KR20120112644A - Loxoprofen-containing pharmaceutical composition - Google Patents

Abstract

Providing the pharmaceutical composition containing loxopropene or its salt, codeine, etc. which are excellent in storage stability.
Codeine, carbinoxamine or salts thereof, clemastine or salts thereof, chlorpheniramine or salts thereof, diphenylpyraline or salts thereof, brohexine or salts thereof, ambroxol or salts thereof, lysozyme or salts and dexes A pharmaceutical composition comprising at least one member selected from the group consisting of tromethorphan or a salt thereof, and a roxofene or a salt thereof not to be in contact with each other substantially.

Description

Roxopropene containing pharmaceutical composition {LOXOPROFEN-CONTAINING PHARMACEUTICAL COMPOSITION}

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

Roxoprofen is a nonsteroidal anti-inflammatory drug (NSAID), which is a type of rheumatoid arthritis, deformed arthrosis, back pain, periarthritis, shoulder pain syndrome, toothache, acute upper respiratory tract, post-traumatic post-traumatic or anti-inflammatory. It is known to be effective for analgesic and antipyretic (Non Patent Literature 1).

Due to its excellent pharmacological action, roxofene has been considered to be combined with various drugs. As an action obtained by the said combination, for example, the reinforcing action of the anti-inflammatory, analgesic, and antipyretic effect by combining with caffeine, ethenamide, and acetaminophen (patent document 1), carbinoxamine maleate, chlorpheniramine maleate , Improvement effect of non-lung symptom by combining with ketotifenfumarate, mequitazine or epinastin hydrochloride (Patent Document 2), inhibitory effect on embryonic cell hyperplasia by combining with azelastine hydrochloride or mequitazine (Patent Document 3 ), And the like.

In addition, the effect of enhancing the effect on cough symptoms (patent document 4) and germ cell hyperplasia inhibitory effect (patent document 5) by combining roxofene with bromine hexene hydrochloride or ambroxole hydrochloride (patent document 5) and roxofene Is known to enhance the anti-inflammatory, analgesic, and antipyretic effect by combining with bromine hexine hydrochloride (Patent Document 6).

Moreover, it is also known that roxofene enhances the antihistamine action of chlorpheniramine maleate and clemastine fumarate (patent document 6). In this patent document, a combination of roxofene and various drugs is studied. Moreover, the formulation example which combined the loxoprofen and various drugs is described. Moreover, the gastric mucosal disorder inhibitory effect (patent document 7) which is a group of roxofene by the combination with an antacid and xanthine derivative is known.

On the other hand, codeine is known to be a narcotic antitussive component having antitussive action by inhibiting the function of the cough center. And based on this effect, it is a drug used for a comprehensive cold medicine and an antitussive expectorant drug as an antitussive component (nonpatent literature 2 etc.).

Moreover, some combinations of the above-mentioned roxofene and codeine are known. For example, the anti-inflammatory action is enhanced by combining roxofene and dihydrocodeine hydrochloride (Patent Document 6), and the combination of roxofene and codeine phosphate exhibits an inhibitory effect on airway germ cell hyperplasia ( Patent document 8) is known.

Moreover, about the formulation containing a roxofene and codeine, a fine granule, a capsule, and tablet (patent document 2, 4, 6, and 8) are known.

However, it is not known whether the interaction between roxofene or a salt thereof and codeine in the formulation occurs that affects the storage stability of these compounds and the like.

Japanese Patent Application Laid-Open No. 11-139971 Japanese Laid-Open Patent Publication 2001-199882 Japanese Unexamined Patent Publication No. 2008-169193 Japanese Laid-Open Patent Publication 2001-172175 Japanese Unexamined Patent Publication No. 2008-13542 Japanese Unexamined Patent Publication No. 2000-143505 Japanese Laid-Open Patent Publication 2006-52210 Japanese Unexamined Patent Publication No. 2007-314517

 The 15th revised Japanese pharmacy room comment book Hirokawa bookstore page C-4790-4795  OTC Handbook 2008-09 Academic Information Center Page 289

The present inventors, first, codeine, carbinoxamine or salts thereof, or clemastine or salts thereof, chlorpheniramine or salts thereof, diphenylpyralline or salts thereof, bromine hexin or salts thereof, ambroxol or salts thereof, To develop a pharmaceutical composition containing at least one selected from the group consisting of lysozyme or its salts and dextromethorphan or its salts (hereinafter also referred to as codeine, etc.) and roxofene or its salts, When storage stability was examined, it was found that mixing and storing codeine and the like and roxofene or salt thereof unexpectedly caused solidification, discoloration, and the like.

Therefore, the subject of this invention is codeine, carbinoxamine or its salt, clemastine or its salt, chlorpheniramine or its salt, diphenylpyraline or its salt, bromine hexine or its salt, ambroxol or its salt. It is the provision of the stable pharmaceutical composition containing 1 or more types chosen from the group which consists of a lysozyme or its salt, dextromethorphan, or its salt, and a roxofene or its salt.

First, the present inventors further investigated in order to solve the problem of storage stability, and found that the interaction caused by the contact of the codeine and the like with roxofene or its salt is the cause of the storage stability problem.

Therefore, the present inventors have found that the above interactions can be suppressed by containing in the pharmaceutical composition such that the codeine and the like and roxofene or its salt are not substantially in contact with each other.

That is, the present invention is codeine, carbinoxamine or salts thereof, clemastine or salts thereof, chlorpheniramine or salts thereof, diphenylpyraline or salts thereof, bromine hexin or salts thereof, ambroxolol or salts thereof, lysozyme Or it provides a pharmaceutical composition containing at least one selected from the group consisting of the salt and dextromethorphan or the salt thereof, and the roxofene or the salt thereof so as not to be substantially in contact with each other.

The pharmaceutical composition of the present invention has excellent storage stability.

In addition, the present inventors have found that the codeine or the like reduces or inhibits digestive tract obstruction caused by roxofene.

Therefore, according to this invention, it is excellent in storage stability, and can provide the pharmaceutical composition in which the digestive tract obstruction resulting from roxofene was reduced or suppressed.

The pharmaceutical composition of the present invention is a codeine, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromine hexin or a salt thereof, ambroxol or a salt thereof, It is characterized by containing at least one selected from the group consisting of lysozyme or its salt and dextromethorphan or its salt, and roxofene or its salt so as not to be substantially in contact with each other.

First, the loxopropene or its salt used by this invention is demonstrated.

The roxofene or salt thereof used in the pharmaceutical composition of the present invention includes not only roxofene but also a pharmaceutically acceptable salt of roxofene, and solvate with water or alcohol. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used. In the present invention, as loxopropene or a salt thereof, loxopropene sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate) is preferable.

What is necessary is just to examine and determine content of the roxofene or its salt in the pharmaceutical composition of this invention suitably according to sex, age, a symptom, etc. of the ingestor, per day, in terms of 10? The amount which can be taken 300 mg is preferable, and 30? The amount which can take 240 mg is more preferable, More preferred is an amount that can be taken at 180 mg.

In this invention, what is necessary is just to examine and determine suitably according to the daily dose mentioned above, and it is 0.4 to 0.4 to a roxofene propane anhydride conversion with respect to the total mass of a pharmaceutical composition. It is preferable to contain 90 mass%, and is 0.4? It is more preferable to contain 50 mass%, and it is 1.2? It is more preferable to contain 30 mass%, and it is 1.2? It is especially preferable to contain 25 mass%.

Codeine used in the pharmaceutical composition of the present invention means one or two or more selected from the group consisting of codeine, dihydrocodeine or salts thereof, and solvates thereof. That is, the codeine includes a pharmaceutically acceptable salt of codeine or dihydrocodeine and solvates thereof in addition to codeine or dihydrocodeine itself.

Preferred examples of codeine 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. Hydrocodein phosphate is preferred. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used.

Next, the codeine used in this invention is demonstrated in detail.

The content of codeine in the pharmaceutical composition of the present invention may be appropriately determined and determined depending on the sex, age, symptoms of the doser, and the reduction or suppression effect of the digestive tract caused by the confirmed roxofene penis. The amount which can take 60 mg is preferable, and 4? The amount which can take 48 mg is more preferable, 6? More preferred is an amount that can be taken 26 mg.

In addition, when codeine phosphate hydrate is used as codeine, it is 4? The amount which can take 60 mg is preferable, and 8? The amount which can take 48 mg is more preferable, More preferred is an amount that can be taken at 36 mg. Moreover, when dihydrocodein phosphate is used, it is 2? The amount which can take 30 mg is preferable, and 4? The amount which can take 24 mg is more preferable, 6? More preferred is an amount that can be taken at 24 mg. In the present invention, the codeine is 0.08? To the total mass of the pharmaceutical composition. It is preferable to contain 4 mass%. Moreover, when codeine is codeine phosphate hydrate, it is 0.15? It is preferable to contain 4 mass%, and it is 0.3? It is more preferable to contain 3 mass%, and it is 0.5? It is more preferable to contain 2.5 mass%. In addition, when codeine is dihydrocodeine phosphate, it is 0.08 to the total mass of the pharmaceutical composition. It is preferable to contain 2 mass%, and is 0.16? It is more preferable to contain 1.5 mass%, and it is 0.24? It is more preferable to contain 1.5 mass%.

What is necessary is just to examine and determine the content of roxofene or its salt and codeine contained in the pharmaceutical composition of this invention suitably according to the daily dose of each component mentioned above, , Codeine is 0.005? To 1 part by mass in terms of roxofene sodium anhydride. It is preferable to contain 4 mass parts, and it is 0.01? It is more preferable to contain 2 mass parts.

Carbinoxamine or its salt used for the pharmaceutical composition of this invention contains the pharmaceutically acceptable salt of carbinoxamine in addition to carbinoxamine itself. As a specific example of carbinoxamine or its salt, carbinoxamine, carbinoxamine maleate, carbinoxamine diphenyl disulfonate, etc. are mentioned, for example, Carbinoxamine maleate is more preferable in this invention. Do. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used.

The content of carbinoxamine or its salt in the pharmaceutical composition of the present invention may be appropriately examined and determined according to the sex, age, symptom, etc. of the ingestor. The amount which can take 60 mg is preferable, and is 0.5? The amount which can take 30 mg is more preferable, and 1? More preferred is an amount that can be taken at 16 mg.

In the present invention, carbinoxamine or its salt is added in an amount of 0.004? To the total mass of the pharmaceutical composition. It is preferable to contain 4 mass%, and it is 0.02? It is more preferable to contain 2 mass%, and it is 0.04? It is especially preferable to contain 1 mass%. In addition, what is necessary is just to determine content of carbinoxamine or its salt according to the daily dose mentioned above.

Although the content ratio of the loxoprofen or its salt contained in the pharmaceutical composition of this invention, and carbinoxamine or its salt is not specifically limited, What is necessary is just to examine and determine suitably according to the daily dose of each component mentioned above. Carvinoxamine or the salt thereof is 0.0003 to 1 part by mass in terms of lysopropene sodium anhydride. It is preferable to contain 6 mass parts, and it is 0.002? It is more preferable to contain 1 mass part, and 0.005? It is more preferable to contain 0.3 mass part.

Clemastine or a salt thereof used in the pharmaceutical composition of the present invention includes, in addition to clemastine itself, a pharmaceutically acceptable salt of clemastine. As a specific example of clemastine or its salt, clemastine, a clemastine fumarate, etc. are mentioned, for example, In this invention, a clemastine fumarate is preferable. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used.

What is necessary is just to examine and determine content of clemastine or its salt in the pharmaceutical composition of this invention suitably according to sex, age, a symptom, etc. of a taker, and it is 0.01? The amount which can be taken 5 mg is preferable, and is 0.05? The amount which can take 3 mg is more preferable, and is 0.1? More preferred is an amount that can be taken at 2 mg. In addition, 1.34 mg of clemastine fumarate is equivalent to 1 mg as a free body of clemastine.

In the present invention, clemastine or a salt thereof is 0.008? It is preferable to contain 0.4 mass%, and it is 0.01? It is more preferable to contain 0.2 mass%, and it is 0.015? It is especially preferable to contain 0.15 mass%. In addition, what is necessary is just to determine content of clemastine or its salt according to the daily dose mentioned above.

Although the content ratio of roxofene or its salt and clemastine or its salt contained in the pharmaceutical composition of this invention is not specifically limited, What is necessary is just to examine and determine suitably according to the daily dose of each component mentioned above. It is 0.0006? With respect to 1 mass part of lofen or its salt in terms of roxofene sodium anhydride, and in terms of free body of clemastine. It is preferable to contain 0.5 mass part, and 0.0012? It is more preferable to contain 0.1 mass part, and 0.002? It is more preferable to contain 0.03 mass part.

The chlorpheniramine or salt thereof used in the pharmaceutical composition of the present invention includes, in addition to chlorpheniramine itself, a pharmaceutically acceptable salt of chlorpheniramine.

Chlorpheniramine has optical isomers because of the presence of subsidiary carbon. In the present invention, any optical isomer is included, and a single optical isomer may be used, or a mixture of various optical isomers may be used. Among these, in this invention, a d-form and a dl-form are preferable. As a specific example of the said chlorpheniramine or its salt, chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl- chlorpheniramine maleate, etc. are mentioned, for example. In this invention, d- chlorpheniramine maleate and dl- chlorpheniramine maleate are preferable, and d- chlorpheniramine maleate is especially preferable. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used.

What is necessary is just to examine and determine content of chlorpheniramine or its salt in the pharmaceutical composition of this invention suitably according to sex, age, a symptom, etc. of a doser, and it is 0.1? The amount which can be taken 20 mg is preferable, and is 0.6? The amount which can take 12 mg is more preferable. In addition, when d-chlorpheniramine maleate is used as chlorpheniramine or its salt, 0.1? The amount which can take 15 mg is preferable, and is 0.6? The amount which can take 6 mg is more preferable, and 1? More preferred is an amount that can be taken at 5 mg. If dl-chlorpheniramine maleate is used, 0.5? The amount which can take 20 mg is preferable, and 1? The amount which can take 12 mg is more preferable, More preferred is an amount that can be taken at 10 mg.

In the present invention, the content of chlorpheniramine or its salt is 0.004? To the total mass of the pharmaceutical composition. It is preferable to contain 1.5 mass%, and it is 0.02? It is more preferable to contain 0.8 mass%, and it is 0.04? It is especially preferable to contain 0.7 mass%. In addition, what is necessary is just to determine content of chlorpheniramine or its salt, according to the daily dose mentioned above.

Although the content ratio of the roxofene or its salt contained in the pharmaceutical composition of this invention, and chlorpheniramine or its salt is not specifically limited, What is necessary is just to examine and determine suitably according to the daily dose of each component mentioned above. Chlorpheniramine or its salt is 0.0001? Against 1 part by mass of lofen or its salt in terms of roxofene sodium anhydride. It is preferable to contain 1.5 mass parts, and it is 0.0005? It is more preferable to contain 0.7 mass part, and 0.001? It is especially preferable to contain 0.5 mass part.

Diphenylpyraline or a salt thereof used in the pharmaceutical composition of the present invention includes, in addition to diphenylpyraline itself, a pharmaceutically acceptable salt of diphenylpyraline. As a specific example of diphenylpyrroline or its salt, diphenylpyraline, diphenylpyralline hydrochloride, diphenylpyralline oxalate, etc. are mentioned, In this invention, diphenylpyralline hydrochloride, Diphenylpyralline oxalate is preferred, and diphenylpyralline hydrochloride is particularly preferred. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used.

What is necessary is just to examine and determine content of the diphenylpyralline or its salt in the pharmaceutical composition of this invention suitably according to the sex, age, symptoms, etc. of the taker, but are 0.1? The amount which can take 13.5 mg is preferable, and 1? The amount which can take 4.5 mg is more preferable. In addition, when diphenylpyrroline hydrochloride is used as diphenylpyraline or its salt, it is 0.1? Per day. The amount which can take 12 mg is preferable, and 1? The amount which can take 4 mg is more preferable. When diphenylpyralline octanate is used, 0.1? The amount which can take 13.5 mg is preferable, and 1? The amount which can take 4.5 mg is more preferable.

In the present invention, the content of diphenylpyraline or its salt is 0.004? To the total mass of the pharmaceutical composition. It is preferable to contain 1.5 mass%, and it is 0.004? It is more preferable to contain 1 mass%. Of these, 0.04? It is preferable to contain 0.5 mass%, and it is 0.04? It is more preferable to contain 0.3 mass%, and it is 0.06? It is especially preferable to contain 0.25 mass%. In addition, what is necessary is just to determine content of diphenylpyrroline or its salt, according to the daily dose mentioned above.

Although the content ratio of roxofene or its salt contained in the pharmaceutical composition of this invention, and diphenylpyraline or its salt is not specifically limited, What is necessary is just to examine and determine suitably according to the daily dose of each component mentioned above, Diphenylpyrroline or its salt is added in 0.0001? It is preferable to contain 3 mass parts, and it is 0.0005? It is more preferable to contain 2.5 mass parts, and 0.001? It is more preferable to contain 1 mass part, and 0.001? It is especially preferable to contain 0.3 mass part.

The bromine hexine or salt thereof used in the pharmaceutical composition of the present invention includes, in addition to bromine hexane itself, a pharmaceutically acceptable salt of bromine hexine. Specific examples of bromine hexine or salts thereof include bromine hexine, bromine hexine hydrochloride, and the like. Bromine hexine hydrochloride is preferred in the present invention. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used.

What is necessary is just to examine and determine content of the bromine hexine or its salt in the pharmaceutical composition of this invention suitably according to the sex, age, symptoms, etc. of the taker, and convert bromine hexine or its salt into bromine hexine hydrochloride per day in 0.1? The amount which can take 50 mg is preferable, and is 0.5? The amount which can take 25 mg is more preferable, and 1? More preferred is an amount that can be taken at 15 mg. In the present invention, the content of bromine hexine or its salt is 0.004? It is preferable to contain 4 mass%, and it is 0.02? It is more preferable to contain 2 mass%, and it is 0.04? It is more preferable to contain 1 mass%. In addition, what is necessary is just to determine content of a bromine hexine or its salt in accordance with the daily dose mentioned above.

Although the content ratio of the roxofene or its salt contained in the pharmaceutical composition of this invention, and bromine hexine or its salt is not specifically limited, What is necessary is just to examine and determine suitably according to the daily dose of each component mentioned above. Bromine hexene or its salt was converted into bromine hexine hydrochloride with respect to 1 part by mass in terms of loxopropene sodium anhydride in terms of 0.0001? It is preferable to contain 10 mass parts, and 0.0005? It is more preferable to contain 2 mass parts, and 0.001? It is more preferable to contain 1 mass part.

Ambroxol or its salt used for the pharmaceutical composition of this invention contains pharmacologically acceptable salt of ambroxol besides ambroxol itself. As an example of an amproxol or its salt, an amproxol, an amproxol hydrochloride, etc. are mentioned, for example, Ambroxol hydrochloride is preferable in this invention. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used.

What is necessary is just to examine and determine content of ambroxol or its salt in the pharmaceutical composition of this invention suitably according to sex, age, a symptom, etc. of a taker, and converting ambroxol or its salt into ambroxol hydrochloride 0.1 per day ? The amount which can take 150 mg is preferable, and 0.5? The amount which can take 100 mg is more preferable, and 1? More preferred is an amount that can be taken at 50 mg.

In the present invention, the content of ambroxol or its salt is 0.004? It is preferable to contain 10 mass%, and it is 0.02? It is more preferable to contain 7 mass%, and it is 0.04? It is more preferable to contain 5 mass%. In addition, what is necessary is just to determine content of ambroxol or its salt according to the daily dose mentioned above.

Although the content ratio of the roxofene or its salt contained in the pharmaceutical composition of this invention, and ambroxol or its salt is not specifically limited, What is necessary is just to examine and determine suitably according to the daily dose of each component mentioned above. Amproxol or its salt was converted into ambroxol hydrochloride in an amount of 0.0001? It is preferable to contain 10 mass parts, and 0.0005? It is more preferable to contain 5 mass parts, and 0.001? It is more preferable to contain 3 mass parts.

Lysozyme or a salt thereof used in the pharmaceutical composition of the present invention includes, in addition to lysozyme itself, a pharmaceutically acceptable salt of lysozyme. Specific examples of lysozyme or salts thereof include lysozyme, lysozyme hydrochloride, and the like, and lysozyme hydrochloride is preferred in the present invention. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used.

The content of lysozyme or its salt in the pharmaceutical composition of the present invention may be appropriately examined and determined according to the sex, age, symptom, etc. of the user, but the lysozyme or its salt per day in terms of the titer of lysozyme hydrochloride is 5? 450 mg (titer) The amount which can be taken is preferable, and 10? 360 mg (titer) The amount which can be taken is more preferable, 270 mg (titer) The amount that can be taken is more preferred. In the present invention, the content of lysozyme or its salt is 0.2 to 0.2 in terms of the titer of lysozyme hydrochloride relative to the total mass of the pharmaceutical composition. It is preferable to contain 30 mass% (titer), and it is 0.4? It is more preferable to contain 25 mass% (titer), and it is 0.6? It is more preferable to contain 20 mass% (titer). In addition, what is necessary is just to determine content of a lysozyme or its salt according to the daily dose mentioned above.

The content ratio of roxofene or its salt and lysozyme or its salt contained in the pharmaceutical composition of this invention is not specifically limited, What is necessary is just to examine and determine suitably according to the daily dose of each component mentioned above. Pen or a salt thereof in an amount of 0.01 parts by mass of lysozyme hydrochloride relative to 1 part by mass in terms of lysopropene sodium anhydride. It is preferable to contain 45 mass parts (titer), and it is 0.04? It is more preferable to contain 12 mass parts (titer), and it is 0.08? It is more preferable to contain 5 mass parts (titer).

The dextromethorphan or salt thereof used in the pharmaceutical composition of the present invention includes, in addition to dextromethorphan itself, a pharmaceutically acceptable salt of dextromethorphan, furthermore, dextromethorphan or dextrome Also included are pharmaceutically acceptable salts of Thorpan and solvates with water or alcohols. Specific examples of dextromethorphan or salts thereof include dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalin salt, and the like. Thorphan hydrobromide hydrate and dextromethorphan phenolphthalin salt are preferable, and dextromethorphan hydrobromide hydrate is more preferable. These are well-known compounds, In addition to what can be manufactured by a well-known method, a commercially available thing can be used.

The content of dextromethorphan or its salt in the pharmaceutical composition of the present invention may be appropriately examined and determined according to the sex, age, symptom, etc. of the person taking it. It is preferable that it can take 270 mg, and is 0.5? It is more preferable that it can take 180 mg, and it is 1? More preferred is an amount that can be taken at 90 mg. When dextromethorphan hydrobromide hydrate is dextromethorphan hydrobromide hydrate, the dextromethorphan hydrobromide hydrate per day is 6? The amount which can take 60 mg is preferable, and is 15? The amount which can take 60 mg is more preferable, More preferred is an amount that can be taken 60 mg. Moreover, when dextromethorphan phenol phthaline salt is dextromethorphan phenol phthalin salt, it is 9? The amount which can take 90 mg is preferable, The amount which can take 90 mg is more preferable, More preferred is an amount that can be taken at 90 mg.

In the present invention, the content of dextromethorphan or its salt is 0.004? To the total mass of the pharmaceutical composition. It is preferable to contain 20 mass%, and it is 0.02? It is more preferable to contain 15 mass%, and it is 0.04? It is more preferable to contain 10 mass%. In addition, what is necessary is just to determine content of dextromethorphan or its salt in accordance with the daily dose mentioned above.

The content ratio of roxofene or its salt contained in the pharmaceutical composition of this invention, and dextromethorphan or its salt is not specifically limited, What is necessary is just to examine and determine suitably according to the daily dose of each component mentioned above. , Dextromethorphan or the salt thereof is 0.0001 to 1 part by mass in terms of roxofene sodium anhydride in terms of It is preferable to contain 20 mass parts, and it is 0.0005? It is more preferable to contain 10 mass parts, and 0.001? It is more preferable to contain 5 mass parts.

In addition, in this invention, "contains so that it may not mutually contact each other" means that it contains so that a roxofene or its salt, codeine, etc. do not contact so that an interaction may not express in a pharmaceutical composition. However, it is preferable to contain roxofene or its salt and codeine so that it may not contact.

Moreover, although the formulation of the pharmaceutical composition of this invention should not be specifically limited, From a viewpoint of the ease of taking, etc., a solid preparation is preferable.

As specific examples of the solid preparation, for example, oral dosage preparations such as capsules, pills, granules, fine granules, powders, tablets, dry syrups, jellies, troches and suppositories, such as suppositories, may be used. Oral solid preparations are preferred. The pharmaceutical composition of this invention may be coat | covered by dragee, film coating, etc. by a well-known method.

As said solid preparation, it contains (A) roxofene or its salt itself, or a solid composition containing roxofene or its salt, (B) itself, such as codeine, or codeine etc. It contains a solid composition and arrange | positions so that roxofene or its salt, codeine, etc. may not mutually contact with the component which comprises these solid compositions, provided that said component (A) is Roxov Lofen or the salt thereof, and the case where component (B) is itself such as codeine). These solid compositions are in the form of powder, granules, tablets, and the like.

As a specific form of the said solid preparation, the following (a)-(h) etc. can be illustrated, These are known by the well-known method as mentioned above, for example, by the well-known method as described in the 15th revised Japanese Pharmacy Room General Regulations etc. It can manufacture and formulate suitably using a preparation additive. In (A)-(H), the specific form of a solid preparation is illustrated using codeine as an example. Instead of codeine, chlorpheniramine or a salt thereof that interacts with loxoprofen or a salt thereof, and the like can also be prepared and formulated in the same manner as in the case of codeine.

(A) Any one of roxofene or its salt and codeine is granulated by a suitable method, and it is made into a granular material, and it is mix | blended without granulating the other roxofene or its salt or codeine. Powder, granules, and the like, and the granules coated with the appropriate granules in a suitable manner.

(B) Loxoprofen or a salt thereof and codeine are separately assembled by a suitable method to form granules, and powders and granules prepared by combining them and the granules are further coated by a suitable method. Formulation.

(C) Capsules filled with a powder or granules prepared in the above (A) or (B) in the capsule.

(D) A tablet obtained by producing a granular product prepared in the above (a) or (b) by a suitable method. Tablet manufacture can also be achieved by shape | molding to a fixed shape by a suitable method besides the compression method.

(E) Multi-layered tablets prepared so that roxofene or a salt thereof and codeine do not substantially come into contact with each other, and a formulation in which the multilayered tablet is further coated in a suitable manner. As the multi-layered tablet, it is preferable to have roxofene or a salt thereof and codeine placed in different layers from each other, and as a multi-layered tablet of three or more layers, a layer containing roxofene or a salt thereof and codeine are contained. It is more preferable to arrange | position so that the layers to contact may not contact each other. In addition, the granules produced in (a) or (b) can be used as roxofene or its salt and codeine.

(F) Manufacture of roxofene or salts thereof and codeine in any one of the core tablets (also called core tablets and central tablets) so that the roxofene or salts thereof and codeine are not substantially in contact with each other. A nucleated tablet and a formulation further coated with the nucleated tablet in a suitable manner. In addition, the granules produced in (a) or (b) can be used as roxofene or its salt and codeine.

(G) Instead of the granules of (a) or (b), any one or both of roxofene or its salt and codeine can be replaced with α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin. A preparation using a clathrate compound encapsulated with cyclodextrins or the like.

(H) A formulation in which any one of roxofene or its salt and codeine is prepared in a conventional method, and a dragee layer or a film coating layer is formed, and the other drag is contained in the dragee layer or the coating layer. , A preparation prepared so that roxofene or its salt and codeine are not substantially in contact with each other (if the tablet is a tablet, it is called dragee or film coated tablet).

The granular materials in (a) and (b) are suitably used as additives by known granulation methods such as extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, crushing granulation, melt granulation and the like. It is good to manufacture. In the present invention, all of the granules containing roxofene or a salt thereof and the granules containing codeine may be produced by the same granulation method, or may be manufactured by different granulation methods.

Granular material containing roxofene or a salt thereof can be produced by granulation by a suitable method based on a known method, but commercially available ones can be used.

As a commercial item, For example, 10% of Rose Orr (trademark) fine grain manufactured by Tatsumi Chemical Co., Ltd. (The fine grain is a roxofene sodium hydrate, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, Magnesium stearate, silicon dioxide, and iron trioxide, containing 113.4 mg of lysopropene sodium hydrate (100 mg as an anhydride) in 1 g, 10% of lysopropene sodium granules manufactured by Super Seido Pharmaceutical Co., Ltd. `` CH '' (the fine granules contain roxofene sodium hydrate, lactose hydrate, hydroxypropyl cellulose, magnesium stearate, talc, silicon dioxide, iron trioxide, polysorbate 40, and 1 g of loxopropene It contains 113.4 mg of sodium hydrate (100 mg as an anhydride), Kentan (trademark) fine grain 10% of Medi Corporation New Drug Co., Ltd. Contains cargo, light silicic anhydride, iron trioxide, magnesium stearate, lactose hydrate, hydroxypropylcellulose, fumaric acid, D-mannitol, and contains 113.4 mg (100 mg as anhydride) of roxofopentium hydrate in 1 g. ), 10% of ponaperto (trademark) fine grains manufactured by BioMedics Co., Ltd. (The fine grains are lysopropene sodium hydrate, lactose hydrate, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, stearic acid Magnesium and iron trioxide, containing 113.4 mg (100 mg as an anhydride) of lysopropene sodium hydrate in 1 g, 10% of Lingeriz® fine granules manufactured by Yoshindo Co., Ltd. Contains Soprofen Sodium Hydrate, Lactose Hydrate, Crospovidone, Hydroxypropylcellulose, Magnesium Stearate, Iron Trioxide, It contains 113.4 mg of sodium hydrate (100 mg as an anhydride), 10% of loxonine (trademark) fine granules from Daiichi Sankyo Co., Ltd. It contains hydroxypropyl cellulose, iron trioxide, lactose hydrate, magnesium stearate, and 113.4 mg (100 mg as an anhydride) of roxofofene sodium hydrate in 1 g of lorfenamine (registered by Nichiiko Co., Ltd.) 10% fine granules (these fine grains contain roxofene sodium hydrate, lactose hydrate, carboxymethyl starch sodium, hydroxypropyl starch, hydroxypropyl cellulose, magnesium stearate, talc, iron trioxide, 1 and 113.4 mg (containing 100 mg as an anhydride) of roxofene sodium hydrate in g. In addition, the fine granules containing 113.4 mg (100 mg as anhydride) of roxofene pentahydrate hydrate in said 1g can be made to increase and decrease content of roxofene pentahydrate hydrate suitably based on a well-known method.

In preparing the pharmaceutical composition of the present invention, the agent additives that can be used include, for example, binders, excipients, disintegrants, lubricants, glidants, colorants and the like.

As the binder, for example, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, sodium carmellose, dextrin, partially alphalated starch, pullulan, gum arabic, agar, gelatin, tra Gantt, sodium alginate, povidone, polyvinyl alcohol, etc. are mentioned. In addition, when melt granulation is used when producing the granular materials in (a) and (b), a binder having a low melting point (solidification point) that is solid at room temperature and melted or softened by heating is used. It is preferable. As melting | fusing point (solidification point) of such a binder, it is preferable that it is lower than melting | fusing point of the component (loxopropene or its salt, codeine, etc.) which concerns on this invention. Specifically, the melting point (solidification point) is 30? The binder which is 100 degreeC is preferable, and 50? It is more preferable that it is 80 degreeC. As such, for example, macrogols (for example, macrogol 4000, macrogol 6000, macrogol 20000, etc.); fats and oils (for example, hardened oil, hardened oil, hydrogenated vegetable oil, soybean cured oil, carnauba wax) Bleached beeswax, beeswax, beeswax, etc .; hydrocarbons (e.g., paraffin, microcrystalline wax, etc.); higher alcohols (e.g. cetyl alcohol, stearyl alcohol, etc.); fatty acids (e.g., Stearic acid etc.) Fatty acid ester (For example, acetylglycerol fatty acid ester, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, glycerol monostearate, etc.) etc. are mentioned.

As excipients, for example, crystalline cellulose, powdered cellulose, lactose hydrate, white sugar, glucose, mannitol, erythritol, xylitol, trehalose, multitol, lactitol, sorbitol, wheat starch, corn starch, potato starch, anhydrous hydrogen phosphate Calcium, calcium carbonate, silicon dioxide, etc. are mentioned.

Examples of the disintegrating agent include carmellose, carmellose calcium, croscarmellose sodium, carboxymethylethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, hydroxypropyl starch and the like. Can be.

Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, sodium stearyl fumarate, and the like.

As a fluidizing agent, hydrous silicon dioxide, a hard silicic acid anhydride, titanium oxide etc. are mentioned, for example.

As a colorant, For example, yellow iron trioxide, iron trioxide, food blue No. 1, food blue No. 2, food yellow No. 4, food yellow No. 5, food green No. 3, food red No. 2, food red No. 3, Food Red 102, Food Red 104, Food Red 105, Food Red 106 and the like can be mentioned.

In the pharmaceutical composition of the present invention, drugs other than roxofene or salts thereof, codeine, and the like, for example, antipyretic analgesics, antihistamines, antitussives, noscarpine, bronchodilators, expectorants, hypnotics, It may contain one or two or more selected from the group consisting of vitamins, anti-inflammatory agents, gastric mucosa protective agents, anticholinergic drugs, herbal medicines, herbal prescriptions, caffeine, xanthine-based ingredients and the like.

Examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, isopropyl antipyrine, ibpropene, ethenamide, sasaprine, salicylate, sodium salicylate, tiaramid hydrochloride, lactylphenetine and the like. Can be.

As antihistamine, For example, azelastine hydrochloride, alimazine zine tartarate, isotifendi hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastin fumarate, ketotifenfumarate, difeterol hydrochloride, dife Terrol Phosphate, Diphenhydramine Hydrochloride, Diphenhydramine Salicylate, Diphenhydramine Tannin Hydrochloride, Triprolidine Hydrochloride, Triprenamine Hydrochloride, Tonzylamine Hydrochloride, Penetazine Hydrochloride, Promethazine Hydrochloride, Promethazinemethylene 2-salicylic Acid Salt, mequitazine, metdilazine hydrochloride, mebhydroline nafadisylate, and the like.

As an antitussive agent, for example, allochloramide hydrochloride, eprazinon hydrochloride, carbetapentane citrate, cloperastine hydrochloride, cloperastene pendizoate, sodium dibutate, dimemorphan phosphate, thifepidine citrate And tifepidinehydrinate.

As noscapine, noscapine hydrochloride, noscapine, etc. are mentioned, for example.

As bronchodilators, for example, trimethoquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, ephedrines (pseudophedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, dl- Methyl ephedrine saccharine salt), a methoxy phenamine hydrochloride, etc. are mentioned.

Examples of the expectorant include ammonia and fennel tablets, ethyl cysteine hydrochloride, ammonium chloride, carbocysteine, guapenesine, potassium guayacholsulfonate, potassium cresolsulfonate, methylcysteine hydrochloride, and l-menthol. have.

As a hypnotic sedative, allyl isopropyl acetyl urea, brom valeryl urea, etc. are mentioned, for example.

Examples of the vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof and their salts (for example, thiamin, thiamine chloride hydrochloride, etc.). , Thiamine nitride, dicetiamine hydrochloride, cetothiamine hydrochloride, fursulthiamine, fursulthiamine hydrochloride, octothiamine, sicothiamine, thiamine disulfide, bisthiamine, bisbenthiamine, prosulthiamine, benfothiamine, riboflavin, riboflavinic acid Esters, riboflavin butyric acid esters, riboflavin sodium sodium, panthenol, panthetin, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxalic acid esters, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc. ).

As anti-inflammatory agents, for example, glycyrrhizin acid and its derivatives and salts thereof (for example, dipotassium glycyrrhinate, monoammonium glycyrrhinate, etc.), seaproses, semialkaliproteinases, serapeptases, tranexamic acid, pros, etc. Kthases, pronases, bromelain and the like.

As gastric mucosa protective agent, For example, aminoacetic acid, aldioxa, magnesium silicate, geparnath, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum-amino acetate (aluminum glycinate), Aluminum hydroxide gel, aluminum hydroxide-magnesium carbonate mixed dry gel, co-precipitation product of aluminum hydroxide-sodium carbonate, co-precipitation product of aluminum hydroxide-calcium carbonate-magnesium carbonate, coprecipitation product of magnesium hydroxide-aluminum potassium sulfate, sucralate, set Lactate hydrochloride, Sofalcone, Magnesium carbonate, Tefrenone, Potassium copper chloropyridine, Copper chloropyrine sodium, Magnesium metasilicate aluminate, Methyl methionine sulfonium chloride, etc. are mentioned.

As anticholinergic agents, for example, oxyphencycline hydrochloride, dicyclomine hydrochloride, meticene hydrochloride, scopolamine hydrobromide, datura extract, tifepidium bromide, methylatropin bromide, methylanisort Ropin bromide, methyl scopolamine bromide, methyl l-hiyostiamine bromide, methylbenacthidium bromide, pyrenezepine hydrochloride, butyl scopolamine bromide, belladonna alkaloid, belladonna extract, belladonna Total alkaloids, isopropionide iodide, diphenylpiperidinomethyldioxolane iodide, scofolia extract, scopolyazine, scopolyazine total alkaloid citrate, and the like.

As herbal medicines, for example, Yedeok tree, subtropical medicine, yinyanggwa, fennel, turmeric, light green, yeonmyeongcho, hwangja, citrine, yellow white, cherries, yellow lotus, grass, azel, green tea, camomile, caronine, licorice, Bellflower, Pedestrian, Wolfberry, Wolfberry, Cinnamon, Cinnamon, Cassia, Gentiana, Cranberry, Hyangbuja, Umbrella, Schisandra chinensis, Sanshin, Anticidal, Phalanx, Peony, Musk, Photograph, Cha-jeon, Chajeoncho, Sudam ) (Including ungdam), ginger, earth dragon, god, stone mountain, Senega, celestial organ, Jeonho, bitter grass, shovel, baekbaekpi, lobule, daesan, bamboo pickled ginseng, cloves, dermis, donkey, tonggi, Namcheonsil, ginseng, Herbs and extracts such as Pamo, Macmundong, Peppermint, Banja, Red flower, Banbi (Aggistrodon quince), White paper, Baekryok, Bokyeong, Charcoal bark, Peel, Ephedra, Deer antler and extracts thereof (extract, tincture, dry extract, etc.) ), And the like.

Examples of herbal medicines include Gyeji-tang, Hyangsosan, Shiho-jiji-tang, Sojaho-tang, Mcmundong-tang, and Banha-hubak-tang.

As caffeine, sodium benzoate caffeine, caffeine hydrate, anhydrous caffeine, etc. are mentioned, for example.

As a xanthine type component, aminopyrin, dipropyrine, theophyrin, proxiphylline, etc. are mentioned, for example.

Moreover, as a pharmaceutical composition of this invention, following (a)? Preference other than (u) is preferable.

(a) tablets containing 180 mg of lysopropene sodium hydrate, 45 mg of codeine phosphate, 110 mg of crystalline cellulose, 40 mg of hydroxypropyl cellulose, 10 mg of magnesium stearate, and an appropriate amount of lactose (in 6 tablets),

(b) Fine granules containing 180 mg of lysopropene sodium hydrate, 20 mg of dihydrocodein phosphate, 140 mg of crystalline cellulose, 100 mg of hydroxypropyl cellulose, 10 mg of magnesium stearate, 190 mg of D-mannitol, and an appropriate amount of lactose (In 3 bags),

(c) capsules (in 6 capsules) containing 180 mg of lysopropene sodium hydrate, 45 mg of codeine phosphate, 10 mg of magnesium stearate, 50 mg of polysorbate, 170 mg of corn starch and an appropriate amount of lactose,

(d) Tablets containing 60 mg of lysopropene sodium hydrate (in anhydride equivalent), 10 mg of dihydrocodein phosphate, 7 mg of magnesium stearate, 60 mg of crystalline cellulose, 200 mg of starch and 13 mg of lactose (350 mg per tablet) ),

(e) 60 mg of roxofene sodium hydrate (anhydride equivalent), 10 mg of dihydrocodein phosphate, 10 mg of cerapeptase, 4 mg of brohexine hydrochloride, 7 mg of magnesium stearate, 60 mg of crystalline cellulose, 186 mg of starch, and Tablets containing 13 mg of lactose (350 mg per tablet),

(f) 60 mg of lysopropene dihydrate (anhydride equivalent), carbinoxamine 4 maleic acid, 20 mg dl-methyl ephedrine hydrochloride, 10 mg cerapeptase, 7 mg magnesium stearate, 60 mg crystalline cellulose, Hard capsules (1 capsule 350 mg) containing 176 mg starch and 13 mg lactose,

(g) 60 mg of lysopropene sodium dihydrate (anhydrous equivalent), carbinoxamine 4 mg maleate, 20 mg dl-methyl ephedrine hydrochloride, 10 mg cerapeptase, 7 mg magnesium stearate, 60 mg crystalline cellulose, Tablets containing 176 mg of starch and 13 mg of lactose (350 mg in 1 tablet),

(h) Tablets containing 60 mg of sodium roxofene dihydrate (in anhydride equivalent), 4 mg of maleic acid carbinoxamine, 7 mg of magnesium stearate, 60 mg of crystalline cellulose, 206 mg of starch and 13 mg of lactose (1 tablet) 350 mg),

(i) Containing 60 mg of sodium roxofene dihydrate (in anhydride equivalent), 4 mg of maleic acid carbinoxamine, 50 mg of lysozyme chloride, 7 mg of magnesium stearate, 60 mg of crystalline cellulose, 156 mg of starch and 13 mg of lactose Tablets (350 mg in 1 tablet),

(j) 60 mg of roxofene sodium dihydrate (anhydride equivalent), carbinoxamine 4 maleic acid, 20 mg dl-methyl-ephedrine hydrochloride, 10 mg serapeptase, 254 mg β-cyclodextrin, 30 mg aspartame, Effervescent tablet (2400 mg in 1 tablet) containing 965 mg of citric acid, 813 mg of sodium bicarbonate, 194 mg of lactose and 50 mg of magnesium stearate,

(k) 60 mg of roxofene sodium dihydrate (anhydride equivalent), 4 mg maleic acid carbinoxamine, 20 mg dl-methylephedrine hydrochloride, 10 mg serapeptase, 300 mg β-cyclodextrin, 30 mg aspartame, Fast-acting tablets or chewable tablets (700 mg in 1 tablet) containing 262 mg of mannitol and 14 mg of magnesium stearate,

(l) A tablet containing 60 mg of sodium roxofene dihydrate (in anhydride equivalent), 5 mg of clemastine fumarate, 7 mg of magnesium stearate, 60 mg of crystalline cellulose, 205 mg of starch and 13 mg of lactose (in 1 tablet) 350 mg),

(m) tablets containing 180 mg of lysopropene sodium, 45 mg of ambroxol hydrochloride, 100 mg of crystalline cellulose, 40 mg of hydroxypropyl cellulose, 10 mg of magnesium stearate and an appropriate amount of lactose (in 6 tablets),

(n) tablets containing 180 mg of lysopropene sodium, 12 mg of bromine hex hydrochloride, 100 mg of crystalline cellulose, 40 mg of hydroxypropyl cellulose, 10 mg of magnesium stearate and an appropriate amount of lactose (in 6 tablets),

(o) 180 mg of lysopropene sodium, 15 mg of ambroxol hydrochloride, 8 mg of bromine hexane hydrochloride, 0.2 mg of belladonna (total) alkaloids, 100 mg of crystalline cellulose, 40 mg of hydroxypropyl cellulose, 10 mg of magnesium stearate And tablets containing an appropriate amount of lactose (in 6 tablets),

(p) Fine granules containing 180 mg of roxofene sodium, 45 mg of ambroxol hydrochloride, 130 mg of crystalline cellulose, 100 mg of hydroxypropyl cellulose, 10 mg of magnesium stearate, 290 mg of D-mannitol and an appropriate amount of lactose ( 3 out of 3),

(q) Fine granules containing 180 mg of lysopropene sodium, 12 mg of bromine hex hydrochloride, 130 mg of crystalline cellulose, 100 mg of hydroxypropyl cellulose, 10 mg of magnesium stearate, 290 mg of D-mannitol and an appropriate amount of lactose (3) Gun),

(r) 180 mg of lysopropene sodium, 15 mg of ambroxol hydrochloride, 8 mg of bromine hexane hydrochloride, 0.2 mg of belladonna (total) alkaloids, 130 mg of crystalline cellulose, 100 mg of hydroxypropyl cellulose, 10 mg of magnesium stearate Fine granules (in 3 sachets) containing 290 mg of D-mannitol and an appropriate amount of lactose,

(s) capsules (in 6 capsules) containing 180 mg of lysopropene sodium, 45 mg of ammonium hydrochloride, 10 mg of magnesium stearate, 50 mg of polysorbate, 180 mg of corn starch and an appropriate amount of lactose,

(t) capsules (in 6 capsules) containing 180 mg of lysopropene sodium, 12 mg of bromine hex hydrochloride, 10 mg of magnesium stearate, 50 mg of polysorbate, 200 mg of corn starch and an appropriate amount of lactose;

(u) 180 mg of lysopropene sodium, 15 mg of ambroxol hydrochloride, 8 mg of bromine hexane hydrochloride, 0.2 mg of belladonna (total) alkaloids, 10 mg of magnesium stearate, 50 mg of polysorbate, 190 mg of corn starch, and Capsules with fine granules containing an appropriate amount of lactose (in 6 capsules).

Examples of the administration route of the pharmaceutical composition of the present invention include oral and parenteral such as rigid rectum and hard, but oral administration is preferable. Moreover, when administering orally, the pharmaceutical composition of this invention is 1? Per day. Divided into about four times, can be taken before meals, between meals, after meals, and before bedtime.

The pharmaceutical composition of this invention may be preserve | saved in the presence of a desiccant from the point of interaction suppression. Hereinafter, what includes the pharmaceutical composition of this invention and a desiccant in a container may be called the "pharmaceutical formulation" of this invention.

In the present invention, the desiccant is not particularly limited. As a desiccant, for example, in silica gel, silica alumina gel (arofen), natural zeolite, synthetic zeolite (molecular), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride and magnesium oxide 1 type (s) or 2 or more types selected are mentioned, and these and the activated carbon may be mixed. Among these, 1 type, or 2 or more types chosen from a silica gel, a silica alumina gel (arofen), a synthetic zeolite (molecular), and calcium chloride are more preferable, and a synthetic zeolite is especially preferable at the point of interaction inhibition.

Moreover, the shape of a desiccant is not specifically limited, either, For example, what was shape | molded in plate shape, the encapsulated sheet form, columnar (tablet form), etc., Even if it was paper-wrapped and the film coating was given to the columnar form. do.

Various drying agents are commercially available, for example, Shirett, MS-tablet, MS-seram W, Tokai gel, Deshikaito 25, Arpite, and Yamane Pharmaceutical Co., Ltd. Registered product) distribution product, dry yarn (registered trademark) tablet, dry yarn (registered trademark) sheet, sekad, allo sheet, zeo sheet manufactured by Shinagawa Hwasung Co., Ltd. OZO of OZO Chemical Technology Research Institute Co., Ltd. Sheet, ID packing desiccant, etc. are mentioned.

The content of the desiccant in the pharmaceutical formulation of the present invention may be appropriately examined and determined, but is 0.05 to 1 part by mass of loxopropene or its salt. 35 mass parts is preferable, and 0.15? 17 mass parts is more preferable.

Moreover, content of a desiccant is 0.001-about 1 mass part of pharmaceutical compositions of this invention containing roxofene or its salt, codeine, etc. 1 mass part is preferable and 0.004? 0.4 mass part is more preferable.

The container used for the pharmaceutical formulation of this invention will not be specifically limited if it can be used as containers, such as a food, a supplement, a medicine, or a health food, Any one of a fixed container and an amorphous container can be used, It is preferable that it can be sealed. As said shaping container, a bottle, a can, a box, etc. are mentioned, for example. As an amorphous container, a bag (pillow packaging, stick packaging, PTP packaging, SP packaging, etc.) etc. are mentioned, for example. Among these containers, specifically, bottles and bags are preferable.

The formation member of a container is not specifically limited, For example, members, such as a paper, glass, resin, or a resin film, or a metal or a metal film, are mentioned, and it is set as the composite structure or multilayer structure which combined these members suitably. It may be. Moreover, it is preferable that the moisture permeation prevention process is given about the member which has moisture permeability, such as paper.

The container may be either transparent, translucent or opaque.

The pharmaceutical composition of this invention and the method of accommodating a desiccant in a container are not specifically limited, Any can be achieved by arrange | positioning by suitable means, such as input into a container.

The storage in the container is, for example, when the container is a bottle, the desiccant (preferably columnar (table type)) is disposed in the bottle, or the inside of the bottle lid (inner cap), while the present invention It can achieve by storing the pharmaceutical composition of this in a bottle. In storing in a bottle, it is preferable that the pharmaceutical composition containing the roxofene or its salt, codeine, etc. of this invention was made into the solid formulation containing these.

Moreover, when a container is a sealing, it can achieve by storing a desiccant (preferably plate-like or a sheet-like sheet form) and the pharmaceutical composition of this invention in a bag. In storing in a bag, it is preferable that the pharmaceutical composition containing the roxofene or its salt, codeine, etc. of this invention was made into the solid formulation containing these.

In addition, the pharmaceutical composition of the present invention may be packaged once by SP packaging, PTP packaging or encapsulation, and then the packaged pharmaceutical composition and a desiccant may be in a form enclosed in a packaging. More specifically, the form which package | fills SP type | mold, PTP-packed solid formulation, and plate-shaped or desiccant sheet-like desiccant together is mentioned. In addition, the thing of the said pillow packaging form may be stored in a box etc.

Since the pharmaceutical composition of the present invention contains roxofene, which is a type of NSAID, or a salt thereof, headache, toothache, pain after extraction, sore throat, pain, joint pain, neuralgia, back pain, muscle pain, stiff neck pain, and headache pain. Fracture pain, sprain pain, dysmenorrhea (physiological pain), traumatic pain, chills, fever during fever, cold symptoms, symptoms (neck pain, cough, chills, fever, headache, joint pain, muscle pain), cough, etc. It has efficacy or effects and is useful as a cold medicine, antipyretic analgesic, or the like.

In addition, codeine used in the pharmaceutical composition of the present invention suppresses and reduces digestive tract obstruction caused by roxofene, as is apparent from the later examples. Therefore, a patient with a peptic ulcer or a patient with a past medical history can also take loxoprofen or its salt without fear of digestive tract obstruction caused by roxofene.

Example

Although an Example etc. are given to the following and this invention is demonstrated in detail, this invention is not limited to these Examples etc. at all.

[Test Example 1]

Review of the interaction

500 mg of lysopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and 60 mg of dihydrocodeine phosphate (the Shiono Pharmaceutical Co., Ltd. make: brand name dihydrocodein phosphate "cyano group") It put in the glass bottle (3K standard bottle), and preserve | saved for one week at 60 degreeC (reference example 1). As a comparative control, loxopropene sodium hydrate alone (control example 1) and dihydrocodein phosphate alone (control example 2) were similarly stored at 60 ° C. for one week. Immediately after the start of storage, after 1 day, after 3 days, the state in the glass bottle after 1 week was evaluated, and the results are shown in Table 1.

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 1 White powder White powder White powder White powder Comparative Example 2 White powder White powder White powder White powder Reference Example 1 White powder White powder solidification White powder solidification Light Yellow Powder Solidification

As is apparent from Table 1, upon preservation of the mixture of sodium xopropene hydrate and dihydrocodein phosphate, the mixture solidified and also discolored (Reference Example 1). On the other hand, there was no change in the storage of the loxopropene sodium hydrate and the dihydrocodein phosphate alone (control examples 1 and 2). In this regard, the state change of the mixture was found to be the result of the interaction between roxofene and codeine.

[Test Example 2]

Review of the interaction

For the composition of Comparative Example 1 below (Formulation (1) substantially free of chloropropene sodium hydrate and dihydrocodein phosphate), and the composition of Comparative Example 1, 1 day later, 3 days later, 1 The state in the glass bottle after one week was evaluated, and the result was shown in Table 2.

68.1 g of lysopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Nippon Pharmacy, Loxpropene sodium hydrate), 29.2 g of macrogol 6000 (Nippon fats and oil manufacture: brand name macrogol 6000P) and corn starch 24.3 g (Nichiden Chemical Manufacture: The brand name corn starch ST-C) was stirred in the glass beaker on 65 degreeC water bath, and then cooled, and it filtered out with the No. 18 sieve, and obtained granulated material. Dihydrocodeine phosphate 8g (Siono group pharmaceutical make: brand name dihydrocodein phosphate "Siono group") was mixed with the obtained granulated material, it put into the glass bottle (13K standard bottle), and preserve | saved for 1 week at 50 degreeC (Example 1 ).

On the other hand, 68.1 g of sodium loxoprofen hydrate (Daiwa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate), 29.2 g of macrogol 6000 (Nippon fats and oils manufacture: brand name macrogol 6000P), corn starch 24.3 g (nichi Den Chemical Co., Ltd .: brand name corn starch ST-C) and 8 g of dihydrocodene phosphate (Siono group Pharmaceutical Co., Ltd. product name: dihydrocodein phosphate "Siono group") are mixed, put into a glass bottle (13K standard bottle) at 50 ℃ One week was preserved (Comparative Example 1).

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 1 White powder solidification White powder solidification White powder solidification White powder solidification Example 1 White figurine White figurine White figurine White figurine

As is clear from Table 2, the preservation by only mixing the roxofene sodium hydrate and the dihydrocodein phosphate, when the interaction occurred, resulted in the mixture being solidified 1 day after the start of the preservation (Comparative Example 1).

On the other hand, the preservation of the granular preparation prepared by mixing dihydrocodein phosphate with the granular material obtained by assembling the loxopropene sodium hydrate was found to maintain the same state as at the time of initiation and to suppress the interaction. (Example 1).

[Example 2]

Preparations substantially free of roxofene sodium hydrate and dihydrocodeine phosphate (2006.01)

68.1 g of lysopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Nippon Pharmacy, Loxpropene sodium hydrate), 29.2 g of macrogol 6000 (Nippon fats and oil manufacture: brand name macrogol 6000P) and corn starch 24.3 g (Nichiden Chemical Manufacture: The brand name corn starch ST-C) was stirred in the glass beaker on 65 degreeC water bath, and then cooled, and it filtered out with the No. 18 sieve, and obtained granulated material. 8 g of dihydrocodeine phosphate (the Shiono group pharmaceutical make: brand name dihydrocodeine "siono group"), 81 g of carmellose calcium (Kotoku Pharmaceutical Co., Ltd. name: ECG505), lactose hydrate 591.3 g (DMV production :) in the obtained granulated material Lactose 200M) and 8.1 g of magnesium stearate (manufactured by Taihei Chemical Co., Ltd.: trade name magnesium stearate (vegetable)), and then a tableting machine equipped with a ball having a diameter of 8.5 mm (manufactured by Hatta Iron Works: HT-AP18SS type) It was tableted using to obtain a tablet having a single mass of 270 mg.

[Example 3]

Formulations substantially free of roxofene sodium hydrate and dihydrocodeine phosphate (2006.01)

Except having changed macrogol 6000 into hardening oil (Kawaken Fine Chemicals make: brand name K-3 wax-200), it carried out similarly and obtained the tablet.

Example 4

Formulations substantially free of roxofene sodium hydrate and dihydrocodeine phosphate (2006.01)

68.1 g of lysopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Nippon Pharmacy, Loxpropene sodium hydrate), 29.2 g of macrogol 6000 (Nippon fats and oil manufacture: brand name macrogol 6000P) and corn starch 24.3 g (Nichiden Chemical Manufacture: The brand name corn starch ST-C) was stirred in the glass beaker on 65 degreeC water bath, and then cooled, and it filtered out with the No. 18 sieve, and obtained granulated material. 8 g of dihydrocodein phosphate (the Shiono group pharmaceutical make: brand name dihydrocodeine "cyano group"), 81 g of carmellose calcium (Kotoku Pharmaceutical Co., Ltd. make: brand name ECG505), lactose hydrate 295.7 g (DMV production :) in the obtained granulated material After mixing a brand name lactose 200M), 295.6 g of crystalline celluloses (made by Asahi Kasei Chemicals: brand name Seuras PH-101), and 8.1 g of magnesium stearate (Taihei Chemical Co., Ltd. make: brand name magnesium stearate (vegetable vegetable)), diameter It tableted using the tableting machine (Hata Iron Works Co., Ltd. make: HT-AP18SS type) which attached the 8.5-mm ball, and obtained the tablet which is 270 mg of 1 mass.

[Example 5]

Formulations substantially free of roxofene sodium hydrate and dihydrocodeine phosphate (2006.01)

8 g of dihydrocodein phosphate (the Shiono group pharmaceutical make: brand name dihydrocodein phosphate "Siono group"), 3.4 g of macrogol 6000 (Nippon fats and oil manufacture: brand name Macrogol 6000P) and corn starch 2.9 g (Nichiden Chemical Co., Ltd.) The brand name Corn Starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, and then cooled, and then filtered through a No. 18 sieve to obtain a granulated product. To the obtained granulated material, 68.1 g of sodium roxofene hydrate (Daiwa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate), carmellose calcium 81 g (Kotoku Pharmaceutical Co., Ltd. name: ECG505), lactose hydrate 638.5 g ( DMV production: Brand name lactose 200M) and 8.1 g of magnesium stearate (Taihei Chemical Co., Ltd. product name: Magnesium stearate (vegetable)), and then a tableting machine equipped with a ball having a diameter of 8.5 mm (manufactured by Hatta Iron Works: HT-AP18SS) Tablet) was used to obtain a tablet having a single mass of 270 mg.

[Example 6]

Preparations substantially free of roxofene sodium hydrate and dihydrocodeine phosphate (2006.01)

68.1 g of lysopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Nippon Drug Store loxopene sodium hydrate), 24.3 g of hydroxypropyl cellulose (Nippon soda make: brand name HPC-L), 81 g of carmellose calcium (Kotoku Chemical manufacture: Brand name ECG505) and 620.5 g of crystalline cellulose (Asahi Kasei Chemicals make: brand name Seoras PH-101) were put into a high speed stirring granulator (Powrek make: VG-05 type), and after mixing, 328.8 g of purified water was added. By kneading. This granulated material was put into a fluidized-bed drier (Flo-5 type) and dried, and was granulated using a squirrel machine (Okada positive hole production: ND-10 type). 793.9 g of this formulation, 8 g of dihydrocodein phosphate (the Shiono group pharmaceutical make: brand name dihydrocodein "cyano group"), and 8.1 g of magnesium stearate (the Taihei Chemical Industries make: brand name magnesium stearate (vegetable vegetable)) After mixing and mixing into a mixer (made by Kotobuki: PM50), tableting was carried out using a tableting machine equipped with a ball having a diameter of 8.5 mm (manufactured by Hata Iron Works: HT-AP18SS type) to obtain a tablet having a defined mass of 270 mg. Got it.

[Example 7]

Formulations substantially free of roxofene sodium hydrate and dihydrocodeine phosphate (2006.01)

8 g of dihydrocodein phosphate (the Shiono group pharmaceutical manufacture: brand name dihydrocodein phosphate "Siono group"), 24.3 g of hydroxypropyl cellulose (Nippon soda make: brand name HPC-L), 81 g of carmellose calcium (Kotoku Pharmaceutical Co., Ltd. manufacture) ： Brand name ECG505) and 620.5 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd., name: Seoras PH-101) were added to a high-speed stirring granulator (Powrec Manufacture: VG-05 type), followed by mixing, followed by addition of 328.8 g of purified water. did. This granulated material was thrown into a fluidized-bed drier (Floth Industrial Co., Ltd. type: FLO-5 type | mold), and after drying, it was stipulated using the sizing machine (Okada positive hole manufacture: ND-10 type). 733.8 g of this formulation, 68.1 g of sodium roxofene pentahydrate (Daiwa Pharmaceutical Co., Ltd. make: brand name Nippon Drug Store Loxopropene sodium hydrate) and magnesium stearate 8.1 g (Taihei Chemical Co., Ltd. make: brand name magnesium stearate (vegetable substance) ) Was mixed into a mixer (Kotobuki Co., Ltd .: PM50 type) and mixed, and tableted using a tableting machine equipped with a ball having a diameter of 8.5 mm (Hita Iron Works Co., Ltd .: HT-AP18SS type), and has a fixed mass of 270 mg. A tablet was obtained.

[Example 8]

Formulations substantially free of roxofene sodium hydrate and dihydrocodeine phosphate (2006.01)

68.1 g of lysopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Nippon Drug Store Loxopene sodium hydrate), 12.1 g of hydroxypropyl cellulose (Nippon soda make: brand name HPC-L), carmellose calcium 40.5 g (Kotoku Chemical manufacture: Brand name ECG505) and 280.2 g of crystalline cellulose (Asahi Kasei Chemicals make: brand name Seoras PH-101) were put into a high speed stirring granulator (Powrek make: VG-05 type), and 164.3 g of purified water was added after mixing. By kneading. This granulated material was put into a fluidized-bed drier (Flo-5 type), and dried, and then granulated using a sizer (Okada Hole: ND-10 type) (Glass A). In addition, 8 g of dihydrocodein phosphates (the Shiono group pharmaceutical make: brand name dihydrocodeine "siono group"), 12.1 g of hydroxypropyl cellulose (Nippon soda make: brand name HPC-L), carmellose calcium 40.5 g (Kotoku Chemical manufacture: Brand name ECG505) and 340.3 g of crystalline cellulose (Asahi Kasei Chemicals make: brand name Seoras PH-101) were put into a high speed stirring granulator (Powrek make: VG-05 type), and 164.3 g of purified water was added after mixing. By kneading. This granulated material was thrown into a fluidized-bed drier (Floth Industrial Co., Ltd .: FLO-5 type), and after drying, it was sized using a sizing machine (Okada Holes: ND-10 type) (Glass B). After mixing 400 g of sieving A, 400 g of sieving B, and 8 g of magnesium stearate (made by Taihei Chemical Co., Ltd .: brand name magnesium stearate (vegetable)) by mixing into a mixer (Kotobuki Co., Ltd. product: PM50 type), 8.5 mm in diameter It tableted using the tableting machine (Hata Iron Works Co., Ltd. make: HT-AP18SS type) equipped with the artificial ball, and obtained the tablet which is 270 mg of 1 mass.

[Test Example 3]

Inhibition of roxofene-induced gut disorder (1)

The test was carried out using 6 groups of 1 group using a Wistar rat (Std: Wistar / ST, male, 8 weeks old, body weight 188.9 to 227.9 g). Rats were fasted from the day before the start of the test (16 hours or more). Intake of water was made free until 1 hour before the start of the test, and then water saving.

As a test drug, dihydrocodein phosphate (DP) was suspended in a 0.5% methyl cellulose (MC) solution, and a predetermined amount (8, 24, 72 mg / 5 ml / kg) was orally administered.

In addition, the control group was orally administered with the same dose (5 ml / kg) only of the solvent (0.5% MC), respectively.

One hour after administration of the test drug, 120 mg / 2 ml physiological saline / kg of loxopropene sodium hydrate was orally administered to each group of rats to cause gastric mucosal obstruction. After 5 hours of administration of the roxofene sodium hydrate, the rats were euthanized by cervical dislocation, the ligature part was ligated, and the stomach was extracted. 10 ml of 1% formalin solution was injected into the stomach from the pyloric region, and after ligation of the pyloric region, the entire stomach was immersed in the formalin solution for about 20 minutes and lightly fixed.

Evaluation of the degree of gastric mucosal injuries was performed by cutting the stomach along the Taiwanese curve and then measuring the length (mm) of individual injuries (dumbs) that occurred in the distal part under a stereoscopic microscope, and totaling the damage per rat. It was calculated as the ulcer index. According to the following formula, the ulcer inhibition rate (%) in the test drug was calculated, and the results are shown in Table 3.

Ulcer inhibition rate (%) = (1-ulcer index of subject drug / ulcer index of control) × 100

As is apparent from Table 3, dihydrocodeine phosphate alleviated gastric mucosal obstruction caused by roxofene.

[Test Example 4]

Review of the interaction

584 mg of loxopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and 10 mg of d-chlorpheniramine maleate (congo chemical make: brand name D-maleic chlorpheniramine) are mixed, It put in the glass bottle (3K standard bottle), and preserve | saved for one week at 60 degreeC (reference example 2). As a comparative control, loxopropene sodium hydrate alone (control example 3) and d-chlorpheniramine maleate alone (control example 4) were similarly stored at 60 ° C. for one week. Immediately after the start of storage, after 1 day, after 3 days, the state in the glass bottle after 1 week was evaluated, and the results are shown in Table 4.

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 3 White powder White powder White powder White powder Comparative Example 4 White powder White powder White powder White powder Reference Example 2 White powder White powder wetting White powder some solidification Some solid yellowish powder

As is apparent from Table 4, when the mixture of sodium xopropene hydrate and chlorpheniramine maleate was preserved, the mixture was wet, solidified, and also discolored (Reference Example 2). On the other hand, there was no change in the storage of the loxopropene sodium hydrate and chlorpheniramine maleate alone (controls 3 and 4). In this respect, it was found that the change of the state of the mixture was the result of the interaction between the roxofene sodium hydrate and the chlorpheniramine maleate.

[Test Example 5]

For Example 9 (Formulation (1) substantially free of sodium chloropropene and d-chlorpheniramine maleate) and the composition of Comparative Example 2, immediately after the start of storage, after 1 day, after 3 days, After 7 days, after 14 days, the state in the glass bottle after 28 days was evaluated.

That is, 8 g of dihydrocodein phosphate was changed to 1.2 g of d-chlorpheniramine maleate (manufactured by Congo Chemical Co., Ltd. name: D-maleic chlorpheniramine), and mixed with roxofene sodium hydrate and d-chlorpheniramine maleate. (Comparative Example 2), a formulation (Example 9) substantially free of sodium roxofene pentahydrate and d-chlorpheniramine maleate was prepared, and stored at 50 ° C for 28 days, immediately after the start of storage, After 1 day, after 3 days, after 7 days, after 14 days, and after 28 days, it tested similarly to Test Example 2. The results are shown in Table 5.

Immediately after commencement of preservation   1 day later    3 days later   7 days later   After 14 days   28 days later Comparative Example 2 White powder White powder White powder
Wetting White powder
Wetting White powder
Wetting White powder
Wetting Example 9 White figurine White figurine White figurine White figurine White figurine White figurine

As is clear from Table 5, the preservation by only mixing the sodium xopropene hydrate and the chlorpheniramine maleate resulted in an interaction, and as a result, the mixture was wet after 3 days from the start of the preservation (Comparative Example 2).

On the other hand, the thing preserved only by mixing chlorpheniramine maleate with the granular material obtained by granulating the loxopropene sodium hydrate can maintain the same state as the time of initiation even after 28 days, and can suppress the said interaction. It turned out (Example 9).

As a result, it has been found that interaction can be suppressed by containing roxofene or its salt and chlorpheniramine or its salt in the pharmaceutical composition so as not to substantially contact each other.

[Example 10]

Preparations substantially free of roxofene sodium and d-chlorpheniramine maleate (2006.01)

The same procedure as in Example 2 was carried out except that 8 g of dihydrocodein phosphate was changed to 1.2 g of d-chlorpheniramine maleate (manufactured by Congo Chemical Co., Ltd .: trade name D-maleic chlorpheniramine) and corn starch was changed to 31.1 g. A tablet was obtained.

[Example 11]

Preparations substantially free of roxofene sodium and d-chlorpheniramine maleate (2006.01)

The tablets were obtained like Example 10 except having changed Macrogol 6000 into hardening oil (Kawaken Fine Chemicals make: brand name K-3 wax-200).

[Test Example 6]

Inhibition of roxofene-induced digestive tract obstruction (2)

As a test drug, oral administration of a predetermined amount (5, 40 mg / 5 ml / kg) using a suspension of d-chlorpheniramine maleate (CM) in a 0.5% methyl cellulose (MC) solution was performed. The test was performed similarly, the ulcer inhibition rate (%) in test drug administration was computed, and the result was shown in Table 6.

As evident in Table 6, chlorpheniramine maleate alleviated gastric mucosal obstruction caused by roxofene.

[Test Example 7]

Review of the interaction

381 mg of lysopropene sodium hydrate (Dawa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and 2.5 mg of clemastine fumarate (manufactured by Daito: brand name clemastine fumarate) were mixed, and a glass bottle ( 3K standard bottle) and preserve | saved for one week at 60 degreeC (reference example 3). As a comparative control, loxopropene sodium hydrate alone (control 5) and clemastine fumarate alone (control 6) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the state in the glass bottle after one day, three days later, and one week later was evaluated, and the results are shown in Table 7.

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 5 White powder White powder White powder White powder Comparative Example 6 White powder White powder White powder White powder Reference Example 3 White powder White powder White powder wetting Light brown powder wetting

As evident in Table 7, upon preservation of the mixture of sodium xopropene hydrate and clemastine fumarate, the mixture was wet and also discolored (Reference Example 3). On the other hand, no change occurred in the storage of the lysopropene sodium hydrate and the clemastine fumarate alone, respectively (controls 5 and 6). In this respect, it was found that the change in the state of the mixture was a result of the interaction between the roxofene sodium hydrate and the clemastine fumarate.

As a result, it has been found that interaction can be suppressed by containing roxofene or its salt and clemastine or its salt in the pharmaceutical composition so as not to substantially contact each other.

[Example 12]

Formulations substantially free of roxofene sodium and clemastine fumarate (1)

A tablet was obtained in the same manner as in Example 2 except that 8 g of dihydrocodein phosphate was changed to 0.5 g of clemastine fumarate (manufactured by Daito Corporation, trade name Clemastine fumarate), and corn starch was changed to 31.8 g. .

[Example 13]

Agents substantially free of roxofene sodium and clemastine fumarate (2006.01)

A tablet was obtained in the same manner as in Example 12 except that Macrogol 6000 was changed to a cured oil (Kawaken Fine Chemicals Co., Ltd. product: K-3 Wax-200).

[Test Example 8]

Inhibition of roxofene-induced digestive tract obstruction (3)

Tested in the same manner as in Test Example 3 by orally administering a predetermined amount (1 mg / 5 ml / kg) using a suspension of clemastine fumarate (CF) in a 0.5% methyl cellulose (MC) solution as a test drug. , The ulcer inhibition rate (%) in the test drug administration was calculated, and the results are shown in Table 8.

As is apparent from Table 8, clemastine fumarate alleviated gastric mucosal obstruction caused by roxofene.

[Test Example 9]

Review of the interaction

482.3 mg of lysopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and carbinoxamine maleate 17.7 mg (congo Chemical make: brand name maleic acid carbinoxamine) are mixed, and a glass bottle is mixed. It put into the (3K standard bottle), and preserve | saved for one week at 60 degreeC (reference example 4). As a comparative control, loxopropene sodium hydrate alone (Control 7) and carbinoxamine maleate alone (Control 8) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, after 1 day, after 2 days, the state in the glass bottle after 1 week was evaluated, and the results are shown in Table 9.

Immediately after preservation starts 1 day later 2 days later In a week Comparative Example 7 White powder White powder White powder White powder Comparative Example 8 White powder White powder White powder White powder Reference Example 4 White powder White powder solidification White powder solidification Light Yellow Powder Solidification

As is clear from Table 9, upon preservation of the mixture of sodium xopropene hydrate and carbinoxamine maleate, the mixture solidified and also discolored (Reference Example 4). On the other hand, there was no change in the storage of the loxopropene sodium hydrate and the carbinoxamine maleate alone, respectively (controls 7 and 8). In this respect, it was found that the change of state of the mixture was a result of the interaction between the roxofene sodium hydrate and the carbinoxamine maleate.

As a result, it has been found that interaction can be suppressed by containing roxofene or its salt and carbinoxamine or its salt in the pharmaceutical composition so as not to be substantially in contact with each other.

Example 14

Formulations substantially free of sodium xopropene and carbinoxamine maleate (1)

Purification was carried out in the same manner as in Example 2, except that 8 g of dihydrocodein phosphate was changed to 2.5 g of carbinoxamine maleate (manufactured by Congo Chemical Co., Ltd., product name: Carbinoxamine), and corn starch was changed to 29.8 g. Get

Example 15

Formulations substantially free of sodium xopropene and carbinoxamine maleate (2006.01)

A tablet was obtained in the same manner as in Example 14 except that Macrogol 6000 was changed to a cured oil (Kawaken Fine Chemical Co., Ltd. product: K-3 Wax-200).

[Test Example 10]

Inhibition of roxofene-induced gut disorder (4)

As the test drug, carbinoxamine maleate (CAM) was suspended in a 0.5% methyl cellulose (MC) solution, and a predetermined amount (0.75, 75 mg / 5 ml / kg) was orally administered, the same as in Test Example 3. The test was conducted and the ulcer inhibition rate (%) in the test drug administration was calculated, and the results are shown in Table 10.

As evident in Table 10, carbinoxamine maleate alleviated gastric mucosal obstruction caused by roxofene.

[Test Example 11]

Review of the interaction

490.4 mg of chlorosopropene sodium hydrate (Dawa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and diphenylpyrroline hydrochloride 9.6 mg (congo chemical make: brand name diphenylpyralline hydrochloride) are mixed, and a glass bottle is mixed. It put into the (3K standard bottle), and preserve | saved for one week at 60 degreeC (reference example 5). As a comparative control, loxopropene sodium hydrate alone (Control 9) and diphenylpyrroline hydrochloride alone (Control 10) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, after 1 day, after 3 days, the state in the glass bottle after 1 week was evaluated, and the results are shown in Table 11.

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 9 White powder White powder White powder White powder Comparative Example 10 White powder White powder White powder White powder Reference Example 5 White powder White powder wetting White powder wetting Light yellow powder wetting

As evident in Table 11, upon preservation of the mixture of sodium xopropene hydrate and diphenylpyraline hydrochloride, the mixture was wet and also discolored (Reference Example 5). On the other hand, there was no change in the storage of the loxopropene sodium hydrate and the diphenylpyralline hydrochloride alone, respectively (controls 9 and 10). In this respect, the change of state of the mixture was found to be the result of the interaction between the roxofene sodium hydrate and the diphenylpyralline hydrochloride.

As a result, it has been found that interaction can be suppressed by containing roxofene or its salt and diphenylpyraline or its salt in the pharmaceutical composition so as not to substantially contact each other.

[Test Example 12]

About the composition of the following Example 16 (formulation (1) which does not substantially contact sodium xopropene sodium and diphenylpyralline hydrochloride), and the composition of the comparative example 3, immediately after a storage start, 1 day, 3 days, 7 After day, after 14 days, the state in the glass bottle after 28 days was evaluated.

That is, 8 g of dihydrocodein phosphate was changed to 1.3 g of diphenylpyrroline hydrochloride (congo Chemical Co., Ltd. name: diphenylpyral hydrochloride), and mixed with roxofene sodium hydrate and diphenylpyralline hydrochloride (Comparative) Example 3) The preparation (Example 16) which substantially does not come in contact with the roxofene sodium hydrate and diphenylpyrroline hydrochloride was prepared, and also it preserve | saved at 50 degreeC for 28 days, immediately after the start of storage, and after 1 day, It tested like Example 2 except having evaluated after 3 days, after 7 days, after 14 days, and after 28 days. The results are shown in Table 12.

At the start of preservation   1 day later    3 days later   7 days later   After 14 days   28 days later Comparative Example 3 White powder White powder
Wetting White Powder Wet Steel White Powder Wet Steel White Powder Wet Steel White Powder Wet Steel Example
16 White figurine White figurine White figurine White figurine White figurine White figurine

As is clear from Table 12, the preservation by only mixing the roxofene sodium hydrate and the diphenylpyraline hydrochloride resulted in interaction, and as a result, the mixture was wet after 3 days from the start of the preservation (Comparative Example 3).

On the other hand, the preservation only by mixing diphenylpyraline hydrochloride with the granular material obtained by granulating the loxopropene sodium hydrate can maintain the same state as the time of initiation even after 28 days, and can suppress the said interaction. It turned out (Example 16).

As a result, it has been found that interaction can be suppressed by containing roxofene or its salt and diphenylpyraline or its salt in the pharmaceutical composition so as not to substantially contact each other.

Example 17

Preparations substantially free of roxofene sodium and diphenylpyral hydrochloride (1)

The purification was carried out in the same manner as in Production Example 2, except that 8 g of dihydrocodein phosphate was changed to 1.3 g of diphenylpyrroline hydrochloride (Congo Chemical Co., Ltd. name: diphenylpyralline hydrochloride), and corn starch was changed to 31 g. Got it.

[Example 18]

Agents substantially free of roxofene sodium and diphenylpyralline hydrochloride (2006.01)

A tablet was obtained in the same manner as in Production Example 17 except that Macrogol 6000 was changed to a curing oil (Kawaken Fine Chemical Co., Ltd. product: K-3 Wax-200).

[Test Example 13]

Inhibition of roxofene-induced gut disorder (5)

As a test drug, a predetermined amount (3, 10 mg / 5 ml / kg) was orally administered using a suspension of diphenylpyraline hydrochloride (PP) in a 0.5% methyl cellulose (MC) solution, the same as in Test Example 3. The test was conducted and the ulcer inhibition rate (%) in the test drug administration was calculated, and the results are shown in Table 13.

As is clear from Table 13, diphenylpyrroline hydrochloride reduced gastric mucosal obstruction caused by roxofene.

[Test Example 14]

Review of the interaction

170 mg of lysopropene sodium hydrate (Dawa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and 10 mg of bromine hexine hydrochloride (Sanyo Chemical make: brand name bromine hex hydrochloride) are mixed, and a glass bottle (3K standard bottle ) Was stored for 1 week at 60 ℃ (Reference Example 6). As a comparative control, loxopropene sodium hydrate alone (control example 11) and bromine hexine hydrochloride alone (control example 12) were similarly stored at 60 ° C. for one week. Immediately after the start of storage, the state in the vial after one day, two days later, and one week later was evaluated, and the results are shown in Table 14.

Immediately after preservation starts 1 day later 2 days later In a week Comparative Example 11 White powder White powder White powder White powder Comparative Example 12 White powder White powder White powder White powder Reference Example 6 White powder White powder solidification White powder solidification Light Yellow Powder Solidification

As evident in Table 14, upon preservation of the mixture of sodium xopropene hydrate and brominehexine hydrochloride, the mixture solidified and discolored (Reference Example 6). On the other hand, there was no change in the storage of the loxopropene sodium hydrate and the bromine hexine hydrochloride alone (controls 11 and 12). In this respect, it was found that the change of state of the mixture was a result of the interaction between the roxofene sodium hydrate and the bromine hexine hydrochloride.

As a result, it has been found that the interaction can be suppressed by not substantially contacting the loxoprofen or its salt and brominehexine or the salt thereof.

[Test Example 15]

For the composition of Example 19 (Formulation (1), wherein the chlorophyll sodium and bromine hexyl hydrochloride were not substantially in contact with) and the composition of Comparative Example 4, immediately after the start of storage, after 1 day, after 3 days, and after 7 days After 14 days, the condition in the vial after 28 days was evaluated.

That is, 8 g of dihydrocodein phosphate was changed to 4 g of bromine hexine hydrochloride (Sanyo Chemical make: brand name brohexine hydrochloride), which mixed the roxofene sodium hydrate and bromine hex hydrochloride (comparative example 4), and Roxov A preparation (Example 19) substantially free of lofensodium hydrate and bromine hexine hydrochloride was prepared, and stored at 50 ° C. for 28 days, immediately after the start of storage, after 1 day, after 3 days, and after 7 days, After 14 days, it tested like Example 2 except having evaluated after 28 days. The results are shown in Table 15.

 Start of preservation   1 day later    3 days later   7 days later   After 14 days   28 days later Comparative Example 4 White powder White powder wetting White powder wetting White powder wetting White powder wetting White powder wetting Example 19 White figurine White figurine White figurine White figurine White figurine White figurine

As is apparent from Table 15, the preservation by only mixing the roxofene sodium hydrate and the bromine hexin hydrochloride resulted in an interaction, and as a result, the mixture was wet after one day of the start of preservation (Comparative Example 4).

On the other hand, it was found that only the bromine hexin hydrochloride was mixed with the granules obtained by assembling the lysopropene sodium hydrate to preserve the same state as the time of initiation even after 28 days, thereby suppressing the interaction. (Example 19).

As a result, it has been found that interaction can be suppressed by containing roxofene or its salt and bromine hexine or its salt in the pharmaceutical composition so as not to be substantially in contact with each other.

[Example 20]

Formulations substantially free of roxofene sodium and brominehexine hydrochloride (2006.01)

A tablet was obtained in the same manner as in Production Example 2 except that 8 g of dihydrocodein phosphate was changed to 4 g of brohexine hydrochloride (Sanyo Chemical Co., Ltd. product: Bromine Hexin hydrochloride), and corn starch was changed to 28.3 g.

Example 21

Preparations substantially free of roxofene sodium and brominehexine hydrochloride (2006.01)

A tablet was obtained in the same manner as in Production Example 20 except that Macrogol 6000 was changed to a curing oil (Kawaken Fine Chemicals Co., Ltd. product: K-3 Wax-200).

[Test Example 16]

Review of the interaction

500 mg of chlorosopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and 500 mg of the ambrosol hydrochloride (manufactured by Shizuoka Caffeine Industry Co., Ltd. name: Ambroxol hydrochloride) It put into the (3K standard bottle), and preserve | saved for one week at 60 degreeC (reference example 7). As a comparative control, loxopropene sodium hydrate alone (control example 13) and ambroxole hydrochloride alone (control example 14) were similarly stored at 60 ° C. for one week. Immediately after the start of storage, after 1 day, after 3 days, the state in the glass bottle after 1 week was evaluated, and the results are shown in Table 16.

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 13 White powder White powder White powder White powder Comparative Example 14 White powder White powder White powder White powder Reference Example 7 White powder White powder solidification Pale yellow powder solidification Pale yellow powder solidification

As is clear from Table 16, upon preservation of the mixture of sodium xopropene hydrate and ambroxole hydrochloride, the mixture solidified and also discolored (Reference Example 7). On the other hand, no change occurred in the storage of the roxofene sodium hydrate and the ambrosol hydrochloride alone, respectively (controls 13 and 14). In this respect, it was found that the change of the state of the mixture was the result of the interaction between the roxofene sodium hydrate and the ambrosol hydrochloride.

As a result, it has been found that the interaction can be suppressed by not making the loxoprofen or its salt and ambroxol or its salt substantially contact.

[Test Example 17]

Regarding the composition of Example 22 (Formulation (1) in which sodium roxofene sodium and ambrosol hydrochloride were not substantially in contact with) and the composition of Comparative Example 5, immediately after the initiation of storage, after 1 day, after 3 days, and 7 days Then, after 14 days, the state in the glass bottle after 28 days was evaluated.

That is, 8 g of dihydrocodein phosphate was changed to 15 g of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industrial Co., Ltd. trade name: Ambroxol hydrochloride), and a mixture of roxofene sodium hydrate and ambroxol hydrochloride (Comparative Example) 5) A preparation (Example 22) substantially free of sodium roxofene pentahydrate and ambroxol hydrochloride was prepared, and stored at 50 ° C. for 28 days, immediately after the start of storage, and after 3 days Then, it tested similarly to the test example 2 except having evaluated after 7 days, after 14 days, and after 28 days. The results are shown in Table 17.

At the start of preservation 1 day later 3 days later 7 days later After 14 days 28 days later Comparative Example 5 White powder White powder solidification White powder solidification White powder solidification White powder solidification White powder solidification Example 22 White figurine White figurine White figurine White figurine White figurine White figurine

As apparent from Table 17, the preservation only by mixing the roxofene sodium hydrate and the ambroxole hydrochloride resulted in an interaction, and as a result, the mixture solidified 1 day after the start of preservation (Comparative Example 5).

On the other hand, the only thing preserved by mixing ambroxol hydrochloride in the granular material obtained by granulating the loxopropene sodium hydrate can maintain the same state as the time of initiation even after 28 days and can suppress the said interaction. It turned out (Example 22).

As a result, it has been found that interaction can be suppressed by containing roxofene or its salt and ambroxol or its salt in the pharmaceutical composition so as not to be substantially in contact with each other.

[Example 23]

Agents substantially free of roxofene sodium and ambroxole hydrochloride (2006.01)

The procedure was carried out except that 8 g of dihydrocodein phosphate was changed to 15 g of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industrial Co., Ltd.: trade name ambroxol), and macrogol 6000 was changed to 25.7 g and corn starch to 20.8 g. In the same manner as in Example 2, a tablet was obtained.

Example 24

Preparations substantially free of roxofene sodium and ambroxole hydrochloride (2006.01)

The tablets were obtained like Example 23 except having changed Macrogol 6000 into hardening oil (Kawaken Fine Chemicals make: brand name K-3 wax-200).

[Test Example 18]

Review of the interaction

224.9 mg of lysopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and 275.1 mg of the guayacol sulfonate potassium (Yonezawa Hamari Pharmaceutical Co., Ltd. make: brand name Guayacol sulfonate) It mixed, and stored in the glass bottle (3K standard bottle) for one week at 60 degreeC (reference example 8). As a comparative control, loxopropene sodium hydrate alone (control 15) and guayacol sulfonate alone (control 16) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, after 1 day, after 3 days, the state in the glass bottle after 1 week was evaluated, and the results are shown in Table 18.

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 15 White powder White powder White powder White powder Comparative Example 16 White powder White powder White powder White powder Reference Example 8 White powder White powder wetting White powder wetting White powder wetting

As is apparent from Table 18, when the mixture of sodium roxofene hydrate and potassium guayacholsulfonate was preserved, the mixture was wet (Reference Example 8). On the other hand, there was no change in the storage of the lysopropene sodium hydrate and potassium guayachol sulfonate alone (controls 15 and 16). In this respect, the state change of the mixture was found to be the result of the interaction between the sodium roxofene hydrate and the potassium guayachol sulfonate.

As a result, it has been found that the interaction can be suppressed by not substantially contacting the loxoprofen or its salt and guayacholsulfonic acid or its salt.

[Example 25]

Formulations substantially free of sodium xopropene and potassium guayacholsulfonate (1)

8 g of dihydrocodein phosphate was changed to 83 g of potassium guayachol sulfonate (Yonezawa Hamari Pharmaceutical Co., Ltd. product name: potassium guayacol sulfonate), macrogol 6000 to 292 g, corn starch to 243 g, A tablet was obtained in the same manner as in Example 2 except that the lactose hydrate was changed to 34.8 g.

Example 26

Formulations substantially free of sodium xopropene and potassium guayacholsulfonate (2006.01)

A tablet was obtained in the same manner as in Example 25 except that Macrogol 6000 was changed to a cured oil (Kawaken Fine Chemical Co., Ltd. product: K-3 Wax-200).

[Test Example 19]

Review of the interaction

347.1 mg of lysopropene sodium hydrate (Dawa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and 152.9 mg of lysozyme hydrochloride (Ezai make: brand name lysozyme chloride) were mixed, and it was made to a glass bottle (3K standard bottle) It put and preserve | saved for one week at 60 degreeC (reference example 9). As a comparative control, loxopropene sodium hydrate alone (control example 17) and lysozyme hydrochloride alone (control example 18) were similarly stored at 60 ° C for one week. Immediately after the start of storage, the state in the vial after one day, three days later, and one week later was evaluated, and the results are shown in Table 19.

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 17 White powder White powder White powder White powder Comparative Example 18 White powder White powder White powder White powder Reference Example 9 White powder White powder wetting White powder solidification White powder solidification

As evident in Table 19, upon preservation of the mixture of sodium xopropene hydrate and lysozyme hydrochloride, the mixture was wet and also solidified (Reference Example 9). On the other hand, no change occurred in the storage of the roxofene sodium hydrate and the lysozyme hydrochloride alone, respectively (controls 17 and 18). In this respect, it was found that the change of the state of the mixture was a result of the interaction between the roxofene sodium hydrate and the lysozyme hydrochloride.

As a result, it has been found that the interaction can be suppressed by not substantially contacting roxofene or its salt with lysozyme or its salt.

[Test Example 20]

For the composition of Example 27 (Formulation (1), wherein the roxoxpropene sodium and lysozyme hydrochloride were not substantially in contact with) and the composition of Comparative Example 6, immediately after the start of storage, after 1 day, after 3 days, and after 7 days, After 14 days, the condition in the vial after 28 days was evaluated.

That is, 8 g of dihydrocodein phosphate was changed to 30 g of lysozyme hydrochloride (manufactured by ESA Co., Ltd., trade name: lysozyme chloride), and a mixture of lysopropene sodium hydrate and lysozyme hydrochloride (Comparative Example 6) and sodium xopropene A preparation (Example 27) substantially free of hydrate and lysozyme hydrochloride was prepared, and stored at 50 ° C. for 28 days, immediately after the start of storage, after 1 day, after 3 days, after 7 days, and after 14 days, The test was conducted in the same manner as in Test Example 2 except that the evaluation was performed after 28 days. The results are shown in Table 20.

At the start of preservation 1 day later 3 days later 7 days later After 14 days 28 days later Comparative Example 6 White powder White powder White powder wetting White powder wetting White powder wetting White Powder Wet Steel Example 27 White figurine White figurine White figurine White figurine White figurine White figurine

As is apparent from Table 20, the preservation by only mixing the lysopropene sodium hydrate and the lysozyme hydrochloride resulted in interaction, and as a result, the mixture was wet after 3 days from the start of the preservation (Comparative Example 6).

On the other hand, what was preserved only by mixing lysozyme hydrochloride with the granule obtained by granulating roxofene sodium hydrate was found to be able to suppress the interaction by maintaining the same state as at the beginning even after 28 days. (Example 27).

As a result, it has been found that interaction can be suppressed by containing roxofene or a salt thereof and lysozyme or a salt thereof in the pharmaceutical composition so as not to substantially contact each other.

[Example 28]

Preparations substantially free of roxofene sodium and lysozyme hydrochloride (2006.01)

In the same manner as in Example 2, except that 8 g of dihydrocodein phosphate was changed to 30 g of lysozyme hydrochloride (manufactured by Esei, trade name: lysozyme chloride), and macrogol 6000 was changed to 25.7 g and corn starch to 20.8 g. A tablet was obtained.

[Example 29]

Formulations substantially free of roxofene sodium and lysozyme hydrochloride (2006.01)

The tablets were obtained like Example 68 except having changed Macrogol 6000 into hardening oil (Kawaken Fine Chemicals make: brand name K-3 wax-200).

[Test Example 21]

Review of the interaction

500 mg of lysopropene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Japan Drugstore Loxofene sodium hydrate) and 150 mg of the dl-methyl ephedrine hydrochloride (Alps Pharmaceutical Co., Ltd. make: brand Nippon Drugstore dl-methyl hydrochloride powder) Then, it put in the glass bottle (3K standard bottle), and preserve | saved for one week at 60 degreeC (reference example 10). As a comparative control, loxopropene sodium hydrate alone (control example 19) and dl-methylephedrine hydrochloride alone (control example 20) were similarly stored at 60 ° C. for one week. Immediately after the start of storage, after 1 day, after 3 days, the state in the glass bottle after 1 week was evaluated, and the results are shown in Table 21.

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 19 White powder White powder White powder White powder Comparative Example 20 White powder White powder White powder White powder Reference Example 10 White powder White powder wetting White powder wetting Light yellow powder wetting

As evident in Table 21, upon preservation of the mixture of sodium xopropene hydrate and dl-methylephedrine hydrochloride, the mixture was wet and also discolored (Reference Example 10). On the other hand, there was no change in the storage of the loxopropene sodium hydrate and the dl-methylephedrine hydrochloride alone, respectively (controls 19 and 20). In this respect, it was found that the change of state of the mixture was the result of the interaction between roxofene sodium hydrate and dl-methylephedrine hydrochloride.

As a result, it has been found that the interaction can be suppressed by not substantially contacting the loxoprofen or its salt and ephedrines.

[Example 30]

Preparations substantially free of roxofene sodium and dl-methylephedrine hydrochloride (1)

8 g of dihydrocodein phosphate was changed to 20 g of dl-methylephedrine hydrochloride (Alps Pharmaceutical Co., Ltd. product name: Nippon Drugstore dl-methyl-ephedrine powder), and macrogol 6000 was changed to 23.2 g and corn starch to 18.3 g. A tablet is obtained in the same manner as in Example 2 except for the above.

[Example 31]

Preparations substantially free of roxofene sodium and dl-methylephedrine hydrochloride (2006.01)

Except having changed macrogol 6000 into hardening oil (Kawaken Fine Chemicals make: brand name K-3 wax-200), it refine | purifies in the same manner as in Example 30, and obtains a tablet.

[Test Example 22]

Inhibition of roxofene-induced gut disorder (6)

Test Example 3 by orally administering a predetermined amount (20, 60, 180 mg / 5 ml / kg) using a suspension of dl-methylephedrine hydrochloride (ME) in a 0.5% methyl cellulose (MC) solution as a test drug. The test was carried out similarly to the above, and the ulcer inhibition rate (%) in the test drug administration was calculated, and the results are shown in Table 22.

As is apparent from Table 22, dl-methylephedrine hydrochloride reduced gastric mucosal obstruction caused by roxofene.

[Test Example 23]

Review of the interaction

Roxopropene sodium hydrate 404.9 mg (Daiwa Pharmaceutical Co., Ltd. Manufacture: trade name Nippon Drug Store Loxopropene sodium hydrate) and dextromethorphan hydrobromide hydrate 95.1 mg (Daiichi Fine Chemical Co., Ltd.) Manufacture name Dextromethorphan HBR ) Were mixed and placed in a glass bottle (3K standard bottle) for 1 week at 60 ° C. (Reference Example 11). As a comparative control, loxopropene sodium hydrate alone (control 21) and dextromethorphan hydrobromide hydrate alone (control 22) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the state in the vial after one day, three days later, and one week later was evaluated, and the results are shown in Table 23.

Immediately after preservation starts 1 day later 3 days later A week later Comparative Example 21 White powder White powder White powder White powder Comparative Example 22 White powder White powder White powder White powder Reference Example 11 White powder White powder wetting White powder wetting White powder wetting

As is apparent from Table 23, when the mixture of roxofene sodium hydrate and dextromethorphan hydrobromide hydrate was preserved, the mixture was wet (Reference Example 11). On the other hand, there was no change in the storage of the loxopropene sodium hydrate and the dextromethorphan hydrobromide hydrate alone, respectively (controls 21 and 22). In this regard, the state change of the mixture was found to be the result of the interaction between the roxofene sodium hydrate and the dextromethorphan hydrobromide hydrate.

As a result, it has been found that the interaction can be suppressed by not substantially contacting the loxoprofen or its salt and dextromethorphan or the salt thereof.

[Test Example 24]

Regarding the following Example 32 (Formulation (1), wherein the chloropropene sodium and dextromethorphan hydrobromide hydrate were not substantially in contact with) and the composition of Comparative Example 7, 1 day after the start of storage, 3 After day, after 7 days, after 14 days, the state in the glass bottle after 28 days was evaluated.

That is, 8 g of dihydrocodein phosphate is changed to 16 g of dextromethorphan hydrobromide hydrate (manufactured by Dai-Ich Fine Chemical Co., Ltd.: trade name dextromethorphan HBR), and the lysopropene sodium hydrate and dextromethor A mixture of the plate hydrobromide hydrates (Comparative Example 7) and a preparation in which substantially no contact of the roxofene sodium hydrate and dextromethorphan hydrobromide hydrate (Example 32) were prepared. The test was carried out in the same manner as in Test Example 2, except that the sample was stored for 28 days at 0 ° C., and evaluated immediately after the start of storage, 1 day later, 3 days later, 7 days later, 14 days later, and 28 days later. The results are shown in Table 24.

 Start of preservation 1 day later 3 days later 7 days later After 14 days 28 days later Comparative Example 7 White powder White powder wetting White Powder Wet Steel White Powder Wet Steel White Powder Wet Steel Light yellow powder wet steel Example 32 White figurine White figurine White figurine White figurine White figurine White figurine

As is apparent from Table 24, the preservation by only mixing the sodium xopropene hydrate and the dextromethorphan hydrobromide hydrate resulted in an interaction, and as a result of the interaction, the mixture was wetted one day after the start of the preservation. Example 7).

On the other hand, the preservation only by mixing dextromethorphan hydrobromide hydrate to the granular material obtained by granulating the loxopropene sodium hydrate maintained the same state as the time of initiation even after 28 days, and the said interaction was carried out. It was found that it could be suppressed (Example 32).

As a result, it has been found that interaction can be suppressed by containing roxofene or its salt and dextromethorphan or its salt in the pharmaceutical composition so as not to be substantially in contact with each other.

[Example 33]

Formulations substantially free of xopropene sodium and dextromethorphan hydrobromide hydrate (2006.01)

8 g of dihydrocodein phosphate was changed to 16 g of dextromethorphan hydrobromide hydrate (Daiichi Fine Chemical Co., Ltd. product name: Dextromethorphan HBR), macrogol 6000 to 25.2 g, and corn starch 20.3 g A tablet was obtained in the same manner as in Example 2 except for changing to.

Example 34

Formulations substantially free of sodium xopropene and dextromethorphan hydrobromide hydrate (2006.01)

A tablet was obtained in the same manner as in Example 33 except that Macrogol 6000 was changed to a cured oil (Kawaken Fine Chemical Co., Ltd. product: trade name K-3 wax-200).

[Test Example 25]

Review of the interaction

224.9 mg of roxofene sodium hydrate (the Daiwa Pharmaceutical Co., Ltd. make: brand name Japan Pharmacy Loxpropene sodium hydrate) and guifenesin 224.9 mg (the Alps drug make: brand name Guipenesin) are mixed, and a glass bottle (3K Standard bottle) and stored at 60 ° C. for 1 week (Reference Example 12). As a comparative control, loxopropene sodium hydrate alone (Control 23) and Guapenesine alone (Control 24) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the state in the glass bottle after one day, three days later, and one week later was evaluated, and the results are shown in Table 25.

Immediately after preservation starts 1 day later 3 days later In a week Comparative Example 23 White powder White powder White powder White powder Comparative Example 24 White powder White powder White powder White powder Reference Example 12 White powder Clear liquid Clear liquid Clear liquid

As evident in Table 25, upon preservation of the mixture of sodium xopropene hydrate and guapenesine, the mixture turned into a clear liquid (Reference Example 12). On the other hand, no change occurred in the storage of loxopropene sodium hydrate and guapenesine alone (controls 23 and 24). In this respect, it was found that the change of state of the mixture was a result of the interaction between roxofene sodium hydrate and guapenesine.

As a result, it has been found that the interaction can be suppressed by not substantially contacting roxofene or its salt and guifenesin.

[Example 35]

Preparations substantially free of roxofene sodium and guapenesine (1)

8 g of dihydrocodein phosphate was changed to 83 g of guapenesine (Alps Pharmaceuticals Co., Ltd. product name: Guapefenesine), macrogol 6000 was changed to 292 g, corn starch to 243 g, and lactose hydrate to 34.8 g. A tablet is obtained in the same manner as in Example 2 except for the one.

Example 36

Preparations substantially free of roxofene sodium and guapenesine (2006.01)

A tablet was obtained in the same manner as in Example 35 except that Macrogol 6000 was changed to a cured oil (Kawaken Fine Chemical Co., Ltd. product: K-3 Wax-200).

Industrial availability

ADVANTAGE OF THE INVENTION According to this invention, a storage stable pharmaceutical composition can be provided by containing in a pharmaceutical composition so that roxofene or its salt, codeine, etc. may not substantially contact each other.

Therefore, according to this invention, the pharmaceutical composition containing loxopropene or its salt, and codeine which are excellent in storage stability, and the gastrointestinal obstruction resulting from roxofene are reduced or suppressed can be provided. .

Claims (11)

Codeine, carbinoxamine or salts thereof, clemastine or salts thereof, chlorpheniramine or salts thereof, diphenylpyraline or salts thereof, brohexine or salts thereof, ambroxol or salts thereof, lysozyme or salts and dexes A pharmaceutical composition comprising at least one member selected from the group consisting of tromethorphan or a salt thereof, and a roxofene or a salt thereof so as not to be substantially in contact with each other. A pharmaceutical composition containing codeine and roxofene or a salt thereof substantially in contact with each other. The method according to claim 1 or 2,
A pharmaceutical composition wherein the lysopropene or a salt thereof is lysopropene sodium hydrate. The method of claim 3, wherein
10% of roxofene sodium hydrate in terms of roxofene sodium anhydride; A pharmaceutical composition containing 300 mg as a daily amount. The method according to any one of claims 1 to 4,
A pharmaceutical composition wherein the codeine is selected from codeine phosphate hydrate and dihydrocodeine phosphate. The method of claim 5, wherein
Codeine Phosphate Heptahydrate, 4? A pharmaceutical composition containing 60 mg as a daily amount. The method of claim 5, wherein
Dihydrocodeine phosphate, 2? A pharmaceutical composition containing 30 mg as a daily amount. The method according to any one of claims 1 to 7,
The pharmaceutical composition wherein roxofene or its salt is a granular material containing roxofene or its salt. The method according to any one of claims 1 to 8,
A pharmaceutical composition in which codeine is a granular material containing codeine. 10. The method according to any one of claims 1 to 9,
Pharmaceutical composition which is a solid formulation. 11. The method according to any one of claims 1 to 10,
A pharmaceutical composition wherein the formulation is a capsule, pill, granule, granule, powder or tablet.