC / PVC, CPP / COC / CPP, PVC / PCTFE, CPP / PCTFE, PVC / AL / PA, PVC / AL, CPP / AL, CPP / CPP / CPP (the sheet shown on the left uses two or more types as CPP), etc., but are limited to these. Is not to be done.

  Examples of commercially available laminated sheets include Sumitomo Bakelite Co., Ltd. Sumitrite (registered trademark) VSS, Sumitrite VSL, Sumitrite NS, Sumitrite FCL, Taisei Kako Co., Ltd. TAS series, Mitsubishi Plastics Co., Ltd. PTP vinyl foil ( Registered trademark), sheets of Super foil for PTP (registered trademark), Nippaku aluminum foil manufactured by Nippon Foil Co., Ltd., aluminum foil for PTP such as aluminum foil silver plain manufactured by Daiwa Chemical Industry Co., Ltd., etc. It is not limited to only.

As a form of PTP packaging, one or each dosage unit of the solid preparation according to the present invention is stored in a pocket of a sheet in which a desired number of pockets are formed by a known method, and then a metal foil such as an aluminum foil is used. It is preferable to use a sheet as a constituent material as a lid material and cover it. Moreover, it is preferable to further pillow-wrap PTP packaging from the viewpoint of interaction suppression, and more preferably, aluminum pillow packaging when pillow-wrapping.
In the so-called “ordinary PTP packaging”, a single-layer sheet or a laminated sheet made of a resin in which pockets are formed is used, but a so-called “double-sided aluminum PTP in which aluminum foil is used as a constituent material for a sheet for forming pockets. It may be “packaging”.
Moreover, as a form of SP packaging or stick packaging, a solid sheet according to the present invention can be packaged one by one or one dosage unit by using a resin sheet, or a sheet having aluminum foil as a constituent material on one side May be used, or “aluminum SP packaging” or “aluminum stick packaging” using sheets made of aluminum foil on both sides may be used. Further, from the viewpoint of suppressing the interaction, it is preferable to further wrap the SP wrapping or stick wrapping, and more preferable to wrap the aluminum pillow when wrapping the pillow.
In addition, the occupation ratio (volume ratio) with respect to the package of the pharmaceutical composition in the pharmaceutical preparation of the present invention is usually 25 to 60%, preferably 28 to 55%, preferably 30 to 30% when the package is a bottle package. 50% is more preferable. In this case, the occupation ratio means the occupation ratio of the pharmaceutical composition with respect to the capacity of the bottle, and the filling or inner plug for preventing damage of the pharmaceutical composition stored in the bottle, or the drying described later. The agent is not taken into account when calculating the occupation ratio.
When the package is an SP package, a PTP package, or a stick package, it is usually 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%. .
The bottle packaging body of the present invention can be further packaged in a box or the like, and the PTP packaging body, the SP packaging body, the stick packaging body, etc. As a packaging unit, secondary packaging can be performed with cans, bottles, bags, and the like.

  In the pharmaceutical composition of the present invention, it is preferable to contain them so as not to substantially contact each other from the viewpoint of suppressing interaction with loxoprofen or a salt thereof and an interactive component. 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 dosage form of the pharmaceutical composition of the present invention is not particularly limited, but a solid preparation is preferable from the viewpoint of ease of taking.
Specific examples of solid preparations include, for example, oral preparations such as capsules, pills, granules, fine granules, powders, tablets, dry syrups, jellies, troches, and parenteral administration such as suppositories. Examples include oral preparations, and oral solid preparations are preferred. Among these, a tablet is particularly preferable.
In addition, the pharmaceutical composition of this invention may be coat | covered with sugar coating, a film coating, etc. by the well-known method.
The dosage form of the solid preparation as the pharmaceutical composition of the present invention is preferably a capsule or tablet as the solid preparation for bottle packaging, preferably a capsule or tablet as the solid preparation for PTP packaging, SP packaging or strip packaging. Preferred solid preparations are pills, granules, fine granules, powders, tablets and dry syrups.

  The solid preparation can be produced and formulated by a known method. From the viewpoint of suppressing interaction, (A) loxoprofen or a salt thereof itself, or a solid composition containing loxoprofen or a salt thereof and (B ) The interactive component itself or a solid composition containing the interactive component is contained, and the components constituting the solid composition prevent loxoprofen or a salt thereof from interacting with the interactive component. What is arranged is given as a specific example. These solid compositions are in the form of powder, granules, tablets, and the like.

  Of the above solid preparations, the following (A)-(C) and the like may be exemplified as specific forms as the loxoprofen or a salt thereof and the interactive component are 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 Fifteenth Revised Japanese Pharmacopoeia General Rules for Preparations.

(I) Either loxoprofen or a salt thereof and an interactive component are 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.
(B) Loxoprofen or a salt thereof, and an interactive component are separately granulated by an appropriate method to form granules, and powders and granules made by containing them, and the granules are further suitable. Formulation coated by the method.
(C) A capsule filled with the powder or granule prepared in (i) or (b) above.
(D) Tablets obtained by tableting the granular material produced in (i) or (b) above 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.
(E) A multilayer 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 multilayer 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, as the loxoprofen or a salt thereof and an interactive component, the granular material produced in the above (i) or (b) can be used.
(F) Arranges either loxoprofen or a salt thereof and an interactive component 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, as the loxoprofen or a salt thereof and an interactive component, the granular material produced in the above (i) or (b) can be used.
(G) In place of the above (i) or (b) granular material, either or both of loxoprofen or a salt thereof and an interactive component may be 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.
(H) Loxoprofen or a salt thereof and an interactive component 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).

  Granules in the above (a) and (b) 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.

  Commercially available products include, for example, Roseol (registered trademark) fine granules 10% manufactured by Sakai Chemical Co., Ltd. (the fine granules are loxoprofen sodium hydrate, lactose hydrate, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, Contains magnesium stearate, silicon dioxide, and iron sesquioxide, containing 113.4 mg of loxoprofen sodium hydrate in 1 g (100 mg as anhydrous)), 10% Loxoprofen sodium fine grain “CH” manufactured by Choseidou Pharmaceutical Co., Ltd. (The fine granules include loxoprofen sodium hydrate, lactose hydrate, hydroxypropylcellulose, magnesium stearate, talc, silicon dioxide, iron trioxide, polysorbate 40, and 113 g of loxoprofen sodium hydrate in 1 g. .4 mg (as anhydride ), Kentan (registered trademark) fine granules 10% manufactured by Medisa Shinyaku Co., Ltd. (the fine granules are loxoprofen sodium hydrate, light anhydrous silicic acid, iron sesquioxide, magnesium stearate, lactose hydrate Product, hydroxypropylcellulose, fumaric acid, D-mannitol, 113.4 mg of loxoprofen sodium hydrate in 1 g (100 mg as an anhydride), Ponaperto (registered trademark) fine particles manufactured by Biomedics Co., Ltd. 10% (The fine granules contain loxoprofen sodium hydrate, lactose hydrate, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate, iron sesquioxide, 1 g of loxoprofen sodium hydrate 113.4 mg (as anhydride) 00mg), 10% Lingeles (registered trademark) manufactured by Yoshindo Co., Ltd. (the fine particles are loxoprofen sodium hydrate, lactose hydrate, crospovidone, hydroxypropylcellulose, magnesium stearate) 1 g of loxoprofen sodium hydrate in an amount of 113.4 mg (100 mg as anhydrous), and 10% of Loxonin (registered trademark) fine particles manufactured by Daiichi Sankyo Co., Ltd. Contains loxoprofen sodium hydrate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, iron sesquioxide, lactose hydrate, magnesium stearate, 113.4 mg of loxoprofen sodium hydrate in 1 g (100 mg as anhydrous) ) Contained)), Rolfena manufactured by Nichi-Iko Min (registered trademark) fine granules 10% (the fine granules contain loxoprofen sodium hydrate, lactose hydrate, carboxymethyl starch sodium, hydroxypropyl starch, hydroxypropyl cellulose, magnesium stearate, talc, iron sesquioxide 13.4 g of loxoprofen sodium hydrate is contained in 1 g (100 mg as anhydrous). ) And the like. In addition, the fine granule containing 113.4 mg of loxoprofen sodium hydrate (100 mg as an anhydride) in 1 g of the left column is obtained by appropriately increasing or decreasing the content of loxoprofen sodium hydrate based on a known method. be able to.

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 melt granulation is used when producing the granular materials in the above (a) and (b), etc., a binder having a low melting point (freezing point) that is solid at room temperature and melts or softens by heating. 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) and (B):
(A) Loxoprofen or a salt thereof;
(B) one or more selected from the group consisting of the following components (B-1-1) to (B-11-1);
(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) diphenylpyrine or a salt thereof (B-2-1) bromohexine or a salt thereof, (B-2-2) ambroxol or a salt thereof, (B-3-1) a guaiacol derivative or a salt thereof, (B-3-2) a cresol derivative or Salts thereof, (B-3-3) acetaminophen, (B-3-4) etenzaamide, (B-4) cysteine derivatives, (B-5) lysozyme or salts thereof, (B-6) codeines, B-7) Ephedrines, (B-8) dextromethorphan or a salt thereof, (B-9-1) caffeine, (B-10-1) bromovalerylurea and allylisopropylacetylurea, (B-11-1) 3- 4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] phenyl} propanoic acid A pharmaceutical composition containing at least one selected from the group consisting of hydrochloride and trans-4- (aminomethyl) cyclohexanecarboxylic acid is preferred. ,

The following components (A) and (B):
(A) Loxoprofen or a salt thereof;
(B) one or more selected from the group consisting of the following components (B-1-1) to (B-11-1-1);
(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) diphenylpyrine 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 its salt, (B-3-2-1) Cresol sulfonic acid or its salt, (B-3-3) Acetaminophen, (B-3-4) Ethenzamid, (B-4) Cysteine derivative (B-5) lysozyme or a salt thereof, (B-6) codeine, (B-7) ephedrine, (B-8) dextromethorphan or a salt thereof, (B-9-1) caffeine, ( B-10-1-1) Bromwa Lil urea, pharmaceutical compositions containing (B-11-1-1) trans-4- (aminomethyl) cyclohexanecarboxylic acid is particularly preferred.

  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, ammonium chloride, and 1-menthol.

Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, Thiamine nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavinline Acid ester, riboflavin butyrate, 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), gentiana, Gennoshouko (current evidence), kobushi (Katsukiko), gooh (beef yellow), trash beet (Gomiko), Saishin (Spicy), Salamander, Zion (Zipa), Jikoppi (Skin Bark), Peonies (Shakuyaku), Musk (Shako), Shajin, Shazenshi, Shazenshi 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).

  In addition to loxoprofen or a salt thereof and an interactive component, the pharmaceutical composition of the present invention may further contain a basic compound having an acid neutralizing ability. In the present invention, “basic compound having acid neutralizing ability” means a basic compound having acid neutralizing ability, and “acid neutralizing ability” is the 15th revised Japanese Pharmacopoeia in general. It can be determined by conducting a test according to the antacid test method described in the test method.

  In the present invention, examples of the basic compound having acid neutralizing ability include alkaline earth metals such as magnesium, aluminum and calcium and / or earth metal basic inorganic compounds, and alkali metal bases such as sodium and potassium. Inorganic compounds, basic inorganic compounds such as amine basic inorganic compounds; alkaline earth metals such as magnesium, aluminum and calcium and / or earth metal basic organic compounds, alkali metal basic such as sodium and potassium Examples include basic organic compounds such as organic compounds and amine-based basic organic compounds.

In the basic inorganic compound, examples of the alkaline earth metal and / or earth metal-based basic inorganic compound include magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, and water. Coprecipitation product of magnesium oxide and potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminate metasilicate, dry aluminum hydroxide gel, synthetic aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, water Alumina magnesium oxide, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / carbonic acid Calcium coprecipitation product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, magnesium such as anhydrous calcium hydrogen phosphate, metal inorganic salts selected from aluminum and calcium and the like.
Examples of the alkali metal basic inorganic compound include dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, tetrasodium pyrophosphate, trisodium phosphate, sodium hydrogen phosphate hydrate, Examples thereof include inorganic salts of metals selected from sodium and potassium such as anhydrous sodium pyrophosphate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate and the like.

  In the present invention, the basic inorganic compound having acid neutralizing ability includes magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide / potassium aluminum sulfate , Magnesium carbonate, Synthetic hydrotalcite, Magnesium aluminate metasilicate, Dry aluminum hydroxide gel, Synthetic aluminum silicate, Synthetic aluminum silicate, Hydroxypropyl starch, Crystalline cellulose, Magnesium aluminate hydroxide, Aluminum hydroxide gel, Water Aluminum oxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, bentonite, silicic acid Calcium, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, calcium hydrogen phosphate anhydrous, sodium bicarbonate is preferred.

In the basic organic compound, examples of the alkaline earth metal and / or earth metal-based basic organic compound include aldioxa, dihydroxyaluminum aminoacetate, sucralfate hydrate, calcium pantothenate, and the like.
Examples of the alkali metal basic organic compound include sodium citrate hydrate, disodium succinate hexahydrate, DL-sodium tartrate, sodium L-tartrate, copper chlorophyllin sodium, sodium polyacrylate, 5 Examples include '-ribonucleotide disodium, copper chlorophyllin potassium and the like.
Examples of the amine basic organic compound include aminoacetic acid, L-arginine, and meglumine.

  In the present invention, as the basic organic compound having acid neutralizing ability, aldioxa, dihydroxyaluminum aminoacetate and sucralfate hydrate are preferable.

  In the present invention, as the basic compound, a crude drug containing a basic compound such as bandit bone, stone decision, or oyster (oyster) may be used.

In the present invention, preferred specific examples of the basic compound having acid neutralizing ability include magnesium aluminate silicate, magnesium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, precipitated calcium carbonate, anhydrous phosphorus 1 or more types selected from the group consisting of calcium oxyhydrogen and magnesium aluminate metasilicate are mentioned, and particularly preferably, in terms of interaction suppression, magnesium aluminate silicate, magnesium silicate, magnesium oxide, magnesium hydroxide, One or more selected from the group consisting of precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, and magnesium aluminate metasilicate can be mentioned.
In addition, the said basic compound may be individual and may combine 2 or more types. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  Moreover, as a basic compound which has the said acid neutralization ability, what can be used as an antacid is mentioned as a preferable specific example. Specific examples of basic compounds having acid neutralizing ability that can be used as antacids include aminoacetic acid, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, and magnesium oxide. , Dihydroxyaluminum aminoacetate, magnesium hydroxide hydroxide, aluminum hydroxide gel, dry aluminum hydroxide gel, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / carbonate Coprecipitation product of calcium / magnesium carbonate, magnesium hydroxide, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium aluminate metasilicate, Water calcium hydrogen phosphate, calcium hydrogen phosphate, cuttlefish bone, stone Ke'Akira, Borei like. Antacids are broadly classified into absorbent antacids and local antacids due to their properties. In the present invention, local antacids are preferred from the viewpoint of preventing alkalosis.

  The content of the basic compound having acid neutralizing ability in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the inhibitory effect of the interaction between loxoprofen and the interactive component, etc. Good. For example, the amount that can be taken 1 to 20000 mg per day is preferred, the amount that can be taken 10 to 10000 mg is more preferred, and the amount that can be taken 20 to 5000 mg is particularly preferred. In this invention, it is preferable to contain 0.04-99.9 mass% of basic compounds which have acid neutralization ability with respect to the pharmaceutical composition total mass, and 0.4-99.9 mass% is contained. Is more preferable, and containing 0.8 to 99.9% by mass is particularly preferable.

In addition, when using an aldioxa as a basic compound which has acid neutralization ability, the quantity which can be taken | dosed 10-800 mg per day is preferable, and the quantity which can be taken | dosed 30-400 mg is more preferable.
When using the bandage bone, the amount that can be taken 10 to 6000 mg per day is preferred, and the amount that can be taken 30 to 3000 mg is more preferred.
When using dry aluminum hydroxide gel, the quantity which can be taken | dosed 10-6000 mg per day is preferable, and the quantity which can be taken | dosed 30-3000 mg is more preferable.
When using magnesium aluminate silicate, the quantity which can be taken | dosed 10-8000 mg per day is preferable, and the quantity which can be taken | dosed 30-4000 mg is more preferable.
When using calcium silicate, the quantity which can be taken | dosed 1-600 mg per day is preferable, and the quantity which can be taken | dosed 30-300 mg is more preferable.
When using magnesium silicate, the quantity which can be taken | dosed 10-12000 mg per day is preferable, and the quantity which can be taken | dosed 30-6000 mg is more preferable.
When using magnesium aluminum silicate, the quantity which can be taken | dosed 1-500 mg per day is preferable, and the quantity which can be taken | dosed 20-225 mg is more preferable.
When using synthetic aluminum silicate, the quantity which can be taken | dosed 10-20000 mg per day is preferable, and the quantity which can be taken | dosed 30-10000 mg is more preferable.
When using synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose, an amount that can be taken 10 to 3500 mg per day is preferable, and an amount that can be taken 30 to 1800 mg is more preferable.

When using a synthetic hydrotalcite, the quantity which can be taken | dosed 10-8000 mg per day is preferable, and the quantity which can be taken | dosed 30-4000 mg is more preferable.
When using magnesium oxide, the quantity which can be taken | dosed 10-2000 mg per day is preferable, and the quantity which can be taken | dosed 30-1000 mg is more preferable.
When dihydroxyaluminum aminoacetate is used, the amount that can be taken 10 to 6000 mg per day is preferred, and the amount that can be taken 30 to 3000 mg is more preferred.
When using an alumina magnesium hydroxide, the quantity which can be taken | dosed 10-8000 mg per day is preferable, and the quantity which can be taken | dosed 30-4000 mg is more preferable.
When using aluminum hydroxide gel, the quantity which can be taken | dosed 10-6000 mg per day in conversion of dry aluminum hydroxide gel is preferable, and the quantity which can be taken | dosed 30-3000 mg is more preferable.
When using an aluminum hydroxide / sodium bicarbonate coprecipitation product, the amount that can be taken 10 to 4000 mg per day is preferable, and the amount that can be taken 30 to 2000 mg is more preferable.
When using an aluminum hydroxide / magnesium carbonate mixed dry gel, the amount that can be taken 10 to 6000 mg per day is preferable, and the amount that can be taken 30 to 3000 mg is more preferable.
When using an aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, an amount that can be taken 10 to 8000 mg per day is preferable, and an amount that can be taken 30 to 4000 mg is more preferable.
When using magnesium hydroxide, the quantity which can be taken | dosed 10-5000 mg per day is preferable, and the quantity which can be taken | dosed 30-2400 mg is more preferable.
When using the coprecipitation product of magnesium hydroxide and potassium aluminum sulfate, the amount that can be taken 10 to 4000 mg per day is preferable, and the amount that can be taken 30 to 2000 mg is more preferable.

When using sucralfate hydrate, the quantity which can be taken | dosed 10-6500 mg per day is preferable, and the quantity which can be taken | dosed 30-3250 mg is more preferable.
When using stone decision, the quantity which can be taken | dosed 10-6000 mg per day is preferable, and the quantity which can be taken | dosed 30-3000 mg is more preferable.
When using sodium hydrogencarbonate, the quantity which can be taken | dosed 10-10000 mg per day is preferable, and the quantity which can be taken | dosed 30-5000 mg is more preferable.
When using calcium carbonate, the quantity which can be taken | dosed 10-1500 mg per day is preferable, and the quantity which can be taken | dosed 30-700 mg is more preferable.
When using magnesium carbonate, the quantity which can be taken | dosed 10-4000 mg per day is preferable, and the quantity which can be taken | dosed 30-2000 mg is more preferable.
When using precipitated calcium carbonate, the amount that can be taken 10 to 6000 mg per day is preferred, and the amount that can be taken 30 to 3000 mg is more preferred.
When using bentonite, the quantity which can be taken | dosed 1-200 mg per day is preferable, and the quantity which can be taken | dosed 10-100 mg is more preferable.
When using a oyster (oyster), the quantity which can be taken | dosed 10-6000 mg per day is preferable, and the quantity which can be taken | dosed 30-3000 mg is more preferable.

When using anhydrous calcium hydrogen phosphate, an amount that can be taken 10 to 5000 mg per day is preferable, and an amount that can be taken 30 to 2400 mg is more preferable.
When using magnesium aluminate metasilicate, the quantity which can be taken | dosed 10-8000 mg per day is preferable, and the quantity which can be taken | dosed 30-4000 mg is more preferable.
When using calcium hydrogen phosphate, the amount that can be taken 10 to 9000 mg per day is preferable, and the amount that can be taken 30 to 4500 mg is more preferable.

  In the pharmaceutical composition of the present invention, the content ratio of loxoprofen or a salt thereof and a basic compound having acid neutralizing ability contained in the pharmaceutical composition is not particularly limited, and inhibition of the interaction between loxoprofen and an interactive component is not limited. What is necessary is just to examine and determine suitably according to an effect, However, Loxoprofen or its salt contains 0.003-2000 mass parts of basic compounds which have acid neutralization ability with respect to 1 mass part of loxoprofen sodium anhydride conversion Those containing 0.01 to 100 parts by mass are more preferred, and those containing 0.02 to 30 parts by mass are particularly preferred.

  The pharmaceutical composition of the present invention may be stored airtight in the presence of a desiccant. That is, the pharmaceutical composition of the present invention may be a pharmaceutical preparation in which a desiccant is further present under airtight storage, or may be a pharmaceutical preparation in which the pharmaceutical composition of the present invention is stored airtight in the presence of a desiccant.

  In the pharmaceutical preparation of the present invention, the desiccant is not particularly limited. Of course, the shape is not limited, for example, a plate-shaped or bag-shaped sheet type, a cylindrical shape (tablet type), etc., and a cylindrical shape 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, one or more selected from the group consisting of silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve), and calcium chloride is more preferable.

  Commercially available products can be used as the desiccant. Examples of commercially available products include Shiblet, MS-Tablet, MS-Serum W, Tokai Gel, Decikait 25, Alp Sheet, Yamanishi Pharmaceutical Co., Ltd., manufactured by Tokai Chemical Industry Co., Ltd. Dryan (registered trademark) packaged product, Dryan (registered trademark) tablet, Dryan (registered trademark) sheet, Sekawa, Allosheet, Zeosheet manufactured by Shinagawa Kasei Co., Ltd., OZO manufactured by OZO Chemical Engineering Co., Ltd. An ID sheet made by the company ID, an ID packing desiccant, etc.

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.

  In the pharmaceutical preparation of the present invention, the form in which the desiccant is present is not particularly limited, and the pharmaceutical composition according to the present invention and the desiccant may be packaged together in a hermetically sealed package. Further, the pharmaceutical composition according to the present invention can be packaged in a hermetically-storable package, and further a desiccant can be present.

  For example, the pharmaceutical composition of the present invention and a desiccant are stored in a bottle, and a stopper or lid is used. The method for storing the pharmaceutical composition of the present invention and the desiccant in the bottle is not particularly limited, and both can be achieved by arranging them by appropriate means such as charging into the bottle. As one aspect of the pharmaceutical preparation of the present invention, for example, a desiccant (preferably a cylindrical shape (tablet type)) is placed in a bottle together with the pharmaceutical composition of the present invention, and a stopper or a lid is formed. Examples include storing the desiccant on the back side (inner cap), storing the pharmaceutical composition of the present invention in a bottle, and plugging or closing the lid.

  For example, as described above, the pharmaceutical composition of the present invention is once packaged by SP packaging, PTP packaging, stick packaging, etc. and stored in an airtight manner, and then the packaged pharmaceutical composition and desiccant are enclosed in a bag. And so on. More specifically, there may be mentioned a form in which pillow packaging is performed by combining a pharmaceutical composition packed in SP packaging, PTP packaging or stick packaging with a sheet-shaped or bag-shaped desiccant. Further, the pillow packaging form may be stored in a box or the like. The material used for pillow packaging is not particularly limited. For example, a resin film such as a polypropylene film, a polyethylene terephthalate film, or a polyethylene film, or a film obtained by attaching an aluminum foil to these resin films can be used.

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), pain relief, chills, antipyretic fever, cold symptoms (throat pain, chills, fever, headache, joint pain, muscles It is useful as a general cold medicine (cold medicine) or antipyretic analgesic.
In addition, as will be apparent from Examples described later, various interactive components suppress and reduce gastrointestinal disorders caused by loxoprofen. Therefore, patients suffering from peptic ulcer and patients with a history of history can also take loxoprofen or a salt thereof without fear of gastrointestinal tract disorders caused by loxoprofen.

  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) 500 mg and dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi”) were mixed and mixed in a glass bottle ( 3K standard bottle) and stored at 60 ° C. for 1 week (Reference Example 1). As comparative controls, loxoprofen sodium hydrate alone (Control Example 1) and dihydrocodeine phosphate alone (Control Example 2) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 1.

  As is clear from Table 1, when the mixture of loxoprofen sodium hydrate and dihydrocodeine phosphate was stored, the mixture solidified and further discolored (Reference Example 1). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and dihydrocodeine phosphate alone (control examples 1 and 2). From this, it was found that the change in the state of the mixture was a result of the interaction between loxoprofen and codeines.

[Test Example 2] Examination of interaction (2)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 g and dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi”) are mixed. To prepare a mixture. Next, 0.5 g of the obtained mixture was placed in a glass bottle (2K standard bottle) and stored at 40 ° C. for 19 days (Comparative Example 1).
On the other hand, 0.5 g of the above-mentioned mixture is put into a pocket portion of a resin sheet (manufactured by Sumitomo Bakelite: trade name Sumilite VSS- 1202) in which a pocket portion is molded in advance, and then an aluminum foil for PTP (manufactured by Daiwa Chemical Industry: product) Name: Aluminum foil (silver plain), covered with PTP, and stored at 40 ° C. for 19 days (Example 1).
Further, the resin sheet was changed from Sumilite VSS-1220 to Sumilite VSL-4603 and stored at 40 ° C. for 19 days in the same manner as in Example 1 (Example 2).
Furthermore, the PTP packaging similar to that in Example 1 was packaged in an aluminum pillow with an aluminum laminate bag (manufactured by Nippon Shokubai Co., Ltd .: trade name Lami Zip AL series) and stored at 40 ° C. for 19 days (Example 3).
In addition, the same PTP packaging as in Example 1 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) are packed together in an aluminum pillow bag (produced by Nippon Shokubai Co., Ltd .: trade name Rami Zip AL series). And stored at 40 ° C. for 19 days (Example 4).
About the comparative example 1, Example 1, and Example 2, the state of the mixture at the time of a storage start, 1 day, 2 days, 6 days, and 19 days after was evaluated. Moreover, about Example 3 and 4, after storage for 19 days, the pillow packaging was opened and the state of the mixture was evaluated. The results are shown in Table 2.

As is apparent from Table 2, the mixture of loxoprofen sodium hydrate and dihydrocodeine phosphate which had been preserved only became wet as a result of the interaction. ).
On the other hand, the same state as at the start was maintained for the mixture of loxoprofen sodium hydrate and dihydrocodeine phosphate that had been stored airtight.
As a result, it was proved that the interaction can be suppressed by air-tightly storing loxoprofen or a salt thereof and codeine (Examples 1 to 4).

[Production Example 1] PTP package (1)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 68.1 g, 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and corn starch (Nissho) 24.3 g of chemical product: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then sieved with a No. 18 sieve to obtain a granulated product. Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name, dihydrocodeine phosphate “Shionogi”) 8 g, carmellose calcium (manufactured by Gotoku Pharmaceutical: trade name ECG505), 81 g of lactose hydrate (manufactured by DMV: A tableting machine (field) with 591.3 g of lactose (200 M) and 8.1 g of magnesium stearate (produced by Taihei Chemical Industry: brand name: magnesium stearate (vegetable)) attached with a 8.5 mm diameter punch. Tableting was performed using a steel factory manufactured by HT-AP18SS type, and a tablet having a mass of 270 mg was obtained. Next, the obtained tablet is put in a pocket portion of a resin sheet (manufactured by Sumitomo Bakelite: trade name Sumilite VSS- 1202) in which a pocket part has been molded in advance, and then an aluminum foil for PTP (manufactured by Yamato Chemical Co., Ltd .: trade name, aluminum foil silver). The lid was covered with plain fabric and PTP packaged to obtain a PTP package.

[Production Example 2] PTP package (2)
A PTP package was obtained in the same manner as in Production Example 1 except that Macrogol 6000 was replaced with hydrogenated oil (product name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Production Example 3] PTP package (3)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 68.1 g, 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and corn starch (Nissho) 24.3 g of chemical product: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then sieved with a No. 18 sieve to obtain a granulated product. Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name, dihydrocodeine phosphate “Shionogi”) 8 g, carmellose calcium (manufactured by Gotoku Pharmaceutical: trade name ECG505), 81 g of lactose hydrate (manufactured by DMV: Trade name Lactose 200M) 295.7 g, crystalline cellulose (product name: Asahi Kasei Chemicals: trade name Theolas PH-101) 295.6 g and magnesium stearate (product name: Taihei Kagaku Kogyo: trade name magnesium stearate (vegetable)) 8.1 g After mixing, tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg. Next, a PTP package was obtained in the same manner as in Production Example 2.

[Production Example 4] PTP package (4)
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”) 8 g, 3.4 g of macrogol 6000 (manufactured by NOF Corporation: trade name Macrogol 6000P) and corn starch (manufactured by Nissho Chemical Co., Ltd .: trade name) 2.9 g of corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then sieved with a No. 18 sieve to obtain a granulated product. In the obtained granulated product, loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 68.1 g, carmellose calcium (manufactured by Gotoku Pharmaceutical: trade name ECG505), 81 g, lactose water After mixing 638.5 g of Japanese product (product name: lactose 200M) and magnesium stearate (product name: Taihei Kagaku Kogyo: product name magnesium stearate (vegetable)), attach a bowl with a diameter of 8.5 mm. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) to obtain a tablet having a mass of 270 mg. Next, a PTP package was obtained in the same manner as in Production Example 2.

[Production Example 5] PTP package (5)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 68.1 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), 24.3 g, carmellose calcium (Gotoku Pharmaceutical) Product: ECG505) 81 g, crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Product name Theolas PH-101) 620.5 g was charged into a high-speed agitation granulator (Paurek: model VG-05), mixed, and purified water 328 .8 g was added and kneaded. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 7. 793.9 g of this sized product, 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) and magnesium stearate (manufactured by Taihei Chemical Industry: trade name: magnesium stearate (vegetable)) 1 g was put into a mixing machine (Kotobuki: PM50 type) and mixed, and then tableted using a tableting machine (Hataseko: HT-AP18SS type) equipped with a 8.5 mm diameter punch. A tablet having a tablet mass of 270 mg was obtained. Next, a PTP package was obtained in the same manner as in Production Example 2.

[Production Example 6] PTP package (6)
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”) 8 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 24.3 g, carmellose calcium (product name: ECG505) ) 81 g, 620.5 g of crystalline cellulose (Asahi Kasei Chemicals: trade name: Theolas PH-101) was charged into a high-speed agitation granulator (Paulec: VG-05 type) and mixed, and then 328.8 g of purified water was added. Kneaded. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 733.8 g of this sized product, loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) 68.1 g, and magnesium stearate (manufactured by Taihei Chemical Industry: trade name: magnesium stearate (plant) Property)) After putting 8.1 g into a mixer (manufactured by Kotobuki: model PM50) and mixing, using a tableting machine (manufactured by Hata Iron Works: model HT-AP18SS) equipped with a 8.5 mm diameter punch. Tableting was performed to obtain a tablet having a mass of 270 mg. Next, a PTP package was obtained in the same manner as in Production Example 2.

[Production Example 7] PTP package (7)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 68.1 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name: HPC-L), carmellose calcium (Gotoku Pharmaceutical) Manufactured: trade name ECG505) 40.5 g, crystalline cellulose (Asahi Kasei Chemicals: trade name Theolas PH-101) 280.2 g was put into a high-speed stirring granulator (Paurek: VG-05 type), mixed and purified. 164.3 g of water was added and kneaded. This granulated product 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) (Granulated product A). ). In addition, 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co .: trade name dihydrocodeine phosphate “Shionogi”), 12.1 g of hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L), carmellose calcium (product of Gotoku Pharmaceutical: product) Name ECG505) 40.5 g and crystalline cellulose (manufactured by Asahi Kasei Chemicals: brand name Theolas PH-101) 340.3 g were charged into a high-speed agitation granulator (manufactured by Paulek: model VG-05), mixed, and purified water 164. 3 g was added and kneaded. This granulated product 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 model) (Granulated product B). ). 400 g of the sized product A, 400 g of the sized product B, and 8 g of magnesium stearate (made by Taihei Chemical Industry: trade name magnesium stearate (vegetable)) were put into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 8.5 mm diameter punch, and tablets with a mass of 270 mg were obtained. Next, a PTP package was obtained in the same manner as in Production Example 2.

[Test Example 3] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (1)
The test was carried out using 6 rats per group using Wistar rats (Std: Wistar / ST, male, 8 weeks old, body weight 188.9 to 227.9 g). Rats were fasted from the day before the test (16 hours or longer). Water intake was free up to 1 hour before the start of the test, and then water was stopped.
As a test drug, dihydrocodeine phosphate (DP) was suspended in a 0.5% methylcellulose (MC) solution and orally administered in predetermined amounts (8, 24, 72 mg / 5 mL / kg).
In the control group, only the solvent (0.5% MC) was orally administered in the same volume (5 mL / kg).
One hour after administration of the test drug, loxoprofen sodium hydrate 120 mg / 2 mL saline / kg was orally administered to each group of rats to induce gastric mucosal damage. Five hours after administration of loxoprofen sodium hydrate, the rats were euthanized by cervical dislocation, the cardia was ligated, and the stomach was removed. After injecting 10 mL of 1% formalin solution into the stomach from the pyloric region and ligating the pyloric region, the entire stomach was immersed in the formalin solution for about 20 minutes and fixed lightly.
Evaluation of the degree of gastric mucosal damage is performed by measuring the length (mm) of individual damage (erosion) occurring in the glandular stomach portion under a stereomicroscope after incising the stomach along the large curvature. The total damage per rat was calculated as the ulcer index. According to the following formula, the ulcer suppression rate (%) in the test drug was calculated, and the results are shown in Table 3.
Ulcer inhibition rate (%) = {1− (ulcer index of test drug / ulcer index of control group)} × 100

  As is apparent from Table 3, dihydrocodeine phosphate reduced gastric mucosal damage caused by loxoprofen.

[Test Example 4] Examination of interaction (3)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 584 mg and d-chlorpheniramine maleate (manufactured by Kongo Chemical: trade name: D-chlorpheniramine maleate) mixed And stored in a glass bottle (3K standard bottle) at 60 ° C. for 1 week (Reference Example 2). As comparative controls, loxoprofen sodium hydrate alone (Control Example 3) and d-chlorpheniramine maleate salt alone (Control Example 4) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 4.

  As is apparent from Table 4, when the mixture of loxoprofen sodium hydrate and chlorpheniramine maleate was stored, the mixture became wet and solidified and further discolored (Reference Example 2). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and chlorpheniramine maleate alone (control examples 3 and 4). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and chlorpheniramine maleate.

[Test Example 5] Examination of interaction (4)
The same as Comparative Example 1 of Test Example 2 except that 2.043 g of dihydrocodeine phosphate was replaced with 3.5 g of d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-chlorpheniramine maleate). 0.5 g of the obtained mixture was put in a glass bottle (2K standard bottle) and stored at 40 ° C. for 19 days (Comparative Example 2).
Further, 0.5 g of the above-mentioned mixture of loxoprofen sodium hydrate and d-chlorpheniramine maleate was subjected to PTP packaging and aluminum pillow packaging as in Example 3 (Example 5). In the same manner as in Example 4, 1 g of PTP packaging and synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) packaged in aluminum pillow (Example 6) was stored at 40 ° C. for 19 days.
For Comparative Example 2, the state of the mixture at the start of storage, 1 day, 2 days, 6 days, and 19 days was evaluated. Moreover, about Example 5 and 6, after the preservation | save for 19 days, the pillow packaging was opened and the state of the mixture was evaluated. The results are shown in Table 5.

As is apparent from Table 5, as a result of interaction between the mixture of loxoprofen sodium hydrate and chlorpheniramine maleate that had been stored alone, the mixture became wet after 6 days from the start of storage (Comparative Example). 2).
On the other hand, the same state as at the beginning was maintained for the mixture of loxoprofen sodium hydrate and chlorpheniramine maleate that was airtightly preserved.
As a result, it was found that the interaction can be suppressed by airtight storage of loxoprofen or a salt thereof and the compound represented by the general formula (1) containing chlorpheniramine or a salt thereof (Examples 5 and 6). .

[Production Example 8] PTP package (8)
Production Example 2 except that 8 g of dihydrocodeine phosphate was replaced with 1.2 g of d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-chlorpheniramine maleate) and corn starch was replaced with 31.1 g. In the same manner as above, a PTP package was obtained.

[Production Example 9] PTP package (9)
A PTP package was obtained in the same manner as in Production Example 8 except that Macrogol 6000 was replaced with hydrogenated oil (product name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 6] Loxoprofen-induced digestive tract disorder inhibitory action (2)
By orally administering a predetermined amount (5, 40 mg / 5 mL / kg) using a suspension of d-chlorpheniramine maleate (CM) in a 0.5% methylcellulose (MC) solution as a test drug The test was carried out in the same manner as in Test Example 3, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 6.

  As is apparent from Table 6, chlorpheniramine maleate reduced gastric mucosal damage caused by loxoprofen.

[Test Example 7] Examination of interaction (5)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 381mg and clemastine fumarate (Daito: trade name: clemastine fumarate) 2.5mg were mixed and mixed into a glass bottle (3K standard). And stored for 1 week at 60 ° C. (Reference Example 3). As comparative controls, loxoprofen sodium hydrate alone (Control Example 5) and clemastine fumarate salt alone (Control Example 6) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the state in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 7.

  As is apparent from Table 7, when the mixture of loxoprofen sodium hydrate and clemastine fumarate was stored, the mixture became wet and further discolored (Reference Example 3). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and clemastine fumarate alone (control examples 5 and 6). From this, it was found that the state change of the mixture was a result of interaction between loxoprofen sodium hydrate and clemastine fumarate.

[Test Example 8] Examination of interaction (6)
Of the mixture obtained in the same manner as in Comparative Example 1 of Test Example 2, except that 2.043 g of dihydrocodeine phosphate was replaced with 1.34 g of clemastine fumarate (product name: clemastine fumarate). 5 g was placed in a glass bottle (2K standard bottle) and stored at 40 ° C. for 19 days (Comparative Example 3).
Also, 0.5 g of the above-mentioned mixture of loxoprofen sodium hydrate and clemastine fumarate was PTP packaged as in Example 1 (Example 7), and PTP packaged as in Example 2. The product (Example 8) was stored at 40 ° C. for 19 days.
Further, 0.5 g of the above-mentioned mixture of loxoprofen sodium hydrate and clemastine fumarate was subjected to PTP packaging and aluminum pillow packaging (Example 9) and Example 4 as in Example 3. In the same manner as above, PTP packaging and synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) 1 g together with aluminum pillow packaging (Example 10) were stored at 40 ° C. for 19 days.
About the comparative example 3, Example 7, and Example 8, the state of the mixture at the time of a storage start, 1 day later, 2 days later, 6 days later, and 19 days after was evaluated. Moreover, about Example 9 and Example 10, after preservation | save for 19 days, the pillow packaging was opened and the state of the mixture was evaluated. The results are shown in Table 8.

As is apparent from Table 8, the mixture of loxoprofen sodium hydrate and clemastine fumarate which had been preserved only became wet as a result of interaction, resulting in the mixture becoming wet (Comparative Example 3). ).
On the other hand, the same state as that at the start was maintained for the mixture of loxoprofen sodium hydrate and clemastine fumarate which was stored airtight.
As a result, it was found that the interaction can be suppressed by airtight preservation of loxoprofen or a salt thereof and the compound represented by the general formula (1) containing clemastine or a salt thereof (Examples 7 to 10).

[Production Example 10] PTP package (10)
A PTP package was prepared in the same manner as in Production Example 2, except that 8 g of dihydrocodeine phosphate was changed to 0.5 g of clemastine fumarate (product name: clemastine fumarate) and corn starch was changed to 31.8 g. Got.

[Production Example 11] PTP package (11)
A PTP package was obtained in the same manner as in Production Example 10 except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 9] Inhibitory action on loxoprofen-induced gastrointestinal tract disorder (3)
As a test drug, a suspension of clemastine fumarate (CF) in a 0.5% methylcellulose (MC) solution was used, and a predetermined amount (1 mg / 5 mL / kg) was orally administered, as in Test Example 3. The test was carried out, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 9.

  As is apparent from Table 9, clemastine fumarate alleviated gastric mucosal damage caused by loxoprofen.

[Test Example 10] Analgesic test The pain threshold value of the right hind paw of Wistar male rats (body weight 102.7 to 120.5 g) aged 5 to 6 weeks was measured and designated as “the pain threshold value 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 (group (ii)-group (ho)) was administered.

Group (I): Loxoprofen sodium hydrate alone administration group (hereinafter referred to as “LX alone”)
Loxoprofen sodium hydrate was administered at a dose of 0.1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
Group (ro): 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 (ha): Two-component combination 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 (ni): 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 (ho): 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 10. The pain improvement rate was expressed as an average value ± standard error for each group.

As is apparent from Table 10, the combination of loxoprofen sodium hydrate and clemastine fumarate was found to have an excellent analgesic action (group (ha) pain improvement rate: about 41%, group ( E) 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 11] Examination of interaction (7)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 482.3 mg and carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) were mixed, It put into the glass bottle (3K specification bottle), and preserve | saved for one week at 60 degreeC (reference example 4). As comparative controls, loxoprofen sodium hydrate alone (Control Example 7) and carbinoxamine maleate salt alone (Control Example 8) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 2 days, and 1 week was evaluated, and the results are shown in Table 11.

  As is apparent from Table 11, when the mixture of loxoprofen sodium hydrate and carbinoxamine maleate was stored, the mixture solidified and further discolored (Reference Example 4). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and carbinoxamine maleate alone (control examples 7 and 8). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and carbinoxamine maleate.

[Production Example 12] PTP package (12)
In the same manner as in Production Example 2, except that 8 g of dihydrocodeine phosphate was changed to 2.5 g of carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) and corn starch was changed to 29.8 g. A package was obtained.

[Production Example 13] PTP package (13)
A PTP package was obtained in the same manner as in Production Example 12 except that Macrogol 6000 was replaced with hydrogenated oil (product name: K-3 Wax-200 manufactured by Kawaken Fine Chemicals).

[Test Example 12] Inhibitory action on loxoprofen-induced gastrointestinal tract disorder (4)
As test drug, carbinoxamine maleate (CAM) suspended in 0.5% methylcellulose (MC) solution and orally administered in a predetermined amount (0.75, 75 mg / 5 mL / kg) The test was conducted in the same manner as in Test Example 3, the ulcer suppression rate (%) in the administration of the test drug was calculated, and the results are shown in Table 12.

  As is apparent from Table 12, carbinoxamine maleate alleviated gastric mucosal damage caused by loxoprofen.

[Test Example 13] Investigation of interaction (7)
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 490.4 mg and diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) 9.6 mg were mixed together and mixed with a glass bottle ( 3K standard bottle) and stored at 60 ° C. for 1 week (Reference Example 5). As comparative controls, loxoprofen sodium hydrate alone (Control Example 9) and diphenylpyraline hydrochloride alone (Control Example 10) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 13.

  As is apparent from Table 13, when the mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochloride was stored, the mixture became wet and further discolored (Reference Example 5). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and diphenylpyraline hydrochloride alone (control examples 9 and 10). From this, it was found that the state change of the mixture was the result of interaction between loxoprofen sodium hydrate and diphenylpyraline hydrochloride.

[Production Example 14] PTP package (14)
A PTP package is obtained in the same manner as in Production Example 2, except that 8 g of dihydrocodeine phosphate is changed to 1.3 g of diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) and corn starch is changed to 31 g. .

[Production Example 15] PTP package (15)
A PTP package is obtained in the same manner as in Production Example 14 except that Macrogol 6000 is replaced with hydrogenated oil (product name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 14] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (5)
As a test drug, a suspension of diphenylpyraline hydrochloride (PP) in a 0.5% methylcellulose (MC) solution was used, and a predetermined amount (3, 10 mg / 5 mL / kg) was orally administered. The test was carried out in the same manner as above, and the ulcer suppression rate (%) in the administration of the test drug was calculated. The results are shown in Table 14.

  As is apparent from Table 14, diphenylpyraline hydrochloride alleviated gastric mucosal damage caused by loxoprofen.

[Test Example 15] Examination of interaction (9)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 170 mg and bromhexine hydrochloride (Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) 10 mg are mixed, and glass bottle (3K standard bottle) And stored at 60 ° C. for 1 week (Reference Example 6). As comparative controls, loxoprofen sodium hydrate alone (Control Example 11) and bromhexine hydrochloride alone (Control Example 12) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 2 days, and 1 week was evaluated, and the results are shown in Table 15.

  As is apparent from Table 15, when the mixture of loxoprofen sodium hydrate and bromhexine hydrochloride was stored, the mixture solidified and further discolored (Reference Example 6). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and bromhexine hydrochloride alone (Control Examples 11 and 12). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and bromhexine hydrochloride.

[Production Example 16] PTP package (16)
A PTP package is obtained in the same manner as in Production Example 2, except that 8 g of dihydrocodeine phosphate is changed to 4 g of bromohexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromohexine hydrochloride) and corn starch is changed to 28.3 g. .

[Production Example 17] PTP package (17)
A PTP package is obtained in the same manner as in Production Example 16 except that Macrogol 6000 is changed to hydrogenated oil (product of Kawaken Fine Chemicals: trade name K-3 wax-200).

[Test Example 16] Investigation of interaction (10)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 500 mg and ambroxol hydrochloride (Shizuoka Caffeine Kogyosho: trade name: Ambroxol hydrochloride) 500 mg are mixed, and glass bottle (3K standard bottle) and stored at 60 ° C. for 1 week (Reference Example 7). As comparative controls, loxoprofen sodium hydrate alone (Control Example 13) and ambroxol hydrochloride alone (Control Example 14) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 16.

  As is apparent from Table 16, when the mixture of loxoprofen sodium hydrate and ambroxol hydrochloride was stored, the mixture solidified and further discolored (Reference Example 7). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and ambroxol hydrochloride alone (control examples 13 and 14). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and ambroxol hydrochloride.

[Production Example 18] PTP package (18)
Except for replacing 8 g of dihydrocodeine phosphate with 15 g of ambroxol hydrochloride (product name: ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industries), macrogol 6000 is changed to 25.7 g, and corn starch is changed to 20.8 g. In the same manner as in Production Example 2, a PTP package is obtained.

[Production Example 19] PTP package (19)
A PTP package is obtained in the same manner as in Production Example 18 except that Macrogol 6000 is changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 wax-200).

[Test Example 17] Investigation of interaction (11)
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 224.9 mg and potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: potassium guaiacol sulfonate) mixed with 275.1 mg And stored in a glass bottle (3K standard bottle) at 60 ° C. for 1 week (Reference Example 8). As comparative controls, loxoprofen sodium hydrate alone (Control Example 15) and potassium guaiacol sulfonate alone (Control Example 16) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 17.

  As is clear from Table 17, when the mixture of loxoprofen sodium hydrate and potassium guaiacol sulfonate was stored, the mixture became wet (Reference Example 8). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and potassium guaiacol sulfonate alone (Control Examples 15 and 16). From this, it was found that the state change of the mixture was a result of interaction between loxoprofen sodium hydrate and potassium guaiacol sulfonate.

[Test Example 18] Examination of interaction (12)
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. for 1 week (Reference Example 9). As comparative controls, loxoprofen sodium hydrate alone (Control Example 17) and lysozyme hydrochloride alone (Control Example 18) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 18.

  As is apparent from Table 18, when the mixture of loxoprofen sodium hydrate and lysozyme hydrochloride was stored, the mixture became wet and further solidified (Reference Example 9). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and lysozyme hydrochloride alone (control examples 17 and 18). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and lysozyme hydrochloride.

[Production Example 20] PTP package (20)
Except for changing 8 g of dihydrocodeine phosphate to 30 g of lysozyme hydrochloride (trade name: lysozyme chloride, manufactured by Eisai), changing Macrogol 6000 to 18.2 g, and corn starch to 13.3 g, as in Production Example 2. To obtain a PTP package.

[Production Example 21] PTP package (21)
A PTP package is obtained in the same manner as in Production Example 20 except that Macrogol 6000 is replaced with hydrogenated oil (product name: K-3 Wax-200 manufactured by Kawaken Fine Chemicals).

[Test Example 19] Examination of interaction (13)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 500 mg and dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 150 mg The mixture was mixed, put into a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 10). As comparative controls, loxoprofen sodium hydrate alone (Control Example 19) and dl-methylephedrine hydrochloride alone (Control Example 20) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 19.

  As is apparent from Table 19, when the mixture of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride was stored, the mixture became wet and further discolored (Reference Example 10). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride alone (Control Examples 19 and 20). From this, it was found that the state change of the mixture was the result of interaction between loxoprofen sodium hydrate and dl-methylephedrine hydrochloride.

[Test Example 20] Examination of interaction (14)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 g and dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 20.43 g was mixed to prepare a mixture. Next, 0.5 g of the obtained mixture was placed in a glass bottle (2K standard bottle) and stored at 40 ° C. for 19 days (Comparative Example 4).
On the other hand, 0.5 g of the aforementioned mixture was packaged in an aluminum pillow with an aluminum laminate bag (manufactured by Nippon Shokubai Co., Ltd .: trade name Lami Zip AL series) and stored at 40 ° C. for 19 days (Example 11).
For Comparative Example 4, the state of the mixture at the start of storage, 1 day, 2 days, 6 days, and 19 days was evaluated. Moreover, about Example 11, after 19 days preservation | save, the pillow packaging was opened and the state of the mixture was evaluated. The results are shown in Table 20.

As can be seen from Table 20, in the case where loxoprofen sodium hydrate and methylephedrine hydrochloride were stored alone, the mixture solidified one day after the start of storage as a result of the interaction (Comparative Example 4). ).
On the other hand, the same state as at the start was maintained for the mixture of loxoprofen sodium hydrate and methylephedrine hydrochloride that had been stored airtight.
As a result, it was found that the interaction can be suppressed by airtight preservation of loxoprofen or a salt thereof and methylephedrine hydrochloride (Example 11).

[Production Example 22] PTP package (22)
8 g of dihydrocodeine phosphate was replaced with 20 g of dl-methylephedrine hydrochloride (trade name: Japanese Pharmacopoeia, dl-methylephedrine hydrochloride, manufactured by Alps Pharmaceutical Industries), macrogol 6000 was changed to 23.2 g, and corn starch was 18.3 g. A PTP package is obtained in the same manner as in Production Example 2 except that.

[Production Example 23] PTP package (23)
A PTP package is obtained in the same manner as in Production Example 22 except that Macrogol 6000 is replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 21] Inhibitory action on loxoprofen-induced gastrointestinal tract disorder (6)
By using dl-methylephedrine hydrochloride (ME) suspended in 0.5% methylcellulose (MC) solution as a test drug and orally administering a predetermined amount (20, 60, 180 mg / 5 mL / kg) The test was conducted in the same manner as in Test Example 3, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 21.

  As is clear from Table 21, dl-methylephedrine hydrochloride alleviated gastric mucosal damage caused by loxoprofen.

[Test Example 22] Examination of interaction (15)
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. for 1 week (Reference Example 11). As comparative controls, loxoprofen sodium hydrate alone (Control Example 21) and dextromethorphan hydrobromide hydrate alone (Control Example 22) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 22.

  As is apparent from Table 22, when the mixture of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate was stored, the mixture became wet (Reference Example 11). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate alone (Control Examples 21 and 22). From this, it was found that the state change of the mixture was the result of interaction between loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate.

[Production Example 24] PTP package (24)
8 g of dihydrocodeine phosphate was replaced with 16 g of dextromethorphan hydrobromide hydrate (Daiichi Fine Chemical, trade name: dextromethorphan HBR), macrogol 6000 was changed to 25.2 g, and corn starch was changed to 20.3 g. A PTP package is obtained in the same manner as in Production Example 2 except that it is changed.

[Production Example 25] PTP package (25)
A PTP package is obtained in the same manner as in Production Example 24 except that Macrogol 6000 is changed to hydrogenated oil (product of Kawaken Fine Chemicals: trade name K-3 wax-200).

[Test Example 23] Investigation of interaction (16)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 224.9 mg and guaifenesin (Alps Pharmaceutical: trade name Guaifenesin) 224.9 mg were mixed and mixed in a glass bottle (3K standard bottle). And stored at 60 ° C. for 1 week (Reference Example 12). As comparative controls, loxoprofen sodium hydrate alone (Control Example 23) and guaifenesin alone (Control Example 24) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 23.

  As is clear from Table 23, when the mixture of loxoprofen sodium hydrate and guaifenesin was stored, the mixture turned into a clear liquid (Reference Example 12). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and guaifenesin alone (Control Examples 23 and 24). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and guaifenesin.

[Production Example 26] PTP package (26)
Production Example 2 except that 8 g of dihydrocodeine phosphate is replaced with 83 g of guaifenesin (product name: Guaifenesin), Macrogol 6000 is replaced with 292 g, corn starch is replaced with 243 g, and lactose hydrate is replaced with 34.8 g. In the same manner as described above, a PTP package is obtained.

[Production Example 27] PTP package (27)
A PTP package is obtained in the same manner as in Production Example 26 except that Macrogol 6000 is replaced with hydrogenated oil (product name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 24] Examination of interaction (17)
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. for 1 week (Reference Example 13). Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 24.

  As is apparent from Table 24, it was found that when a mixture of loxoprofen sodium hydrate and sodium caffeine benzoate was stored, the mixture solidified and interaction occurred after 1 day of storage.

[Production Example 28] PTP package (28)
8 g of dihydrocodeine phosphate was replaced with 100 g of sodium benzoate caffeine (product name: sodium benzoate caffeine, manufactured by Shizuoka Caffeine Industry), macrogol 6000 was changed to 292 g, corn starch was changed to 243 g, and lactose hydrate was added. A PTP package is obtained in the same manner as in Production Example 2 except that the amount is changed to 17.8 g.

[Production Example 29] PTP package (29)
A PTP package is obtained in the same manner as in Production Example 28 except that Macrogol 6000 is replaced with hydrogenated oil (product name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 25] Examination of interaction (18)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 g and anhydrous caffeine (Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 250 g were mixed, and the mixture was mixed. Prepared. Next, 0.5 g of the obtained mixture was placed in a glass bottle (2K standard bottle) and stored at 40 ° C. and 75% RH for 6 days (Comparative Example 5).
On the other hand, 0.5 g of the above mixture is put into a pocket portion of a resin sheet (manufactured by Sumitomo Bakelite: trade name Sumilite VSL-4603) in which a pocket portion has been molded in advance, and then an aluminum foil for PTP (made by Daiwa Chemical Industry: trade name) The product was covered with PTP and covered with aluminum foil (silver plain) and stored at 40 ° C. for 19 days (Example 12).
About Comparative Example 5 and Example 12, the state of the mixture immediately after the start of storage, 1 day, 2 days and 6 days after was evaluated. The results are shown in Table 25.

As can be seen from Table 25, in the case where loxoprofen sodium hydrate and anhydrous caffeine were mixed and stored, the mixture was moistened after 6 days from the start of storage as a result of the interaction (Comparative Example 5). .
On the other hand, about the thing which mixed loxoprofen sodium hydrate and anhydrous caffeine and preserve | saved airtightly, the same state as the start was maintained.
As a result, it was found that the interaction can be suppressed by air-tightly storing loxoprofen or a salt thereof and anhydrous caffeine (Example 12).

[Test Example 26] Examination of interaction (19)
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 127 mg and bromvaleryl urea (manufactured by Yatsushiro Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Bromovaleryl Urea P) 373 mg are mixed together, and a glass bottle (3K standard bottle) ) And stored at 60 ° C. for 1 week (Reference Example 14). Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 26.

As is clear from Table 26, it was found that when the mixture of loxoprofen sodium hydrate and bromvaleryl urea was stored, the mixture solidified and interaction occurred after 1 day from the start of storage.
As a result, it was found that the interaction can be suppressed unless loxoprofen or a salt thereof and the isovalerylurea derivative are substantially brought into contact with each other.

[Production Example 30] PTP package (30)
8 g of dihydrocodeine phosphate is replaced with 67 g of bromvaleryl urea (trade name: Japanese pharmacopoeia bromovaleryl urea P), and Macrogol 6000 is changed to 233.6 g, corn starch is changed to 194.4 g, and lactose hydrate is changed to 157 A PTP package is obtained in the same manner as in Production Example 2 except that the amount is changed to 0.8 g.

[Production Example 31] PTP package (31)
A PTP package is obtained in the same manner as in Production Example 30, except that the macrogol 6000 is changed to a hardened oil (manufactured by Kawaken Fine Chemicals: trade name K-3 wax-200).

[Test Example 27] Investigation of interaction (20)
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg and carbocysteine (Myonaka Mining Co., Ltd .: trade name: Carbocysteine) 1500 mg are mixed, and glass bottle (3K standard bottle) And stored at 60 ° C. for 1 week (Reference Example 15). Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 27.

  As is apparent from Table 27, it was found that when a mixture of loxoprofen sodium hydrate and carbocysteine was stored, the mixture solidified and interaction occurred 1 day after the start of storage.

[Test Example 28] Examination of interaction (21)
8 g of dihydrocodeine phosphate was changed to 100 g of carbocysteine (manufactured by Myoko Mining Co., Ltd .: trade name carbocysteine), loxoprofen sodium hydrate and carbocysteine were mixed (Comparative Example 6), and stored at 50 ° C. for 28 days. The test was conducted in the same manner as in Test Example 2, except that the evaluation was performed immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, and 28 days. The results are shown in Table 28.

  As is apparent from Table 28, as a result of the interaction between the loxoprofen sodium hydrate and carbocysteine stored alone, the mixture solidified after 1 day of storage, and discolored after 7 days. (Comparative Example 6).

[Production Example 32] PTP package (32)
Except that 8 g of dihydrocodeine phosphate is changed to 100 g of carbocysteine (product name: Carbocysteine manufactured by Myonaka Mining Co., Ltd.), Macrogol 6000 is changed to 292 g, corn starch is changed to 243 g, and lactose hydrate is changed to 17.8 g. In the same manner as in Production Example 2, a PTP package is obtained.

[Production Example 33] PTP package (33)
A PTP package is obtained in the same manner as in Production Example 32 except that Macrogol 6000 is replaced with hydrogenated oil (product name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 29] Examination of interaction (22)
8 g of dihydrocodeine phosphate was replaced with 100 g of acetaminophen (product name: acetaminophen, manufactured by Fuji Chemicals), loxoprofen sodium hydrate and acetaminophen were mixed (Comparative Example 7), and 28 at 50 ° C. The test was carried out in the same manner as in Test Example 2 except that the samples were stored for 1 day, immediately after the start of storage, and after 1 day, 3 days, 7 days, 14 days, and 28 days. The results are shown in Table 29.

  As is clear from Table 29, as a result of the interaction between the mixture of loxoprofen sodium hydrate and acetaminophen that had been stored alone, the mixture became wet after 7 days from the start of storage, and extremely high after 14 days. It was strongly wetted (Comparative Example 7).

[Production Example 34] PTP package (34)
8 g of dihydrocodeine phosphate is changed to 100 g of acetaminophen (product name: acetaminophen manufactured by Fuji Chemicals), macrogol 6000 is changed to 292 g, corn starch is changed to 243 g, and lactose hydrate is changed to 17.8 g. Except for the above, a PTP package is obtained in the same manner as in Production Example 2.

[Production Example 35] PTP package (35)
A PTP package is obtained in the same manner as in Production Example 34 except that Macrogol 6000 is replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 30] Investigation of interaction (23)
8 g of dihydrocodeine phosphate was changed to 100 g of etenzamide (manufactured by API Corporation: trade name etenzamide), loxoprofen sodium hydrate and ethenamide were mixed (Comparative Example 8), stored at 50 ° C. for 28 days, immediately after the start of storage The test was conducted in the same manner as in Test Example 2 except that the evaluation was performed after 1 day, 3 days, 7 days, 14 days, and 28 days. The results are shown in Table 30.

  As is clear from Table 30, as a result of interaction between the mixture of loxoprofen sodium hydrate and etezamide that had been stored alone, the mixture became wet 14 days after the start of storage (Comparative Example 8).

[Production Example 36] PTP package (36)
Production Example, except that 8 g of dihydrocodeine phosphate was changed to 100 g of etenzamide (trade name etenzamide, manufactured by API Corporation), macrogol 6000 was changed to 292 g, corn starch was changed to 243 g, and lactose hydrate was changed to 17.8 g. In the same manner as in 2, a PTP package is obtained.

[Production Example 37] PTP package (37)
A PTP package is obtained in the same manner as in Production Example 36 except that Macrogol 6000 is changed to hydrogenated oil (product of Kawaken Fine Chemicals: trade name K-3 wax-200).

[Test Example 31] Examination of interaction (24)
Loxoprofen sodium hydrate (trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.5 g and 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] phenyl} propanoic acid monohydrochloride 0.5 g of salt (manufactured by Daiichi Sankyo Propharma: trade name: Japanese Pharmacopoeia Setraxate hydrochloride) was mixed, placed in a glass bottle (3K standard bottle) (Comparative Example 9), and stored at 60 ° C. Immediately after the start of storage, the state of the mixture after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 31.

  As is apparent from Table 31, the loxoprofen sodium hydrate and 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] -phenyl} propanoic acid monohydrochloride were stored and mixed. As a result of the interaction, the mixture turned discolored 1 day after the start of storage and changed to a solidified state.

[Production Example 38] SP package (general cold medicine) containing granules containing loxoprofen sodium hydrate and an interactive component
In accordance with the method described in Production Example 2, an SP package is produced using granules containing the following components in 3 packets (daily dose).
Loxoprofen sodium hydrate 204.3mg
Clemastine fumarate 1.34 mg (1 mg as clemastine)
Bromhexine hydrochloride 12mg
dl-Methylephedrine hydrochloride 60mg
Dihydrocodeine phosphate 24mg
Thiamine nitrate 25mg
Riboflavin 12mg
Aminoalkyl methacrylate copolymer RS 96mg
Erythritol 973.5mg
Trehalose 590.2mg
Crystalline cellulose 300mg
Pullulan 184mg
Croscarmellose sodium 40mg
Aspartame 82mg

[Test Example 32] Examination of interaction (25)
The storage stability of a solid preparation containing loxoprofen sodium hydrate and an interactive component was examined.
First, tablets containing the following components in 9 tablets (daily dose) were produced according to the method described in Production Example 5.
Loxoprofen sodium hydrate 204.3mg
d-Chlorpheniramine maleate 3.5mg
Dihydrocodeine phosphate 24mg
dl-Methylephedrine hydrochloride 60mg
Anhydrous caffeine 40mg
Guayphenesin 250mg
Hydroxypropylcellulose 50mg
Carmellose calcium 200mg
Crystalline cellulose 450mg
Lactose hydrate 1000mg
Calcium silicate 100mg
Magnesium stearate 48.2mg
Next, 5 tablets each having a mass of 270 mg per tablet were placed in a glass bottle (2K standard bottle) and stored at 40 ° C. and 75% RH for 1 month (Comparative Example 10).
On the other hand, the above 5 tablets are put in a pocket portion of a resin sheet (manufactured by Sumitomo Bakelite: trade name Sumilite VSL-4603) in which a pocket portion has been formed in advance, and then an aluminum foil for PTP (manufactured by Daiwa Chemical Industry: trade name, aluminum foil) The lid was covered with silver plain), PTP packed, and stored at 40 ° C. and 75% RH for 1 month (Example 13).
Moreover, after putting 5 said tablets into a glass bottle (2K specification bottle), and making a metal lid | cover, it preserve | saved for one month at 40 degreeC75% RH (Example 14).
Furthermore, after putting 5 tablets of the above and 1 g of synthetic zeolite (manufactured by Shin-Etsu Kasei Kogyo Co., Ltd .: trade name MS-W1506) into a glass bottle (2K standard bottle), a metal lid, and storing at 40 ° C. and 75% RH for 1 month. (Example 15).
Further, the above five tablets were packaged in an aluminum pillow with an aluminum laminate bag (manufactured by Nippon Shokubai Co., Ltd .: trade name Lami Zip AL series) and stored at 40 ° C. and 75% RH for one month (Example 16).
For Comparative Example 10 and Examples 13 to 16, the state of the tablets at the start of storage, 2 weeks later and 1 month later was evaluated. The evaluation was performed by measuring the tablet diameter and tablet thickness of each tablet at the start of storage, after 2 weeks and after storage for 1 month, and further calculating the average value of the increase rate (%). The results (average values of tablet diameter and tablet thickness increase rate per 5 tablets) are shown in Table 32.

As is apparent from Table 32, the tablets containing the loxoprofen sodium hydrate and the interactive component simply preserved, and as a result of the interaction, the tablet diameter and the tablet thickness increased, and the tablet expanded. (Comparative Example 10).
On the other hand, in the case where the tablet containing loxoprofen sodium hydrate and the interactive component was stored in an airtight manner, the tablet diameter and the tablet thickness were hardly changed, and the expansion of the tablet was suppressed.
From the above test results, it was found that when the solid preparation containing loxoprofen or a salt thereof and an interactive component was stored in an airtight manner, the solid preparation was suppressed in terms of swelling over time and was excellent in stability ( Examples 13-16).

[Production Example 39] PTP package (38)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 68.1 g, 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and corn starch (Nissho) 24.3 g of chemical product: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then sieved with a No. 18 sieve to obtain a granulated product. Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name, dihydrocodeine phosphate “Shionogi”) 8 g, carmellose calcium (manufactured by Gotoku Pharmaceutical: trade name ECG505), 81 g of lactose hydrate (manufactured by DMV: Trade name Lactose 200M) 524.6 g, Magnesium hydroxide (Kyowa Chemical Industry: trade name Kyowasui Mug) 66.7 g and Magnesium stearate (Taihei Chemical Industry: trade name Magnesium stearate (vegetable)) 8.1 g After mixing, tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 8.5 mm diameter punch to obtain a tablet having a mass of 270 mg. Next, the obtained tablet is put in a pocket portion of a resin sheet (manufactured by Sumitomo Bakelite: trade name Sumilite VSS- 1202) in which a pocket part has been molded in advance, and then an aluminum foil for PTP (manufactured by Yamato Chemical Co., Ltd .: trade name, aluminum foil silver). The lid was covered with plain fabric and PTP packaged to obtain a PTP package.

[Production Example 40] PTP package (39)
A PTP package containing tablets having the following components and amounts in 9 tablets was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Dihydrocodeine phosphate 24mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg

[Production Example 41] PTP package (40)
A PTP package containing tablets having the following components and amounts in 9 tablets was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Dihydrocodeine phosphate 24mg
Hardened oil (manufactured by Kawaken Fine Chemicals: Trade name K-3 Wax-200) 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg

[Production Example 42] PTP package (41)
A PTP package containing tablets having the following components and amounts in 9 tablets was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Dihydrocodeine phosphate 24mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Magnesium stearate 24.3mg

[Production Example 43] PTP package (42)
A PTP package containing tablets having the following ingredients and amounts in 9 tablets was produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Dihydrocodeine phosphate 24mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg

[Production Example 44] PTP package (43)
A PTP package containing tablets having the following components and amounts in 9 tablets was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Dihydrocodeine phosphate 24mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1573.9mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg

[Production Example 45] PTP package (44)
A PTP package containing tablets having the following components and amounts in 9 tablets was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
d-Chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd., trade name: D-chlorpheniramine maleate) 3.5 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1594.4mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg

[Production Example 46] PTP package (45)
A PTP package containing tablets having the following ingredients and amounts in 9 tablets was produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
d-Chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd., trade name: D-chlorpheniramine maleate) 3.5 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1594.4mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg

[Production Example 47] PTP package (46)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 1.34 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1596.6mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg

[Production Example 48] PTP package (47)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1590.4mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg

[Production Example 49] PTP package (48)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1590.4mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Magnesium stearate 24.3mg

[Production Example 50] PTP package (49)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Carbinoxamine maleate (manufactured by Kongo Chemicals: trade name carbinoxamine maleate) 7.5mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1590.4mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg

[Production Example 51] PTP package (50)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Diphenylpyraline hydrochloride (product of Kongo Chemicals: trade name diphenylpyraline hydrochloride) 4mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1593.9mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg

[Production Example 52] PTP package (51)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Diphenylpyraline hydrochloride (product of Kongo Chemicals: trade name diphenylpyraline hydrochloride) 4mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1593.9mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg

[Production Example 53] PTP package (52)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Bromhexine hydrochloride (trade name: Bromhexine hydrochloride, manufactured by Sanyo Chemical) 12 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1585.9mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg

[Production Example 54] PTP package (53)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Bromhexine hydrochloride (trade name: Bromhexine hydrochloride, manufactured by Sanyo Chemical) 12 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1585.9mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg

[Production Example 55] PTP package (54)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Bromhexine hydrochloride (trade name: Bromhexine hydrochloride, manufactured by Sanyo Chemical) 12 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1585.9mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Magnesium stearate 24.3mg

[Production Example 56] PTP package (55)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1552.9mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry Co., Ltd .: trade name anhydrous calcium hydrogen phosphate magnesium stearate 24.3mg

[Production Example 57] PTP package (56)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1552.9mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg

[Production Example 58] PTP package (57)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Ambroxol hydrochloride (product name: Ambroxol hydrochloride, manufactured by Shizuoka Caffeine Industry) 45 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1552.9mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Magnesium stearate 24.3mg

[Production Example 59] PTP package (58)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) is produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Potassium guaiacol sulfonate (trade name: Potassium guaiacol sulfonate manufactured by Yonezawa Hamari Chemical Co., Ltd.) 250mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1347.9mg
Magnesium hydroxide (manufactured by Kyowa Chemical Industry Co., Ltd .: Kyowasui Mug) 200mg
Magnesium stearate 24.3mg

[Production Example 60] PTP package (59)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) is produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Potassium guaiacol sulfonate (trade name: Potassium guaiacol sulfonate manufactured by Yonezawa Hamari Chemical Co., Ltd.) 250mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1347.9mg
Magnesium aluminate silicate (Tonda Pharmaceutical: Brand name Magnesium aluminate) 200mg
Magnesium stearate 24.3mg

[Production Example 61] PTP package (60)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) is produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Sodium benzoate caffeine (manufactured by Shizuoka Caffeine: trade name sodium benzoate caffeine) 300 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 1297.9mg
Anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry: trade name anhydrous calcium hydrogen phosphate GS-H) 200 mg
Magnesium stearate 24.3mg

[Production Example 62] PTP package (61)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) is produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Bromvaleryl urea (trade name: Japanese Pharmacopoeia Bromovaleryl Urea P) 600mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 997.9mg
Magnesium oxide (trade name: Heavy magnesium oxide manufactured by Tomita Pharmaceutical) 200mg
Magnesium stearate 24.3mg

[Production Example 63] PTP package (62)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 39.
Loxoprofen sodium hydrate 204.3mg
Acetaminophen (product name: acetaminophen manufactured by Fuji Chemicals) 900 mg
Macrogol 6000 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 697.9mg
Magnesium aluminate metasilicate (manufactured by Fuji Chemical Co., Ltd .: trade name Neusilin UFL2) 200mg
Magnesium stearate 24.3mg

[Production Example 64] PTP package (63)
A PTP package containing tablets containing the following components in 9 tablets (daily dose) was produced in the same manner as in Production Example 41.
Loxoprofen sodium hydrate 204.3mg
Ethenzamid (Product name: Ethenzamid, manufactured by API Corporation) 1000 mg
Hardened oil 87.6mg
Corn starch 72.9mg
Carmellose calcium 243mg
Lactose hydrate 597.9mg
Precipitated calcium carbonate (Sankyo Seiyaku: Product name Precipitated Carbonate CA) 200mg
Magnesium stearate 24.3mg

[Production Example 65] Bottle package (1)
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 340.5 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical: trade name: D-chlorpheniramine maleate) 5 .8 g, dl-methylephedrine hydrochloride (manufactured by Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 100.0 g, guaifenesin (manufactured by Alps Yakuhin Kogyo: trade name: Japanese Pharmacopoeia Guayphenesine) 416.7 g, anhydrous Caffeine (manufactured by Shizuoka Caffeine Industry: trade name anhydrous caffeine) 66.7 g, hydroxypropylcellulose (manufactured by Nippon Soda: trade name HPC-L) 121.5 g, carmellose calcium (product name: ECG505) 405 g, lactose hydrate (DMV: trade name: lactose 00M) 494.3 g and crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd .: trade name: Ceolas PH-101) 1917.0 g were charged into a high-speed agitating granulator (Paurek: model VG-25) and mixed, and then 230 g of purified water was added. The mixture 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). 3.87.5 g of this sized product and 182.5 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a blender (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and tablets with a mass of 270 mg were obtained. The obtained 50 tablets were put into a glass bottle (2K standard bottle) and covered with a metal lid to obtain a bottle package having a tablet occupation ratio of about 33% in the package.

[Production Example 66] Bottle Packaging (2)
Ninety tablets obtained in Production Example 65 were placed in a glass bottle (4K standard bottle) and covered with a metal lid to obtain a bottle package having a tablet occupation ratio of about 38%.

[Production Example 67] Bottle package (3)
110 tablets obtained in Production Example 65 were placed in a glass bottle (5K standard bottle) and covered with a metal lid to obtain a bottle package having a tablet occupation ratio of about 37%.

[Production Example 68] Bottle package (4)
Thirty-five tablets obtained in Test Example 31 were placed in a glass bottle (2K standard bottle) and covered with a metal lid to obtain a bottle package having a tablet occupation ratio of about 33% in the package.

[Production Example 69] Bottle package (5)
Sixty tablets obtained in Production Example 65 were put in a glass bottle (4K standard bottle), covered with a metal lid, and a bottle package having a tablet occupation ratio of about 37% was obtained.

[Production Example 70] Bottle package (6)
80 tablets obtained in Production Example 65 were placed in a glass bottle (4K standard bottle) and covered with a metal lid to obtain a bottle package having a tablet occupation ratio of about 35%.

  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 (5)

The pharmaceutical formulation which packaged the solid formulation containing the following component (A) and (B) with the package which can be airtight-preserved.
(A) Loxoprofen or a salt thereof,
(B) One or more selected from the group consisting of the following components (B-1) to (B-11) (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. ]
(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. ]
(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. ]
(B-4) Cysteine derivatives (B-5) Lysozyme or salts thereof (B-6) Codeines (B-7) Ephedrines (B-8) Dextromethorphan or salts thereof B-9) xanthine derivative (B-10) isovaleryl urea derivative, and (B-11) a compound represented by the following general formula (4) or a salt thereof

[In Formula (4), A shows a C5-C8 cycloalkylene group, Q shows a carboxyalkylphenyl group or a hydrogen atom. ]   The pharmaceutical preparation according to claim 1, wherein the solid preparation is a tablet.   The pharmaceutical preparation according to claim 1 or 2, wherein the loxoprofen or a salt thereof is loxoprofen sodium hydrate.   4. The pharmaceutical preparation according to claim 3, comprising loxoprofen sodium hydrate in an amount of 10 to 300 mg per day in terms of loxoprofen sodium anhydride.   The pharmaceutical preparation according to any one of claims 1 to 4, wherein the hermetically storable packaging is a bottle packaging, a PTP packaging, an SP packaging or a stick packaging with a stopper or a lid.