CN102740854A

CN102740854A - Loxoprofen-containing pharmaceutical composition

Info

Publication number: CN102740854A
Application number: CN2011800077046A
Authority: CN
Inventors: 薄井俊树; 春原政明; 高宫雅哉
Original assignee: Kowa Co Ltd
Current assignee: Kowa Co Ltd
Priority date: 2010-01-29
Filing date: 2011-01-31
Publication date: 2012-10-17
Also published as: JP2014169345A; JP5809736B2; WO2011093498A1; JP4787912B2; JP2012031131A; JP2012031147A; JP5575961B2; JPWO2011093498A1; JP2013237710A; KR20120112644A

Abstract

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

Description

The medical composition that contains loxoprofen

Technical field

The present invention relates to contain the medical composition of loxoprofen or its salt.

Background technology

Loxoprofen is a kind of of non-steroid class analgesic agent (NSAID), after known, operation back scorching to rheumatoid arthritis, arthronosos deformans, pain in the lumbar region disease, scapulohumeral periarthritis, neck shoulder wrist syndrome, toothache, acute upper respiratory tract, the wound, the antiinflammatory after the exodontia, analgesia, analgesic effectively (non-patent literature 1).

From its excellent pharmacological action, the combination of loxoprofen and various medicines is studied.As through the effect that this combination produced, for example, can enumerate through making up the antiinflammatory that is produced, the potentiation (patent documentation 1) that eases pain, separates thermal effect with caffeine, ethenzamide and acetaminophen; Through making up the nasal obstruction doing well,improving effect (patent documentation 2) that is produced with carbinoxamine maleate, chlorphenamine maleate, ketotifen fumarate, mequitazine and epinastine hydrochlorate; Through the outgrowth effect of inhibition goblet cell (patent documentation 3) that produced with the combination of azelastine hydrochloride and mequitazine etc.

In addition; Known through loxoprofen and bromhexine salt hydrochlorate and the combination of ambroxol salt hydrochlorate are produced to the effect potentiation (patent documentation 4) of cough symptom with suppress the outgrowth effect of goblet cell (patent documentation 5), and through loxoprofen and bromhexine salt hydrochlorate are made up the antiinflammatory that is produced, the potentiation (patent documentation 6) that eases pain, separates thermal effect etc.

In addition; Also known loxoprofen strengthens the antihistamine effect (patent documentation 6) of chlorphenamine maleate and mecloprodin fumarate, in this patent documentation, has studied the combination of loxoprofen and various medicines; In addition, put down in writing the example that makes up the preparation that loxoprofen and various medicines are arranged.Also known inhibitory action (patent documentation 7) through the gastric mucosa injury that loxoprofen is caused that produced with the combination of antacid and xanthine derivative.

On the other hand, known codeine is the narcoticness antitussive composition that has antitussive effect through the function that suppresses coughing centre.So based on this effect, it is for being used as the medicine (non-patent literature 2 and other) of antitussive composition in comprehensive coldrex and relieving cough and eliminating sputum medicine.

In addition, the combination of known some above-mentioned loxoprofens and codeine class.For example, known to combination loxoprofen and dihydrocodeine hydrochlorate, anti-inflammatory effect strengthens (patent documentation 6), if combination loxoprofen and codeine phosphate then show the outgrowth effect of respiratory tract goblet cell (patent documentation 8) that suppresses.

In addition, for the preparation that comprises loxoprofen and codeine class, known granula subtilis, capsule, tablet (patent documentation 2,4,6,8).

But, about whether producing the interaction that the storage stability of these chemical compounds etc. is brought influence between the loxoprofen in the preparation or its salt and the codeine class, still unknown.

The prior art document

Patent documentation

Patent documentation 1: japanese kokai publication hei 11-139971 communique

Patent documentation 2: TOHKEMY 2001-199882 communique

Patent documentation 3: TOHKEMY 2008-169193 communique

Patent documentation 4: TOHKEMY 2001-172175 communique

Patent documentation 5: TOHKEMY 2008-13542 communique

Patent documentation 6: TOHKEMY 2000-143505 communique

Patent documentation 7: TOHKEMY 2006-52210 communique

Patent documentation 8: TOHKEMY 2007-314517 communique

Non-patent literature

1: the 15 editions revision Japanese Pharmacopoeia of non-patent literature are separated the monologue story-telling with gestures Co., Ltd. wide river C-4790-4795 of bookstore page or leaf

The 289th page at non-patent literature 2:OTC handbook 2008-09 Co., Ltd. academic intelligence center

Summary of the invention

The problem that invention will solve

Inventor of the present invention is at first contained the medical composition of (below be also referred to as codeine class etc.) and loxoprofen or its salt more than a kind that is selected from codeine class, carbinoxamine or its salt, clemastine or its salt, chlorphenamine or its salt, diphenylpyraline or its salt, bromhexine or its salt, ambroxol or its salt, lysozyme or its salt, dextromethorphan or its salt in order to develop; Storage stability to them is studied; If finding to mix above-mentioned codeine class etc. preserves with loxoprofen or its salt; Then all of a sudden produce curing, variable color etc., on storage stability, go wrong.

Therefore, problem of the present invention be to provide a kind of contain be selected from codeine class, carbinoxamine or its salt, clemastine or its salt, chlorphenamine or its salt, diphenylpyraline or its salt, bromhexine or its salt, ambroxol or its salt, lysozyme or its salt, dextromethorphan or its salt more than a kind with the stable medical composition of loxoprofen or its salt.

Be used to solve the method for problem

At first, inventor of the present invention further studies for the problem that solves above-mentioned storage stability, and clear and definite above-mentioned codeine class etc. and loxoprofen or its salt are because of contacting the reason that the interaction that produces is the storage stability problem.

Therefore, inventor of the present invention finds, contains in medical composition with discontiguous in fact mode with loxoprofen or its salt through making above-mentioned codeine class etc., can suppress above-mentioned interaction.

Promptly; The present invention provides a kind of medical composition, its with mutually non-touching in fact mode contain be selected from codeine class, carbinoxamine or its salt, clemastine or its salt, chlorphenamine or its salt, diphenylpyraline or its salt, bromhexine or its salt, ambroxol or its salt, lysozyme or its salt and dextromethorphan or its salt more than a kind with loxoprofen or its salt.

The effect of invention

Medical composition of the present invention has excellent storage stability.

In addition, inventor of the present invention finds, the digestive tract damage that above-mentioned codeine class etc. alleviates or suppresses to be caused by loxoprofen.

Therefore, if according to the present invention, a kind of excellent storage stability just can be provided and alleviate or the medical composition of the digestive tract that suppressed to cause damage by loxoprofen.

The specific embodiment

The characteristic of medical composition of the present invention is, with mutually non-touching in fact mode contain be selected from codeine class, carbinoxamine or its salt, clemastine or its salt, chlorphenamine or its salt, diphenylpyraline or its salt, bromhexine or its salt, ambroxol or its salt, lysozyme or its salt and dextromethorphan or its salt more than a kind with loxoprofen or its salt.

Loxoprofen or its salt that uses in the present invention at first is described.

In the loxoprofen that in medical composition of the present invention, uses or its salt, not only comprise loxoprofen, and comprise the pharmaceutically acceptable salt of loxoprofen, also comprise solvate with water and alcohol etc.These are known chemical compounds, except can using commercially available article by the known method manufacturing.In the present invention; As loxoprofen or its salt, preferred loxoprofen sodium hydrate (chemical name: 2-[4-[(2-oxocyclopentyl) methyl] phenyl] sodium propionate dihydrate (Monosodium 2-[4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate)).

The loxoprofen in medical composition of the present invention or the content of its salt can be according to suitably research decisions such as user's sex, age, symptom; Convert with the loxoprofen sodium anhydride; The per amount that preferably can take 10～300mg on the 1st; More preferably can take the amount of 30～240mg, be more preferably the amount that to take 60～180mg.

In the present invention; Can suitably study decision according to above-mentioned per 1 day dose, but, convert with loxoprofen or its salt anhydride with respect to the medical composition all-mass; Preferably contain 0.4～90 quality %; More preferably contain 0.4～50 quality %, be more preferably and contain 1.2～30 quality %, especially preferably contain 1.2～25 quality % loxoprofens or its salt.

So-called in medical composition of the present invention operable codeine class, mean be selected from codeine, dihydrocodeine or their salt and their solvate more than a kind or 2 kinds.That is,,, also comprise codeine and dihydrocodeine at pharmaceutically acceptable salt and their solvate except codeine with the dihydrocodeine itself at the codeine apoplexy due to endogenous wind.

As the suitable object lesson of codeine class; Viewpoint when medical composition of the present invention is utilized as comprehensive coldrex etc.; Can enumerate codeine, dihydrocodeine, codeine phosphate hydrate, dihydrocodeine phosphate etc., but preferred codeine phosphate hydrate, dihydrocodeine phosphate.These are known chemical compounds, except can using commercially available article by the known method manufacturing.

Then, specify the codeine class used in the present invention etc.

The content of the codeine class in medical composition of the present invention; The digestive tract damage of can be according to user's sex, age, symptom and being conceived to cause by loxoprofen alleviate, suppress effect etc. suitably research determine; But the preferred per amount that can take 2～60mg on the 1st; More preferably can take the amount of 4～48mg, be more preferably the amount that to take 6～26mg.

In addition, as the codeine class, when using the codeine phosphate hydrate, the preferred per amount that can take 4～60mg on the 1st, the amount that more preferably can take 8～48mg is more preferably the amount that can take 12～36mg.In addition, when using dihydrocodeine aqueous phosphate compound, the preferred per amount that can take 2～30mg on the 1st, the amount that more preferably can take 4～24mg is more preferably the amount that can take 6～24mg.In the present invention, with respect to the medical composition all-mass, preferably contain 0.08～4 quality %.In addition, when the codeine class is the codeine phosphate hydrate,, preferably contain 0.15～4 quality %, more preferably contain 0.3～3 quality %, be more preferably and contain 0.5～2.5 quality % with respect to the medical composition all-mass.In addition, when the codeine class is dihydrocodeine phosphoric acid,, preferably contain 0.08～2 quality %, more preferably contain 0.16～1.5 quality %, be more preferably and contain 0.24～1.5 quality % with respect to the medical composition all-mass.

The ratio that contains of the loxoprofen that in medical composition of the present invention, comprises or its salt and codeine class; Can suitably study decision according to per 1 day dose of above-mentioned each composition; But preferably loxoprofen or its salt are converted with the loxoprofen sodium anhydride; Contain 0.005～4 mass parts codeine class with respect to 1 mass parts, more preferably contain 0.01～2 mass parts codeine class.

In the carbinoxamine that in medical composition of the present invention, uses or its salt, except carbinoxamine itself, also comprise carbinoxamine at pharmaceutically acceptable salt.As the object lesson of carbinoxamine or its salt, for example, can enumerate carbinoxamine, carbinoxamine maleate, carbinoxamine diphenyl disulfonate etc., in the present invention, more preferably carbinoxamine maleate.These are known chemical compounds, except can using commercially available article by the known method manufacturing.

The carbinoxamine in medical composition of the present invention or the content of its salt; Can be according to suitably research decision such as user's sex, age, symptom; The preferred per amount that can take 0.1～60mg on the 1st; More preferably can take the amount of 0.5～30mg, be more preferably the amount that to take 1～16mg.

In the present invention,, preferably contain carbinoxamine or its salt 0.004～4 quality %, more preferably contain 0.02～2 quality %, especially preferably contain 0.04～1 quality % with respect to the medical composition all-mass.In addition, the content of carbinoxamine or its salt can be according to above-mentioned per 1 day dose decision.

The loxoprofen that in medical composition of the present invention, comprises or its salt and carbinoxamine or its salt contain than have special qualification; Can suitably study decision according to per 1 day dose of above-mentioned each composition; But preferably loxoprofen or its salt are converted with the loxoprofen sodium anhydride; Contain 0.0003～6 mass parts carbinoxamine or its salt with respect to 1 mass parts, more preferably contain 0.002～1 mass parts, be more preferably and contain 0.005～0.3 mass parts.

In the clemastine that in medical composition of the present invention, uses or its salt, except clemastine itself, also comprise clemastine at pharmaceutically acceptable salt.As the object lesson of clemastine or its salt, for example, can enumerate clemastine, mecloprodin fumarate etc., preferred in the present invention mecloprodin fumarate.These are known chemical compounds, except can using commercially available article by the known method manufacturing.

The clemastine in medical composition of the present invention or the content of its salt; Can be according to suitably research decision such as user's sex, age, symptom; Convert with the clemastine episome; The per amount that preferably can take 0.01～5mg on the 1st, the amount that more preferably can take 0.05～3mg is more preferably the amount that can take 0.1～2mg.In addition, the 1.34mg mecloprodin fumarate is equivalent to the episome of 1mg clemastine.

In the present invention, the episome conversion with clemastine with respect to the medical composition all-mass, preferably contains clemastine or its salt 0.008～0.4 quality %, more preferably contains 0.01～0.2 quality %, especially preferably contains 0.015～0.15 quality %.In addition, the content of clemastine or its salt can be according to above-mentioned per 1 day dose decision.

The loxoprofen that in medical composition of the present invention, comprises or its salt and clemastine or its salt contain than have special qualification; Can suitably study decision according to per 1 day dose of above-mentioned each composition; But preferably loxoprofen or its salt are converted with the loxoprofen sodium anhydride; With respect to 1 mass parts, the episome conversion with clemastine contains clemastine or its salt 0.0006～0.5 mass parts; More preferably contain 0.0012～0.1 mass parts, be more preferably and contain 0.002～0.03 mass parts.

In the chlorphenamine that in medical composition of the present invention, uses or its salt, except chlorphenamine itself, also comprise chlorphenamine at pharmaceutically acceptable salt.

Owing in chlorphenamine, there is asymmetric carbon, therefore have optical isomer, but in the present invention, also comprise optical isomer arbitrarily, both can be single optical isomer, also can be the mixture of various optical isomers.Wherein, in the present invention, preferred d-body, dl-body.Object lesson as this chlorphenamine or its salt; For example; Can enumerate chlorphenamine, chlorphenamine maleate, d-chlorphenamine maleate, dl-chlorphenamine maleate etc.; In the present invention, preferred d-chlorphenamine maleate, dl-chlorphenamine maleate, preferred especially d-chlorphenamine maleate.These are known chemical compounds, except can using commercially available article by the known method manufacturing.

The chlorphenamine in medical composition of the present invention or the content of its salt can be according to suitably research decision such as user's sex, age, symptom, the per amount that preferably can take 0.1～20mg on the 1st, the amounts that more preferably can take 0.6～12mg.In addition, as chlorphenamine or its salt, when using d-chlorphenamine maleate, the per amount that preferably can take 0.1～15mg on the 1st, the amount that more preferably can take 0.6～6mg is more preferably the amount that can take 1～5mg.When using dl-chlorphenamine maleate, the per amount that preferably can take 0.5～20mg on the 1st, the amount that more preferably can take 1～12mg is more preferably the amount that can take 2～10mg.

In the present invention, with respect to the medical composition all-mass, the content of chlorphenamine or its salt preferably contains 0.004～1.5 quality %, more preferably contains 0.02～0.8 quality %, especially preferably contains 0.04～0.7 quality %.In addition, the content of chlorphenamine or its salt can be according to above-mentioned per 1 day dose decision.

The loxoprofen that in medical composition of the present invention, comprises or its salt and chlorphenamine or its salt contain than have special qualification; Can suitably study decision according to per 1 day dose of above-mentioned each composition; But preferably loxoprofen or its salt are converted with the loxoprofen sodium anhydride; Contain 0.0001～1.5 mass parts chlorphenamine or its salt with respect to 1 mass parts, more preferably contain 0.0005～0.7 mass parts, especially preferably contain 0.001～0.5 mass parts.

In the diphenylpyraline that in medical composition of the present invention, uses or its salt, except diphenylpyraline itself, also comprise diphenylpyraline at pharmaceutically acceptable salt.Object lesson as diphenylpyraline or its salt; For example; Can enumerate diphenylpyraline, diphenylpyraline hydrochlorate, diphenylpyraline teoclate etc., preferred in the present invention diphenylpyraline hydrochlorate, diphenylpyraline teoclate, preferred especially diphenylpyraline teoclate.These are known chemical compounds, except can using commercially available article by the known method manufacturing.

The diphenylpyraline in medical composition of the present invention or the content of its salt can be according to suitably research decisions such as user's sex, age, symptom, preferably can take the amount of 0.1～13.5mg in per 1 day, more preferably can take the amount of 1～4.5mg.In addition, as diphenylpyraline or its salt, when using the diphenylpyraline hydrochlorate, the per amount that preferably can take 0.1～12mg on the 1st, the amount that more preferably can take 1～4mg.When using the diphenylpyraline teoclate, the per amount that preferably can take 0.1～13.5mg on the 1st, the amount that more preferably can take 1～4.5mg.

In the present invention, the content of diphenylpyraline or its salt preferably contains 0.004～1.5 quality % with respect to the medical composition all-mass, more preferably contains 0.004～1 quality %.Wherein, preferably contain 0.04～0.5 quality %, more preferably contain 0.04～0.3 quality %, especially preferably contain 0.06～0.25 quality %.In addition, the content of diphenylpyraline or its salt can be according to above-mentioned per 1 day dose decision.

The loxoprofen that in medical composition of the present invention, comprises or its salt and diphenylpyraline or its salt contain than have special qualification; Can suitably study decision according to per 1 day dose of above-mentioned each composition; But preferably loxoprofen or its salt are converted with the loxoprofen sodium anhydride; Relative 1 mass parts contains diphenylpyraline or its salt 0.0001～3 mass parts; More preferably contain 0.0005～2.5 mass parts, be more preferably and contain 0.001～1 mass parts, especially preferably contain 0.001～0.3 mass parts.

In the bromhexine that in medical composition of the present invention, uses or its salt, except bromhexine itself, also comprise bromhexine at pharmaceutically acceptable salt.As the object lesson of bromhexine or its salt, for example, can enumerate bromhexine, bromhexine salt hydrochlorate etc., preferred in the present invention bromhexine salt hydrochlorate.These are known chemical compounds, except can using commercially available article by the known method manufacturing.

The bromhexine in medical composition of the present invention or the content of its salt; Can be according to suitably research decision such as user's sex, age, symptom; But preferably bromhexine or its salt are scaled the bromhexine salt hydrochlorate; The per amount that can take 0.1～50mg on the 1st, the amount that more preferably can take 0.5～25mg is more preferably the amount that can take 1～15mg.In the present invention, the content of bromhexine or its salt with respect to the medical composition all-mass, is scaled the bromhexine salt hydrochlorate, preferably contains 0.004～4 quality %, more preferably contains 0.02～2 quality %, is more preferably and contains 0.04～1 quality %.In addition, the content of bromhexine or its salt can be according to above-mentioned per 1 day dose decision.

The loxoprofen that in medical composition of the present invention, comprises or its salt and bromhexine or its salt contain than have special qualification; Can suitably study decision according to per 1 day dose of above-mentioned each composition; But preferably loxoprofen or its salt are converted with the loxoprofen sodium anhydride; With respect to 1 mass parts, bromhexine or its salt are scaled the bromhexine salt hydrochlorate, contain bromhexine or its salt 0.0001～10 mass parts; More preferably contain 0.0005～2 mass parts, be more preferably and contain 0.001～1 mass parts.

In the ambroxol that in medical composition of the present invention, uses or its salt, except ambroxol itself, also comprise ambroxol at pharmaceutically acceptable salt.As the object lesson of ambroxol or its salt, for example, can enumerate ambroxol, ambroxol salt hydrochlorate etc., preferred in the present invention ambroxol ambroxol salt hydrochlorate.These are known chemical compounds, except can using commercially available article by the known method manufacturing.

The ambroxol in medical composition of the present invention or the content of its salt; Can be according to suitably research decision such as user's sex, age, symptom; But preferably ambroxol or its salt are scaled the ambroxol salt hydrochlorate; The per amount that can take 0.1～150mg on the 1st, the amount that more preferably can take 0.5～100mg is more preferably the amount that can take 1～50mg.

In the present invention, the content of ambroxol or its salt with respect to the medical composition all-mass, is scaled the ambroxol salt hydrochlorate, preferably contains 0.004～10 quality %, more preferably contains 0.02～7 quality %, is more preferably and contains 0.04～5 quality %.In addition, the content of ambroxol or its salt can be according to above-mentioned per 1 day dose decision.

The loxoprofen that in medical composition of the present invention, comprises or its salt and ambroxol or its salt contain than have special qualification; Can suitably study decision according to per 1 day dose of above-mentioned each composition; But preferably loxoprofen or its salt are converted with the loxoprofen sodium anhydride; Relative 1 mass parts is scaled the ambroxol salt hydrochlorate with ambroxol or its salt, contains ambroxol or its salt 0.0001～10 mass parts; More preferably contain 0.0005～5 mass parts, be more preferably and contain 0.001～3 mass parts.

In the lysozyme that in medical composition of the present invention, uses or its salt, except lysozyme itself, also comprise lysozyme at pharmaceutically acceptable salt.As the object lesson of lysozyme or its salt, for example, can enumerate lysozyme, lysozyme salt hydrochlorate etc., preferred in the present invention lysozyme salt hydrochlorate.These are known chemical compounds, except can using commercially available article by the known method manufacturing.

The lysozyme in medical composition of the present invention or the content of its salt; Can be according to suitably research decision such as user's sex, age, symptom; But preferably lysozyme or its salt are scaled tiring of lysozyme salt hydrochlorate; The preferred per amount (tiring) that can take 5～450mg on the 1st, the amount (tiring) that more preferably can take 10～360mg is more preferably the amount (tiring) that can take 15～270mg.In the present invention, the content of lysozyme or its salt is with respect to the medical composition all-mass; Be scaled tiring of lysozyme salt hydrochlorate; Preferably contain 0.2～30 quality % (tiring), more preferably contain 0.4～25 quality % (tiring), be more preferably and contain 0.6～20 quality % (tiring).In addition, the content of lysozyme or its salt can be according to above-mentioned per 1 day dose decision.

The loxoprofen that in medical composition of the present invention, comprises or its salt and lysozyme or its salt contain than have special qualification; Can suitably study decision according to per 1 day dose of above-mentioned each composition; But preferably loxoprofen or its salt are converted with the loxoprofen sodium anhydride; With respect to 1 mass parts, lysozyme or its salt are scaled tiring of lysozyme salt hydrochlorate, contain loxoprofen or its salt 0.01～45 mass parts (tiring); More preferably contain 0.04～12 mass parts (tiring), be more preferably and contain 0.08～5 mass parts (tiring).

In the dextromethorphan that in medical composition of the present invention, uses or its salt; Except dextromethorphan itself; Also comprise dextromethorphan at pharmaceutically acceptable salt, also comprise dextromethorphan and dextromethorphan solvate at pharmaceutically acceptable salt and water and alcohol etc.As the object lesson of dextromethorphan or its salt, for example, can enumerate dextromethorphan, dextromethmorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt etc., preferred dextromethmorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt.These are known chemical compounds, except can using commercially available article by the known method manufacturing.

The dextromethorphan in medical composition of the present invention or the content of its salt; Can be according to suitably research decision such as user's sex, age, symptom; Can take dextromethorphan or its salt 0.1～270mg in preferred per 1 day; More preferably can take 0.5～180mg, be more preferably and to take 1～90mg.When dextromethorphan or its salt are the dextromethmorphan hydrobromide hydrate, the preferred per amount that can take dextromethmorphan hydrobromide 6～60mg on the 1st, the amount that more preferably can obey 15～60mg is more preferably the amount that can take 20～60mg.In addition, when dextromethorphan or its salt are dextromethorphan phenolphthalein salt, the amount that preferably can take dextromethorphan phenolphthalein salt 9～90mg in per 1 day, the amount that more preferably can obey 22～90mg is more preferably the amount that can take 30～90mg.

Among the present invention, with respect to the medical composition all-mass, the content of dextromethorphan or its salt preferably contains 0.004～20 quality %, more preferably contains 0.02～15 quality %, is more preferably and contains 0.04～10 quality %.In addition, the content of dextromethorphan or its salt can be according to above-mentioned per 1 day dose decision.

The loxoprofen that in medical composition of the present invention, comprises or its salt and dextromethorphan or its salt contain than have special qualification; Can suitably study decision according to per 1 day dose of above-mentioned each composition; But preferably loxoprofen or its salt are converted with the loxoprofen sodium anhydride, relative 1 mass parts contains 0.0001～20 mass parts; More preferably contain 0.0005～10 mass parts, be more preferably and contain 0.001～5 mass parts dextromethorphan or its salt.

In addition; In the present invention; So-called " containing " with mutually non-touching in fact mode; Mean in medical composition, loxoprofen or its salt and codeine class etc. contain not show the discontiguous mode of interactional degree ground, but preferred loxoprofen or its salt and codeine class etc. contain with discontiguous mode.

In addition, the dosage form of medical composition of the present invention should not receive special qualification, but the viewpoints such as easy property from taking, preferred solid preparation.

Wherein, Object lesson as solid preparation; For example, can enumerate non-oral Preparations such as oral Preparations such as capsule, pill, granule, granula subtilis, powder, tablet, dry syrup, gel, buccal tablet and suppository, but the preferred oral solid preparation.Medical composition of the present invention can be through known method by coatings such as sugar-coat or film coatings.

As above-mentioned solid preparation; Can enumerate the solid composite that contains (A) loxoprofen or its salt itself or contain loxoprofen or its salt, with (B) codeine class etc. itself or contain the solid composite of codeine class etc.; Through constituting the composition of these solid composites; The preparation that loxoprofen or its salt are disposed with mutually non-touching mode in codeine class etc. (still, removing mentioned component (A) is that loxoprofen or its salt itself and composition (B) are the situation of codeine class etc. itself).The form of these solid composites is powdery, the such form of granular, tablet shape.

Concrete form as above-mentioned solid preparation; (first)～(suffering) below can illustration, these can pass through aforesaid known method, for example; Through the method for record in the 15 edition revision Japanese Pharmacopoeia preparation general provisions etc., use the manufacturing of appropriate formulations additive, preparationization.In (first)～(suffering), be example with the codeine class, the concrete form of illustration solid preparation.When use and loxoprofen or its salt produce interactional chlorphenamine or its salt etc. replacing the codeine class, also can likewise make solid preparation, preparationization with the codeine class.

(first) becomes shot-like particle with appropriate method with any side's pelletize of loxoprofen or its salt and codeine apoplexy due to endogenous wind; The opposing party's loxoprofen or its salt or the pelletize of codeine class are not engaged in powder or the granule of wherein manufacturing etc., and the preparation that coats this shot-like particle again with appropriate method.

(second) with appropriate method with loxoprofen or its salt and codeine class respectively pelletize become shot-like particle, their are cooperated powder or the granule etc. of manufacturing, and the preparation that coats this shot-like particle again with appropriate method.

(the third) in capsule, fills the capsule of the powder made with above-mentioned (first) or (second) or granule etc.

The resulting tablet of tablettings such as shot-like particle that (fourth) made above-mentioned (first) or (second) with appropriate method.Tabletting also can be configured as certain shape and be realized except that compression method by appropriate method.

(penta) multilayer tablet made with mutually non-touching in fact mode of loxoprofen or its salt and codeine class and the preparation that coats this multilayer tablet again with appropriate method.As this multilayer tablet; Preferably make loxoprofen or its salt and codeine class be positioned at the multilayer tablet of different each other layers; As the multilayer tablet more than three layers, more preferably make layer that comprises loxoprofen or its salt and the layer that comprises the codeine class be positioned at the multilayer tablet of mutually non-touching position.Wherein, as loxoprofen or its salt and codeine class, the shot-like particle that can use above-mentioned (first) or (second) to make.

(own) disposes any side of loxoprofen or its salt and codeine class in core sheet (being also referred to as chip, centre slice); The dry-pressing coated tablet that loxoprofen or its salt and codeine class are made with mutually non-touching in fact mode, and the preparation that coats this dry-pressing coated tablet again with appropriate method.Wherein, as loxoprofen or its salt and codeine class, the shot-like particle that can use above-mentioned (first) or (second) to make.

(heptan) replaces the shot-like particle of above-mentioned (first) or (second), uses with bags such as cyclodextrin such as alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrins and connects the preparation that any side of loxoprofen or its salt and codeine class or bag that two sides obtain connect chemical compound.

(suffering) is any side of in the preparation with the usual way manufacturing, containing loxoprofen or its salt and codeine class; Be provided with sugarcoating layer or film coating layer; In this sugarcoating layer or coatings, contain the opposing party; The preparation (when dosage form is tablet, being called coated tablet or thin membrane coated tablet) that loxoprofen or its salt and codeine class are made with mutually non-touching in fact mode.

Shot-like particle in above-mentioned (first) and (second) etc. can pass through extruding pelletization, rotate known prilling process such as pelletize, stirring-granulating, fluidized bed pelletize, spray drying granulation, broken pelletize, melt pelletization, uses the manufacturing of appropriate formulations additive.In the present invention, any side of shot-like particle that contains loxoprofen or its salt and the shot-like particle that contains the codeine class both can be by same prilling process manufacturing, also can be by different prilling process manufacturings.

The shot-like particle that contains loxoprofen or its salt can be according to known method by the appropriate method pelletize, but can use commercially available article.

As commercially available article; For example; Can enumerate Roseol (registered trade mark) particulate 10% (this particulate comprises loxoprofen sodium hydrate, lactose hydrate, low degree of substitution hydroxypropyl cellulose, hydroxypropyl cellulose, magnesium stearate, silicon dioxide, iron sesquioxide, contains 113.4mg loxoprofen hydrate (as anhydride 100mg) among the 1g) that occasion KCC in the sixth of the twelve Earthly Branches produces; (this particulate comprises loxoprofen sodium hydrate, lactose hydrate, hydroxypropyl cellulose, magnesium stearate, Pulvis Talci, silicon dioxide, iron sesquioxide to the loxoprofen sodium particulate 10% " CH " of long-living Pharmaceutical Co., Ltd's production; Polysorbate 40 contains 113.4mg loxoprofen hydrate (as anhydride 100mg) among the 1g); KENTAN (registered trade mark) 10% particulate (this particulate comprises loxoprofen sodium hydrate, light silicon dioxide, iron sesquioxide, magnesium stearate, lactose hydrate, hydroxypropyl cellulose, fumaric acid, D-mannitol, contains 113.4mg loxoprofen hydrate (as anhydride 100mg) among the 1g) that Medisa new drug Co., Ltd. produces; PONAPELT (registered trade mark) 10% particulate (this particulate comprises loxoprofen sodium hydrate, lactose hydrate, crospovidone, low degree of substitution hydroxypropyl cellulose, hydroxypropyl cellulose, magnesium stearate, iron sesquioxide, contains 113.4mg loxoprofen hydrate (as anhydride 100mg) among the 1g) that the ioMedix of Co., Ltd. B produces; Co., Ltd.'s sun advances RINGEREAZE (registered trade mark) 10% particulate (this particulate comprises loxoprofen sodium hydrate, lactose hydrate, crospovidone, hydroxypropyl cellulose, magnesium stearate, iron sesquioxide, contains 113.4mg loxoprofen hydrate (as anhydride 100mg) among the 1g) that hall is produced; Loxonin (registered trade mark) 10% particulate (this particulate comprises loxoprofen sodium hydrate, hydroxypropyl cellulose, low degree of substitution hydroxypropyl cellulose, iron sesquioxide, lactose hydrate, magnesium stearate, contains 113.4mg loxoprofen hydrate (as anhydride 100mg) among the 1g) that Sankyo Co. produces; Lorfenamin (registered trade mark) 10% particulate (this particulate comprises loxoprofen sodium hydrate, lactose hydrate, carboxymethyl starch sodium, hydroxypropyl starch, hydroxypropyl cellulose, magnesium stearate, Pulvis Talci, iron sesquioxide, contains 113.4mg loxoprofen hydrate (as anhydride 100mg) among the 1g) of day medical professionals Co., Ltd. production etc.Wherein, in above-mentioned 1g, contain 113.4mg loxoprofen hydrate (as anhydride 100mg)) particulate, can the content of loxoprofen hydrate suitably be increased and decreased according to known method.

When making medical composition of the present invention,, for example, can enumerate binding agent, excipient, disintegrating agent, lubricant, plasticiser, coloring agent etc. as the preparation additive that can use.

As binding agent; For example, can enumerate methylcellulose, hydroxypropyl cellulose, low degree of substitution hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, dextrin, part alphalysed starch, amylopectin, arabic gum, agar, gelatin, Tragacanth, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol etc.Wherein, when when making above-mentioned (first) and (second) shot-like particle in waiting, using melt pelletization, preferably use is solid at normal temperatures, the fusion or soften so low binding agent of fusing point (freezing point) through heating.As the fusing point (freezing point) of such binding agent, preferably be lower than the fusing point of the composition (loxoprofen or its salt and codeine class etc.) that the present invention is correlated with.Particularly, preferred fusing point (freezing point) is 30～100 ℃ binding agent, more preferably 50～80 ℃ binding agent.As such binding agent, for example, can enumerate polyethylene glycols (for example, Macrogol 4000, polyethylene glycol 6000, Macrogol 2000 0 etc.); Oils (for example, Adeps Bovis seu Bubali fixed oil, fixed oil, hydrogenated vegetable oil, soybean hardened oil, Brazil wax, white beeswax, Cera Flava, haze tallow etc.); Hydro carbons (for example, paraffin, microwax etc.); Higher alcohols (for example, palmityl alcohol, stearyl alcohol etc.); Fatty acid (for example, stearic acid etc.); Fatty acid ester (for example, acetylated glycerol fatty acid ester, fatty acid glyceride, sucrose fatty acid ester, sorbitan fatty acid esters, glyceryl monostearate etc.) etc.

As excipient; For example, can enumerate crystalline cellulose, cellulose powder, lactose hydrate, white sugar, glucose, mannitol, erythritol, xylitol, trehalose, maltose alcohol, lactose, Sorbitol, wheaten starch, corn starch, potato starch, calcium phosphate dibasic anhydrous, calcium carbonate, silicon dioxide etc.

As disintegrating agent, for example, can enumerate carboxymethyl cellulose, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, carboxymethylethylcellulose, carboxymethyl starch sodium, low degree of substitution hydroxypropyl cellulose, crospovidone, hydroxypropyl starch etc.

As lubricant, for example, can enumerate stearic acid, calcium stearate, magnesium stearate, Pulvis Talci, fumaric acid sodium stearate etc.

As plasticiser, for example, can enumerate aqueous silicon dioxide, light silicon dioxide, titanium oxide etc.

As coloring agent; For example, can enumerate yellow iron sesquioxide, iron sesquioxide, edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible yellow No. 5, edible green No. 3, edible red No. 2, edible red No. 3, edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106 etc.

In medical composition of the present invention; As medical components; Can contain the medicine beyond loxoprofen or its salt and the codeine class etc.; For example, can contain be selected from antipyretic-antalgic agent, hydryllin, anti-tussive agents, oscapine class, bronchodilator, expectorant, hypnosis tranquilizer, vitamins, anti-inflammatory agent, gastric mucosa protectant, cholilytic drug, crude drug class, prescriptions of Chinese medicine, caffeine class, xanthine in becoming to grade more than a kind or 2 kinds.

As the antipyretic-antalgic agent; For example, can enumerate aspirin, aluminium aspirin, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, disalicylic acid, salicylamide, sodium salicylate, tiaramide hydrochlorate, lactophenin etc.

As hydryllin; For example, can enumerate azelastine hydrochloride, alimemazine tartrate, isothipendyl hydrochlorate, iproheptine hydrochlorate, epinastine hydrochlorate, emedastine fumarate, ketotifen fumarate, difeterol hydrochlorate, difeterol phosphate, diphenhydramine hydrochloride, diphenhydramine Salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochlorate, fenethazine hydrochlorate, promethazine hydrochloride, promethazine methylenedisalicylic acid salt, mequitazine, methdilazine hydrochlorate, mebhydrolin napadisilate etc.

As anti-tussive agents; For example, can enumerate alloclamide hydrochlorate, eprazinone hydrochlorate, carbetapentane citrate citrate, cloperastine hydrochlorate, cloperastine fendizoate, sodium dibunate, dimemorfan phosphate, tipepidine citrate, tipepidine hybenzate etc.

As the oscapine class, for example, can enumerate oscapine hydrochlorate, oscapine etc.

As bronchodilator; For example, can enumerate tretoquinol hydrochlorate, phenyl propanolamine hydrochloride, phenylephrine hydrochloride, ephedrines (pseudoephedrine hydrochlorate, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochlorate, l-methylephedrine hydrochlorate, dl-methylephedrine saccharin salt), methoxiphenadrin hydrochlorate etc.

As expectorant, for example, can enumerate ammonia-anise spirit, ethylcysteine hydrochloride, ammonium chloride, carbocisteine, guaifenesin, sulfogaiacol, cresol sulfonic acid potassium, acthiol-J hydrochlorate, l-menthol etc.

As the hypnosis tranquilizer, for example, can enumerate allyl isopropylacetyl urea and bromisovalum etc.

As vitamins, for example, can enumerate vitamin B ₁, vitamin B ₂, vitamin B ₅, vitamin B ₆, vitamin B ₁₂, vitamin C, hesperidin and derivant and their salt etc. (for example, thiamine, thiamine chloride hydrochloride, thiamine itrated compound, match thiamine hydrochloride, cetotiamine hydrochlorate, fursultiamine, fursultiamine hydrochlorate, octotiamine, cycotiamine, TATD, vitaberin, bisbentiamine, prosulthiamine, benfotiamine, riboflavin, cytoflavin, riboflavin ethyl butyrate, Riboflavin Sodium Phosphate, pantothenylol, pantethine, calcium pantothenate, sodium pantothenate, Benadon hydrochlorate, codecarboxylase, cobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin etc.).

As anti-inflammatory agent; For example; Can enumerate glycyrrhizic acid and derivant thereof and their salt (for example, glycyrrhizic acid dipotassium, glycyrrhizic acid one ammonium etc.), half basonuclin enzyme, semialkaline protease, Serrapeptase, tranexamic acid, acid protease (proctase), pronase, bromelain etc.

As gastric mucosa protectant; For example, can enumerate the heavy altogether product, sucralfate, cetraxate hydrochlorate, sofalcone, magnesium carbonate, teprenone, potassium copperchlorophyllin, Sodium Copper Chlorophyllin, Magnesiumaluminumsilicate, chloromethyl methionine sulfonium etc. of heavy altogether product, the magnesium hydroxide-aluminium potassium sulfate of heavy altogether product, the aluminium hydroxide-calcium carbonate-magnesium carbonate of glycine, aldioxa, magnesium silicate, gefarnate, synthetic aluminium silicate, synthetic hydrotalcite, magnesium oxide, dihydroxy aluminum-Glycinates (aluminum glycinate), gel aluminum hydroxide, aluminium hydroxide-magnesium carbonate combination drying gel, aluminium hydroxide-sodium bicarbonate.

As anticholinergic agent; For example, can enumerate oxyphencyclimine hydrochloride, dicycloverine (dicyclomine) hydrochlorate, methixene hydrochlorate, scopolamine hydrobromide, Flos Daturae extract, timepidium bromide, methyl atropine bromide, methyl Anisotropine bromide, epoxytropine tropate bromide, methyl-l-hyoscyamine bromide, methyl benactyzine bromide, pirenzepine hydrochlorate, butyl scopolamine bromide, belladonna alkaloids, Semen daturae extractum, Semen daturae total alkaloids, isopropamide iodide, diphenyl-piperidine ylmethyl dioxolanes iodide, hyoscyamus extract, Radix Hyoscyami, Radix Hyoscyami total alkaloids citrate etc.

As the crude drug class; For example, can enumerate Cortex malloti japonici, gambir, Herba Epimedii, Fructus Foeniculi, Radix Curcumae, Rhizoma Corydalis, prolong life grass, Radix Scutellariae, Rhizoma Polygonati, Cortex Phellodendri, bark of cherry, Rhizoma Coptidis, Radix Polygalae, Rhizoma Curcumae, Rhizoma et radix valerianae, Flos Matricariae chamomillae, Fructus Trichosanthis seed, Radix Glycyrrhizae, Radix Platycodonis, Semen Armeniacae Amarum, Fructus Lycii, Folium Lycii, Herba Schizonepetae, Cortex cinnamomi japonici (Ramulus Cinnamomi), Semen Cassiae, Radix Gentianae, geranium, Rhizoma Cyperi, Calculus Bovis, Fructus Schisandrae Chinensis, Herba Asari, Pericarpium Zanthoxyli, Radix Asteris, Cortex Lycii, Radix Paeoniae, Moschus, Radix Adenophorae (Radix Glehniae), Semen Plantaginis, Herba Plantaginis, beastly gallbladder (comprising Fel Ursi), Rhizoma Zingiberis Recens, Pheretima, Flos Magnoliae, Bulbus Lycoridis Radiatae, Rhizoma Chuanxiong, Radix Peucedani, when crude drug such as medicine, Rhizoma Atractylodis, Cortex Mori, Folium Perillae, Bulbus Allii, panax japonicus, Flos Caryophylli, Pericarpium Citri Reticulatae, Radix Angelicae Sinensis, hippo, Nan Tian's reality, Radix Ginseng, Bulbus Fritillariae Uninbracteatae, Radix Ophiopogonis, Herba Menthae, the Rhizoma Pinelliae, Stigma Croci, anti-nose, the Radix Angelicae Dahuricae, the Rhizoma Atractylodis Macrocephalae, Poria, Cortex Moutan, Concha Ostreae, Herba Ephedrae, Cornu Cervi Pantotrichum and their extract (extract, tincture, dry extract etc.) etc.

As prescriptions of Chinese medicine, for example, can enumerate guizhi decoction, Xiangsu San, CHAIHU GUIZHI TANG, Herba Sidae Rhombifoliae soup, Ophiopogonis Decoction, BANXIA HOUPU TANG etc.

As the caffeine class, for example, can enumerate caffeine sodium benzoate, caffeine hydrate, Caffeine Anhydrous etc.

As the xanthine composition, for example, can enumerate aminophylline, diprophylline, theophylline, brontyl etc.

In addition, as medical composition of the present invention, preferred following (a)～(u) compositions in addition.

(a) contain the tablet (in 6) of 180mg loxoprofen sodium hydrate, 45mg codeine phosphate, 110mg crystalline cellulose, 40mg hydroxypropyl cellulose, 10mg magnesium stearate, an amount of lactose;

(b) contain the granula subtilis (in 3 bags) of 180mg loxoprofen sodium, 20mg dihydrocodeine phosphate, 140mg crystalline cellulose, 100mg hydroxypropyl cellulose, 10mg magnesium stearate, 190mg D-mannitol and an amount of lactose;

(c) contain the capsule (in 6 capsules) of 180mg loxoprofen sodium, 45mg codeine phosphate, 10mg magnesium stearate, 50mg Polysorbate, 170mg corn starch and an amount of lactose;

(d) contain the tablet (1 350mg) of 60mg loxoprofen sodium hydrate (being scaled anhydride), 10mg dihydrocodeine phosphate, 7mg magnesium stearate, 60mg crystalline cellulose, 200mg starch and 13mg lactose;

(e) contain the tablet (1 350mg) of 60mg loxoprofen sodium hydrate (being scaled anhydride), 10mg dihydrocodeine phosphate, 10mg serrapeptass, 4mg bromhexine salt hydrochlorate, 7mg magnesium stearate, 60mg crystalline cellulose, 186mg starch and 13mg lactose;

(f) contain the hard capsule (1 capsule 350mg) of 60mg loxoprofen sodium dihydrate (being scaled anhydride), 4mg carbinoxamine maleate, 20mg dl-mephedrine, 10mg serrapeptass, 7mg magnesium stearate, 60mg crystalline cellulose, 176mg starch and 13mg lactose;

(g) contain the tablet (1 middle 350mg) of 60mg loxoprofen sodium dihydrate (being scaled anhydride), 4mg carbinoxamine maleate, 20mg dl-mephedrine, 10mg serrapeptass, 7mg magnesium stearate, 60mg crystalline cellulose, 176mg starch and 13mg lactose;

(h) contain the tablet (1 middle 350mg) of 60mg loxoprofen sodium dihydrate (being scaled anhydride), 4mg carbinoxamine maleate, 7mg magnesium stearate, 60mg crystalline cellulose, 206mg starch and 13mg lactose;

(i) contain the tablet (1 middle 350mg) of 60mg loxoprofen sodium dihydrate (being scaled anhydride), 4mg carbinoxamine maleate, 50mg lysozyme chloride, 7mg magnesium stearate, 60mg crystalline cellulose, 156mg starch and 13mg lactose;

(j) contain the effervescent tablet (1 middle 2400mg) of 60mg loxoprofen sodium dihydrate (being scaled anhydride), 4mg carbinoxamine maleate, 20mg dl-mephedrine, 10mg serrapeptass, 254mg beta-schardinger dextrin-, 30mg aspartame, 965mg citric acid, 813mg sodium bicarbonate, 194mg lactose and 50mg magnesium stearate;

(k) contain instant or chewable tablet (1 middle 700mg) of 60mg loxoprofen sodium dihydrate (being scaled anhydride), 4mg carbinoxamine maleate, 20mg dl-mephedrine, 10mg serrapeptass, 300mg beta-schardinger dextrin-, 30mg aspartame, 262mg mannitol and 14mg magnesium stearate;

(l) contain the tablet (1 middle 350mg) of 60mg loxoprofen sodium dihydrate (being scaled anhydride), 5mg clemastine fumarate, 7mg magnesium stearate, 60mg crystalline cellulose, 205mg starch and 13mg lactose;

(m) contain the tablet (in 6) of 180mg loxoprofen sodium, 45mg ambroxol hydrochloride, 100mg crystalline cellulose, 40mg hydroxypropyl cellulose, 10mg magnesium stearate and an amount of lactose;

(n) contain the tablet (in 6) of 180mg loxoprofen sodium, 12mg Bisolvon, 100mg crystalline cellulose, 40mg hydroxypropyl cellulose, 10mg magnesium stearate and an amount of lactose;

(o) contain the tablet (in 6) of 180mg loxoprofen sodium, 15mg ambroxol hydrochloride, 8mg Bisolvon, 0.2mg Semen daturae (always) alkaloid, 100mg crystalline cellulose, 40mg hydroxypropyl cellulose, 10mg magnesium stearate and an amount of lactose;

(p) contain the granula subtilis (in 3 bags) of 180mg loxoprofen sodium, 45mg ambroxol hydrochloride, 130mg crystalline cellulose, 100mg hydroxypropyl cellulose, 10mg magnesium stearate, 290mg D-mannitol and an amount of lactose;

(q) contain the granula subtilis (in 3 bags) of 180mg loxoprofen sodium, 12mg Bisolvon, 130mg crystalline cellulose, 100mg hydroxypropyl cellulose, 10mg magnesium stearate, 290mg D-mannitol and an amount of lactose;

(r) contain the granula subtilis (in 3 bags) of 180mg loxoprofen sodium, 15mg ambroxol hydrochloride, 8mg Bisolvon, 0.2mg Semen daturae (always) alkaloid, 130mg crystalline cellulose, 100mg hydroxypropyl cellulose, 10mg magnesium stearate, 290mg D-mannitol and an amount of lactose;

(s) contain the capsule (in 6 capsules) of 180mg loxoprofen sodium, 45mg ambroxol hydrochloride, 10mg magnesium stearate, 50mg Polysorbate, 180mg corn starch and an amount of lactose;

(t) contain the capsule (in 6 capsules) of 180mg loxoprofen sodium, 12mg ambroxol hydrochloride, 10mg magnesium stearate, 50mg Polysorbate, 200mg corn starch and an amount of lactose; With

(u) filled the capsule (in 6 capsules) of the granula subtilis that contains 180mg loxoprofen sodium, 15mg ambroxol hydrochloride, 8mg Bisolvon, 0.2mg Semen daturae (always) alkaloid, 10mg magnesium stearate, 50mg Polysorbate, 190mg corn starch and an amount of lactose.

As the route of administration of medical composition of the present invention, it is non-oral to enumerate oral and per rectum and transvaginal etc., but the preferred oral administration.In addition, medical composition of the present invention can 1 bu about 1～4 time when oral administration, in ante cibum, meal, after meal, take before sleeping etc.

From suppressing interactional viewpoint, medical composition of the present invention can also be preserved in the presence of desiccant.Below, the situation that also will in container, comprise medical composition of the present invention and desiccant sometimes is called " pharmaceutical preparation " of the present invention.

In the present invention, desiccant is not special limits.As desiccant; For example; Can enumerate be selected from silica dioxide gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), POLARGEL NF (montorillonite clay), magnesium chloride and the magnesium oxide more than a kind or 2 kinds, also can be the mixture that mixes these and activated carbon.Wherein, more preferably be selected from silica dioxide gel, silica alumina gel (pure phenolic resin), synthetic zeolite (molecular sieve), more than a kind or 2 kinds of calcium chloride, from suppressing interactional viewpoint, preferred especially synthetic zeolite.

In addition, the shape of desiccant is not special yet to be limited, and for example, can enumerate being configured as tabular and the sheet type of bag shape, the desiccant of cylindric (tablet form) etc., also can be on cylindric desiccant, to apply paper bag to wrap up in and film-coated desiccant.

Desiccant has multiple commercially available, for example, can enumerate シ Block レ Star ト, MS-タ Block レ Star ト, MS-セラ system W, ト one カイゲ Le, デシカイト 25, ア Le プシ one ト that Tokai Corp.'s chemical industry is produced; De ライヤ one Application (registered trade mark) subpackage article, De ライヤ one Application (registered trade mark) sheet (tablet), De ライヤ one Application (registered trade mark) sheet (sheet) that mountain core medicine Co., Ltd. produces; The article river changes into セカ one De, アロシ one ト, ゼオシ one ト that Co., Ltd. produces; The ZO of Co., Ltd. O chemistry skill is ground the OZO of production; ID sheet, the ID that the ID of Co., Ltd. the produces drying prescription etc. of being responsible for a task until it is completed.

Desiccant content in medical composition of the present invention can suitably be studied decision, but preferably contains 0.05～35 mass parts with respect to 1 mass parts loxoprofen or its salt, more preferably contains 0.15～17 mass parts.

In addition, the content of desiccant preferably contains the medical composition of the present invention of loxoprofen or its salt and codeine class with respect to 1 mass parts, contain 0.001～1 mass parts, more preferably contains 0.004～0.4 mass parts.

Operable container in pharmaceutical preparation of the present invention; So long as can be as food, augment that the container of article, pharmaceuticals and health food etc. uses; Just not special the qualification can be used any one of setting container, unsetting container, the container that preferably can seal.As this setting container, for example, can enumerate bottle, jar, case etc.As unsetting container, for example, can enumerate bag (pillow type packing, excellent type packing, PTP packing, SP packing etc.) etc.In these containers, particularly, preferred bottle, bag.

The formation member of container is not special to be limited, and for example, can enumerate the member of paper, glass, resin or resin molding or metal or metal film etc., also can be the composite construction that these member appropriate combination are obtained or the member of multiple structure.In addition, the member for paper etc. has poisture-penetrability preferably applies the permeation-proof wet process.

This container can be transparent, translucent, opaque any one.

In container, take in not special qualification of method of medical composition of the present invention and desiccant, all can reach through the configuration of proper methods such as input in container.

Taking in container, for example, when container is bottle, can be through desiccant (preferably cylindric (tablet form)) being configured in the bottle or being collected in bottle cap inboard (inner cap), and medical composition of the present invention is collected in the bottle etc. reaches.When in bottle, collecting, the medical composition that contains loxoprofen or its salt and codeine class etc. of the present invention is preferably processed the solid preparation that comprises them.

In addition, when container is bag, can reach through in bag, collecting the desiccant sheet type of bag shape (preferred tabular with) and medical composition of the present invention etc.When in bag, collecting, the medical composition that contains loxoprofen or its salt and codeine class etc. of the present invention is preferably processed the solid preparation that comprises them.

Can also be by SP packing, PTP packing or bag medical composition of the present invention to be packed earlier, then medical composition of being packed and desiccant together enclosed the form in the bag.More specifically, can enumerate the form of the sheet type desiccant of the solid preparation of SP packing or PTP packing and tabular or bag shape pillow type packing together etc.

Because medical composition of the present invention contains as a kind of loxoprofen of NSAID or its salt; So; For pain, throat pain, otalgia, arthralgia, neuralgia, lumbago, myalgia after headache, toothache, the exodontia, pain in my shoulder, traumatic injury pain, fracture pain, twist with the fingers analgesic, the various symptoms (throat pain, cough, aversion to cold, heating, headache, arthralgia, myalgia) of catching a cold when frustrating pain, menstrual pain (dysmenorrhea), outer grieved analgesia, fever with aversion to cold, cough etc. and have usefulness or effect, useful as coldrex, antipyretic-antalgic agent etc.

In addition, as by after the embodiment that states also can be clear and definite, employed codeine class suppresses, alleviates the digestive tract damage that is caused by loxoprofen in the medical composition of the present invention.Therefore, even the patient that suffers from of peptic ulcer does not worry that with the patient that medical history is arranged the digestive tract that is caused by loxoprofen damages, and can take loxoprofen or its salt yet.

Embodiment

Below enumerate embodiment and wait detailed description the present invention, but the present invention does not receive any qualification of these embodiment.

［ Test Example 1 ］ interactional discussion

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and (the Shionogi production: trade name dihydrocodeine phosphate " SHIONOGI ") of 60mg dihydrocodeine phosphate mix (the big and pharmaceutical industries production: of 500mg loxoprofen sodium hydrate; The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 1) at 60 ℃.As comparative control, (reference examples 1), dihydrocodeine phosphate independent (reference examples 2) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 1.

［ table 1 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 1	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 2	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 1	The white powder body	The white powder body solidifies	The white powder body solidifies	Little yellow powder body solidifies

As knowing according to table 1, if preserve loxoprofen sodium hydrate and the phosphatic mixture of dihydrocodeine, mixture just solidifies, and then variable color (reference example 1).On the other hand, when preserving loxoprofen sodium hydrate and dihydrocodeine phosphate respectively separately, do not change (reference examples 1 and 2).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and dihydrocodeine class produce results of interaction.

［ Test Example 2 ］ interactional discussion

About the compositions of following embodiment 1 (the discontiguous in fact preparation of loxoprofen sodium and dihydrocodeine phosphate (1)) and comparative example 1, estimate the state that has just begun in back, the vial after 1 day, after 3 days, after 1 week of preserving.Ecbatic in table 2.

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate), 29.2g polyethylene glycol 6000 (Japanese grease production stir (the big and pharmaceutical industries production: of 68.1g loxoprofen sodium hydrate in the beaker in 65 ℃ of water-baths; Trade name polyethylene glycol 6000 P) and 24.3g corn starch (day shallow lake chemical production: trade name corn starch ST-C); Then; After the cooling, sieve, obtain the pelletize thing with No. 18 sieves.(Shionogi production: trade name dihydrocodeine phosphate " SHIONOGI "), the vial of packing into (13K specification bottle) is preserved 1 week (embodiment 1) for 50 ℃ in resulting pelletize thing, to mix 8g dihydrocodeine phosphate

On the other hand; Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate), 29.2g polyethylene glycol 6000 (Japanese grease production mix (the big and pharmaceutical industries production: of 68.1g loxoprofen sodium hydrate; Trade name corn starch ST-C) and (the Shionogi production: trade name dihydrocodeine phosphate " SHIONOGI ") of 8g dihydrocodeine phosphate trade name polyethylene glycol 6000 P), 24.3g corn starch (day shallow lake chemical production:; The vial (13K specification bottle) of packing into is preserved 1 weeks (comparative example 1) for 50 ℃

［ table 2 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Comparative example 1	The white powder body solidifies	The white powder body solidifies	The white powder body solidifies	The white powder body solidifies
Embodiment 1	The white particulate thing	The white particulate thing	The white particulate thing	The white particulate thing

As can knowing according to table 2, only mix and preserve the loxoprofen sodium hydrate and produce interaction with the phosphatic mixture of dihydrocodeine, the result after beginning to preserve 1, mixture solidified (comparative example 1).

On the other hand, in the shot-like particle that the pelletize of loxoprofen sodium hydrate is obtained, mix dihydrocodeine phosphate and the granular preparation made, preserve the back and keep state identical when beginning, judgement can suppress this interaction (embodiment 1).

The discontiguous in fact preparation of ［ embodiment 2 ］ loxoprofen sodium hydrate and dihydrocodeine phosphate (2)

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate), 29.2g polyethylene glycol 6000 (Japanese grease production stir (the big and pharmaceutical industries production: of 68.1g loxoprofen sodium hydrate in the glass beaker in 65 ℃ of water-baths; Trade name polyethylene glycol 6000 P) and 24.3g corn starch (day shallow lake chemical production: trade name corn starch ST-C); Then; After the cooling, sieve, obtain the pelletize thing with No. 18 sieves.Trade name dihydrocodeine phosphate " SHIONOGI "), (the five moral pharmaceutical production of 81g carboxymethylcellulose calcium in resulting pelletize thing, mix (the Shionogi production: of 8g dihydrocodeine phosphate; Trade name ECG505), (DMV produces the 591.3g lactose; Trade name lactose 200M) and (the peaceful chemical industry production of 8.1g magnesium stearate; Trade name magnesium stearate (vegetalitas)) after; The tablet machine ianthone field ironworker that use is equipped with diameter 8.5mm drift produces the HT-AP18SS type) tabletting, the quality that obtains 1 is the tablet of 270mg.

The discontiguous in fact preparation of ［ embodiment 3 ］ loxoprofen sodium and dihydrocodeine phosphate (3)

(Kawaken Fine Chemical produces: trade name K-3WAX-200), same operation obtains tablet except polyethylene glycol 6000 being substituted by fixed oil.

The discontiguous in fact preparation of ［ embodiment 4 ］ loxoprofen sodium hydrate and dihydrocodeine phosphate (4)

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate), 29.2g polyethylene glycol 6000 (Japanese grease production stir (the big and pharmaceutical industries production: of 68.1g loxoprofen sodium hydrate in the glass beaker in 65 ℃ of water-baths; Trade name polyethylene glycol 6000 P) and 24.3g corn starch (day shallow lake chemical production: trade name corn starch ST-C); Then; After the cooling, sieve, obtain the pelletize thing with No. 18 sieves.Trade name dihydrocodeine phosphate " SHIONOGI "), (the five moral pharmaceutical production of 81g carboxymethylcellulose calcium in resulting pelletize thing, mix (the Shionogi production: of 8g dihydrocodeine phosphate; Trade name ECG505), (DMV produces 295.7g lactose hydrate; Trade name lactose 200M), (Asahi Kasei Chemicals Corporation produces the 295.6g crystalline cellulose; Trade name CEOLUS PH-101) and (the peaceful chemical industry production of 8.1g magnesium stearate; Trade name magnesium stearate (vegetalitas)) after; The tablet machine ianthone field ironworker that use is equipped with diameter 8.5mm drift produces the HT-AP18SS type) tabletting, the quality that obtains 1 is the tablet of 270mg.

The discontiguous in fact preparation of ［ embodiment 5 ］ loxoprofen sodium hydrate and dihydrocodeine phosphate (5)

Trade name dihydrocodeine phosphate " SHIONOGI "), 3.4g polyethylene glycol 6000 (Japanese grease production stir (the Shionogi production: of 8g dihydrocodeine phosphate in the glass beaker in 65 ℃ of water-baths; Trade name polyethylene glycol 6000 P) and 2.9g corn starch (day shallow lake chemical production: trade name corn starch ST-C); Then; After the cooling, sieve, obtain the pelletize thing with No. 18 sieves.Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate), (the five moral pharmaceutical production of 81g carboxymethylcellulose calcium in resulting pelletize thing, mix (the big and pharmaceutical industries production: of 68.1g loxoprofen sodium hydrate; Trade name ECG505), (DMV produces 638.5g lactose hydrate; Trade name lactose 200M) and (the peaceful chemical industry production of 8.1g magnesium stearate; Trade name magnesium stearate (vegetalitas)) after; The tablet machine ianthone field ironworker that use is equipped with diameter 8.5mm drift produces the HT-AP18SS type) tabletting, the quality that obtains 1 is the tablet of 270mg.

The discontiguous in fact preparation of ［ embodiment 6 ］ loxoprofen sodium hydrate and dihydrocodeine phosphate (6)

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate), (the Japanese Cao Da production of 24.3g hydroxypropyl cellulose (Powrex Corporation produces: drop into (the big and pharmaceutical industries production: of 68.1g loxoprofen sodium hydrate the VG-05 type) at the high-speed stirred comminutor; Trade name HPC-L), 81g carboxymethylcellulose calcium (five moral pharmaceutical production; Trade name ECG505), (Asahi Kasei Chemicals Corporation produces the 620.5g crystalline cellulose; Trade name CEOLUSPH-101) after the mixing, adds the refining of 328.8g Purified Water and close.(Freund Corporation produces: after dropping into this granulation thing drying the FLO-5 type), (Seiko of field, ridge is produced: the ND-10 type) whole to use pelletizing machine at the fluidized bed drying machine.Trade name dihydrocodeine phosphate " SHIONOGI ") and (the peaceful chemical industry production of 8.1g magnesium stearate (KOTOBUKI produces: (the Shionogi production: of this granulate thing of the input 793.9g PM50 type) in, 8g dihydrocodeine phosphate at mixer; Trade name magnesium stearate (vegetalitas)) after the mixing; The tablet machine ianthone field ironworker that use is equipped with diameter 8.5mm drift produces; The HT-AP18SS type) tabletting, the quality that obtains 1 is the tablet of 270mg.

The discontiguous in fact preparation of ［ embodiment 7 ］ loxoprofen sodium hydrate and dihydrocodeine phosphate (7)

Trade name dihydrocodeine phosphate " SHIONOGI "), (the Japanese Cao Da production of 24.3g hydroxypropyl cellulose (Powrex Corporation produces: drop into (the Shionogi production: of 8g dihydrocodeine phosphate the VG-05 type) at the high-speed stirred comminutor; Trade name HPC-L), 81g carboxymethylcellulose calcium (five moral pharmaceutical production; Trade name ECG505), (Asahi Kasei Chemicals Corporation produces the 620.5g crystalline cellulose; Trade name CEOLUSPH-101) after the mixing, adds the refining of 328.8g Purified Water and close.(Freund Corporation produces: after dropping into this granulation thing drying the FLO-5 type), (Seiko of field, ridge is produced: the ND-10 type) whole to use pelletizing machine at the fluidized bed drying machine.Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and (the peaceful chemical industry production of 8.1g magnesium stearate (KOTOBUKI produces: the PM50 type) drop into (the big and pharmaceutical industries production: of this granulate thing of 733.8g, 68.1g loxoprofen sodium hydrate at mixer; Trade name magnesium stearate (vegetalitas)) after the mixing; The tablet machine ianthone field ironworker that use is equipped with diameter 8.5mm drift produces; The HT-AP18SS type) tabletting, the quality that obtains 1 is the tablet of 270mg.

The discontiguous in fact preparation of ［ embodiment 8 ］ loxoprofen sodium hydrate and dihydrocodeine phosphate (8)

(Powrex Corporation produces at the high-speed stirred comminutor; Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate), (the Japanese Cao Da production of 12.1g hydroxypropyl cellulose the VG-05 type) drop into 68.1g loxoprofen sodium hydrate (big and pharmaceutical industries production: in; Trade name HPC-L), 40.5g carboxymethylcellulose calcium (five moral pharmaceutical production; Trade name ECG505), (Asahi Kasei Chemicals Corporation produces the 280.2g crystalline cellulose; Trade name CEOLUSPH-101) after the mixing, adds the refining of 164.3g Purified Water and close.(FreundCorporation produces: after dropping into this granulation thing drying the FLO-5 type), (Seiko of field, ridge is produced: whole grain (whole grain thing A) the ND-10 type) to use pelletizing machine at the fluidized bed drying machine.In addition; At high-speed stirred comminutor (Powrex Corporation; Trade name dihydrocodeine phosphate " SHIONOGI "), (Japanese Cao Da produces the 12.1g hydroxypropyl cellulose VG-05 type) drop into (the Shionogi production: of 8g dihydrocodeine phosphate in; Trade name HPC-L), 40.5g carboxymethylcellulose calcium (five moral pharmaceutical production; Trade name ECG505), after 340.3g crystalline cellulose (Asahi Kasei Chemicals Corporation produce, trade name CEOLUS PH-101) mixes, add the refining of 164.3g Purified Water and close.(Freund Corporation produces: after dropping into this granulation thing drying the FLO-5 type), (Seiko of field, ridge is produced: whole grain (whole grain thing B) the ND-10 type) to use pelletizing machine at the fluidized bed drying machine.(KOTOBUKI produces: drop into 400g granulate thing A, 400g granulate thing B and (the peaceful chemical industry production of 8g magnesium stearate the PM50 type) at mixer; Trade name magnesium stearate (vegetalitas)) after the mixing; The tablet machine ianthone field ironworker that use is equipped with diameter 8.5mm drift produces; The HT-AP18SS type) tabletting, the quality that obtains 1 is the tablet of 270mg.

［ Test Example 3 ］ loxoprofen brings out digestive tract damage inhibitory action (1)

Using Wistar is that rat (in 8 ages in week, establish 1 group 6 and implement test for Std:Wistar/ST, hero by body weight 188.9～227.9g).Rat was gone on a hunger strike from day before yesterday on-test (more than 16 hours).The picked-up of water was freely to absorb in preceding 1 hour to on-test, cut off the water supply later on.

As being verified medicine, dihydrocodeine phosphate (DP) is outstanding turbid in 0.5% methylcellulose (MC) solution, oral administration ormal weight (8,24,72mg/5mL/kg).

In addition, in matched group, only solvent (0.5%MC) is distinguished oral administration same capability (5mL/kg).

Throwing and be verified medicine after 1 hour, oral administration 120mg loxoprofen sodium hydrate/2mL normal saline solution/kg in each group Mus brings out gastric mucosa injury.Throwing and loxoprofen sodium hydrate made rat euthanasia through the cervical vertebra dislocation after 5 hours, ligation cardia, extraction stomach.From 1% formalin solution of pyloric part to gastric injection 10mL, behind the ligation pyloric part, whole stomach was flooded in identical formalin solution about 20 minutes, slight fixing.

The evaluation of gastric mucosa injury degree is through bending after the stomach incision along big, and the length (mm) that under stereomicroscope, is determined at each damage (erosion) of glandular stomach portion generation is carried out, and the damage summation of per 1 rat is calculated as UI.Calculate the ulcer inhibition rate (%) that is verified medicine, ecbatic in table 3 according to following formula.

Ulcer inhibition rate (%)=(1-is verified the UI of the UI/matched group of medicine) * 100

［ table 3 ］

Group	UI (mm)	Ulcer inhibition rate (%)
			Contrast (0.5%MC)	18.1±2.7
?DP（8mg/kg）	5.2±2.1	71.3
			?DP（24mg/kg）	2.6±1.3	85.6
?DP（72mg/kg）	2.1±1.6	88.4

As knowing according to table 3, dihydrocodeine phosphate alleviates the gastric mucosa injury that is caused by loxoprofen sodium.

［ Test Example 4 ］ interactional discussion

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and 10mg d-chlorphenamine maleate (Buddha's warrior attendant chemical production: trade name D-chlorphenamine maleate) mix (the big and pharmaceutical industries production: of 584mg loxoprofen sodium hydrate; The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 2) for 60 ℃.As comparative control, (reference examples 3), d-chlorphenamine maleate independent (reference examples 4) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 4.

［ table 4 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 3	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 4	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 2	The white powder body	The white powder body is moistening	A white powder body part is solidified	A little yellow powder body part is solidified

As knowing according to table 4, if preserve the mixture of loxoprofen sodium hydrate and chlorphenamine maleate, mixture is with regard to moistening, curing, and then variable color (reference example 2).On the other hand, when preserving loxoprofen sodium hydrate, chlorphenamine maleate respectively separately, do not change (reference examples 3 and 4).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and chlorphenamine maleate produce results of interaction.

［ Test Example 5 ］

For the compositions of following embodiment 9 (loxoprofen sodium and the discontiguous in fact preparation of d-chlorphenamine maleate (1)) and comparative example 2, estimate the state that has just begun in back, the vial after 1 day, after 3 days, after 7 days, after 14 days, after 28 days of preserving.

Promptly; 8g dihydrocodeine phosphate is substituted by 1.2g d-chlorphenamine maleate (Buddha's warrior attendant chemical production: trade name D-chlorphenamine maleate); The preparation (comparative example 2) and loxoprofen sodium hydrate and the discontiguous in fact preparation of d-chlorphenamine maleate (embodiment 9) that are mixed with loxoprofen sodium hydrate and d-chlorphenamine maleate have been prepared; And, with 50 ℃ of preservations 28 days, after evaluation is preserved and just begun, after 1 day, after 3 days, after 7 days, after 14 days, after 28 days; In addition and Test Example 2 likewise implement the test.Ecbatic in table 5.

［ table 5 ］

As knowing according to table 5, only mix loxoprofen sodium hydrate and chlorphenamine maleate and the preparation preserved produces and interacts, the result after beginning to preserve 3, mixture moistening (comparative example 2).

On the other hand, only in the shot-like particle that the pelletize of loxoprofen sodium hydrate obtains, mix the chlorphenamine maleate and the preparation preserved, even through 28 days, also keep and same state when beginning, judgement can suppress this interaction (embodiment 9).

Its result judges through loxoprofen or its salt are contained in medical composition with mutually non-touching in fact mode with chlorphenamine or its salt, can suppress to interact.

［ embodiment 10 ］ loxoprofen sodium and the discontiguous in fact preparation of d-chlorphenamine maleate (2)

With 8g dihydrocodeine phosphate be substituted by 1.2g d-chlorphenamine maleate (the Buddha's warrior attendant chemical production: trade name D-chlorphenamine maleate), corn starch is substituted by 31.1g, in addition and embodiment 2 operate equally, obtain tablet.

［ embodiment 11 ］ loxoprofen sodium and the discontiguous in fact preparation of d-chlorphenamine maleate (3)

Except polyethylene glycol 6000 is substituted by fixed oil (Kawaken Fine Chemical produces: trade name K-3WAX-200) and embodiment 10 operate equally, obtain tablet.［ Test Example 6 ］ loxoprofen brings out digestive tract damage inhibitory action (2)

As being verified medicine; Use is with d-chlorphenamine maleate (CM) outstanding turbid suspension in 0.5% methylcellulose (MC) solution; Oral administration ormal weight (5,40mg/5mL/kg); Likewise implement test with Test Example 3 thus, calculate the ulcer inhibition rate (%) when being verified drug administration, ecbatic in table 6.

［ table 6 ］

Group	UI (mm)	Ulcer inhibition rate (%)
			Contrast (0.5%MC)	23.6±3.6
?CM（5mg/kg）	14.1±3.0	40.3
			?CM（40mg/kg）	1.5±0.4	93.6

As knowing according to table 6, the chlorphenamine maleate alleviates the gastric mucosa injury that is caused by loxoprofen sodium.

［ Test Example 7 ］ interactional discussion

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and (the DAITO production: the trade name mecloprodin fumarate) of 2.5mg mecloprodin fumarate mix 381mg loxoprofen sodium hydrate (big and pharmaceutical industries production:; The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 3) for 60 ℃.As comparative control, (reference examples 5), mecloprodin fumarate independent (reference examples 6) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 7.

［ table 7 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 5	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 6	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 3	The white powder body	The white powder body	The white powder body is moistening	Little brown powder body is moistening

As knowing according to table 7, if preserve the mixture of loxoprofen sodium hydrate and mecloprodin fumarate, mixture is just moistening, and then variable color (reference example 3).Do not change when on the other hand, preserving loxoprofen sodium hydrate, mecloprodin fumarate separately respectively (reference examples 5 and 6).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and mecloprodin fumarate produce results of interaction.

Its result judges through loxoprofen or its salt are contained in medical composition with mutually non-touching in fact mode with clemastine richness or its salt, can suppress to interact.

(DAITO produces the discontiguous in fact preparation of ［ embodiment 12 ］ loxoprofen sodium and mecloprodin fumarate (1): the trade name mecloprodin fumarate) except 8g dihydrocodeine phosphate being substituted by the 0.5g mecloprodin fumarate; Corn starch is substituted by beyond the 31.8g; Operate equally with embodiment 2, obtain tablet.

(Kawaken Fine Chemical produces the discontiguous in fact preparation of ［ embodiment 13 ］ loxoprofen sodium and mecloprodin fumarate (2): trade name K-3WAX-200) except polyethylene glycol 6000 being substituted by fixed oil; Operate equally with embodiment 12, obtain tablet.

［ Test Example 8 ］ loxoprofen brings out digestive tract damage inhibitory action (3)

As being verified medicine; Use is with mecloprodin fumarate (CF) outstanding turbid suspension in 0.5% methylcellulose (MC) solution; Oral administration ormal weight (1mg/5mL/kg); Likewise implement test with Test Example 3 thus, calculate the ulcer inhibition rate (%) when being verified drug administration, ecbatic in table 8.

［ table 8 ］

Group	UI (mm)	Ulcer inhibition rate (%)
			Contrast (0.5%MC)	23.9±4.4
?CF（1mg/kg）	14.6±2.7	38.9

As knowing according to table 8, mecloprodin fumarate alleviates the gastric mucosa injury that is caused by loxoprofen sodium.

［ Test Example 9 ］ interactional discussion

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and 17.7mg carbinoxamine maleate (Buddha's warrior attendant chemical production: the trade name carbinoxamine maleate) mix (the big and pharmaceutical industries production: of 482.3mg loxoprofen sodium hydrate; The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 4) for 60 ℃.As comparative control, (reference examples 7), carbinoxamine maleate independent (reference examples 8) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 2 days, after 1 week, ecbatic in table 9.

［ table 9 ］

	After just having begun to preserve	After 1 day	After 2 days	After 1 week
					Reference examples 7	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 8	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 4	The white powder body	The white powder body solidifies	The white powder body solidifies	Little yellow powder body solidifies

As knowing according to table 9, if preserve the mixture of loxoprofen sodium hydrate and carbinoxamine maleate, mixture just solidifies, and then variable color (reference example 4).On the other hand, when preserving loxoprofen sodium hydrate, carbinoxamine maleate separately respectively, do not change (reference examples 7 and 8).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and carbinoxamine maleate produce results of interaction.

Its result judges through loxoprofen or its salt are contained in medical composition with mutually non-touching in fact mode with carbinoxamine or its salt, can suppress to interact.

The discontiguous in fact preparation of ［ embodiment 14 ］ loxoprofen sodium and carbinoxamine maleate (1)

With 8g dihydrocodeine phosphate be substituted by the 2.5g carbinoxamine maleate (the Buddha's warrior attendant chemical production: the trade name carbinoxamine maleate), corn starch is substituted by 29.8g, in addition and embodiment 2 operate equally, obtain tablet.

The discontiguous in fact preparation of ［ embodiment 15 ］ loxoprofen sodium and carbinoxamine maleate (2)

(Kawaken Fine Chemical produces: trade name K-3WAX-200) and make example 14 operation equally, obtain tablet except polyethylene glycol 6000 being substituted by fixed oil.

［ Test Example 10 ］ loxoprofen brings out digestive tract damage inhibitory action (4)

As being verified medicine; Use is with carbinoxamine maleate (CAM) outstanding turbid suspension in 0.5% methylcellulose (MC) solution; Oral administration ormal weight (0.75,75mg/5mL/kg); Likewise implement test with Test Example 3 thus, calculate the ulcer inhibition rate (%) when being verified drug administration, ecbatic in table 10.

［ table 10 ］

Group	UI (mm)	Ulcer inhibition rate (%)
			Contrast (0.5%MC)	29.0±5.7
CAM（0.75mg/kg）	19.6±5.2	32.4
			CAM（75mg/kg）	10.8±6.5	62.8

As knowing according to table 10, carbinoxamine maleate alleviates the gastric mucosa injury that is caused by loxoprofen sodium.

［ Test Example 11 ］ interactional discussion

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and 9.6mg diphenylpyraline hydrochlorate (Buddha's warrior attendant chemical production: the trade name diphenylpyraline hydrochloride) mix (the big and pharmaceutical industries production: of 490.4mg loxoprofen sodium hydrate; The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 5) for 60 ℃.As comparative control, (reference examples 9), diphenylpyraline hydrochlorate independent (reference examples 10) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 11.

［ table 11 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 9	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 10	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 5	The white powder body	The white powder body is moistening	The white powder body is moistening	Little yellow powder body is moistening

As knowing according to table 11, if preserve the mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochlorate, mixture is just moistening, and then variable color (reference example 5).Do not change when on the other hand, preserving loxoprofen sodium hydrate and diphenylpyraline hydrochlorate respectively separately (reference examples 9 and 10).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and diphenylpyraline hydrochlorate produce results of interaction.

Its result judges through loxoprofen or its salt are contained in medical composition with mutually non-touching in fact mode with diphenylpyraline or its salt, can suppress to interact.

［ Test Example 12 ］

For the compositions of following embodiment 16 (the discontiguous in fact preparation of loxoprofen sodium and diphenylpyraline hydrochlorate (1)) and comparative example 3, estimate the state that has just begun in back, the vial after 1 day, after 3 days, after 7 days, after 14 days, after 28 days of preserving.

Promptly; 8g dihydrocodeine phosphate is substituted by 1.3g diphenylpyraline hydrochlorate (Buddha's warrior attendant chemical production: the trade name diphenylpyraline hydrochloride); The preparation (comparative example 3) and loxoprofen sodium hydrate and the discontiguous in fact preparation of diphenylpyraline hydrochlorate (embodiment 16) that are mixed with loxoprofen sodium hydrate and diphenylpyraline hydrochlorate have been prepared; And, with 50 ℃ of preservations 28 days, after evaluation is preserved and just begun, after 1 day, after 3 days, after 7 days, after 14 days, after 28 days; In addition and Test Example 2 likewise implement the test.Ecbatic in table 12.

［ table 12 ］

As knowing according to table 12, only mix loxoprofen sodium hydrate and diphenylpyraline hydrochlorate and the preparation preserved produces results of interaction, after beginning to preserve 3, mixture is with regard to moistening (comparative example 3).

On the other hand, mix the diphenylpyraline hydrochlorate in the shot-like particle that only pelletize of loxoprofen sodium hydrate is obtained and the reagent preserved, even through 28 days, also keep and same state when beginning, judgement can suppress this interaction (embodiment 16).

The discontiguous in fact preparation of ［ embodiment 17 ］ loxoprofen sodium and diphenylpyraline hydrochlorate (1)

8g dihydrocodeine phosphate is substituted by 1.3g diphenylpyraline hydrochlorate (Buddha's warrior attendant chemical production: the trade name diphenylpyraline hydrochloride), corn starch is substituted by 31g, in addition and make example 2 operation equally, obtains tablet.

The discontiguous in fact preparation of ［ embodiment 18 ］ loxoprofen sodium and diphenylpyraline hydrochlorate (2)

(Kawaken Fine Chemical produces: trade name K-3WAX-200) and make example 17 operation equally, obtain tablet except polyethylene glycol 6000 being substituted by fixed oil.

［ Test Example 13 ］ loxoprofen brings out digestive tract damage inhibitory action (5)

As being verified medicine; Use is with diphenylpyraline hydrochlorate (PP) outstanding turbid suspension in 0.5% methylcellulose (MC) solution; Oral administration ormal weight (3,10mg/5mL/kg); Likewise implement test with Test Example 3 thus, calculate the ulcer inhibition rate (%) when being verified drug administration, ecbatic in table 13.

［ table 13 ］

Group	UI (mm)	Ulcer inhibition rate (%)
			Contrast (0.5%MC)	29.7±8.0
?PP（3mg/kg）	21.0±4.5	29.3
			?PP（10mg/kg）	16.6±4.4	44.1

As knowing according to table 13, the diphenylpyraline hydrochlorate alleviates the gastric mucosa injury that is caused by loxoprofen sodium.

［ Test Example 14 ］ interactional discussion

Mix 170mg loxoprofen sodium hydrate (big and pharmaceutical industries production: trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and 10mg bromhexine salt hydrochlorate (student's product is foreignized on the mountain: trade name bromhexine salt hydrochlorate); The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 6) for 60 ℃.As comparative control, (reference examples 11), bromhexine salt hydrochlorate independent (reference examples 12) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 2 days, after 1 week, ecbatic in table 14.

［ table 14 ］

	After just having begun to preserve	After 1 day	After 2 days	After 1 week
					Reference examples 11	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 12	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 6	The white powder body	The white powder body solidifies	The white powder body solidifies	Little yellow powder body solidifies

As knowing according to table 14, if preserve the mixture of loxoprofen sodium hydrate and bromhexine salt hydrochlorate, mixture just solidifies, and then variable color (reference example 6).On the other hand, preserve loxoprofen sodium hydrate and bromhexine salt hydrochlorate do not change (reference examples 11 and 12) respectively separately.Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and bromhexine salt hydrochlorate produce results of interaction.

Its result judges through loxoprofen or its salt are not contacted in fact with bromhexine or its salt, can suppress to interact.

［ Test Example 15 ］

For the compositions of following embodiment 19 (the discontiguous in fact preparation of loxoprofen sodium and bromhexine salt hydrochlorate (1)) and comparative example 4, estimate the state that has just begun in back, the vial after 1 day, after 3 days, after 7 days, after 14 days, after 28 days of preserving.

Promptly; 8g dihydrocodeine phosphate is substituted by 4g bromhexine salt hydrochlorate, and (student's product is foreignized on the mountain: trade name bromhexine salt hydrochlorate); The mixture (comparative example 4) and loxoprofen sodium hydrate and the discontiguous in fact preparation of bromhexine salt hydrochlorate (embodiment 19) that are mixed with loxoprofen sodium hydrate and bromhexine salt hydrochlorate have been prepared; And, with 50 ℃ of preservations 28 days, after evaluation is preserved and just begun, after 1 day, after 3 days, after 7 days, after 14 days, after 28 days; In addition and Test Example 2 likewise implement the test.Ecbatic in table 15.

［ table 15 ］

As knowing according to table 15, the preparation that only mixes loxoprofen sodium hydrate and bromhexine salt hydrochlorate produce to interact, the result after beginning to preserve 1, mixture moistening (comparative example 4).

On the other hand, mix the bromhexine salt hydrochlorate in the shot-like particle that only pelletize of loxoprofen sodium hydrate is obtained and the preparation preserved, even through 28 days, also keep and same state when beginning, judgement can suppress this interaction (embodiment 19).

Its result judges through loxoprofen or its salt are contained in medical composition with mutually non-touching in fact mode with bromhexine or its salt, can suppress to interact.

The discontiguous in fact preparation of ［ embodiment 20 ］ loxoprofen sodium and bromhexine salt hydrochlorate (2)

8g dihydrocodeine phosphate is substituted by 4g bromhexine salt hydrochlorate, and (student's product is foreignized on the mountain: trade name bromhexine salt hydrochlorate), corn starch is substituted by 28.3g, in addition and make example 2 operation equally, obtains tablet.

The discontiguous in fact preparation of ［ embodiment 21 ］ loxoprofen sodium and bromhexine salt hydrochlorate (3)

(Kawaken Fine Chemical produces: trade name K-3WAX-200) and make example 20 operation equally, obtain tablet except polyethylene glycol 6000 being substituted by fixed oil.

［ Test Example 16 ］ interactional discussion

Mix 500g loxoprofen sodium hydrate (big and pharmaceutical industries production: trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and 500mg ambroxol salt hydrochlorate (Shizuoka is industrial to produce: the trade name ambroxol hydrochloride); The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 7) for 60 ℃.As comparative control, (reference examples 13), ambroxol salt hydrochlorate independent (reference examples 14) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 16.

［ table 16 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 13	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 14	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 7	The white powder body	The white powder body solidifies	Little yellow powder body solidifies	Little yellow powder body solidifies

As knowing according to table 16, if preserve the mixture of loxoprofen sodium hydrate and ambroxol salt hydrochlorate, then mixture just solidifies, and then variable color (reference example 7).Do not change when on the other hand, preserving loxoprofen sodium hydrate and ambroxol salt hydrochlorate respectively separately (reference examples 13 and 14).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and ambroxol salt hydrochlorate produce results of interaction.

Its result judges through loxoprofen or its salt are not contacted in fact with ambroxol or its salt, can suppress to interact.

［ Test Example 17 ］

For the compositions of following embodiment 22 (the discontiguous in fact preparation of loxoprofen sodium and ambroxol salt hydrochlorate (1)) and comparative example 5, estimate the state that has just begun in back, the vial after 1 day, after 3 days, after 7 days, after 14 days, after 28 days of preserving.

Promptly; 8g Dihydrocodeine phosphate is substituted by 15g ambroxol salt hydrochlorate, and (industry of Shizuoka カ Off エイ Application is produced: the trade name ambroxol hydrochloride); Preparation is mixed with preparation (comparative example 5) and the loxoprofen sodium hydrate and the discontiguous in fact preparation of ambroxol salt hydrochlorate (embodiment 22) of loxoprofen sodium hydrate and ambroxol salt hydrochlorate; And; Preserved 28 with 50 ℃; After evaluation is preserved and has just been begun, after 1 day, after 3 days, after 7 days, after 14 days, after 28 days; In addition and Test Example 2 likewise implement the test.Ecbatic in table 17.

［ table 17 ］

As knowing according to table 17, only mix loxoprofen sodium hydrate and ambroxol salt hydrochlorate and the reagent preserved produces and interacts, the result is after beginning to preserve 1, and mixture just solidifies (comparative example 5).

On the other hand, only in the shot-like particle that the pelletize of loxoprofen sodium hydrate is obtained, mix the ambroxol salt hydrochlorate and the reagent preserved, even through 28 days, identical state when also keeping with beginning, judgement can suppress this interaction (embodiment 22).

Its result judges through loxoprofen or its salt are contained in medical composition with mutually non-touching in fact mode with ambroxol or its salt, can suppress to interact.

The discontiguous in fact preparation of ［ embodiment 23 ］ loxoprofen sodium and ambroxol salt hydrochlorate (2)

8g Dihydrocodeine phosphate is substituted by 15g ambroxol salt hydrochlorate, and (industry of Shizuoka カ Off エイ Application is produced: the acid of trade name hydrochloric acid ammonia Xiu Suo salt); Macrogol 6000 is substituted by 25.7g, cornstarch is substituted by 20.8g, in addition; Operate equally with embodiment 2, obtain tablet.

The discontiguous in fact preparation of ［ embodiment 24 ］ loxoprofen sodium and ambroxol salt hydrochlorate (3)

Except polyethylene glycol 6000 is substituted by fixed oil (Kawaken Fine Chemical produces: trade name K-3WAX-200) and embodiment 23 operate equally, obtain tablet.

［ Test Example 18 ］ interactional discussion

Mix 224.9mg loxoprofen sodium hydrate (big and pharmaceutical industries production: trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and 275.1mg sulfogaiacol rice swamp creek manage pharmaceutical industries production: the trade name sulfogaiacol); The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 8) for 60 ℃.As comparative control, (reference examples 15), sulfogaiacol independent (reference examples 16) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 18.

［ table 18 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 15	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 16	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 8	The white powder body	The white powder body is moistening	The white powder body is moistening	The white powder body is moistening

As knowing according to table 18, if preserve the mixture of loxoprofen sodium hydrate and sulfogaiacol, then mixture is with regard to moistening (reference example 8).On the other hand, when loxoprofen sodium hydrate, sulfogaiacol are preserved separately respectively, do not change (reference examples 15 and 16).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and sulfogaiacol produce results of interaction.

Its result judges through loxoprofen or its salt are not contacted in fact with Guaiacolsulfonic acid. or its salt, can suppress to interact.

The discontiguous in fact preparation of ［ embodiment 25 ］ loxoprofen sodium and sulfogaiacol (1)

8g dihydrocodeine phosphate is substituted by the production of 83g sulfogaiacol ianthone Mi swamp creek reason pharmaceutical industries: the trade name sulfogaiacol); Polyethylene glycol 6000 is substituted by 292g; Corn starch is substituted by 243g, the lactose hydrate is substituted by 34.8g, in addition; Operate equally with embodiment 2, obtain tablet.

The discontiguous in fact preparation of ［ embodiment 26 ］ loxoprofen sodium and sulfogaiacol (2)

Except polyethylene glycol 6000 is substituted by fixed oil (Kawaken Fine Chemical produces: trade name K-3WAX-200) and embodiment 25 operate equally, obtain tablet.

［ Test Example 19 ］ interactional discussion

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and (the Eisai production: the trade name lysozyme chloride) of 152.9mg lysozyme salt hydrochlorate mix 347.1mg loxoprofen sodium hydrate (big and pharmaceutical industries production:; The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 9) for 60 ℃.As comparative control, (reference examples 17), lysozyme salt hydrochlorate independent (reference examples 18) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 19.

［ table 19 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 17	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 18	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 9	The white powder body	The white powder body is moistening	The white powder body solidifies	The white powder body solidifies

As knowing according to table 19, if preserve the mixture of loxoprofen sodium hydrate and lysozyme salt hydrochlorate, then mixture is just moistening, and then curing (reference example 9).On the other hand, when loxoprofen sodium hydrate, lysozyme salt hydrochlorate are preserved separately respectively, do not change (reference examples 17 and 18).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and lysozyme salt hydrochlorate produce results of interaction.

Its result judges through loxoprofen or its salt are not contacted in fact with lysozyme or its salt, can suppress to interact.

［ Test Example 20 ］

For the compositions of following embodiment 27 (the discontiguous in fact preparation of loxoprofen sodium and lysozyme salt hydrochlorate (1)) and comparative example 6, estimate the state that has just begun in back, the vial after 1 day, after 3 days, after 7 days, after 14 days, after 28 days of preserving.

Promptly; 8g dihydrocodeine phosphate is substituted by 30g lysozyme salt hydrochlorate, and (Eisai produces: the trade name lysozyme chloride); Preparation is mixed with preparation (comparative example 6) and the loxoprofen sodium hydrate and the discontiguous in fact preparation of lysozyme salt hydrochlorate (embodiment 27) of loxoprofen sodium hydrate and lysozyme salt hydrochlorate; In addition, with 50 ℃ of preservations 28 days, after evaluation is preserved and just begun, after 1 day, after 3 days, after 7 days, after 14 days, after 28 days; In addition and Test Example 2 likewise implement the test.Ecbatic in table 20.

［ table 20 ］

As knowing according to table 20, only mix loxoprofen sodium hydrate and lysozyme salt hydrochlorate and the mixture preserved produces and interacts, the result preserved beginning after 3 days, and mixture is with regard to moistening (comparative example 6).

On the other hand, only in the shot-like particle that the pelletize of loxoprofen sodium hydrate is obtained, mix the lysozyme salt hydrochlorate and the mixture preserved, even through 28 days, identical state when also keeping with beginning, judgement can suppress this interaction (embodiment 27).

Its result judges through loxoprofen or its salt and lysozyme or its salt are contained in medical composition with discontiguous in fact mode, can suppress to interact.

The discontiguous in fact preparation of ［ embodiment 28 ］ loxoprofen sodium and lysozyme salt hydrochlorate (2)

With 8g dihydrocodeine phosphate be substituted by 30g lysozyme salt hydrochlorate (Eisai produces: the trade name lysozyme chloride), polyethylene glycol 6000 is substituted by 25.7g, corn starch is substituted by 20.8g, in addition and embodiment 2 operate equally, obtain tablet.

The discontiguous in fact preparation of ［ embodiment 29 ］ loxoprofen sodium and lysozyme salt hydrochlorate (3)

Except polyethylene glycol 6000 is substituted by fixed oil (Kawaken Fine Chemical produces: trade name K-3WAX-200) and embodiment 68 operate equally, obtain tablet.

［ Test Example 21 ］ interactional discussion

Mix 500mg loxoprofen sodium hydrate (big and pharmaceutical industries production: trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) with 150mgdl-methylephedrine hydrochlorate (Alps Pharmaceutical Industry production: trade name Japanese Pharmacopoeia dl-methylephedrine hydrochlorate is last); The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 10) for 60 ℃.As comparative control, (reference examples 19), dl-methylephedrine hydrochlorate independent (reference examples 20) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 21.

［ table 21 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 19	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 20	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 10	The white powder body	The white powder body is moistening	The white powder body is moistening	Little yellow powder body is moistening

As knowing according to table 21, if preserve the mixture of loxoprofen sodium hydrate and dl-methylephedrine hydrochlorate, then mixture is just moistening, and then variable color (reference example 10).On the other hand, in loxoprofen sodium hydrate, dl-methylephedrine hydrochlorate are not changed when preserving separately respectively (reference examples 19 and 20).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and dl-methylephedrine hydrochlorate produce results of interaction.

Its result judges through loxoprofen or its salt are not contacted in fact with ephedrines, can suppress to interact.

［ embodiment 30 ］ loxoprofen sodium and the discontiguous in fact preparation of dl-methylephedrine hydrochlorate (1)

8g dihydrocodeine phosphate is substituted by 20g dl-methylephedrine hydrochlorate, and (AlpsPharmaceutical Industry produces: trade name Japanese Pharmacopoeia dl-methylephedrine hydrochlorate end); Polyethylene glycol 6000 is substituted by 23.2g; Corn starch is substituted by 18.3g; In addition and embodiment 2 operate equally, obtain tablet.

［ embodiment 31 ］ loxoprofen sodium and the discontiguous in fact preparation of dl-methylephedrine hydrochlorate (2)

Except polyethylene glycol 6000 is substituted by fixed oil (Kawaken Fine Chemical produces: trade name K-3WAX-200) and embodiment 30 operate equally, obtain tablet.［ Test Example 22 ］ loxoprofen brings out digestive tract damage inhibitory action (6)

As being verified medicine; Use is hanged turbid suspension with dl-methylephedrine hydrochlorate (ME) at 0.5% methylcellulose (MC); Oral administration ormal weight (20,60,180mg/5mL/kg); Likewise implement test with Test Example 3 thus, calculate the ulcer inhibition rate (%) when being verified drug administration, ecbatic in table 22.

［ table 22 ］

Group	UI (mm)	Ulcer inhibition rate (%)
			Contrast (0.5%MC)	28.5±4.5
?ME（20mg/kg）	18.3±5.0	35.8
			?ME（60mg/kg）	13.2±1.7	53.7
ME（180mg/kg）	8.9±2.1	68.8

As knowing according to table 22, dl-methylephedrine hydrochlorate alleviates the gastric mucosa injury that is caused by loxoprofen.

［ Test Example 23 ］ interactional discussion

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and (the Daiichi Fine Chemical production: trade name dextromethorphan HBR) of 95.1mg dextromethmorphan hydrobromide hydrate mix 404.9mg loxoprofen sodium hydrate (big and pharmaceutical industries production:; The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 11) for 60 ℃.As comparative control, (reference examples 21), dextromethmorphan hydrobromide hydrate independent (reference examples 22) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 23.

［ table 23 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 21	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 22	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 11	The white powder body	The white powder body is moistening	The white powder body is moistening	The white powder body is moistening

As knowing according to table 23, if preserve the mixture of loxoprofen sodium hydrate and dextromethmorphan hydrobromide hydrate, then mixture is with regard to moistening (reference example 11).On the other hand, when loxoprofen sodium hydrate, dextromethmorphan hydrobromide hydrate are preserved separately respectively, do not change (reference examples 21 and 22).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and dextromethmorphan hydrobromide hydrate produce results of interaction.

Its result judges through loxoprofen or its salt are not contacted in fact with dextromethorphan or its salt, can suppress to interact.

［ Test Example 24 ］

For the compositions of following embodiment 32 (the discontiguous in fact preparation of loxoprofen sodium and dextromethmorphan hydrobromide hydrate (1)) and comparative example 7, estimate the state that has just begun in back, the vial after 1 day, after 3 days, after 7 days, after 14 days, after 28 days of preserving.

Promptly; 8g dihydrocodeine phosphate is substituted by 16g dextromethmorphan hydrobromide hydrate, and (Daiichi Fine Chemical produces: trade name dextromethorphan HBR); Preparation is mixed with preparation (comparative example 7) and the loxoprofen sodium hydrate and the discontiguous in fact preparation of dextromethmorphan hydrobromide hydrate (embodiment 32) of loxoprofen sodium hydrate and dextromethmorphan hydrobromide hydrate; And, with 50 ℃ of preservations 28 days, after evaluation is preserved and just begun, after 1 day, after 3 days, after 7 days, after 14 days, after 28 days; In addition and Test Example 2 likewise implement the test.Ecbatic in table 24.

［ table 24 ］

As knowing according to table 24, only mix loxoprofen sodium hydrate and dextromethmorphan hydrobromide hydrate and the reagent preserved produces and interacts, the result preserved beginning after 1 day, mixture moistening (comparative example 7).

On the other hand; The reagent that only in the shot-like particle that the pelletize of loxoprofen sodium hydrate is obtained, mixes the dextromethmorphan hydrobromide hydrate and preserve; Even through 28 days, also keep the state identical with when beginning, judgement can suppress this interaction (embodiment 32).

Its result judges through loxoprofen or its salt are contained in medical composition with mutually non-touching in fact mode with dextromethorphan or its salt, can suppress to interact.

The discontiguous in fact preparation of ［ embodiment 33 ］ loxoprofen sodium and dextromethmorphan hydrobromide hydrate (2)

8g dihydrocodeine phosphate is substituted by 16g dextromethmorphan hydrobromide hydrate, and (Daiichi Fine Chemical produces: trade name dextromethorphan HBR); Polyethylene glycol 6000 is substituted by 25.2g; Corn starch is substituted by 20.3g; In addition and embodiment 2 operate equally, obtain tablet.

The discontiguous in fact preparation of ［ embodiment 34 ］ loxoprofen sodium and dextromethmorphan hydrobromide hydrate (3)

Except polyethylene glycol 6000 is substituted by fixed oil (Kawaken Fine Chemical produces: trade name K-3WAX-200) and embodiment 33 operate equally, obtain tablet.

［ Test Example 25 ］ interactional discussion

Trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) and (the Alps Pharmaceutical Industry production: the trade name guaifenesin) of 224.9mg guaifenesin mix 224.9mg loxoprofen sodium hydrate (big and pharmaceutical industries production:; The vial (3K specification bottle) of packing into is preserved 1 weeks (reference example 12) for 60 ℃.As comparative control, (reference examples 23), guaifenesin independent (reference examples 24) preserved for 1 weeks at 60 ℃ equally separately with the loxoprofen sodium hydrate.Estimate and just begun to preserve back, the vial internal state after 1 day, after 3 days, after 1 week, ecbatic in table 25.

［ table 25 ］

	After just having begun to preserve	After 1 day	After 3 days	After 1 week
					Reference examples 23	The white powder body	The white powder body	The white powder body	The white powder body
Reference examples 24	The white powder body	The white powder body	The white powder body	The white powder body
					Reference example 12	The white powder body	Transparency liquid	Transparency liquid	Transparency liquid

As knowing according to table 25, if preserve the mixture of loxoprofen sodium hydrate and guaifenesin, then mixture just is changed to transparency liquid (reference example 12).On the other hand, when loxoprofen sodium and guaifenesin are preserved separately respectively, do not change (reference examples 23 and 24).Judge that thus the change of state of mixture is that loxoprofen sodium hydrate and guaifenesin produce results of interaction.

Its result judges through loxoprofen or its salt are not contacted in fact with guaifenesin, can suppress to interact.

The discontiguous in fact preparation of ［ embodiment 35 ］ loxoprofen sodium and guaifenesin (1)

8g dihydrocodeine phosphate is substituted by the 83g guaifenesin, and (Alps Pharmaceutical Industry produces: the trade name guaifenesin); Polyethylene glycol 6000 is substituted by 292g; Corn starch is substituted by 243g, the lactose hydrate is substituted by 34.8g, in addition; Operate equally with embodiment 2, obtain tablet.

The discontiguous in fact preparation of ［ embodiment 36 ］ loxoprofen sodium and guaifenesin (2)

Except polyethylene glycol 6000 is substituted by fixed oil (Kawaken Fine Chemical produces: trade name K-3WAX-200) and embodiment 35 operate equally, obtain tablet.Utilizability on the industry

If according to the present invention, in medical composition, contain with mutually non-touching in fact mode through making loxoprofen or its salt and codeine class etc., can provide and preserve stable medical composition.

Therefore,, just excellent storage stability can be provided, and damage the medical composition that contains loxoprofen or its salt and codeine class that is alleviated or suppress by the digestive tract that loxoprofen causes if according to the present invention.

Claims

1. medical composition is characterized in that:

With mutually non-touching in fact mode contain be selected from codeine class, carbinoxamine or its salt, clemastine or its salt, chlorphenamine or its salt, diphenylpyraline or its salt, bromhexine or its salt, ambroxol or its salt, lysozyme or its salt and dextromethorphan or its salt more than a kind with loxoprofen or its salt.

2. medical composition is characterized in that:

Contain codeine class and loxoprofen or its salt with mutually non-touching in fact mode.

3. according to claim 1 or claim 2 medical composition is characterized in that:

Loxoprofen or its salt are the loxoprofen sodium hydrates.

4. medical composition as claimed in claim 3 is characterized in that:

Convert with the loxoprofen sodium anhydride,, contain 10～300mg loxoprofen sodium hydrate as 1 feed ration.

5. like each described medical composition in the claim 1～4, it is characterized in that:

The codeine class is to be selected from codeine phosphate hydrate and the phosphatic codeine class of dihydrocodeine.

6. medical composition as claimed in claim 5 is characterized in that:

As 1 feed ration, contain 4～60mg codeine phosphate hydrate.

7. medical composition as claimed in claim 5 is characterized in that:

As 1 feed ration, contain 2～30mg dihydrocodeine phosphate.

8. like each described medical composition in the claim 1～7, it is characterized in that:

Loxoprofen or its salt are the shot-like particles that contains loxoprofen or its salt.

9. like each described medical composition in the claim 1～8, it is characterized in that:

The codeine class is the shot-like particle that contains the codeine class.

10. like each described medical composition in the claim 1～9, it is characterized in that:

It is a solid preparation.

11., it is characterized in that like each described medical composition in the claim 1～10:

Dosage form is capsule, pill, granule, granula subtilis, powder or tablet.