WO2011093498A1

WO2011093498A1 - Loxoprofen-containing pharmaceutical composition

Info

Publication number: WO2011093498A1
Application number: PCT/JP2011/051945
Authority: WO
Inventors: 俊樹薄井; 政明春原; 雅哉高宮
Original assignee: 興和株式会社
Priority date: 2010-01-29
Filing date: 2011-01-31
Publication date: 2011-08-04
Also published as: JP5809736B2; KR20120112644A; JP2012031131A; JP4787912B2; JPWO2011093498A1; JP2014169345A; CN102740854A; JP5575961B2; JP2012031147A; JP2013237710A

Abstract

Disclosed is a pharmaceutical composition containing loxoprofen or a salt thereof and codeine or the like, which has excellent storage stability. Specifically disclosed is a pharmaceutical composition which contains at least one component selected from the group consisting of codeine, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyrraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof and dextromethorphan or a salt thereof and loxoprofen or a salt thereof in such a manner that the at least one component and loxoprofen or a salt thereof are substantially not in contact with each other.

Description

Loxoprofen-containing pharmaceutical composition

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

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

Loxoprofen has been studied for combining with various drugs because of its excellent pharmacological action. Examples of the action obtained by the combination include enhancement of anti-inflammatory, analgesic and antipyretic effects by combining with caffeine, ethenamide and acetaminophen (Patent Document 1), carbinoxamine maleate, chlorpheniramine malee Of nasal congestion by combining with acid salt, ketotifen fumarate, mequitazine and epinastine hydrochloride (Patent Document 2), inhibitory effect on goblet cell hyperplasia by combining with azelastine hydrochloride and mequitazine (Patent Document 3), etc. Is mentioned.
Further, combining loxoprofen with bromhexine hydrochloride or ambroxol hydrochloride enhances the effect on cough symptoms (Patent Document 4) and suppresses goblet cell hyperplasia (Patent Document 5), and combines loxoprofen with bromhexine hydrochloride. There are known anti-inflammatory, analgesic and antipyretic effects (Patent Document 6).

It is also known that loxoprofen enhances the antihistamine action of chlorpheniramine maleate and clemastine fumarate (Patent Document 6). In this patent document, combinations of loxoprofen with various drugs are studied. In addition, formulation examples in which loxoprofen and various drugs are combined are described. Furthermore, a gastric mucosal disorder inhibiting action caused by loxoprofen by combining with an antacid and a xanthine derivative is known (Patent Document 7).

On the other hand, codeines are known to be narcotic antitussive components having an antitussive action by suppressing the function of the cough center. And based on this action, it is a drug used as a general cold medicine and antitussive expectorant as an antitussive component (Non-patent Document 2 and others).
Some combinations of loxoprofen and codeines are known. For example, the combination of loxoprofen and dihydrocodeine hydrochloride enhances the anti-inflammatory effect (Patent Document 6), and the combination of loxoprofen and codeine phosphate exhibits an airway goblet cell hyperplasia inhibitory effect (Patent Document 8). Are known.
In addition, fine granules, capsules, and tablets (Patent Documents 2, 4, 6, and 8) are known for preparations containing loxoprofen and codeine.
However, it is not known whether or not an interaction that affects the storage stability of these compounds occurs between loxoprofen or a salt thereof and codeines in the preparation.

JP-A-11-139971 JP 2001-199882 A JP 2008-169193 A JP 2001-172175 A JP 2008-13542 A JP 2000-143505 A JP 2006-52210 A JP 2007-314517 A

The present inventors first of all, codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof In order to develop a pharmaceutical composition containing at least one selected from the group consisting of dextromethorphan and salts thereof (hereinafter also referred to as codeines) and loxoprofen or a salt thereof, the storage stability thereof is examined. As a result, it has been found that when the above codeines and the like and loxoprofen or a salt thereof are mixed and stored, solidification, discoloration, etc. occur unexpectedly, resulting in problems in storage stability.
Accordingly, the object of the present invention is to provide codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof. And a stable pharmaceutical composition comprising at least one member selected from the group consisting of dextromethorphan or a salt thereof and loxoprofen or a salt thereof.

First, the present inventors have further studied to solve the above storage stability problem, and the interaction caused by the contact between the codeines and loxoprofen or a salt thereof is the cause of the storage stability problem. It revealed that.
Therefore, the present inventors have found that the above-mentioned interaction can be suppressed by incorporating the above-mentioned codeine or the like and loxoprofen or a salt thereof in the pharmaceutical composition so as not to substantially contact.

That is, the present invention relates to codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof and dextst The present invention provides a pharmaceutical composition comprising at least one member selected from the group consisting of lometrphan or a salt thereof and loxoprofen or a salt thereof so as not to substantially contact each other.

The pharmaceutical composition of the present invention has excellent storage stability.
In addition, the present inventors have found that the above codeines and the like reduce or suppress gastrointestinal disorders caused by loxoprofen.
Therefore, according to the present invention, it is possible to provide a pharmaceutical composition having excellent storage stability and reducing or suppressing gastrointestinal disorders caused by loxoprofen.

The pharmaceutical composition of the present invention comprises codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof And at least one member selected from the group consisting of dextromethorphan or a salt thereof and loxoprofen or a salt thereof so as not to substantially contact each other.
First, loxoprofen or a salt thereof used in the present invention will be described.

The loxoprofen or a salt thereof used in the pharmaceutical composition of the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate with water, alcohol or the like. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).

The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but 10 per day in terms of loxoprofen sodium anhydride. An amount that can be taken in an amount of ˜300 mg is preferred, an amount that can be taken in an amount of 30 to 240 mg is more preferred, and an amount that can be taken in an amount of 60 to 180 mg is more preferred.
In the present invention, it may be determined by appropriate examination according to the above-mentioned daily dose. However, loxoprofen or a salt thereof is 0. 0 in terms of loxoprofen sodium anhydride relative to the total mass of the pharmaceutical composition. It is preferably contained in an amount of 4 to 90% by mass, more preferably 0.4 to 50% by mass, further preferably 1.2 to 30% by mass, and more preferably 1.2 to 25% by mass. Particularly preferred.

The codeines used in the pharmaceutical composition of the present invention mean one or more selected from the group consisting of codeine, dihydrocodeine or salts thereof, and solvates thereof. That is, codeines include not only codeine and dihydrocodeine itself, but also pharmaceutically acceptable salts of codeine and dihydrocodeine and solvates thereof.
Specific examples of codeines include codeine, dihydrocodeine, codeine phosphate hydrate, dihydrocodeine phosphate and the like from the viewpoint of using the pharmaceutical composition of the present invention as a general cold medicine. Acid salt hydrate and dihydrocodeine phosphate are preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.

Next, the codeines used in the present invention will be described in detail.
The content of codeine in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the gender, age, symptom of the user, and the effect of reducing or suppressing the gastrointestinal tract disorder caused by the observed loxoprofen, The amount that can be taken 2 to 60 mg per day is preferred, the amount that can be taken 4 to 48 mg is more preferred, and the amount that can be taken 6 to 26 mg is more preferred.
When codeine phosphate hydrate is used as the codeine, the amount that can be taken 4 to 60 mg per day is preferable, the amount that can be taken 8 to 48 mg is more preferable, and the amount that can be taken 12 to 36 mg is more preferable. When dihydrocodeine phosphate is used, the amount that can be taken 2 to 30 mg per day is preferred, the amount that can be taken 4 to 24 mg is more preferred, and the amount that can be taken 6 to 24 mg is more preferred. In the present invention, the codeine is preferably contained in an amount of 0.08 to 4% by mass based on the total mass of the pharmaceutical composition. When the codeine is codeine phosphate hydrate, it is preferably contained in an amount of 0.15 to 4% by mass, more preferably 0.3 to 3% by mass, based on the total mass of the pharmaceutical composition. More preferably, the content is 0.5 to 2.5% by mass. Further, when the codeine is dihydrocodeine phosphate, the content is preferably 0.08 to 2% by mass, more preferably 0.16 to 1.5% by mass, based on the total mass of the pharmaceutical composition, More preferably, the content is 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 may be appropriately determined and determined according to the daily dose of each component described above. The salt preferably contains 0.005 to 4 parts by mass of codeine, and more preferably 0.01 to 2 parts by mass, based on 1 part by mass in terms of loxoprofen sodium anhydride.

The carbinoxamine or a salt thereof used in the pharmaceutical composition of the present invention 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 may be appropriately determined and determined according to the sex, age, symptoms, etc. of the user, but can be taken 0.1 to 60 mg per day. The amount is preferably, more preferably 0.5 to 30 mg, more preferably 1 to 16 mg.
In the present invention, the carbinoxamine or a salt thereof is preferably contained in an amount of 0.004 to 4% by mass, more preferably 0.02 to 2% by mass, more preferably 0.04 to 1%, based on the total mass of the pharmaceutical composition. The content by mass is particularly preferred. The content of carbinoxamine or a salt thereof may be determined according to the above-mentioned daily dose.

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, it is preferable that loxoprofen or a salt thereof is contained in an amount of 0.0003 to 6 parts by mass, more preferably 0.002 to 1 part by mass with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. More preferably, 0.005 to 0.3 parts by mass is contained.

The clemastine or a salt thereof used in the pharmaceutical composition of the present invention 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 may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but per day, in terms of clemastine free body, The amount that can be taken 0.01 to 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 even more preferred. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
In the present invention, clemastine or a salt thereof is preferably contained in an amount of 0.008 to 0.4% by mass in terms of a free form of clemastine, preferably 0.01 to 0.2% by mass, based on the total mass of the pharmaceutical composition. Is more preferable, and 0.015 to 0.15% by mass is particularly preferable. In addition, what is necessary is just to determine the content of a clemastine or its salt according to the dose per day mentioned above.

The content ratio of loxoprofen or a salt thereof and clemastine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined according to the daily dose of each component described above. In addition, it is preferable that loxoprofen or a salt thereof contains 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. Those containing 1 part by mass are more preferred, and those containing 0.002 to 0.03 parts by mass are more preferred.

The chlorpheniramine or a salt thereof used in the pharmaceutical composition of the present invention includes chlorpheniramine itself and 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. . Of these, d-form and dl-form are preferred in the present invention. 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 may be appropriately determined and determined according to the sex, age, symptoms, etc. of the user, but is 0.1 to 20 mg per day. The amount that can be taken is preferred, and the amount that can be taken 0.6 to 12 mg is more preferred. In addition, when d-chlorpheniramine maleate is used as chlorpheniramine or a salt thereof, an amount that can be taken 0.1 to 15 mg per day is preferable, and an amount that can be taken 0.6 to 6 mg is more preferable. An amount that can be taken up to 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 present invention, the content of chlorpheniramine or a salt thereof is preferably 0.004 to 1.5% by mass, more preferably 0.02 to 0.8% by mass, based on the total mass of the pharmaceutical composition. Is more preferable, and it is particularly preferable to contain 0.04 to 0.7% by mass. In addition, what is necessary is just to determine the content of chlorpheniramine or its salt according to the dose per day mentioned above.

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, and 0.0005 to 0.7 Those containing parts by mass are more preferred, and those containing 0.001 to 0.5 parts by mass are particularly preferred.

The diphenylpyralin or a salt thereof used in the pharmaceutical composition of the present invention includes not only diphenylpyralin itself but also a pharmaceutically acceptable salt of diphenylpyralin. 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 may be appropriately determined and determined according to the sex, age, symptom, etc. of the user, but from 0.1 to 13 per day. The amount that can be taken 5 mg is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred. When diphenylpyraline hydrochloride is used as diphenylpyraline or a salt thereof, the amount that can be taken 0.1 to 12 mg per day is preferable, and the amount that can be taken 1 to 4 mg is more preferable. When using diphenylpyraline theocuroate, the amount that can be taken 0.1 to 13.5 mg per day is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred.
In the present invention, the content of diphenylpyralin or a salt thereof is preferably 0.004 to 1.5% by mass, more preferably 0.004 to 1% by mass, based on the total mass of the pharmaceutical composition. . Of these, 0.04 to 0.5% by mass is preferable, 0.04 to 0.3% by mass is more preferable, and 0.06 to 0.25% by mass is particularly preferable. In addition, what is necessary is just to determine the content of diphenyl pyralin or its salt according to the dose per day mentioned above.

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. However, it is preferable that loxoprofen or a salt thereof contains 0.0001 to 3 parts by mass of diphenylpyraline or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 2.5 parts by mass. More preferred are those containing 0.001 to 1 part by mass, and particularly preferred are those containing 0.001 to 0.3 part by mass.

The bromhexine or a salt thereof used in the pharmaceutical composition of the present invention includes not only bromhexine itself but also a pharmaceutically acceptable salt of bromhexine. Specific examples of bromhexine or a salt thereof include, for example, bromhexine and bromhexine hydrochloride. In the present invention, bromhexine hydrochloride is preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.

The content of bromhexine or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptom, etc. of the user, but bromhexine or a salt thereof is bromhexine hydrochloride per day. The amount that can be taken 0.1 to 50 mg in terms of salt is preferred, the amount that can be taken 0.5 to 25 mg is more preferred, and the amount that can be taken 1 to 15 mg is even more preferred. In the present invention, the content of bromhexine or a salt thereof is preferably 0.004 to 4% by mass, preferably 0.02 to 2% by mass in terms of bromhexine hydrochloride, based on the total mass of the pharmaceutical composition. More preferably, the content is 0.04 to 1% by mass. In addition, what is necessary is just to determine the content of bromhexine or its salt according to the daily dose mentioned above.

The content ratio of loxoprofen or a salt thereof and bromhexine 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 to contain 0.0001 to 10 parts by mass of loxoprofen or a salt thereof in terms of loxoprofen sodium anhydride in terms of 1 part by mass of bromhexine or a salt thereof in terms of bromhexine hydrochloride, and 0.0005 to 2 parts by mass. More preferably, it contains 0.001 to 1 part by mass.

The ambroxol or a salt thereof used in the pharmaceutical composition of the present invention includes not only ambroxol itself but also a pharmaceutically acceptable salt of ambroxol. Specific examples of ambroxol or a salt thereof include, for example, ambroxol, ambroxol hydrochloride and the like. In the present invention, ambroxol hydrochloride is preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.

The content of ambroxol or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but per day, ambroxol or a salt thereof The amount that can be taken 0.1 to 150 mg in terms of ambroxol hydrochloride is preferred, the amount that can be taken 0.5 to 100 mg is more preferred, and the amount that can be taken 1 to 50 mg is more preferred.
In the present invention, the content of ambroxol or a salt thereof is preferably 0.004 to 10% by mass in terms of ambroxol hydrochloride relative to the total mass of the pharmaceutical composition, and preferably 0.02 to 7%. More preferably, it is contained in an amount of 0.04 to 5% by mass. The content of ambroxol or a salt thereof may be determined according to the above-mentioned daily dose.

The content ratio of loxoprofen or a salt thereof and ambroxol 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 is contained in an amount of 0.0001 to 10 parts by mass in terms of 1 part by mass in terms of loxoprofen sodium anhydride and ambroxol or a salt in terms of ambroxol hydrochloride. Those containing 0.0005 to 5 parts by mass are more preferred, and those containing 0.001 to 3 parts by mass are more preferred.

The lysozyme or a salt thereof used in the pharmaceutical composition of the present invention includes lysozyme itself and a pharmaceutically acceptable salt of lysozyme. Specific examples of lysozyme or a salt thereof include lysozyme, lysozyme hydrochloride and the like, and lysozyme hydrochloride is 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 lysozyme or a salt thereof in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the sex, age, symptom, etc. of the user, but lysozyme or a salt thereof is lysozyme hydrochloride per day. In terms of salt titer, an amount that can be taken from 5 to 450 mg (titer) is preferred, an amount that can be taken from 10 to 360 mg (titer) is more preferred, and an amount that can be taken from 15 to 270 mg (titer) is even more preferred. In the present invention, the content of lysozyme or a salt thereof is preferably 0.2 to 30% by mass (titer) in terms of titer of lysozyme hydrochloride with respect to the total mass of the pharmaceutical composition. More preferably, it is contained in an amount of ˜25% by mass (titer), more preferably 0.6-20% by mass (titer). In addition, what is necessary is just to determine the content of a lysozyme or its salt according to the dose per day mentioned above.

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. Those containing 0.04 to 12 parts by mass (titer) are more preferred, and those containing 0.08 to 5 parts by mass (titer) are more preferred.

Dextromethorphan or a salt thereof used in the pharmaceutical composition of the present invention includes dextromethorphan itself, pharmaceutically acceptable salts of dextromethorphan, and pharmaceutically acceptable dextromethorphan and dextromethorphan. And solvates of water and alcohol. 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 more 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 may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but per day, dextromethorphan or its It is preferable to take 0.1 to 270 mg of salt, more preferably 0.5 to 180 mg, and even more preferably 1 to 90 mg. When dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate, an amount capable of taking 6 to 60 mg of dextromethorphan hydrobromide hydrate per day is preferable, and 15 to 60 mg The amount that can be taken is more preferred, and the amount that can be taken 20 to 60 mg is more preferred. In addition, when dextromethorphan or a salt thereof is dextromethorphan phenol phthaline salt, an amount capable of taking 9 to 90 mg of dextromethorphan phenol phthalin salt per day is preferable, and an amount capable of taking 22 to 90 mg is more preferable. More preferably, the dose is 30 to 90 mg.
In the present invention, the content of dextromethorphan or a salt thereof is preferably 0.004 to 20% by mass, more preferably 0.02 to 15% by mass with respect to the total mass of the pharmaceutical composition, More preferably, the content is 0.04 to 10% by mass. In addition, what is necessary is just to determine the content of dextromethorphan or its salt according to the dose per day mentioned above.

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 may be appropriately determined and determined according to the daily dose of each component described above. 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 parts by mass. More preferably, the content is 0.001 to 5 parts by mass.

Further, in the present invention, “containing so as not to substantially contact each other” means containing in a pharmaceutical composition so that loxoprofen or a salt thereof, codeine, and the like do not come into contact with each other so as not to exhibit an interaction. Although it means, it is preferable to contain so that a loxoprofen or its salt, codeines, etc. may not contact.
The dosage form of the pharmaceutical composition of the present invention is not particularly limited, but a solid preparation is preferable from the viewpoint of ease of taking.

Specific examples of solid preparations include, for example, oral preparations such as capsules, pills, granules, fine granules, powders, tablets, dry syrups, jellies, troches, and parenteral administration such as suppositories. Examples include oral preparations, and oral solid preparations are preferred. The pharmaceutical composition of the present invention may be coated with a sugar coating or a film coating by a known method.

The solid preparation contains (A) loxoprofen or a salt thereof, or a solid composition containing loxoprofen or a salt thereof, and (B) a codeine or the like itself, or a solid composition containing codeine or the like. The components constituting these solid compositions include those in which loxoprofen or a salt thereof and codeine are arranged so as not to contact each other (however, the component (A) is composed of loxoprofen or a salt thereof itself). And the component (B) is codeine or the like itself). These solid compositions are in the form of powder, granules, tablets, and the like.

As specific forms of the solid preparation, the following (a) to (h) can be exemplified, and these are described in known methods as described above, for example, the 15th revised Japanese Pharmacopoeia General Rules for Preparations, etc. According to the known methods, it can be produced and formulated using appropriate formulation additives. In (i)-(h), specific forms of solid preparations are exemplified by taking codeines as examples. In the case of using chlorpheniramine or a salt thereof that interacts with loxoprofen or a salt thereof instead of codeine, a solid preparation can be produced and formulated in the same manner as codeine.

(I) Either loxoprofen or a salt thereof and codeine are granulated by an appropriate method to form a granule, and the other loxoprofen or a salt thereof or codeine is blended without granulation. Powders, granules, etc., as well as preparations in which the granules are further coated by an appropriate method.
(B) Loxoprofen or a salt thereof and codeine are separately granulated by an appropriate method to form granules, and powders and granules produced by blending these, and the granules are further processed by an appropriate method. Coated formulation.
(C) A capsule filled with the powder or granule prepared in (i) or (b) above.
(D) Tablets obtained by tableting the granular material produced in (i) or (b) above by an appropriate method. Tableting can be achieved not only by the compression method but also by molding into a certain shape by an appropriate method.
(E) A multilayer tablet prepared so that loxoprofen or a salt thereof and codeine are not substantially in contact with each other, and a preparation in which the multilayer tablet is further coated by an appropriate method. The multi-layered tablet is preferably one in which loxoprofen or a salt thereof and codeine are located in different layers, and as a multi-layered tablet having three or more layers, a layer containing loxoprofen or a salt thereof and a layer containing codeine are mutually attached. What was located so that it may not contact | connect is more preferable. In addition, as the loxoprofen or a salt thereof and codeine, the granular material produced in the above (i) or (b) can be used.
(F) One of loxoprofen or a salt thereof and codeine is arranged in a core tablet (also referred to as a core tablet or a central tablet) so that loxoprofen or a salt thereof and codeine are not substantially in contact with each other. Nucleated tablets, and preparations obtained by coating the nucleated tablets with an appropriate method. In addition, as the loxoprofen or a salt thereof and codeine, the granular material produced in the above (i) or (b) can be used.
(G) In place of the above-mentioned particulate matter (a) or (b), either or both of loxoprofen or a salt thereof and codeine is added to a cyclodextrin such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. A preparation using an inclusion compound included in dextrins.
(H) Loxoprofen or a salt thereof and codeine are contained in a preparation prepared by a usual method, and are provided with a sugar coating layer or a film coating layer, and the other sugar coating layer or coating layer is provided on the other side. And a preparation prepared so that loxoprofen or a salt thereof and codeine are not substantially in contact with each other (when the dosage form is a tablet, it is called a sugar-coated tablet or a film-coated tablet).

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

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

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

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

Excipients include, for example, crystalline cellulose, powdered cellulose, lactose hydrate, sucrose, glucose, mannitol, erythritol, xylitol, trehalose, maltitol, lactitol, sorbitol, wheat starch, corn starch, potato starch, phosphoric anhydride Examples thereof include calcium hydrogen, calcium carbonate, silicon dioxide and the like.

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

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

In the pharmaceutical composition of the present invention, as a pharmaceutical ingredient, a drug other than loxoprofen or a salt thereof, and codeine, such as antipyretic analgesic, antihistamine, antitussive, noscapine, bronchodilator, expectorant, hypnotic sedative, It may contain one or more selected from the group consisting of vitamins, anti-inflammatory agents, gastric mucosa protective agents, anticholinergics, herbal medicines, Chinese herbal formulas, caffeine, xanthine components and the like.

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, difeterol hydrochloride, dipheterol phosphate, diphenhydramine Hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, mequitazine, methodirazine hydrochloride, mebhydrolinapadi Silates and the like can be mentioned.

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 bronchodilators include trimethquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, ephedrines (pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride Salt, dl-methylephedrine saccharin salt), methoxyphenamine hydrochloride and the like.

Examples of expectorants include ammonia fennel, ethyl cysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacol sulfonate, potassium cresol sulfonate, methyl cysteine hydrochloride, 1-menthol and the like.
Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromvalerylurea.

Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, Thiamine nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavinline Acid ester, riboflavin butyrate, sodium riboflavin phosphate, panthenol, pantethine, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecoba Lamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

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

Examples of the gastric mucosa protective agent include aminoacetic acid, aldioxa, magnesium silicate, gefarnate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product , Sucralfate, cetraxate hydrochloride, sofalcone, magnesium carbonate, teprenone, copper chlorophyllin potassium, copper chlorophyllin sodium, magnesium metasilicate aluminate, methylmethionine Honiumukurorido, and the like.

Examples of the anticholinergic agent include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipedium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl- l-hyostiamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodopropamide iodide, diphenylpiperidinomethyldioxolane, funnel extract, funnel root, funnel Examples include root total alkaloid citrate.

Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyokaku (horny sheep), fennel (mushrooms), turmeric (depressed gold), engosaku (yenkogong), enmeisou (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Oubak (yellow twilight), Spruce (cherry skin), Auren (yellow ream), Onji (distant), Gajutsu (we), Ganoderma (deer herb), Chamomile, Caronin (Karojin), Licorice (licorice), Kyokyo (Kikkyo), Kyonin (Kyojin), Kukoshi (Isogo), Kukoyo (Kashiwaha), Keigai (Kashiwagi), Keihi (Kinseido), Ketsumeishi (Kameko), Gentiana, Gennoshouko (current evidence), Koubushi (Katsukiko), Gooh (beef yellow), Goshi (Gomiko), Saishin (Spicy), Salamander (Sansho), Zion (Purple), Zykopi (Peel), Peonies (Glue), Musk, Shajin, Shazenshi (car front child), Shazenso (car front grass), Beast gall (including Yutan (bear gall)), Shakyo (ginger), Giryu (land dragon), Xinyi ), Sexan (Ishizuchi), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Oiso), Chixetsu carrot (bamboo ginseng), clove (clove), chimpi (chonse), touki (to home), tokong (napping root), Nantenjitsu (southern), carrot (carrot), baimo (shellfish), bacmond (wheat) Gate winter), mint (light load), Hange (semi-summer), bankouka (banka), hampi (anti-nose), juniper (white bean), juniper (white moth), bukkuri (茯苓), button pi (peony skin), volley (Oysters), maou (mao), rokjo (deer) Herbal medicines such as 茸) and extracts thereof (extract, tincture, dry extract, etc.) and the like.

Examples of Kampo prescriptions include Keishi-yu, Kosou-san, Saiko-Kei-do, Sho-saiko-yu, Bakumon-fu-to, Hanka-koboku-yu, and the like.
Examples of caffeine include sodium benzoate caffeine, caffeine hydrate, and anhydrous caffeine.
Examples of the xanthine component include aminophylline, diprofylline, theophylline, proxyphylline and the like.

In addition, as the pharmaceutical composition of the present invention, those other than the following (a) to (u) are preferable.

(A) Loxoprofen sodium hydrate 180 mg, codeine phosphate 45 mg, crystalline cellulose 110 mg, hydroxypropylcellulose 40 mg, magnesium stearate 10 mg, lactose tablets (in 6 tablets) containing appropriate amounts,
(B) Loxoprofen sodium hydrate 180 mg, dihydrocodeine phosphate 20 mg, crystalline cellulose 140 mg, hydroxypropylcellulose 100 mg, magnesium stearate 10 mg, D-mannitol 190 mg and lactose in appropriate amounts (in 3 capsules),
(C) Loxoprofen sodium hydrate 180 mg, codeine phosphate 45 mg, magnesium stearate 10 mg, polysorbate 50 mg, corn starch 170 mg and lactose in appropriate amounts (in 6 capsules),

(D) Loxoprofen sodium hydrate 60 mg (anhydrous equivalent), dihydrocodeine phosphate 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 200 mg and lactose 13 mg (one tablet 350 mg),
(E) Loxoprofen sodium hydrate 60 mg (anhydrous equivalent), dihydrocodeine phosphate 10 mg, serrapeptase 10 mg, bromhexine hydrochloride 4 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 186 mg and lactose 13 mg (1 tablet) 350 mg),
(f) Hard capsule containing 60 mg of loxoprofen sodium dihydrate (anhydrous equivalent), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 176 mg and lactose 13 mg (1 capsule 350mg),

(g) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 176 mg and lactose 13 mg ( 350mg in a tablet)
(h) Loxoprofen sodium dihydrate 60 mg (in terms of anhydride), carbinoxamine maleate 4 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 206 mg and lactose 13 mg (350 mg in one tablet),
(i) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), carbinoxamine maleate 4 mg, lysozyme chloride 50 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 156 mg and lactose 13 mg (350 mg in one tablet),

(j) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, β-cyclodextrin 254 mg, aspartame 30 mg, citric acid 965 mg, sodium bicarbonate 813 mg, lactose Effervescent tablets (2400 mg in one tablet) containing 194 mg and 50 mg magnesium stearate,
(K) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, β-cyclodextrin 300 mg, aspartame 30 mg, mannitol 262 mg and magnesium stearate 14 mg Fast dissolving tablets or chewable tablets (700mg in each tablet),
(L) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), clemastine fumarate 5 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 205 mg and lactose 13 mg (350 mg in one tablet),

(M) Loxoprofen sodium 180 mg, ambroxol hydrochloride 45 mg, crystalline cellulose 100 mg, hydroxypropylcellulose 40 mg, magnesium stearate 10 mg and lactose in appropriate amounts (in 6 tablets),
(N) Loxoprofen sodium 180 mg, bromhexine hydrochloride 12 mg, crystalline cellulose 100 mg, hydroxypropylcellulose 40 mg, magnesium stearate 10 mg and lactose in appropriate amounts (in 6 tablets),
(O) Loxoprofen sodium 180 mg, ambroxol hydrochloride 15 mg, bromhexine hydrochloride 8 mg, belladonna (total) alkaloid 0.2 mg, crystalline cellulose 100 mg, hydroxypropylcellulose 40 mg, magnesium stearate 10 mg and lactose ),

(P) Loxoprofen sodium 180 mg, ambroxol hydrochloride 45 mg, crystalline cellulose 130 mg, hydroxypropylcellulose 100 mg, magnesium stearate 10 mg, D-mannitol 290 mg and lactose in appropriate amounts (in 3 packages),
(Q) loxoprofen sodium 180 mg, bromhexine hydrochloride 12 mg, crystalline cellulose 130 mg, hydroxypropylcellulose 100 mg, magnesium stearate 10 mg, D-mannitol 290 mg and lactose in appropriate amounts (in 3 capsules),
(R) Loxoprofen sodium 180 mg, ambroxol hydrochloride 15 mg, bromhexine hydrochloride 8 mg, belladonna (total) alkaloid 0.2 mg, crystalline cellulose 130 mg, hydroxypropylcellulose 100 mg, magnesium stearate 10 mg, D-mannitol 290 mg and lactose in appropriate amounts Fine granules (in 3 packages),

(S) Loxoprofen sodium 180 mg, ambroxol hydrochloride 45 mg, magnesium stearate 10 mg, polysorbate 50 mg, corn starch 180 mg and lactose in appropriate amounts (in 6 capsules),
(T) Loxoprofen sodium 180 mg, bromhexine hydrochloride 12 mg, magnesium stearate 10 mg, polysorbate 50 mg, corn starch 200 mg and lactose in appropriate capsules (in 6 capsules), and (u) loxoprofen sodium 180 mg, ambroxol hydrochloride 15 mg, Capsules filled with fine granules containing 8 mg of bromhexine hydrochloride, 0.2 mg of belladonna (total) alkaloids, 10 mg of magnesium stearate, 50 mg of polysorbate, 190 mg of corn starch and lactose (in 6 capsules).

The route of administration of the pharmaceutical composition of the present invention includes oral and parenteral such as rectal and vaginal, but oral administration is preferred. In addition, when administered orally, the pharmaceutical composition of the present invention can be taken 1 to 4 times per day before meals, between meals, after meals, before going to bed, etc.

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

In the present invention, the desiccant is not particularly limited. Examples of the desiccant include silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride and magnesium oxide. 1 type or 2 types or more are mentioned, What mixed these and activated carbon may be sufficient. Among these, one or more selected from silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve) and calcium chloride are more preferable, and synthetic zeolite is particularly preferable from the viewpoint of interaction suppression.
In addition, the shape of the desiccant is not particularly limited, and examples thereof include a plate-shaped or bag-shaped sheet mold, a cylinder-shaped (tablet mold), and the like. A film-coated one may also be used.

Various desiccants are commercially available. For example, Shiblet, MS-Tablet, MS-Serum W, Tokai Gel, Decite Kite 25, Alp sheet, Toray Chemical Co., Ltd. ) Packaged items, Dryan (registered trademark) tablets, Dryan (registered trademark) sheets, Sekawa, Allosheet, Zeosheet, Shinzo Kasei Co., Ltd., OZO Co., Ltd. OZO, IDi Co., Ltd. IDi-packing desiccant and the like.

The content of the desiccant in the pharmaceutical preparation of the present invention may be determined by appropriate examination, but is preferably 0.05 to 35 parts by weight, preferably 0.15 to 17 parts by weight with respect to 1 part by weight of loxoprofen or a salt thereof. Part is more preferred.
In addition, the content of the desiccant is preferably 0.001 to 1 part by weight, and 0.004 to 0.00 parts per 1 part by weight of the pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, codeine and the like. 4 parts by mass 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, etc., and any of a fixed container and an amorphous container can be used and sealed. What is possible is preferred. Examples of the fixed container include bottles, cans, and boxes. Examples of the amorphous container include bags (pillow packaging, stick packaging, PTP packaging, SP packaging, etc.) and the like. Of these containers, specifically, bottles and bags are preferable.

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

The method of storing the pharmaceutical composition of the present invention and the desiccant in a container is not particularly limited, and any of them 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 storing in a bottle, the pharmaceutical composition containing loxoprofen of the present invention or a salt thereof, codeine and the like is preferably a solid preparation containing these.

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 storing in a bag, the pharmaceutical composition containing loxoprofen or a salt thereof, codeine or the like of the present invention is preferably a solid preparation containing these.

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

Since the pharmaceutical composition of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain・ Bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain), pain relief, chills, antipyretic fever, cold symptoms (sore throat, cough, chills, fever, headache, joint pain) , Muscle pain), cough, etc., and is useful as a cold medicine, antipyretic analgesic and the like.
Moreover, the codeines etc. which are used for the pharmaceutical composition of this invention suppress / reduce the digestive tract disorder | damage | failure resulting from a loxoprofen as evident also from a postscript Example. Therefore, patients suffering from peptic ulcer and patients with a history of history can also take loxoprofen or a salt thereof without fear of gastrointestinal tract disorders caused by loxoprofen.

Hereinafter, the present invention will be described in detail with reference to examples and the like, but the present invention is not limited to these examples and the like.

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

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

Test Example 2 Examination of Interaction Regarding the composition of Example 1 below (formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (1)) and Comparative Example 1, The state in the glass bottle after 1 day, 3 days and 1 week was evaluated, and the results are shown in Table 2.
Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and 24.3 g of corn starch (Nippon Chemical Co., Ltd .: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then passed through a No. 18 sieve to obtain a granulated product. 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) was mixed with the obtained granulated product, placed in a glass bottle (13K standard bottle), and stored at 50 ° C. for 1 week (Example) 1).
Meanwhile, loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P), corn starch 24 3 g (manufactured by Nissho Chemical Co., Ltd .: trade name corn starch ST-C) and 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”) are mixed and placed in a glass bottle (13K standard bottle) It was stored at 50 ° C. for 1 week (Comparative Example 1).

As is apparent from Table 2, the mixture of loxoprofen sodium hydrate and dihydrocodeine phosphate which had been preserved by mixing had solidified after 1 day from the start of storage as a result of the interaction (Comparative Example 1). ).
On the other hand, a granule prepared by mixing loxoprofen sodium hydrate with a granule prepared by mixing dihydrocodeine phosphate can maintain the same state as the start and suppress the interaction. (Example 1).

[Example 2] Formulation (2) in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact with each other
Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and corn starch 24.3 g (Nippon Chemical Co., Ltd .: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then passed through a No. 18 sieve to obtain a granulated product. The obtained granulated product was mixed with 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”), 81 g of carmellose calcium (trade name: ECG505 by Gotoku Pharmaceutical), 591.3 g of lactose hydrate ( Made by DMV: trade name: lactose 200M) and magnesium stearate 8.1 g (produced by Taihei Chemical Industry: trade name: magnesium stearate (vegetable)), and then a tableting machine with a 8.5 mm diameter punch (field) Tableting was performed using a steelworks manufactured by HT-AP18SS type, and tablets having a mass of 270 mg were obtained.

[Example 3] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (3)
Tablets were obtained in the same manner except that Macrogol 6000 was replaced with hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).

[Example 4] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (4)
Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and corn starch 24.3 g (Nippon Chemical Co., Ltd .: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then passed through a No. 18 sieve to obtain a granulated product. The obtained granulated product was mixed with 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”), 81 g of carmellose calcium (trade name: ECG505 by Gotoku Pharmaceutical), and 295.7 g of lactose hydrate ( Made by DMV: Trade name Lactose 200M), 295.6 g of crystalline cellulose (made by Asahi Kasei Chemicals: trade name Theolas PH-101) and 8.1 g magnesium stearate (made by Taihei Chemical Industry: trade name magnesium stearate (vegetable)) After mixing, tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a punch with a diameter of 8.5 mm to obtain a tablet having a mass of 270 mg.

[Example 5] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (5)
8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”), 3.4 g of macrogol 6000 (manufactured by NOF Corporation: trade name Macrogol 6000P) and 2.9 g of corn starch (manufactured by Nissho Chemical Co., Ltd.) : Product name Corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then sieved with a No. 18 sieve to obtain a granulated product. To the obtained granulated product, loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate), carmellose calcium 81 g (manufactured by Gotoku Pharmaceutical: trade name ECG505), lactose water 638.5 g of Japanese product (manufactured by DMV: trade name: lactose 200M) and 8.1 g of magnesium stearate (manufactured by Taihei Chemical Industry: trade name: magnesium stearate (vegetable)) were mixed, and a bowl with a diameter of 8.5 mm was attached. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) to obtain tablets each having a mass of 270 mg.

[Example 6] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate do not substantially contact (6)
Loxoprofen sodium hydrate 68.1 g (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate), hydroxypropylcellulose 24.3 g (manufactured by Nippon Soda: trade name HPC-L), carmellose calcium 81 g (Gotoku) Made by chemicals: trade name ECG505), 620.5 g of crystalline cellulose (made by Asahi Kasei Chemicals: trade name Theolas PH-101) were put into a high-speed stirring granulator (manufactured by Paulek: model VG-05), mixed and purified water 328 .8 g was added and kneaded. This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 793.9 g of this sized product, 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) and magnesium stearate 8.1 g (manufactured by Taihei Chemical Industry: trade name: magnesium stearate (vegetable)) ) Into a blender (Kotobuki: PM50 type) and mixed, and then tableted using a tableting machine (Hatetsu Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch. A tablet having a tablet mass of 270 mg was obtained.

[Example 7] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (7)
8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”), 24.3 g of hydroxypropyl cellulose (trade name: HPC-L, manufactured by Nippon Soda), 81 g of carmellose calcium (trade name, manufactured by Gotoku Yakuhin Co. ECG505), 620.5 g of crystalline cellulose (product name: Asahi Kasei Chemicals: trade name: Theolas PH-101) were charged into a high-speed stirring granulator (manufactured by Paulek: VG-05 type) and mixed, and then 328.8 g of purified water was added. Kneaded. This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 733.8 g of this sized product, 68.1 g of loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) and 8.1 g of magnesium stearate (manufactured by Taihei Chemical Industry: trade name, stearic acid) Magnesium (vegetable)) was put into a mixer (Kotobuki: PM50 type) and mixed, and then used with a tableting machine (Hatetsu Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch. Tableting was performed to obtain a tablet having a mass of 270 mg.

[Example 8] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (8)
Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate), hydroxypropylcellulose 12.1 g (manufactured by Nippon Soda: trade name HPC-L), carmellose calcium 40.5 g (Product name: ECG505 manufactured by Gotoku Pharmaceutical Co., Ltd.), 280.2 g of crystalline cellulose (product name: Asola Chemical PH-101 manufactured by Asahi Kasei Chemicals Co., Ltd.) are charged into a high-speed stirring granulator (manufactured by Paulek: Model VG-05), mixed and purified. 164.3 g of water was added and kneaded. This granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried and then sized using a granulator (Okada Seiko: ND-10 type) (Granulated product A). ). In addition, 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”), 12.1 g of hydroxypropyl cellulose (manufactured by Nippon Soda: trade name: HPC-L), 40.5 g of carmellose calcium (Gotoku Pharmaceutical) Product: ECG505), 340.3 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas PH-101) were put into a high-speed agitation granulator (Paurek: Model VG-05), mixed, and purified water 164. 3 g was added and kneaded. This granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then sized using a granulator (Okada Seiko: ND-10 type) (Granulated product B). ). 400 g of the sized product A, 400 g of the sized product B and 8 g of magnesium stearate (manufactured by Taihei Kagaku Kogyo: trade name magnesium stearate (vegetable)) were put into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 8.5 mm diameter punch, and tablets with a mass of 270 mg were obtained.

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

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

[Experiment 4] Examination of interaction 584 mg of loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) and 10 mg of d-chlorpheniramine maleate (trade name, manufactured by Kongo Chemical Co., Ltd.) -Chlorpheniramine maleate) was mixed and placed in a glass bottle (3K standard bottle) and stored at 60 ° C for 1 week (Reference Example 2). As comparative controls, loxoprofen sodium hydrate alone (Control Example 3) and d-chlorpheniramine maleate alone (Control Example 4) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 4.

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

[Test Example 5]
The following Example 9 (formulation in which loxoprofen sodium and d-chlorpheniramine maleate are not substantially in contact (1)) and the composition of Comparative Example 2 were immediately after storage, 1 day, 3 days, and 7 days The condition in the glass bottle after 14 days and after 28 days was evaluated.
That is, loxoprofen sodium hydrate and d-chlorpheniramine maleate were replaced by replacing 8 g of dihydrocodeine phosphate with 1.2 g of d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd., trade name: D-chlorpheniramine maleate). A mixture (Example 9) in which a mixture of an acid salt (Comparative Example 2), loxoprofen sodium hydrate, and d-chlorpheniramine maleate are not substantially in contact with each other was prepared. The test was carried out in the same manner as in Test Example 2 except that the samples were stored for 1 day, immediately after the start of storage, and after 1 day, 3 days, 7 days, 14 days, and 28 days. The results are shown in Table 5.

As is clear from Table 5, the mixture of loxoprofen sodium hydrate and chlorpheniramine maleate that had been preserved only became wet after 3 days from the start of storage as a result of the interaction. Example 2).
On the other hand, a granulated product obtained by granulating loxoprofen sodium hydrate and stored by simply mixing chlorpheniramine maleate maintains the same state as at the start even after 28 days, and the interaction is maintained. It was found that it can be suppressed (Example 9).
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in a pharmaceutical composition so as not to contact each other.

[Example 10] Formulation in which loxoprofen sodium and d-chlorpheniramine maleate are not substantially in contact (2)
Example 2 except that 8 g of dihydrocodeine phosphate was replaced with 1.2 g of d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-chlorpheniramine maleate), and corn starch was replaced with 31.1 g. In the same manner, tablets were obtained.

[Example 11] Formulation in which loxoprofen sodium and d-chlorpheniramine maleate are not substantially in contact (3)
Tablets were obtained in the same manner as in Example 10, except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

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

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

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

As is apparent from Table 7, when the mixture of loxoprofen sodium hydrate and clemastine fumarate was stored, the mixture became wet and further discolored (Reference Example 3). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and clemastine fumarate alone (control examples 5 and 6). From this, it was found that the state change of the mixture was a result of interaction between loxoprofen sodium hydrate and clemastine fumarate.
As a result, it was found that the interaction can be suppressed by incorporating loxoprofen or a salt thereof and clemastine or a salt thereof in the pharmaceutical composition so as not to contact each other.

[Example 12] Formulation in which loxoprofen sodium and clemastine fumarate are not in substantial contact (1)
A tablet is obtained in the same manner as in Example 2 except that 8 g of dihydrocodeine phosphate is changed to 0.5 g of clemastine fumarate (product name: clemastine fumarate, manufactured by Daito) and corn starch is changed to 31.8 g. .

[Example 13] Formulation in which loxoprofen sodium and clemastine fumarate do not substantially contact (2)
Tablets are obtained in the same manner as in Example 12 except that the macrogol 6000 is changed to hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 8] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (3)
As a test drug, a suspension of clemastine fumarate (CF) in a 0.5% methylcellulose (MC) solution was used, and a predetermined amount (1 mg / 5 mL / kg) was orally administered, as in Test Example 3. The test was carried out, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 8.

As is apparent from Table 8, clemastine fumarate reduced gastric mucosal damage caused by loxoprofen.

[Test Example 9] Investigation of interaction Loxoprofen sodium hydrate 482.3 mg (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and carbinoxamine maleate 17.7 mg (Kongo Chemical: product) Name Carbinoxamine maleate) was mixed and placed in a glass bottle (3K standard bottle) and stored at 60 ° C. for 1 week (Reference Example 4). As comparative controls, loxoprofen sodium hydrate alone (Control Example 7) and carbinoxamine maleate salt alone (Control Example 8) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 2 days, and 1 week was evaluated, and the results are shown in Table 9.

As is apparent from Table 9, when the mixture of loxoprofen sodium hydrate and carbinoxamine maleate was stored, the mixture solidified and further discolored (Reference Example 4). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and carbinoxamine maleate alone (control examples 7 and 8). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and carbinoxamine maleate.
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and carbinoxamine or a salt thereof in a pharmaceutical composition so as not to contact each other.

[Example 14] Formulation in which loxoprofen sodium and carbinoxamine maleate do not substantially contact (1)
In the same manner as in Example 2, except that 8 g of dihydrocodeine phosphate was replaced with 2.5 g of carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) and corn starch was replaced with 29.8 g. Get.

[Example 15] Formulation in which loxoprofen sodium and carbinoxamine maleate do not substantially contact (2)
Tablets are obtained in the same manner as in Example 14 except that Macrogol 6000 is replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 10] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (4)
As test drug, carbinoxamine maleate (CAM) suspended in 0.5% methylcellulose (MC) solution and orally administered in a predetermined amount (0.75, 75 mg / 5 mL / kg) The test was carried out in the same manner as in Test Example 3, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 10.

As is clear from Table 10, carbinoxamine maleate reduced gastric mucosal damage caused by loxoprofen.

[Test Example 11] Examination of interaction Loxoprofen sodium hydrate 490.4 mg (manufactured by Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and diphenylpyraline hydrochloride 9.6 mg (manufactured by Kongo Chemical: trade name: hydrochloric acid) Diphenylpyralin) was mixed, placed in a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 5). As comparative controls, loxoprofen sodium hydrate alone (Control Example 9) and diphenylpyraline hydrochloride alone (Control Example 10) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 11.

As is apparent from Table 11, when the mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochloride was stored, the mixture became wet and further discolored (Reference Example 5). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and diphenylpyraline hydrochloride alone (control examples 9 and 10). From this, it was found that the state change of the mixture was the result of interaction between loxoprofen sodium hydrate and diphenylpyraline hydrochloride.
As a result, it was found that the interaction can be suppressed by incorporating loxoprofen or a salt thereof and diphenylpyraline or a salt thereof in a pharmaceutical composition so as not to contact each other.

[Test Example 12]
The following Example 16 (formulation in which loxoprofen sodium and diphenylpyraline hydrochloride are not substantially in contact with each other) (1) and the composition of Comparative Example 3, immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, The state in the glass bottle after 28 days was evaluated.
That is, a mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochloride in place of 8 g of dihydrocodeine phosphate 1.3 g (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) (Comparative Example 3) , Loxoprofen sodium hydrate, and diphenylpyraline hydrochloride (Example 16) were prepared, and stored at 50 ° C. for 28 days. Immediately after the start of storage, 1 day, 3 days, and 7 days later The test was conducted in the same manner as in Test Example 2 except that the evaluation was made after 14 days and 28 days. The results are shown in Table 12.

As is apparent from Table 12, the mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochloride which had been preserved only became wet as a result of the interaction, resulting in the mixture becoming wet after 3 days from the start of storage (Comparative Example 3). ).
On the other hand, a granulated product obtained by granulating loxoprofen sodium hydrate, which is preserved just by mixing diphenylpyraline hydrochloride, can maintain the same state as at the beginning even after 28 days and can suppress the interaction Was found (Example 16).
As a result, it was found that the interaction can be suppressed by incorporating loxoprofen or a salt thereof and diphenylpyraline or a salt thereof in a pharmaceutical composition so as not to contact each other.

[Example 17] Formulation in which loxoprofen sodium and diphenylpyraline hydrochloride are not substantially in contact (1)
Tablets were obtained in the same manner as in Production Example 2 except that 8 g of dihydrocodeine phosphate was changed to 1.3 g of diphenylpyraline hydrochloride (Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) and corn starch was changed to 31 g.

[Example 18] Formulation in which loxoprofen sodium and diphenylpyraline hydrochloride are not substantially in contact (2)
Tablets were obtained in the same manner as in Production Example 17 except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 13] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (5)
As a test drug, a suspension of diphenylpyraline hydrochloride (PP) in a 0.5% methylcellulose (MC) solution was used, and a predetermined amount (3, 10 mg / 5 mL / kg) was orally administered. The test was carried out in the same manner as described above, and the ulcer suppression rate (%) in the test drug administration was calculated. The results are shown in Table 13.

As is clear from Table 13, diphenylpyraline hydrochloride reduced gastric mucosal damage caused by loxoprofen.

[Test Example 14] Examination of interaction 170 mg of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) and 10 mg of bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) They were mixed, put in a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 6). As comparative controls, loxoprofen sodium hydrate alone (Control Example 11) and bromhexine hydrochloride alone (Control Example 12) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 2 days, and 1 week was evaluated, and the results are shown in Table 14.

As is clear from Table 14, when the mixture of loxoprofen sodium hydrate and bromhexine hydrochloride was stored, the mixture solidified and further discolored (Reference Example 6). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and bromhexine hydrochloride alone (Control Examples 11 and 12). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and bromhexine hydrochloride.
As a result, it has been found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and bromhexine or a salt thereof into contact with each other.

[Test Example 15]
The following Example 19 (formulation in which loxoprofen sodium and bromhexine hydrochloride are not substantially in contact (1)) and the composition of Comparative Example 4 were used immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, 28 The state in the glass bottle after a day was evaluated.
That is, 8 g of dihydrocodeine phosphate is replaced with 4 g of bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride), and a mixture of loxoprofen sodium hydrate and bromhexine hydrochloride (Comparative Example 4) and loxoprofen sodium A preparation in which hydrate and bromhexine hydrochloride are not substantially in contact with each other (Example 19) was prepared, and stored at 50 ° C. for 28 days. Immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, The test was performed in the same manner as in Test Example 2 except that the evaluation was made after 28 days. The results are shown in Table 15.

As is apparent from Table 15, in the case where loxoprofen sodium hydrate and bromhexine hydrochloride were stored, the mixture was wetted after 1 day from the start of storage as a result of the interaction (Comparative Example 4). .
On the other hand, a granule obtained by granulating loxoprofen sodium hydrate and stored by simply mixing bromhexine hydrochloride can maintain the same state as at the start even after 28 days and can suppress the interaction. Was found (Example 19).
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and bromhexine or a salt thereof in a pharmaceutical composition so as not to contact each other.

[Example 20] Formulation in which loxoprofen sodium and bromhexine hydrochloride do not substantially contact (2)
Tablets were obtained in the same manner as in Production Example 2 except that 8 g of dihydrocodeine phosphate was changed to 4 g of bromohexine hydrochloride (trade name: bromohexine hydrochloride manufactured by Sanyo Chemical Co., Ltd.) and corn starch was changed to 28.3 g.

[Example 21] Preparation in which loxoprofen sodium and bromhexine hydrochloride do not substantially contact (3)
Tablets were obtained in the same manner as in Production Example 20, except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

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

As is apparent from Table 16, when the mixture of loxoprofen sodium hydrate and ambroxol hydrochloride was stored, the mixture solidified and further discolored (Reference Example 7). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and ambroxol hydrochloride alone (control examples 13 and 14). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and ambroxol hydrochloride.
As a result, it was found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and ambroxol or a salt thereof into contact with each other.

[Test Example 17]
The following Example 22 (formulation in which loxoprofen sodium and ambroxol hydrochloride are not substantially in contact with each other (1)) and the composition of Comparative Example 5 were immediately after the start of storage, 1 day, 3 days, 7 days, and 14 days later. The state in the glass bottle after 28 days was evaluated.
That is, 8 g of dihydrocodeine phosphate was replaced with 15 g of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: ambroxol hydrochloride), and a mixture of loxoprofen sodium hydrate and ambroxol hydrochloride ( Comparative Example 5), a preparation (Example 22) in which loxoprofen sodium hydrate and ambroxol hydrochloride are not substantially in contact with each other was prepared and stored at 50 ° C. for 28 days. The test was conducted in the same manner as in Test Example 2 except that the evaluation was made after 3 days, 7 days, 14 days, and 28 days. The results are shown in Table 17.

As is apparent from Table 17, the mixture of loxoprofen sodium hydrate and ambroxol hydrochloride which had been stored was solidified after 1 day from the start of storage as a result of interaction. 5).
On the other hand, the granule obtained by granulating loxoprofen sodium hydrate and stored by simply mixing ambroxol hydrochloride maintains the same state as the start even after 28 days and suppresses the interaction It was found that this was possible (Example 22).
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and ambroxol or a salt thereof in a pharmaceutical composition so as not to contact each other.

[Example 23] Formulation in which loxoprofen sodium and ambroxol hydrochloride are not substantially in contact (2)
Except that 8g of dihydrocodeine phosphate is replaced with 15g of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Kogyosho: trade name ambroxol hydrochloride), Macrogol 6000 is replaced with 25.7g, and corn starch is replaced with 20.8g. In the same manner as in Example 2, tablets were obtained.

[Example 24] Formulation in which loxoprofen sodium and ambroxol hydrochloride are not substantially in contact (3)
Tablets were obtained in the same manner as in Example 23 except that Macrogol 6000 was changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).

[Test Example 18] Examination of interaction Loxoprofen sodium hydrate 224.9 mg (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) and 275.1 mg potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: Trade name: Potassium guaiacol sulfonate) was mixed, put into a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 8). As comparative controls, loxoprofen sodium hydrate alone (Control Example 15) and potassium guaiacol sulfonate alone (Control Example 16) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 18.

As is clear from Table 18, when the mixture of loxoprofen sodium hydrate and potassium guaiacol sulfonate was stored, the mixture became wet (Reference Example 8). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and potassium guaiacol sulfonate alone (Control Examples 15 and 16). From this, it was found that the state change of the mixture was a result of interaction between loxoprofen sodium hydrate and potassium guaiacol sulfonate.
As a result, it was found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and guaiacol sulfonic acid or a salt thereof into contact with each other.

[Example 25] Formulation (1) in which loxoprofen sodium and potassium guaiacol sulfonate are not substantially in contact with each other
8 g of dihydrocodeine phosphate is replaced with 83 g of potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name potassium guaiacol sulfonate), 292 g of macrogol 6000, 243 g of corn starch and 34. lactose hydrate. A tablet is obtained in the same manner as in Example 2 except that the amount is changed to 8 g.

[Example 26] Formulation in which loxoprofen sodium and guaiacol potassium sulfonate are not substantially in contact (2)
Tablets are obtained in the same manner as in Example 25 except that Macrogol 6000 is changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).

[Test Example 19] Examination of interaction Loxoprofen sodium hydrate 347.1 mg (manufactured by Daiwa Pharmaceutical, trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and lysozyme hydrochloride 152.9 mg (manufactured by Eisai: trade name, lysozyme chloride) Were put in a glass bottle (3K standard bottle) and stored at 60 ° C. for 1 week (Reference Example 9). As comparative controls, loxoprofen sodium hydrate alone (Control Example 17) and lysozyme hydrochloride alone (Control Example 18) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 19.

As is apparent from Table 19, when the mixture of loxoprofen sodium hydrate and lysozyme hydrochloride was stored, the mixture became wet and further solidified (Reference Example 9). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and lysozyme hydrochloride alone (control examples 17 and 18). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and lysozyme hydrochloride.
As a result, it was found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and lysozyme or a salt thereof into contact with each other.

[Test Example 20]
The following Example 27 (formulation in which loxoprofen sodium and lysozyme hydrochloride are not substantially contacted (1)) and the composition of Comparative Example 6 were immediately after storage, 1 day, 3 days, 7 days, 14 days, 28 The state in the glass bottle after a day was evaluated.
That is, a mixture of loxoprofen sodium hydrate and lysozyme hydrochloride (Comparative Example 6) and loxoprofen sodium hydrate in which 8 g of dihydrocodeine phosphate is replaced with 30 g of lysozyme hydrochloride (manufactured by Eisai: trade name lysozyme chloride) And a lysozyme hydrochloride substantially free from contact with lysozyme hydrochloride (Example 27) was prepared and stored at 50 ° C. for 28 days, immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, and 28 days later. Except for the evaluation, the test was performed in the same manner as in Test Example 2. The results are shown in Table 20.

As is apparent from Table 20, in the case where the mixture of loxoprofen sodium hydrate and lysozyme hydrochloride was stored, the mixture became wet after 3 days from the start of storage as a result of the interaction (Comparative Example 6). .
On the other hand, a granulated product obtained by granulating loxoprofen sodium hydrate, which is preserved by simply mixing lysozyme hydrochloride, can maintain the same state as at the beginning even after 28 days and can suppress the interaction. (Example 27).
As a result, it was found that the interaction can be suppressed by incorporating loxoprofen or a salt thereof and lysozyme or a salt thereof in a pharmaceutical composition so as not to contact each other.

[Example 28] Formulation in which loxoprofen sodium and lysozyme hydrochloride are not substantially in contact (2)
Example 2 except that 8 g of dihydrocodeine phosphate was changed to 30 g of lysozyme hydrochloride (manufactured by Eisai: trade name: lysozyme chloride), macrogol 6000 was changed to 25.7 g, and corn starch was changed to 20.8 g. A pill was obtained.

[Example 29] Formulation in which loxoprofen sodium and lysozyme hydrochloride are not substantially in contact (3)
Tablets were obtained in the same manner as in Example 68 except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 21] Examination of interaction Loxoprofen sodium hydrate 500 mg (Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and dl-methylephedrine hydrochloride 150 mg (Alps Pharmaceutical Industries, Ltd .: trade name Japan Pharmacy) Dl-methylephedrine hydrochloride powder) was mixed and placed in a glass bottle (3K standard bottle) and stored at 60 ° C. for 1 week (Reference Example 10). As comparative controls, loxoprofen sodium hydrate alone (Control Example 19) and dl-methylephedrine hydrochloride alone (Control Example 20) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated. The results are shown in Table 21.

As is apparent from Table 21, when the mixture of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride was stored, the mixture became wet and further discolored (Reference Example 10). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride alone (Control Examples 19 and 20). From this, it was found that the state change of the mixture was the result of interaction between loxoprofen sodium hydrate and dl-methylephedrine hydrochloride.
As a result, it was found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and ephedrine into contact with each other.

[Example 30] Formulation in which loxoprofen sodium and dl-methylephedrine hydrochloride do not substantially contact (1)
8 g of dihydrocodeine phosphate was replaced with 20 g of dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia, dl-methylephedrine hydrochloride powder), Macrogol 6000 was changed to 23.2 g, and corn starch was 18.3 g. A tablet is obtained in the same manner as in Example 2 except that.

[Example 31] Formulation in which loxoprofen sodium and dl-methylephedrine hydrochloride are not substantially in contact (2)
Tablets are obtained in the same manner as in Example 30, except that Macrogol 6000 is changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).

[Test Example 22] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (6)
As a test drug, dl-methylephedrine hydrochloride (ME) suspended in 0.5% methylcellulose (MC) solution was orally administered in a predetermined amount (20, 60, 180 mg / 5 mL / kg). The test was conducted in the same manner as in Test Example 3, the ulcer suppression rate (%) in the administration of the test drug was calculated, and the results are shown in Table 22.

As is apparent from Table 22, dl-methylephedrine hydrochloride alleviated gastric mucosal damage caused by loxoprofen.

[Test Example 23] Examination of interaction Loxoprofen sodium hydrate 404.9 mg (manufactured by Yamato Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and dextromethorphan hydrobromide hydrate 95.1 mg (No. 1) One fine chemical product: trade name: Dextromethorphan HBR) was mixed, put into a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 11). As comparative controls, loxoprofen sodium hydrate alone (Control Example 21) and dextromethorphan hydrobromide hydrate alone (Control Example 22) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated. The results are shown in Table 23.

As is apparent from Table 23, when the mixture of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate was stored, the mixture became wet (Reference Example 11). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate alone (Control Examples 21 and 22). From this, it was found that the state change of the mixture was the result of interaction between loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate.
As a result, it has been found that the interaction can be suppressed by not substantially contacting loxoprofen or a salt thereof and dextromethorphan or a salt thereof.

[Test Example 24]
For the composition of Example 32 (formulation (1) in which loxoprofen sodium and dextromethorphan hydrobromide hydrate are not substantially in contact with each other) and the composition of Comparative Example 7, The state in the glass bottle after 7 days, 14 days, and 28 days was evaluated.
That is, loxoprofen sodium hydrate and dextromethorphan hydrobromide water are used by replacing 8 g of dihydrocodeine phosphate with 16 g of dextromethorphan hydrobromide hydrate (product name: Dextromethorphan HBR manufactured by Daiichi Fine Chemical). A preparation (Example 32) in which a mixture of a Japanese product (Comparative Example 7), loxoprofen sodium hydrate, and dextromethorphan hydrobromide hydrate are substantially not in contact is produced, The test was carried out in the same manner as in Test Example 2 except that the evaluation was performed immediately after the start of storage, after 1 day, after 3 days, after 7 days, after 14 days, and after 28 days. The results are shown in Table 24.

As can be seen from Table 24, the mixture of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate which had been preserved by mixing had an interaction. Wet (Comparative Example 7).
On the other hand, what was preserved by simply mixing dextromethorphan hydrobromide hydrate with granulate obtained by granulating loxoprofen sodium hydrate, kept the same state as the start even after 28 days, It was found that this interaction can be suppressed (Example 32).
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and dextromethorphan or a salt thereof in a pharmaceutical composition so as not to contact each other.

[Example 33] Formulation in which loxoprofen sodium and dextromethorphan hydrobromide hydrate are not substantially in contact (2)
8 g of dihydrocodeine phosphate was replaced with 16 g of dextromethorphan hydrobromide hydrate (product name: Dextromethorphan HBR manufactured by Daiichi Fine Chemical Co., Ltd.). Macrogol 6000 was changed to 25.2 g and corn starch was changed to 20.3 g. A tablet is obtained in the same manner as in Example 2 except for changing.

[Example 34] Formulation in which loxoprofen sodium and dextromethorphan hydrobromide hydrate are not substantially in contact (3)
Tablets are obtained in the same manner as in Example 33 except that Macrogol 6000 is replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

[Test Example 25] Examination of interaction Mixing 224.9 mg of loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia, loxoprofen sodium hydrate) and 224.9 mg of guaifenesin (trade name: guaifenesin, manufactured by Alps) And stored in a glass bottle (3K standard bottle) at 60 ° C. for 1 week (Reference Example 12). As comparative controls, loxoprofen sodium hydrate alone (Control Example 23) and guaifenesin alone (Control Example 24) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the state in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 25.

As is clear from Table 25, when the mixture of loxoprofen sodium hydrate and guaifenesin was stored, the mixture turned into a clear liquid (Reference Example 12). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and guaifenesin alone (Control Examples 23 and 24). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and guaifenesin.
As a result, it has been found that the interaction can be suppressed by not substantially contacting loxoprofen or a salt thereof and guaifenesin.

[Example 35] Formulation in which loxoprofen sodium and guaifenesin are not substantially in contact (1)
Example 2 except that 8 g of dihydrocodeine phosphate was replaced with 83 g of guaifenesin (manufactured by Alps Pharmaceuticals: trade name Guaifenesin), macrogol 6000 was replaced with 292 g, corn starch was replaced with 243 g, and lactose hydrate was replaced with 34.8 g. In the same manner, a tablet is obtained.

[Example 36] Formulation in which loxoprofen sodium and guaifenesin are not substantially in contact (2)
Tablets are obtained in the same manner as in Example 35 except that Macrogol 6000 is replaced with hydrogenated oil (product name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).

According to the present invention, a storage-stable pharmaceutical composition can be provided by containing loxoprofen or a salt thereof and codeine or the like in the pharmaceutical composition so that they do not substantially contact each other.
Therefore, according to the present invention, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and codeine, which is excellent in storage stability and reduces or suppresses gastrointestinal disorders caused by loxoprofen.

Claims

Codeine, carbinoxamine or salt thereof, clemastine or salt thereof, chlorpheniramine or salt thereof, diphenylpyraline or salt thereof, bromhexine or salt thereof, ambroxol or salt thereof, lysozyme or salt thereof, and dextromethorphan or salt thereof A pharmaceutical composition comprising at least one selected from the group consisting of and loxoprofen or a salt thereof so as not to substantially contact each other.
A pharmaceutical composition containing codeine and loxoprofen or a salt thereof so as not to substantially contact each other.
The pharmaceutical composition according to claim 1 or 2, wherein loxoprofen or a salt thereof is loxoprofen sodium hydrate.
The pharmaceutical composition according to claim 3, comprising loxoprofen sodium hydrate in an amount of 10 to 300 mg per day in terms of loxoprofen sodium anhydride.
The pharmaceutical composition according to any one of claims 1 to 4, wherein the codeines are selected from codeine phosphate hydrate and dihydrocodeine phosphate.
The pharmaceutical composition according to claim 5, comprising 4-60 mg of codeine phosphate hydrate as a daily dose.
The pharmaceutical composition according to claim 5, comprising 2 to 30 mg of dihydrocodeine phosphate as a daily dose.
The pharmaceutical composition according to any one of claims 1 to 7, wherein the loxoprofen or a salt thereof is a granular material containing loxoprofen or a salt thereof.
The pharmaceutical composition according to any one of claims 1 to 8, wherein the codeine is a granular material containing codeine.
The pharmaceutical composition according to any one of claims 1 to 9, which is a solid preparation.
The pharmaceutical composition according to any one of claims 1 to 10, wherein the dosage form is a capsule, pill, granule, fine granule, powder or tablet.