JP5844976B2 - Pharmaceutical composition containing loxoprofen or a salt thereof - Google Patents

Description

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

  Loxoprofen is a type of non-steroidal anti-inflammatory analgesic (NSAID), including rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, cervical-shoulder arm syndrome, toothache, acute upper respiratory inflammation, post-surgical / post-traumatic It is known as effective for anti-inflammatory, analgesic and antipyretic after tooth extraction (Non-Patent Document 1), and its excellent antipyretic analgesic action is expected to be incorporated into a general cold medicine.

  On the other hand, so far, in general cold medicine, in addition to antipyretic analgesic components, there are various types such as antihistamine component, expectorant component, anti-inflammatory enzyme component, antitussive component, central nervous excitable component, antiacetylcholine component, antiplasmin component, herbal medicine component A combination of these ingredients is 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. Among the above, clemastine has the following formula:

It is a compound represented by these. Of the above, carbinoxamine has the following formula:

It is a compound represented by these. Of the above, diphenylpyrine is represented by the following formula:

It is a compound represented by these. These compounds all have a diarylmethyl structure as a common skeleton, and their chemical structures are very similar to each other.

Specific examples of the expectorant component include bromhexine or a salt thereof; ambroxol or a salt thereof; a phenol derivative such as guaiacol sulfonic acid or a salt thereof, guaifenesin, cresolsulfonic acid or a salt thereof; or a carbocysteine or a salt thereof Examples thereof include cysteine derivatives such as a salt, methylcysteine or a salt thereof, and ethylcysteine or a salt thereof.
Of the above, bromhexine has the following formula:

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

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

In addition, phenol derivatives such as guaiacol sulfonic acid or a salt thereof, guaifenesin, cresol sulfonic acid or a salt thereof, or a salt thereof are components having an airway secretion promoting action or the like (Non-patent Document 8).
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 as an internal medicine for rhinitis for the purpose of relieving 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 etc. other than 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.

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.

JP 2000-143505 A JP 2001-199882 A JP 2001-172175 A JP 2008-13542 A JP 2007-314517 A

Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd. C-4790-4759 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 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. pp.232-233 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 Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd. C-2743-2749 OTC Handbook 2008-09 Academic Information Distribution Center Co., Ltd. Pages 693-694

However, it is not known at all whether or not an interaction that affects storage stability occurs between loxoprofen or a salt thereof and one or more components selected from the following 1 to 9.
Therefore, the present inventors first examined the storage stability of loxoprofen or a salt thereof and various components, and as a result, any one of loxoprofen or a salt thereof and the following components 1 to 9:

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 a salt thereof 3 including guaiacol sulfonic acid or a salt thereof, guaifenesin, cresol sulfonic acid or a salt thereof, and the like.

[In the formula (3), R ⁶ represents an alkyl group or an alkoxy group which may have a substituent, and R ⁷ represents a hydrogen atom 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 (in this specification, 1 of the components selected from 1 to 9 above) Species or more may be referred to as “interactive ingredients”.)

When mixed and stored, unexpectedly, an interaction occurs between these components, and this interaction causes changes in the state of the mixture such as wetting, solidification, and discoloration over time, which causes problems in stability. Found out that it would occur.

  Accordingly, an object of the present invention is to provide a pharmaceutical composition in which the interaction between loxoprofen or a salt thereof and the interactive component is suppressed.

  Therefore, the present inventors further studied to solve this problem, and as a result, it was possible to suppress the interaction by allowing tranexamic acid or a salt thereof to coexist in loxoprofen or a salt thereof and the interactive component. The present invention has been completed.

That is, the present invention includes the following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof (B) One or more selected from the group consisting of the following components (B-1) to (B-9) (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 an alkyl group or an alkoxy group which may have a substituent, and R ⁷ represents a hydrogen atom or a sulfo group. In addition, the phenolic hydroxyl group in Formula (3) may be etherified. ]
(B-4) Cysteine derivative (B-5) Lysozyme or salt thereof (B-6) Codeine (B-7) Ephedrine (B-8) Dextromethorphan or salt thereof B-9) A xanthine derivative (C) relates to a pharmaceutical composition containing tranexamic acid or a salt thereof.

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

  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, loxoprofen or a salt thereof is preferably contained in an amount of 0.4 to 50% by mass, more preferably 1.2 to 30% by mass, in terms of anhydrous loxoprofen sodium, based on the total mass of the pharmaceutical composition. Preferably, the content is 1.2 to 25% by mass. Among these, it is more preferable to contain 1.2-20 mass%, it is still more preferable to contain 2.4-15 mass%, and it is especially preferable to contain 2.4-12 mass%.

  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 or 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.

In the present invention, specific examples of the compound represented by the general formula (1) or a salt thereof include ebastine or a salt thereof; oxatomide or a salt thereof; carbinoxamine diphenyl disulfonate, carbinoxamine maleate Carbinoxamine such as clemastine fumarate or the like; Clemastine such as clemastine fumarate or a salt thereof; Chlorpheniramine or a salt thereof such as d-chlorpheniramine maleate or dl-chlorpheniramine maleate; Difeterol hydrochloride, diphete Dipheterol or its salt such as roll phosphate; diphenylpyraline or its salt such as diphenylpyraline hydrochloride or diphenylpyraline theocrate; diphenhydramine or its salt such as diphenhydramine hydrochloride, diphenhydramine salicylate or diphenhydramine tannate Cetirizine such as cetirizine hydrochloride or a salt thereof; fexofenadine or a salt thereof; bepotastine or a salt thereof such as bepotastine besylate; a homochlorcyclidine such as homochlorcyclidine hydrochloride or a salt thereof It is done.
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 be taken | dosed 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. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.

  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. The content is preferably 0.004 to 1% by mass, more preferably 0.004 to 0.5% by mass, and still more preferably 0.04 to 0.3% by mass based on the total mass of the product. 0.06 to 0.25% by mass is particularly preferable.

  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.

  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.

  In the present invention, the following general formula (3)

[In the formula (3), R ⁶ represents an alkyl group or an alkoxy group which may have a substituent, and R ⁷ represents a hydrogen atom 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 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, linear or branched polyhydric alcohols having 1 to 3 carbon atoms, particularly those having a phenolic hydroxyl group etherified with glycerin are preferred. When the phenolic hydroxyl group is etherified, the etherification reaction is not particularly limited.

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.
The compound represented by the general formula (3) or a salt thereof is preferably a guaiacol derivative or a salt thereof, more preferably guaiacol sulfonic acid or a salt thereof, or guaifenesin, particularly preferably potassium guaiacol sulfonate or guaifenesin.
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 600 mg, more preferably 10 to 450 mg, and particularly preferably 25 to 300 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.
In this invention, it is preferable to contain 0.2-40 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.

  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 60 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 anhydride in terms of the amount. What contains 0.04-15 mass parts is more preferable, and what contains 0.13-5 mass parts is still more preferable.

  In the present invention, the “cysteine derivative” is preferably a compound represented by the following general formula (4) or a salt thereof.

[In Formula (4), 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 above general formula (4), R ⁸ is preferably a hydrogen atom, R ⁹ is preferably a carboxyalkyl group, and particularly preferably a carboxymethyl group.

The compound represented by the general formula (4) or a salt thereof includes not only the compound represented by the general formula (4) but also a pharmaceutically acceptable salt thereof. Specific examples of the compound represented by the general formula (4) or a salt thereof include, for example, an inorganic acid salt such as a compound represented by the general formula (4), a hydrochloride of the compound represented by the general formula (4), and the like. Organic acid salt is mentioned, The hydrochloride of the compound represented by General formula (4) is more preferable.
In addition, since the compound represented by the general formula (4) has an asymmetric carbon, it has an optical isomer, but in the present invention, any optical isomer is included. It may be a mixture of various optical isomers. Among these, in the present invention, the configuration of cysteine constituting the basic skeleton according to the general formula (4) is preferably L-type.

In the general formula (4),
(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 compound represented by the general formula (4) 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.

  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.

  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, and 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.

  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 ephedrines, for example, 0.1 to 25 g (powder equivalent) of maou per day, more preferably 0.25 to 10 g (powder equivalent), particularly preferably 0 .4 to 4 g (concentration in bulk drug substance) can be included.
In this invention, it is preferable to contain 0.1-40 mass% of ephedrine with respect to pharmaceutical composition total mass, It is more preferable to contain 0.5-20 mass%, It contains 1-10 mass%. Is more preferable, and 2 to 10% by mass is particularly preferable. Moreover, when using maou as ephedrine, it is preferable to contain 1 to 98 mass% of maou with respect to the total mass of the pharmaceutical composition, more preferably 2 to 50 mass%, and more preferably 4 to 20 mass%. It is particularly 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.

  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, 1-270 mg of dextromethorphan or a salt thereof can be contained per day, more preferably 0.5-180 mg, particularly preferably 1-90 mg. 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.

  In the present invention, the “xanthine derivative” is preferably a compound represented by the following general formula (5).

[In Formula (5), 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 (5), in R ¹² , the monohydroxypropyl group is preferably a 2-hydroxypropyl group. The dihydroxypropyl group is preferably a 2,3-dihydroxypropyl group.

In the above general formula (5),
(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, those wherein R ¹² is 2,3-dihydroxypropyl group is intended to mean the diprophylline.

The compounds of the general formula (5), 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 xanthine derivative, in addition to the compound itself represented by the general formula (5), a pharmaceutically acceptable salt thereof (for example, a double salt formed (sodium benzoate caffeine (sodium benzoate and caffeine)). Indium salt), aminophylline (theophylline and ethylenediamine double salt))), compounds represented by the general formula (5) or salts thereof and water, alcohol or the like solvates. Are also included in the “xanthine derivative”, and the above-mentioned compounds (caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprofylline) also include the compound, a salt thereof, and a solvate thereof. In the present invention, one or more of these xanthine derivatives can be used.

  In the present invention, the xanthine derivative is preferably one or more selected from the group consisting of caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprofylline. In particular, the pharmaceutical composition of the present invention is used as an antipyretic analgesic or a general cold medicine. Caffeine is preferred from the standpoint of use as a etc. 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, particularly preferably 40 to 600 mg of xanthine derivative can be contained 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 content ratio of loxoprofen or a salt thereof and xanthine derivative contained in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the daily dose of each component described above. Or it is preferable that the salt contains 0.03 to 100 parts by mass, more preferably 0.08 to 27 parts by mass of xanthine derivative with respect to 1 part by mass in terms of loxoprofen sodium anhydride. What contains 2-10 mass parts is further more preferable.

  In the present invention, “tranexamic acid or a salt thereof” includes tranexamic acid itself, a pharmaceutically acceptable salt of tranexamic acid, and a solvent of tranexamic acid or a pharmaceutically acceptable salt thereof, water, alcohol, and the like. Japanese products are also included. Tranexamic acid or its salts have antiplasmin, antiallergic, and antiinflammatory effects, and tend to be associated with increased systemic fibrinolysis, sore throat, redness, and hyperemia in diseases such as tonsillitis and sore throat -Known compounds (Non-Patent Documents 17 and 18) that are used for symptoms such as swelling and sore throat in stomatitis, and also used for liver, senile pigmentation, post-inflammation pigmentation, etc. In addition to the above, commercially available products can be used. In the present invention, tranexamic acid or a salt thereof is preferably tranexamic acid (chemical name: trans-4- (Aminomethyl) cyclohexanecarboxylic acid).

The content of tranexamic acid 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, an amount that can be taken per day is 50 to 2000 mg, more preferably 70 to 750 mg, particularly preferably 400 to 750 mg in terms of free form of tranexamic acid.
In the present invention, from the viewpoint of suppressing interaction, it is preferable to contain 1 to 90% by mass of tranexamic acid or a salt thereof in terms of free form of tranexamic acid with respect to the total mass of the pharmaceutical composition, and 1 to 80% by mass. % Is more preferable, and 1 to 75% by mass is more preferable. Among these, it is preferable to contain 5-70 mass%, it is more preferable to contain 5-60 mass%, and it is especially preferable to contain 7-50 mass%.

  The content ratio of loxoprofen or a salt thereof and tranexamic acid 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 inhibitory effect of the interaction between loxoprofen and the interactive component. However, from the viewpoint of interaction suppression, loxoprofen or a salt thereof is contained in an amount of 0.1 to 25 parts by mass of tranexamic acid or a salt thereof in terms of a free form of tranexamic acid with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. What contains is preferable, What contains 0.2-15 mass parts is more preferable, What contains 0.5-10 mass parts is especially preferable.

The pharmaceutical composition of the present invention includes the following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof;
(B) One or more selected from the group consisting of the following components (B-1-1) to (B-9-1);
(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 Its salt, (B-4-1) Carbocysteine or its salt, (B-4-2) Methylcysteine or its salt, (B-4-3) Ethylcysteine or its salt, (B-5) Lysozyme or its Salt, (B-6) codeines, (B-7) ephedrines, (B-8) dextromethorphan or a salt thereof, (B-9-1) caffeine (C) tranexamic acid or a salt thereof;
A pharmaceutical composition containing
The following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof;
(B) One or more selected from the group consisting of the following components (B-1-1) to (B-9-1);
(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) Guaiacol sulfonic acid or a salt thereof, (B-3-2-1) cresol sulfonic acid or a salt thereof, (B-4-1) carbocysteine or a salt thereof, (B-5) lysozyme or a salt thereof, (B-6) ) Codeines, (B-7) ephedrines, (B-8) dextromethorphan or a salt thereof, (B-9-1) caffeine (C) tranexamic acid or a salt thereof;
Particularly preferred are pharmaceutical compositions containing

Loxoprofen is a kind of NSAID, and as with other NSAIDs, gastrointestinal disorders (gastric mucosal irritation, ulceration, etc.) are problematic, but as described in Test Example 15 below, One compound selected from the group consisting of a compound represented by (1) or a salt thereof, a compound represented by the above general formula (2) or a salt thereof, codeine, ephedrine, dextromethorphan or a salt thereof and a xanthine derivative Alternatively, the combination of two or more interactive components and tranexamic acid has an inhibitory effect on gastrointestinal disorders caused by the loxoprofen.
Therefore, the pharmaceutical composition of the present invention comprises the following (A), (B) and (C):
(A) Loxoprofen or a salt thereof;
(B) One type selected from the group consisting of the following components (B-1), (B-2), (B-6), (B-7), (B-8) and (B-9) or 2 or more types;
(B-1) Compound represented by the above general formula (1) or a salt thereof (B-2) Compound represented by the above general formula (2) or a salt thereof (B-6) Codeine (B-7) Ephedrines (B-8) dextromethorphan or a salt thereof (B-9) xanthine derivative (C) tranexamic acid or a salt thereof;
More preferably, the following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof;
(B) From the following components (B-1-1), (B-2-1-1), (B-6), (B-7), (B-8) and (B-9-1) One or more selected from the group consisting of:
(B-1-1) Chlorpheniramine or a salt thereof (B-2-1) Bromhexine or a salt thereof (B-6) Codeine (B-7) Ephedrine (B-8) Dextromethorphan or a salt thereof B-9-1) In the case of a pharmaceutical composition containing caffeine (C) tranexamic acid or a salt thereof, since the interaction between loxoprofen or a salt thereof and an interactive component is suppressed, the storage stability is improved. It is excellent and safe because it prevents gastrointestinal disorders caused by loxoprofen. Therefore, even patients with peptic ulcers that have been contraindicated for drugs containing loxoprofen in the past and patients with a history of peptic ulcers that have been carefully administered can be safely taken. It is particularly preferable because it can be used as a pharmaceutical composition for administration to a patient suffering from peptic ulcer and / or a person with a history of peptic ulcer. Furthermore, the present invention is 1 selected from the group consisting of the above components (B-1), (B-2), (B-6), (B-7), (B-8) and (B-9). Aluminoprofen, ampiroxicam, ampenac sodium, ibuprofen, indomethacin, etodolac, epilysole, oxaprozin, ketoprofen, zaltoprofen, diclofenac, sulindac, celecoxib, thiaprofen, which comprises one or more species and component (C) as active ingredients Non-steroidal properties such as acid, thiaramid, tenoxicam, tolfenamic acid, nabumetone, naproxen, piroxicam, pranoprofen, flufenamic acid, flurbiprofen, progouritacin, mefenamic acid, meloxicam, mofezolac, loxoprofen and lornoxicam and their salts Disappear Gastrointestinal disorders caused by analgesics (preferably loxoprofen or a salt thereof) (e.g., NSAID ulcer) is to provide relief or inhibitor.

The pharmaceutical composition of the present invention can be produced by, for example, a known method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations. The dosage form is not particularly limited, and may be any of solid, semi-solid, and liquid shapes, and may be a shape usually used in pharmaceuticals depending on the purpose of use and the like. it can. Specifically, for example, tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets), troches, drops, hard capsules, soft capsules, granules, fine granules, powders, pills, dry syrup Solid preparations such as suppositories, suppositories, poultices, plasters; lozenges, chewing gums, jelly agents, jelly drops, whipped agents, ointments, creams, foams, inhalers, nazar gels, etc. Semi-solid preparations; syrups, drinks, suspensions, spirits, liquids, eye drops, aerosols, sprays, sprays, and other liquid preparations, etc. It can be made into a dosage form.
In the present invention, it is preferably a solid preparation from the viewpoint of ease of administration and management of drug dosage, and is selected from the group consisting of tablets, capsules, pills, granules, powders and fine granules. A solid preparation is more preferable, and a tablet or capsule is particularly preferable.

  In the case where the pharmaceutical composition of the present invention is a solid preparation, in terms of inhibiting the interaction, loxoprofen or a salt thereof and the interactive component in the solid preparation are contained so as not to come into contact with each other. More preferably. The preparations prepared so as to be substantially in contact with each other can be easily understood by general pharmaceutical technology researchers, using appropriate formulation additives based on known methods. Can be manufactured and formulated. Specifically, as the form of the solid preparation, the following (a) to (f) can be exemplified, and these can be produced and formulated by a known method.

(I) Loxoprofen or a salt thereof, and any one of the interactive components are granulated by an appropriate method to form a granular material, and the other is not granulated. In addition, a preparation in which the granular material is further coated by an appropriate method. In addition, the tranexamic acid or its salt used by this invention may be contained in a granular material, and may be contained separately from a granular material.
(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. In addition, tranexamic acid or a salt thereof used in the present invention may be contained in any one of the granular materials, or may be contained in both granular materials, or contained separately from these granular materials. You may let them.
(C) A capsule filled with the powder or granule prepared in (i) or (b) above.
(D) Tablets obtained by tableting the granular material produced in (b) or (b) above.
(E) A multilayer tablet prepared so that loxoprofen or a salt thereof and an interactive component do not come into contact with 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. In the multilayer tablet, tranexamic acid or a salt thereof may be located in either the layer containing loxoprofen or a salt thereof or the layer containing an interactive component, or may be located separately in both layers. Furthermore, you may locate in the intermediate | middle layer of either layer.
(F) A dry-coated tablet in which either one of loxoprofen or a salt thereof and an interactive component is arranged in a core tablet and the other is arranged in an outer shell, 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. In the dry-coated tablet, tranexamic acid or a salt thereof may be located in the nuclear tablet, may be located in the outer shell, or may be separately located in either the nuclear tablet or the outer shell.
The above-mentioned solid preparation may be coated with sugar coating, film coating or the like by a known method.

  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.

  In the pharmaceutical composition of the present invention, as a pharmaceutical ingredient, loxoprofen or a salt thereof, an interactive ingredient, and a drug other than tranexamic acid or a salt thereof such as an antipyretic analgesic, an antihistamine, an antitussive, noscapine, a bronchodilator, It may contain one or more selected from the group consisting of expectorants, hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosal protective agents, antacids, anticholinergics, herbal medicines, Kampo prescriptions, etc. Good.

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

  Antihistamines include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, 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 the hypnotic sedative include allyl isopropyl acetyl urea and bromvalerylurea.
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 nitrification) , Dicetiamine hydrochloride, cetothiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisivethiamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate , Riboflavin butyrate, sodium riboflavin phosphate, panthenol, panthetin, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, ascorb Sodium binate, calcium ascorbate, hesperidin, etc.).

  Examples of the anti-inflammatory agent include glycyrrhizic acid and derivatives thereof and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, proctase, pronase, bromelain and the like.

Examples of the gastric mucosa protective agent include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride and the like.
Antacids include aminoacetic acid, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, magnesium alumina hydroxide, aluminum hydroxide gel, dry hydroxide Aluminum gel, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide, magnesium hydroxide / sulfuric acid Co-precipitation product of aluminum potassium, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium metasilicate magnesium aluminate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, bandit bone, stone decision, Rei, and the like.

  Anticholinergics include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipidium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl-1- Hyoscyamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodide isopropamide, iodide diphenylpiperidinomethyldioxolane, funnel extract, funnel root, funnel root total Examples include alkaloid citrate.

  Herbal medicines include Akamegashiwa (red buds), Asenyaku (Asen Yaku), Inyo-kaku (Ryokan), Fennel (Yongxiang), Engosaku (Yancho), Ogon (Yellow), Ousei (Yellow), Oubak (Yellow), Spruce (Cherry bark), auren (yellow ream), onji (distant), gadgets (garbage), valerian grass (kashikoshi), chamomile, caronin (karojin), kyokyo (kikyo), kyonin (kyojin), kokushi (枸杞) Child), Kukoyo (Kashiwaha), Keigai (Kashiwa), Keihi (Katsuhashi), Ketsumeishi (Kemeko), Gentiana, Gennoshouko (current evidence), Koubushi (Katsukiko), Gooh (oxen yellow), Goshi (Gomiko), Saishin ( Spicy, Salamander, Zion, Zipoppi, Peonies, Shako, Shajin, Shazenshi, Shazenso, Car Grass), animal gall (including yutan (bear gall)), gyoza (ginger), giraffe (earth dragon), shin ii (spicy potato), sexan (stone urn), senega, senkyu (river cucumber), zenko (maehu) ), Sembli (Senri), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Daiseng), Chiksetsu carrot (Bamboo ginseng), Clove (Chiko), Chimpi (Chen), Touki ( Toko (Togyo), Nantenjitsu (Nan Tenji), Carrot (Ginseng), Baimo (Scarlet mother), Bacmondou (Wheat Gate Winter), Hange (Halfsummer), Bankouka (Banka Flower), Hampi (Antinas) ), Juniper (white bean), juniper jutsu (white birch), bukuryu (pepper), button pi (peony skin), rotsum (deer moth) and the like, and extracts thereof (extract, tincture, dry extract, etc.) and the like.

  Herbal formulas include Keishito (Keishaeyu), Kousosan (Kousosan), Psychokeito (Shibako Keiedo), Shosai Koto (Koshisaifuto), Bakumondou (Bakumon Fuyuto), Hangekou Bokuto (Hankatsu Koboku-yu).

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

  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 preferably 0.05 to 35 parts by weight, and 0.15 to 17 parts by weight with respect to 1 part by weight of loxoprofen or a salt thereof. Part is more preferred.
Moreover, 0.001-1 mass part is preferable with respect to 1 mass part of pharmaceutical composition of this invention, and 0.004-0.4 mass part is more preferable.

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

The forming member of the container is not particularly limited, and examples thereof include paper, glass, a resin or a resin film, or a member such as a metal or metal film. It may be a thing. Moreover, it is preferable that moisture permeation prevention processing is performed about the member which has moisture permeability, such as paper.
The container may be transparent, translucent, or opaque.

  The method for storing the pharmaceutical composition and the desiccant of the present invention in a container is not particularly limited, and both can be achieved by arranging them by appropriate means such as charging into the container.

  For example, when the container is a bottle, the desiccant (preferably, a columnar shape (tablet shape)) is placed in the bottle, or stored in the back side (inner cap) of the bottle lid, and stored in the container. This can be achieved by storing the pharmaceutical composition in a bottle or the like. When stored in a bottle, the pharmaceutical composition of the present invention is preferably a solid preparation.

  Further, when the container is a bag, it can be achieved by storing the desiccant (preferably, a plate-like or bag-like sheet type) and the pharmaceutical composition of the present invention in the bag. When stored in the bag, the pharmaceutical composition of the present invention is preferably a solid preparation.

  Further, the pharmaceutical composition of the present invention may be once packaged by SP packaging, PTP packaging or a bag, and then the packaged pharmaceutical composition and desiccant may be enclosed in a bag. More specifically, the form which carries out pillow packaging, combining the pharmaceutical composition which carried out SP packaging or PTP packaging, and a plate-shaped or bag-shaped sheet type desiccant etc. is mentioned. Further, the pillow packaging form may be stored in a box or the like. When the pharmaceutical composition is once packaged by SP packaging, PTP packaging or a bag, the pharmaceutical composition of the present invention is preferably a solid preparation.

  Since the pharmaceutical composition of the present invention contains loxoprofen or a salt thereof, which is a kind of NSAID, and tranexamic acid having an anti-inflammatory action, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, Neuralgia, low back pain, muscle pain, shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain, menstrual pain, pain relief, chills, antipyretic fever, cold symptoms (sore pain, chills, It has effects or effects such as relief of fever, headache, joint pain, muscle pain) and is useful as a general cold medicine (cold medicine) or antipyretic analgesic.

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
[Test Example 1] Examination of interaction between loxoprofen sodium hydrate and chlorpheniramine maleate Samples 1-A to 1-B shown below were each prepared and stored at 60 ° C for 1 week. The state of the mixture in the sample after 3 days and 1 week later was evaluated to confirm the presence or absence of interaction. The results are shown in Table 1.

[Sample 1-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg and d-chlorpheniramine maleate (manufactured by Kongo Chemicals: trade name: D-chlorpheniramine maleate) 3 .5 mg was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 1-A.
[Sample 1-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-chlorpheniramine maleate) 3 5 mg and 750 mg of tranexamic acid (Daiichi Sankyo Propharma, trade name: Japanese Pharmacopoeia, tranexamic acid) were mixed to obtain a mixture, and placed in a glass bottle (3K standard bottle) to obtain Sample 1-B.

From the test results shown in Table 1, it was found that in a mixture in which only loxoprofen sodium hydrate and d-chlorpheniramine maleate were mixed, an interaction occurred and the mixture solidified.
On the other hand, in a mixture prepared by adding tranexamic acid to loxoprofen sodium hydrate and d-chlorpheniramine maleate, the white powder state is maintained even after storage for 1 week, just after the start of storage. It has been found.
From the above test results, tranexamic acid or a salt thereof has an action of suppressing an interaction between loxoprofen or a salt thereof and a compound represented by the general formula (1) including chlorpheniramine or a salt thereof or a salt thereof. It became clear to have.

[Test Example 2] Examination of interaction between loxoprofen sodium hydrate and clemastine fumarate Samples 2-A to 2-C shown below were each stored at 60 ° C. for 1 week, immediately after the start of storage, after 1 day, The state of the mixture in the sample after 3 days and 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 2.

[Sample 2-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg and clemastine fumarate (Dite: trade name: clemastine fumarate) 1.34 mg Obtained and put into a glass bottle (3K standard bottle) to obtain Sample 2-A.
[Sample 2-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, clemastine fumarate (trade name: clemastine fumarate) 1.34 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: trade name: Japanese Pharmacopoeia Tranexamic acid (750 mg) was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 2-B.
[Sample 2-C]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, clemastine fumarate (trade name: clemastine fumarate) 1.34 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: Trade name Pharmacopeia Tranexamic acid (750 mg) was mixed to obtain a mixture, and 1 g of synthetic zeolite (product name: MS-W1506), a desiccant, glass bottle (3K standard bottle) Into Sample 2-C.

From the test results shown in Table 2, it was found that in a mixture in which only loxoprofen sodium hydrate and clemastine fumarate were mixed, an interaction occurred and the mixture became wet.
On the other hand, in the mixture of loxoprofen sodium hydrate and clemastine fumarate added with tranexamic acid, it was found that the white powder state was maintained even after storage for 1 week, just after the start of storage. .
From the above test results, tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and the compound represented by the general formula (1) including clemastine or a salt thereof or the salt thereof. Became clear.

[Test Example 3] Examination of interaction between loxoprofen sodium hydrate and carbinoxamine maleate Samples 3-A to 3-B shown below were each stored for 1 week at 60 ° C. The state of the mixture in the sample after 3 days and 1 week later was evaluated to confirm the presence or absence of interaction. The results are shown in Table 3.

[Sample 3-A]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg and carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) were mixed. A mixture was obtained and put into a glass bottle (3K standard bottle) together with 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) as a desiccant to obtain Sample 3-A.
[Sample 3-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, carbinoxamine maleate (trade name: carbinoxamine maleate: 7.5 mg) and tranexamic acid ( Daiichi Sankyo Propharma Co., Ltd .: Brand name: Japanese Pharmacopoeia Tranexamic acid (750 mg) is mixed to obtain a mixture, and a glass bottle (3K standard) with 1 g of synthetic zeolite (made by Shin-Koshi Chemical Co., Ltd .: trade name MS-W1506) as a desiccant. Sample 3-B was obtained.

From the test results shown in Table 3, it was found that in a mixture in which only loxoprofen sodium hydrate and carbinoxamine maleate were mixed, an interaction occurred and the mixture solidified and then changed color.
On the other hand, in a mixture of loxoprofen sodium hydrate and carbinoxamine maleate added with tranexamic acid, the white powder state can be maintained even after storage for 1 week, just after the start of storage. found.
From the above test results, tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and the compound represented by the general formula (1) including the carbinoxamine or a salt thereof or the salt thereof. Became clear.

[Test Example 4] Examination of interaction between loxoprofen sodium hydrate and diphenylpyraline hydrochloride Samples 4-A to 4-B shown below were each stored at 60 ° C for 1 week, immediately after the start of storage, after 1 day, The state of the mixture in the sample after 3 days and 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 4.

[Sample 4-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg and diphenylpyraline hydrochloride (manufactured by Kongo Chemical Co., Ltd .: trade name: diphenylpyraline hydrochloride) were mixed to obtain a mixture, Sample 4-A was obtained in a glass bottle (3K standard bottle).
[Sample 4-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, diphenylpyraline hydrochloride (product of Kongo Chemicals: trade name: diphenylpyraline hydrochloride) and tranexamic acid (Daiichi Sankyo) Propharma: Trade name: Japanese Pharmacopoeia Tranexamic acid (750 mg) was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 4-B.

From the test results shown in Table 4, it was found that in a mixture in which only loxoprofen sodium hydrate and diphenylpyraline hydrochloride were mixed, an interaction occurred and the mixture became wet and then discolored.
On the other hand, in the mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochloride added with tranexamic acid, it was found that the white powder state was maintained even after storage for 1 week, just after the start of storage. .
From the above test results, tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and the compound represented by the general formula (1) including diphenylpyraline or a salt thereof or the salt thereof. It became clear.

[Test Example 5] Examination of interaction between loxoprofen sodium hydrate and bromhexine hydrochloride Each of Samples 5-A to 5-B shown below was stored at 60 ° C. for 1 week after preparation, immediately after the start of storage, 1 day later, The state of the mixture in the sample after 1 day and after 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 5.

[Sample 5-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg and bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) were mixed to obtain a mixture, Sample 5-A was obtained in a glass bottle (3K standard bottle).
[Sample 5-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, Bromohexine hydrochloride (trade name: Bromohexine hydrochloride: 12 mg) and Tranexamic acid (Daiichi Sankyo) Propharma: Trade name: Japanese Pharmacopoeia Tranexamic acid (750 mg) was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 5-B.

From the test results shown in Table 5, it was found that in a mixture in which only loxoprofen sodium hydrate and bromohexine hydrochloride were mixed, an interaction occurred and the mixture solidified and then discolored.
On the other hand, it was found that in the mixture of loxoprofen sodium hydrate and bromhexine hydrochloride added with tranexamic acid, the white powder state was maintained even after storage for 1 week, just after the start of storage.
From the above test results, tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and the compound represented by the general formula (2) including bromhexine or a salt thereof or the salt thereof. Became clear.

[Test Example 6] Examination of interaction between loxoprofen sodium hydrate and ambroxol hydrochloride Samples 6-A to 6-C shown below were each prepared and stored at 60 ° C for 1 week, immediately after the start of storage, 1 day later The state of the mixture in the sample after 3 days and 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 6.

[Sample 6-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg and Ambroxol hydrochloride (Shizuoka Caffeine Industry: trade name: Ambroxol hydrochloride) 45 mg were mixed. Thus, a mixture was obtained and placed in a glass bottle (3K standard bottle) to obtain Sample 6-A.
[Sample 6-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: ambroxol hydrochloride) 45 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: trade name: Japanese Pharmacopoeia Tranexamic acid) 750 mg was mixed to obtain a mixture, which was put into a glass bottle (3K standard bottle) to obtain Sample 6-B.
[Sample 6-C]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: ambroxol hydrochloride) 45 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: trade name: Japanese Pharmacopoeia, tranexamic acid) 750 mg was mixed to obtain a mixture. Sample 6-C was placed in a standard bottle.

From the test results shown in Table 6, it was found that in a mixture in which only loxoprofen sodium hydrate and ambroxol hydrochloride were mixed, an interaction occurred and the mixture was strongly wetted and then changed in color.
On the other hand, in the mixture of loxoprofen sodium hydrate and ambroxol hydrochloride added with tranexamic acid, it was found that the white powder state was maintained even after storage for 1 week, just after the start of storage. did.
From the above test results, tranexamic acid or a salt thereof has an action of suppressing an interaction between loxoprofen or a salt thereof and a compound represented by the general formula (2) including ambroxol or a salt thereof or a salt thereof. It became clear to have.

[Test Example 7] Examination of interaction between loxoprofen sodium hydrate and potassium guaiacol sulfonate Samples 7-A to 7-C shown below were each prepared and stored at 60 ° C for 1 week, immediately after the start of storage, 1 day later, The state of the mixture in the sample after 3 days and 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 7.

[Sample 7-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg and potassium guaiacol sulfonate (product name: Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name, guaiacol potassium sulfonate) 250mg A mixture was obtained and placed in a glass bottle (3K standard bottle) to obtain Sample 7-A.
[Sample 7-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, potassium guaiacol sulfonate (trade name: Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: potassium guaiacol sulfonate) and tranexamic acid ( 750 mg manufactured by Daiichi Sankyo Propharma Co., Ltd. (trade name: Japanese Pharmacopoeia Tranexamic acid) was mixed to obtain a mixture, which was placed in a glass bottle (3K standard bottle) to obtain Sample 7-B.
[Sample 7-C]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, potassium guaiacol sulfonate (trade name: Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name: potassium guaiacol sulfonate) and tranexamic acid ( Daiichi Sankyo Propharma Co., Ltd .: Brand name: Japanese Pharmacopoeia, Tranexamic acid (750 mg) was mixed to obtain a mixture. Sample 7-C was obtained.

From the test results shown in Table 7, it was found that in a mixture in which only loxoprofen sodium hydrate and potassium guaiacol sulfonate were mixed, an interaction occurred and the mixture became wet.
On the other hand, in the mixture of loxoprofen sodium hydrate and potassium guaiacol sulfonate added with tranexamic acid, it was found that the white powder state was maintained even after storage for 1 week, just after the start of storage. .
From the above test results, tranexamic acid or a salt thereof has an action of suppressing an interaction between loxoprofen or a salt thereof and a compound represented by the general formula (3) including a guaiacol sulfonic acid or a salt thereof or a salt thereof. It became clear to have.

[Test Example 8] Examination of interaction between loxoprofen sodium hydrate and guaifenesin Samples 8-A to 8-C shown below were each stored at 40 ° C for 1 week, immediately after the start of storage, 1 day, 3 days later, and The state of the mixture in the sample after 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 8.

[Sample 8-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 450 mg and guaifenesin (Alps Yakuhin Kogyo: trade name: Guaifenesin) 550 mg were mixed to obtain a mixture, and a glass bottle (3K standard bottle) And sample 8-A was obtained.
[Sample 8-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 450 mg, Guaifenesin (Alps Yakuhin Kogyo: trade name: Guaifenesin) 550 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: trade name) Japanese Pharmacopoeia tranexamic acid (4000 mg) was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 8-B.
[Sample 8-C]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 450 mg, Guaifenesin (Alps Yakuhin Kogyo: trade name: Guaifenesin) 550 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: trade name) Japanese Pharmacopoeia tranexamic acid (4000 mg) is mixed to obtain a mixture, and put into a glass bottle (3K standard bottle) together with 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) as a desiccant, and sample 8-C Got.

From the test results shown in Table 8, it was found that in a mixture in which only loxoprofen sodium hydrate and guaifenesin were mixed, interaction occurred and the mixture solidified.
On the other hand, it was found that in a mixture of loxoprofen sodium hydrate and guaifenesin added with tranexamic acid, a white powder state was maintained even after storage for 1 week, just after the start of storage.
From the above test results, it is clear that tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and the compound represented by the general formula (3) including guaifenesin or a salt thereof. became.

[Test Example 9] Examination of interaction between loxoprofen sodium hydrate and carbocysteine Samples 9-A to 9-B shown below were each prepared and stored at 60 ° C. for 1 week, immediately after the start of storage, 1 day later, 3 days later And the state of the mixture in the sample after 1 week was evaluated, and the presence or absence of interaction was confirmed. The results are shown in Table 9.

[Sample 9-A]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg and carbocysteine (product of Myonaka Mining Co., Ltd .: trade name: carbocysteine) were mixed to obtain a mixture. Into a 3K standard bottle) to obtain Sample 9-A.
[Sample 9-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, Carbocysteine (Myonaka Mining: trade name: Carbocysteine) 1500 mg and Tranexamic acid (Daiichi Sankyo Propharma) Product: 750 mg of Japanese Pharmacopoeia Tranexamic acid) is mixed to obtain a mixture, and put into a glass bottle (3K standard bottle) with 1 g of synthetic zeolite (made by Shin-Koshisei Kogyo: trade name MS-W1506) as a desiccant, Sample 9-B was obtained.

From the test results shown in Table 9, it was found that in a mixture in which only loxoprofen sodium hydrate and carbocysteine were mixed, an interaction occurred, the mixture solidified, and then discolored.
On the other hand, it was found that a mixture of loxoprofen sodium hydrate and carbocysteine added with tranexamic acid was kept in a white powder state even after storage for 1 week, just after the start of storage.
From the above test results, it was revealed that tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and a cysteine derivative.

[Test Example 10] Examination of interaction between loxoprofen sodium hydrate and lysozyme hydrochloride Samples 10-A to 10-C shown below were each prepared and stored at 60 ° C for 1 week, immediately after the start of storage, 1 day later, The state of the mixture in the sample after 1 day and after 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 10.

[Sample 10-A]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg and lysozyme hydrochloride (manufactured by Eisai: trade name, lysozyme chloride) 90 mg were mixed to obtain a mixture, and a glass bottle (3K) Into a standard bottle) to obtain Sample 10-A.
[Sample 10-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg, lysozyme hydrochloride (product of Eisai: trade name: lysozyme chloride) 90 mg and tranexamic acid (Daiichi Sankyo Propharma) : Brand name Japanese Pharmacopoeia Tranexamic acid (750 mg) was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 10-B.
[Sample 10-C]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg, lysozyme hydrochloride (product of Eisai: trade name: lysozyme chloride) 90 mg and tranexamic acid (Daiichi Sankyo Propharma) : Product name: Japanese Pharmacopoeia Tranexamic acid (750 mg) is mixed to obtain a mixture, and put into a glass bottle (3K standard bottle) together with 1 g of synthetic zeolite (product name: MS-W1506) as a desiccant. 10-C was obtained.

From the test results shown in Table 10, it was found that in a mixture in which only loxoprofen sodium hydrate and lysozyme hydrochloride were mixed, an interaction occurred and the mixture became wet and then solidified.
On the other hand, it was found that in a mixture of loxoprofen sodium hydrate and lysozyme hydrochloride added with tranexamic acid and mixed, the white powder state was maintained even after storage for 1 week, just after the start of storage.
From the above test results, it was revealed that tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and lysozyme or a salt thereof.

[Test Example 11] Examination of interaction between loxoprofen sodium hydrate and dihydrocodeine phosphate Samples 11-A to 11-C shown below were each stored at 60 ° C for 1 week, immediately after the start of storage, 1 day later, The state of the mixture in the sample after 3 days and 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 11.

[Sample 11-A]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 990 mg and dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”) were mixed to prepare a mixture. Obtained and put into a glass bottle (3K standard bottle) to obtain Sample 11-A.
[Sample 11-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 990 mg, dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi”) and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd. (trade name: Japanese Pharmacopoeia, Tranexamic acid) (750 mg) was mixed to obtain a mixture, which was placed in a glass bottle (3K standard bottle) to obtain Sample 11-B.
[Sample 11-C]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 990 mg, dihydrocodeine phosphate (manufactured by Shionogi Pharmaceutical: trade name: dihydrocodeine phosphate “Shionogi”) and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: Trade name Pharmacopeia Tranexamic acid (750 mg) was mixed to obtain a mixture, and 1 g of synthetic zeolite (product name: MS-W1506), a desiccant, glass bottle (3K standard bottle) And sample 11-C was obtained.

From the test results shown in Table 11, it was found that in a mixture in which only loxoprofen sodium hydrate and dihydrocodeine phosphate were mixed, an interaction occurred and the mixture solidified and then changed color.
On the other hand, in the mixture of loxoprofen sodium hydrate and dihydrocodeine phosphate added with tranexamic acid, it was found that the white powder state was maintained even after storage for 1 week, just after the start of storage. .
From the above test results, it was revealed that tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and codeines.

[Test Example 12] Examination of interaction between loxoprofen sodium hydrate and dl-methylephedrine hydrochloride Samples 12-A to 12-C shown below were each prepared and stored at 40 ° C. and 75% RH for 6 days, and then storage was started. Immediately after that, the state of the mixture in the sample after 1 day, 2 days and 6 days was evaluated to confirm the presence or absence of interaction. The results are shown in Table 12.

[Sample 12-A]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 900 mg and dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 100 mg Mixing was performed to obtain a mixture, which was then placed in a glass bottle (3K standard bottle) to obtain Sample 12-A.
[Sample 12-B]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 900 mg, dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 100 mg and 2000 mg of tranexamic acid (manufactured by Daiichi Sankyo Propharma Co., Ltd .: trade name Japanese Pharmacopoeia, tranexamic acid) was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 12-B.
[Sample 12-C]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 900 mg, dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 100 mg and 2000 mg of tranexamic acid (Daiichi Sankyo Propharma, trade name: Japanese Pharmacopoeia, Tranexamic acid) was mixed to obtain a mixture, and a glass bottle with 1 g of synthetic zeolite (trade name MS-W1506) as a desiccant. (3K standard bottle) to obtain Sample 12-C.

From the test results shown in Table 12, it was found that in a mixture in which only loxoprofen sodium hydrate and dl-methylephedrine hydrochloride were mixed, an interaction occurred and the mixture became wet.
On the other hand, in a mixture of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride added with tranexamic acid, the white powder state can be maintained even after 6 days of storage, just after the start of storage. found.
From the above test results, it was revealed that tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and ephedrines.

[Test Example 13] Examination of interaction between loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate Samples 13-A to 13-C shown below were each stored at 60 ° C. for 1 week and stored. Immediately after the start, the state of the mixture in the sample after 1 day, 3 days and 1 week was evaluated, and the presence or absence of interaction was confirmed. The results are shown in Table 13.

[Sample 13-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 810mg and dextromethorphan hydrobromide hydrate (Daiichi Fine Chemical: trade name dextromethorphan HBR) 190mg Thus, a mixture was obtained and placed in a glass bottle (3K standard bottle) to obtain Sample 13-A.
[Sample 13-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 810 mg, dextromethorphan hydrobromide hydrate (Daiichi Fine Chemical: trade name dextromethorphan HBR) 190 mg and tranexam 1000 mg of acid (manufactured by Daiichi Sankyo Propharma Co., Ltd .: trade name, Japanese Pharmacopoeia, Tranexamic acid) was mixed to obtain a mixture, which was placed in a glass bottle (3K standard bottle) to obtain Sample 13-B.
[Sample 13-C]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 810 mg, dextromethorphan hydrobromide hydrate (Daiichi Fine Chemical: trade name dextromethorphan HBR) 190 mg and tranexam 1000 mg of acid (Daiichi Sankyo Propharma Co., Ltd., trade name: Japanese Pharmacopoeia, tranexamic acid) was mixed to obtain a mixture, and a glass bottle with 1 g of synthetic zeolite (trade name MS-W1506) as a desiccant. 3K standard bottle) to obtain Sample 13-C.

From the test results shown in Table 13, it was found that in a mixture in which only loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate were mixed, an interaction occurred and the mixture became wet.
On the other hand, in the mixture of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate added with tranexamic acid, the white powder remains in the same state after storage for 1 week, just after the start of storage. It turned out to be dripping.
From the above test results, it was revealed that tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and dextromethorphan or a salt thereof.

[Test Example 14] Examination of interaction between loxoprofen sodium hydrate and anhydrous caffeine Samples 14-A to 14-C shown below were each prepared and stored at 40 ° C. and 75% RH for 1 week. The state of the mixture in the sample after 3 days and 1 week later was evaluated to confirm the presence or absence of interaction. The results are shown in Table 14.

[Sample 14-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg and anhydrous caffeine (Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 250 mg were mixed to obtain a mixture. Obtained and put in a glass bottle (3K standard bottle) to obtain Sample 14-A.
[Sample 14-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg, anhydrous caffeine (Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 250 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: trade name: Japanese Pharmacopoeia Tranexamic acid (750 mg) was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 14-B.
[Sample 14-C]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg, anhydrous caffeine (Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 250 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: Trade name Pharmacopeia Tranexamic acid (750 mg) was mixed to obtain a mixture, and 1 g of synthetic zeolite (product name: MS-W1506), a desiccant, glass bottle (3K standard bottle) To obtain Sample 14-C.

From the test results shown in Table 14, it was found that in a mixture in which only loxoprofen sodium hydrate and anhydrous caffeine were mixed, an interaction occurred and the mixture solidified.
On the other hand, it was found that a mixture of loxoprofen sodium hydrate and anhydrous caffeine added with tranexamic acid was kept in a white powder state even after storage for 1 week, just after the start of storage.
From the above test results, it was revealed that tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and a xanthine derivative.

[Test Example 15] Examination of inhibitory action of loxoprofen-induced gastrointestinal disorder by combination of interactive component and tranexamic acid Test Example 15-1 Examination of inhibitory action of loxoprofen-induced gastrointestinal disorder by tranexamic acid Wistar rats ( (Std: Wistar / ST, male, 8 weeks old), the test drug administration group and the control group were each tested as 6 animals per group. Rats were fasted at least 16 hours before the start of the study. Water intake was free up to 1 hour before the start of the test, and then water was stopped.
As a test drug, tranexamic acid (TXA) was suspended in a 0.5% methylcellulose (MC) solution and orally administered in predetermined amounts (100, 400 mg / 5 mL / kg body weight). In the control group, only the solvent (0.5% MC solution) was orally administered in the same volume (5 mL / kg body weight).
One hour after administration of the test drug or solvent, loxoprofen sodium hydrate 100 mg / 2 mL physiological saline / kg body weight was orally administered 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 gastric mucosal damage was carried out by measuring the length (mm) of individual lesions (erosion) that occurred in the glandular stomach area under a stereomicroscope after incising the stomach along the large fistula. The total length of damage per animal was taken as the ulcer index (UI), and the ulcer index (mean ± standard error) was calculated for each group administered with the test drug and the control group. Moreover, according to the following formula | equation, when the average value of the ulcer index | exponent of a control group was set to 100%, the ulcer suppression rate (%) by the test drug was computed. The results are shown in Table 15.

Ulcer inhibition rate (%) = (average value of ulcer index in control group−average value of ulcer index in test drug administration group) / average value of ulcer index in control group × 100

Test Example 15-2 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory Effect by Combination of Chlorpheniramine Maleate and Tranexamic Acid As test drugs, tranexamic acid (TXA) and d-chlorpheniramine maleate (CM ) Was suspended in a 0.5% methylcellulose (MC) solution, and a predetermined amount ((TXA 400 mg + CM 3 mg) / 5 mL / kg body weight) was orally administered to conduct a test in the same manner as in Test Example 15-1. . The results are shown in Table 16.

Test Example 15-3 Examination of Loxoprofen-induced Gastrointestinal Disorder Inhibitory Effect by Combination of Bromhexine Hydrochloride and Tranexamic Acid As test drugs, tranexamic acid (TXA) and bromhexine hydrochloride (BH) were added in 0.5% methylcellulose (B) MC) was suspended in a solution, and a predetermined amount ((TXA 400 mg + BH 4 mg) / 5 mL / kg body weight) was orally administered.
Gastric mucosal injury was induced by oral administration of loxoprofen sodium hydrate 120 mg / 2 mL saline / kg body weight.
Except for the above, the test was performed as in Test Example 15-1. The results are shown in Table 17.

Test Example 15-4 Examination of Loxoprofen-induced Gastrointestinal Disorder Inhibitory Effect by Combination of Dihydrocodeine Phosphate and Tranexamic Acid 0.5% of tranexamic acid (TXA) and dihydrocodeine phosphate (DP) as test drugs The test was carried out in the same manner as in Test Example 15-3 by orally administering a predetermined amount ((TXA 400 mg + DP 24 mg) / 5 mL / kg body weight) using a suspension in a methylcellulose (MC) solution. The results are shown in Table 18.

Test Example 15-5 Examination of inhibitory action of loxoprofen-induced gastrointestinal tract disorder by combination of dl-methylephedrine hydrochloride and tranexamic acid As test drugs, tranexamic acid (TXA) and dl-methylephedrine hydrochloride (ME) were used. The test was carried out in the same manner as in Test Example 15-3 by using a suspension in a 0.5% methylcellulose (MC) solution and orally administering a predetermined amount ((TXA 400 mg + ME 60 mg) / 5 mL / kg body weight). The results are shown in Table 19.

Test Example 15-6 Examination of Loxoprofen-induced Gastrointestinal Disorder Inhibition by Combination of Dextromethorphan Hydrobromide Hydrate and Tranexamic Acid As test drugs, tranexamic acid (TXA) and dextromethorphan hydrobromide Using a suspension of acid salt hydrate (DH) in a 0.5% methylcellulose (MC) solution and orally administering a predetermined amount ((TXA 400 mg + DH 48 mg) / 5 mL / kg body weight), Test Example 15-3 and A similar test was conducted. The results are shown in Table 20.

Test Example 15-7 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory Effect by Combination of Anhydrous Caffeine and Tranexamic Acid As test drugs, tranexamic acid (TXA) and anhydrous caffeine (Caf) were added with 0.5% methylcellulose ( MC) The test was conducted in the same manner as in Test Example 15-1 by orally administering a predetermined amount ((TXA 400 mg + Caf 100 mg) / 5 mL / kg body weight) using the suspension in the solution. The results are shown in Table 21.

From the test results shown in Tables 15 to 21, 45.9% of ulcer suppressive action was observed with loxoprofen-induced gastrointestinal tract disorders when tranexamic acid alone was administered (400 mg / kg).
On the other hand, the combination of tranexamic acid and d-chlorpheniramine maleate (400 mg / kg + 3 mg / kg) was 67.9%, and the combination of tranexamic acid and bromhexine hydrochloride (400 mg / kg + 4 mg / kg) was 54.4%. The combination of tranexamic acid and dihydrocodeine phosphate (400 mg / kg + 24 mg / kg) is 98.0%, the combination of tranexamic acid and dl-methylephedrine hydrochloride (400 mg / kg + 60 mg / kg) is 63.4%, tranexam 81.4% for the combination of acid and dextromethorphan hydrobromide hydrate (400mg / kg + 48mg / kg), 72.9% for the combination of tranexamic acid and caffeine anhydride (400mg / kg + 100mg / kg) Antiulcer action was observed.

  From the above test results, the compound represented by the general formula (1) including chlorpheniramine or a salt thereof or a salt thereof, the compound represented by the general formula (2) including bromohexine or the salt thereof, codeine , Ephedrines, dextromethorphan or a salt thereof, and a combination of one or more interactive components selected from the group consisting of xanthine derivatives and tranexamic acid are excellent for gastrointestinal disorders caused by loxoprofen It became clear that it has an inhibitory action. Moreover, it was thought that the same inhibitory effect was shown also with respect to other NSAID causing a digestive tract disorder like loxoprofen.

[Example 1]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
d-Chlorpheniramine maleate 3.5mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1132mg
Magnesium stearate 24.3mg

[Example 2]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Cremastine fumarate 1.34mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1134.16mg
Magnesium stearate 24.3mg

[Example 3]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Carbinoxamine maleate 7.5mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1128mg
Magnesium stearate 24.3mg

[Example 4]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Diphenylpyraline hydrochloride 4mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1131.5mg
Magnesium stearate 24.3mg

[Example 5]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Ebastine 10mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1125.5mg
Magnesium stearate 24.3mg

[Example 6]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Oxatimide 60mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1075.5mg
Magnesium stearate 24.3mg

[Example 7]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Dipheterol hydrochloride 90mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1045.5mg
Magnesium stearate 24.3mg

[Example 8]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Diphenhydramine hydrochloride 75mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1060.5mg
Magnesium stearate 24.3mg

[Example 9]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Cetirizine hydrochloride 10mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1125.5mg
Magnesium stearate 24.3mg

[Example 10]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Fexofenadine hydrochloride 120mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1015.5mg
Magnesium stearate 24.3mg

[Example 11]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Bepotastine besylate 20mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1115.5mg
Magnesium stearate 24.3mg

[Example 12]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Homochlorocyclidine hydrochloride 60mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1075.5mg
Magnesium stearate 24.3mg

[Example 13]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Bromhexine hydrochloride 12mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1123.5mg
Magnesium stearate 24.3mg

[Example 14]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Ambroxol hydrochloride 45mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1090.5mg
Magnesium stearate 24.3mg

[Example 15]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Guayphenesin 250mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 885.5mg
Magnesium stearate 24.3mg

[Example 16]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Guayacol sulfonate potassium 250mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 885.5mg
Magnesium stearate 24.3mg

[Example 17]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Carbocysteine 750mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 385.5mg
Magnesium stearate 24.3mg

[Example 18]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Ethylcysteine hydrochloride 300mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 835.5mg
Magnesium stearate 24.3mg

[Example 19]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Lysozyme hydrochloride 60mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1075.5mg
Magnesium stearate 24.3mg

[Example 20]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Dihydrocodeine phosphate 24mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1111.5mg
Magnesium stearate 24.3mg

[Example 21]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
dl-Methylephedrine hydrochloride 60mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1075.5mg
Magnesium stearate 24.3mg

[Example 22]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Dextromethorphan hydrobromide hydrate 48mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1087.5mg
Magnesium stearate 24.3mg

[Example 23]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 204.3mg
Anhydrous caffeine 150mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 985.5mg
Magnesium stearate 24.3mg

[Example 24]
Tablets containing the following components in 6 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Tranexamic acid 750mg
Loxoprofen sodium hydrate 204.3mg
Cremastine fumarate 1.34mg
Bromhexine hydrochloride 12mg
dl-Methylephedrine hydrochloride 60mg
Dihydrocodeine phosphate 24mg
Thiamine nitrate (vitamin B1 nitrate) 25mg
Riboflavin (vitamin B2) 12mg
Trehalose 600mg
Crystalline cellulose 467.36mg
Macrogol 6000 60mg
Croscarmellose sodium 80mg
Polyvinyl alcohol 1mg
Light anhydrous silicic acid 24mg
Hardened oil 65mg
Magnesium stearate 44mg

[Example 25]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Tranexamic acid 750mg
Loxoprofen sodium hydrate 204.3mg
Diphenylpyraline hydrochloride 4mg
Dihydrocodeine phosphate 24mg
dl-Methylephedrine hydrochloride 60mg
150 mg guaiacol potassium sulfonate
Anhydrous caffeine 75mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 822.5mg
Magnesium stearate 24.3mg

[Example 26]
Tablets containing the following components in 2 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate 136.2mg
Anhydrous caffeine 75mg
Tranexamic acid 400mg
Hydroxypropylcellulose 54.8mg
Lactose hydrate 110mg
Magnesium stearate 16mg
Iron trioxide 8mg

[Example 27]
Thirty tablets obtained in Example 1 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 28]
30 tablets obtained in Example 2 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 29]
Thirty tablets obtained in Example 3 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 30]
Thirty tablets obtained in Example 4 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 31]
Thirty tablets obtained in Example 5 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 32]
Thirty tablets obtained in Example 6 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 33]
Thirty tablets obtained in Example 7 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 34]
30 tablets obtained in Example 8 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 35]
Thirty tablets obtained in Example 9 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 36]
Thirty tablets obtained in Example 10 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 37]
Thirty tablets obtained in Example 11 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 38]
Thirty tablets obtained in Example 12 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 39]
Thirty tablets obtained in Example 13 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 40]
Thirty tablets obtained in Example 14 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 41]
Thirty tablets obtained in Example 15 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 42]
Thirty tablets obtained in Example 16 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 43]
Thirty tablets obtained in Example 17 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 44]
Thirty tablets obtained in Example 18 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 45]
Thirty tablets obtained in Example 19 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 46]
Thirty tablets obtained in Example 20 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 47]
Thirty tablets obtained in Example 21 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 48]
Thirty tablets obtained in Example 22 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 49]
Thirty tablets obtained in Example 23 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 50]
Twelve tablets obtained in Example 24 were packaged in aluminum PTP.

[Example 51]
30 tablets obtained in Example 25 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 52]
Twelve tablets obtained in Example 26 were PTP packed.

  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. In the pharmaceutical composition of the present invention, the two anti-inflammatory components tranexamic acid and loxoprofen suppress inflammation that is a cause of painful symptoms and exert excellent effects on sore throat, fever, etc. It can be suitably used as (cold medicine) and can be used in the pharmaceutical industry and the like.

Claims (4)

The following components (A), (B) and (C):
(A) loxoprofen or a salt thereof (B) 1, two or more selected from the following adult divided Ranaru group
Ebastine or a salt thereof, oxatomide or a salt thereof, carbinoxamine or a salt thereof, clemastine or a salt thereof, dipheterol or a salt thereof, diphenylpyraline or a salt thereof, diphenhydramine or a salt thereof, cetirizine or a salt thereof, fexofenadine or a salt thereof, bepotastine or A pharmaceutical composition comprising a salt thereof, homochlorcyclidine or a salt thereof (C) tranexamic acid or a salt thereof. Component (B) is one or more selected from the group consisting of the following components
The pharmaceutical composition according to claim 1, which is ( B-1-2) clemastine or a salt thereof, (B-1-3) carbinoxamine or a salt thereof, or (B-1-4) diphenylpyrine or a salt thereof. object. The pharmaceutical composition according to claim 1 or 2 , which is a solid preparation. The pharmaceutical composition according to any one of claims 1 to 3 , wherein the dosage form is a tablet, powder, granule, fine granule, pill or capsule.