WO2011093498A1 - Loxoprofen-containing pharmaceutical composition - Google Patents
Loxoprofen-containing pharmaceutical composition Download PDFInfo
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- WO2011093498A1 WO2011093498A1 PCT/JP2011/051945 JP2011051945W WO2011093498A1 WO 2011093498 A1 WO2011093498 A1 WO 2011093498A1 JP 2011051945 W JP2011051945 W JP 2011051945W WO 2011093498 A1 WO2011093498 A1 WO 2011093498A1
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- salt
- loxoprofen
- hydrochloride
- loxoprofen sodium
- pharmaceutical composition
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
Definitions
- the present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof.
- Loxoprofen is a type of non-steroidal anti-inflammatory analgesic (NSAID), including rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, cervical-shoulder arm syndrome, toothache, acute upper respiratory inflammation, post-surgical / post-traumatic It is known as effective for anti-inflammatory, analgesic and antipyretic after tooth extraction (Non-patent Document 1).
- NSAID non-steroidal anti-inflammatory analgesic
- Loxoprofen has been studied for combining with various drugs because of its excellent pharmacological action.
- Examples of the action obtained by the combination include enhancement of anti-inflammatory, analgesic and antipyretic effects by combining with caffeine, ethenamide and acetaminophen (Patent Document 1), carbinoxamine maleate, chlorpheniramine malee Of nasal congestion by combining with acid salt, ketotifen fumarate, mequitazine and epinastine hydrochloride (Patent Document 2), inhibitory effect on goblet cell hyperplasia by combining with azelastine hydrochloride and mequitazine (Patent Document 3), etc. Is mentioned.
- combining loxoprofen with bromhexine hydrochloride or ambroxol hydrochloride enhances the effect on cough symptoms (Patent Document 4) and suppresses goblet cell hyperplasia (Patent Document 5), and combines loxoprofen with bromhexine hydrochloride.
- Patent Document 6 There are known anti-inflammatory, analgesic and antipyretic effects (Patent Document 6).
- loxoprofen enhances the antihistamine action of chlorpheniramine maleate and clemastine fumarate (Patent Document 6).
- combinations of loxoprofen with various drugs are studied.
- formulation examples in which loxoprofen and various drugs are combined are described.
- a gastric mucosal disorder inhibiting action caused by loxoprofen by combining with an antacid and a xanthine derivative is known (Patent Document 7).
- codeines are known to be narcotic antitussive components having an antitussive action by suppressing the function of the cough center. And based on this action, it is a drug used as a general cold medicine and antitussive expectorant as an antitussive component (Non-patent Document 2 and others).
- Some combinations of loxoprofen and codeines are known.
- the combination of loxoprofen and dihydrocodeine hydrochloride enhances the anti-inflammatory effect (Patent Document 6)
- the combination of loxoprofen and codeine phosphate exhibits an airway goblet cell hyperplasia inhibitory effect (Patent Document 8).
- Patent Document 6 the combination of loxoprofen and codeine phosphate exhibits an airway goblet cell hyperplasia inhibitory effect
- Patent Documents 2, 4, 6, and 8 are known for preparations containing loxoprofen and codeine. However, it is not known whether or not an interaction that affects the storage stability of these compounds occurs between loxoprofen or a salt thereof and codeines in the preparation.
- the present inventors first of all, codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof
- codeines dextromethorphan and salts thereof
- loxoprofen or a salt thereof the storage stability thereof is examined.
- the object of the present invention is to provide codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof.
- a stable pharmaceutical composition comprising at least one member selected from the group consisting of dextromethorphan or a salt thereof and loxoprofen or a salt thereof.
- the present inventors have further studied to solve the above storage stability problem, and the interaction caused by the contact between the codeines and loxoprofen or a salt thereof is the cause of the storage stability problem. It revealed that. Therefore, the present inventors have found that the above-mentioned interaction can be suppressed by incorporating the above-mentioned codeine or the like and loxoprofen or a salt thereof in the pharmaceutical composition so as not to substantially contact.
- the present invention relates to codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof and dextst
- the present invention provides a pharmaceutical composition comprising at least one member selected from the group consisting of lometrphan or a salt thereof and loxoprofen or a salt thereof so as not to substantially contact each other.
- the pharmaceutical composition of the present invention has excellent storage stability.
- the present inventors have found that the above codeines and the like reduce or suppress gastrointestinal disorders caused by loxoprofen. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition having excellent storage stability and reducing or suppressing gastrointestinal disorders caused by loxoprofen.
- the pharmaceutical composition of the present invention comprises codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof And at least one member selected from the group consisting of dextromethorphan or a salt thereof and loxoprofen or a salt thereof so as not to substantially contact each other.
- loxoprofen or a salt thereof used in the present invention will be described.
- loxoprofen or a salt thereof used in the pharmaceutical composition of the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate with water, alcohol or the like. These are known compounds, and can be produced by known methods, or commercially available products can be used.
- loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).
- the content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but 10 per day in terms of loxoprofen sodium anhydride.
- An amount that can be taken in an amount of ⁇ 300 mg is preferred, an amount that can be taken in an amount of 30 to 240 mg is more preferred, and an amount that can be taken in an amount of 60 to 180 mg is more preferred.
- it may be determined by appropriate examination according to the above-mentioned daily dose.
- loxoprofen or a salt thereof is 0. 0 in terms of loxoprofen sodium anhydride relative to the total mass of the pharmaceutical composition. It is preferably contained in an amount of 4 to 90% by mass, more preferably 0.4 to 50% by mass, further preferably 1.2 to 30% by mass, and more preferably 1.2 to 25% by mass. Particularly preferred.
- codeines used in the pharmaceutical composition of the present invention mean one or more selected from the group consisting of codeine, dihydrocodeine or salts thereof, and solvates thereof. That is, codeines include not only codeine and dihydrocodeine itself, but also pharmaceutically acceptable salts of codeine and dihydrocodeine and solvates thereof. Specific examples of codeines include codeine, dihydrocodeine, codeine phosphate hydrate, dihydrocodeine phosphate and the like from the viewpoint of using the pharmaceutical composition of the present invention as a general cold medicine. Acid salt hydrate and dihydrocodeine phosphate are preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
- the content of codeine in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the gender, age, symptom of the user, and the effect of reducing or suppressing the gastrointestinal tract disorder caused by the observed loxoprofen,
- the amount that can be taken 2 to 60 mg per day is preferred, the amount that can be taken 4 to 48 mg is more preferred, and the amount that can be taken 6 to 26 mg is more preferred.
- codeine phosphate hydrate is used as the codeine, the amount that can be taken 4 to 60 mg per day is preferable, the amount that can be taken 8 to 48 mg is more preferable, and the amount that can be taken 12 to 36 mg is more preferable.
- the codeine is preferably contained in an amount of 0.08 to 4% by mass based on the total mass of the pharmaceutical composition.
- the codeine is codeine phosphate hydrate, it is preferably contained in an amount of 0.15 to 4% by mass, more preferably 0.3 to 3% by mass, based on the total mass of the pharmaceutical composition. More preferably, the content is 0.5 to 2.5% by mass.
- the content is preferably 0.08 to 2% by mass, more preferably 0.16 to 1.5% by mass, based on the total mass of the pharmaceutical composition, More preferably, the content is 0.24 to 1.5% by mass.
- the content ratio of loxoprofen or a salt thereof and codeines contained in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the daily dose of each component described above.
- the salt preferably contains 0.005 to 4 parts by mass of codeine, and more preferably 0.01 to 2 parts by mass, based on 1 part by mass in terms of loxoprofen sodium anhydride.
- the carbinoxamine or a salt thereof used in the pharmaceutical composition of the present invention includes not only carbinoxamine itself but also a pharmaceutically acceptable salt of carbinoxamine.
- Specific examples of carbinoxamine or a salt thereof include carbinoxamine, carbinoxamine maleate, carbinoxamine diphenyl disulfonate, and the like, and carbinoxamine maleate is more preferable in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.
- the content of carbinoxamine or a salt thereof in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the sex, age, symptoms, etc. of the user, but can be taken 0.1 to 60 mg per day.
- the amount is preferably, more preferably 0.5 to 30 mg, more preferably 1 to 16 mg.
- the carbinoxamine or a salt thereof is preferably contained in an amount of 0.004 to 4% by mass, more preferably 0.02 to 2% by mass, more preferably 0.04 to 1%, based on the total mass of the pharmaceutical composition.
- the content by mass is particularly preferred.
- the content of carbinoxamine or a salt thereof may be determined according to the above-mentioned daily dose.
- the content ratio of loxoprofen or a salt thereof and carbinoxamine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof is contained in an amount of 0.0003 to 6 parts by mass, more preferably 0.002 to 1 part by mass with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. More preferably, 0.005 to 0.3 parts by mass is contained.
- the clemastine or a salt thereof used in the pharmaceutical composition of the present invention includes not only clemastine itself but also a pharmaceutically acceptable salt of clemastine.
- Specific examples of clemastine or a salt thereof include, for example, clemastine, clemastine fumarate, etc.
- clemastine fumarate is preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
- the content of clemastine or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but per day, in terms of clemastine free body, The amount that can be taken 0.01 to 5 mg is preferred, the amount that can be taken 0.05 to 3 mg is more preferred, and the amount that can be taken 0.1 to 2 mg is even more preferred. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
- clemastine or a salt thereof is preferably contained in an amount of 0.008 to 0.4% by mass in terms of a free form of clemastine, preferably 0.01 to 0.2% by mass, based on the total mass of the pharmaceutical composition. Is more preferable, and 0.015 to 0.15% by mass is particularly preferable. In addition, what is necessary is just to determine the content of a clemastine or its salt according to the dose per day mentioned above.
- loxoprofen or a salt thereof and clemastine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined according to the daily dose of each component described above.
- loxoprofen or a salt thereof contains 0.0006 to 0.5 parts by mass of clemastine or a salt thereof in terms of a free form of clemastine with respect to 1 part by mass of loxoprofen sodium anhydride. Those containing 1 part by mass are more preferred, and those containing 0.002 to 0.03 parts by mass are more preferred.
- the chlorpheniramine or a salt thereof used in the pharmaceutical composition of the present invention includes chlorpheniramine itself and a pharmaceutically acceptable salt of chlorpheniramine. Since chlorpheniramine has an asymmetric carbon, it has an optical isomer, but in the present invention, any optical isomer may be included, which may be a single optical isomer or a mixture of various optical isomers. . Of these, d-form and dl-form are preferred in the present invention. Specific examples of the chlorpheniramine or a salt thereof include chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate and the like.
- d-chlorpheniramine maleate and dl-chlorpheniramine maleate are preferable, and d-chlorpheniramine maleate is particularly preferable.
- d-chlorpheniramine maleate and dl-chlorpheniramine maleate are preferable, and d-chlorpheniramine maleate is particularly preferable.
- These are known compounds, and can be produced by known methods, or commercially available products can be used.
- the content of chlorpheniramine or a salt thereof in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the sex, age, symptoms, etc. of the user, but is 0.1 to 20 mg per day.
- the amount that can be taken is preferred, and the amount that can be taken 0.6 to 12 mg is more preferred.
- an amount that can be taken 0.1 to 15 mg per day is preferable, and an amount that can be taken 0.6 to 6 mg is more preferable.
- An amount that can be taken up to 5 mg is more preferred.
- the amount that can be taken from 0.5 to 20 mg per day is preferred, the amount that can be taken from 1 to 12 mg is more preferred, and the amount that can be taken from 2 to 10 mg is even more preferred.
- the content of chlorpheniramine or a salt thereof is preferably 0.004 to 1.5% by mass, more preferably 0.02 to 0.8% by mass, based on the total mass of the pharmaceutical composition. Is more preferable, and it is particularly preferable to contain 0.04 to 0.7% by mass. In addition, what is necessary is just to determine the content of chlorpheniramine or its salt according to the dose per day mentioned above.
- loxoprofen or a salt thereof and chlorpheniramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the daily dose of each component described above.
- loxoprofen or a salt thereof contains 0.0001 to 1.5 parts by mass of chlorpheniramine or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 0.7 Those containing parts by mass are more preferred, and those containing 0.001 to 0.5 parts by mass are particularly preferred.
- the diphenylpyralin or a salt thereof used in the pharmaceutical composition of the present invention includes not only diphenylpyralin itself but also a pharmaceutically acceptable salt of diphenylpyralin.
- Specific examples of diphenylpyraline or a salt thereof include, for example, diphenylpyraline, diphenylpyraline hydrochloride, diphenylpyraline theocuroate and the like.
- diphenylpyraline hydrochloride and diphenylpyraline theocuroate are preferable, Diphenylpyraline hydrochloride is particularly preferred.
- the content of diphenylpyralin or a salt thereof in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the sex, age, symptom, etc. of the user, but from 0.1 to 13 per day.
- the amount that can be taken 5 mg is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred.
- diphenylpyraline hydrochloride is used as diphenylpyraline or a salt thereof, the amount that can be taken 0.1 to 12 mg per day is preferable, and the amount that can be taken 1 to 4 mg is more preferable.
- diphenylpyraline theocuroate the amount that can be taken 0.1 to 13.5 mg per day is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred.
- the content of diphenylpyralin or a salt thereof is preferably 0.004 to 1.5% by mass, more preferably 0.004 to 1% by mass, based on the total mass of the pharmaceutical composition. .
- 0.04 to 0.5% by mass is preferable, 0.04 to 0.3% by mass is more preferable, and 0.06 to 0.25% by mass is particularly preferable.
- what is necessary is just to determine the content of diphenyl pyralin or its salt according to the dose per day mentioned above.
- loxoprofen or a salt thereof and diphenylpyraline or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above.
- loxoprofen or a salt thereof contains 0.0001 to 3 parts by mass of diphenylpyraline or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 2.5 parts by mass. More preferred are those containing 0.001 to 1 part by mass, and particularly preferred are those containing 0.001 to 0.3 part by mass.
- the bromhexine or a salt thereof used in the pharmaceutical composition of the present invention includes not only bromhexine itself but also a pharmaceutically acceptable salt of bromhexine.
- Specific examples of bromhexine or a salt thereof include, for example, bromhexine and bromhexine hydrochloride.
- bromhexine hydrochloride is preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.
- the content of bromhexine or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptom, etc. of the user, but bromhexine or a salt thereof is bromhexine hydrochloride per day.
- the amount that can be taken 0.1 to 50 mg in terms of salt is preferred, the amount that can be taken 0.5 to 25 mg is more preferred, and the amount that can be taken 1 to 15 mg is even more preferred.
- the content of bromhexine or a salt thereof is preferably 0.004 to 4% by mass, preferably 0.02 to 2% by mass in terms of bromhexine hydrochloride, based on the total mass of the pharmaceutical composition. More preferably, the content is 0.04 to 1% by mass.
- what is necessary is just to determine the content of bromhexine or its salt according to the daily dose mentioned above.
- the content ratio of loxoprofen or a salt thereof and bromhexine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, it is preferable to contain 0.0001 to 10 parts by mass of loxoprofen or a salt thereof in terms of loxoprofen sodium anhydride in terms of 1 part by mass of bromhexine or a salt thereof in terms of bromhexine hydrochloride, and 0.0005 to 2 parts by mass. More preferably, it contains 0.001 to 1 part by mass.
- ambroxol or a salt thereof used in the pharmaceutical composition of the present invention includes not only ambroxol itself but also a pharmaceutically acceptable salt of ambroxol.
- Specific examples of ambroxol or a salt thereof include, for example, ambroxol, ambroxol hydrochloride and the like.
- ambroxol hydrochloride is preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.
- the content of ambroxol or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but per day, ambroxol or a salt thereof
- the amount that can be taken 0.1 to 150 mg in terms of ambroxol hydrochloride is preferred, the amount that can be taken 0.5 to 100 mg is more preferred, and the amount that can be taken 1 to 50 mg is more preferred.
- the content of ambroxol or a salt thereof is preferably 0.004 to 10% by mass in terms of ambroxol hydrochloride relative to the total mass of the pharmaceutical composition, and preferably 0.02 to 7%. More preferably, it is contained in an amount of 0.04 to 5% by mass.
- the content of ambroxol or a salt thereof may be determined according to the above-mentioned daily dose.
- the content ratio of loxoprofen or a salt thereof and ambroxol or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof is contained in an amount of 0.0001 to 10 parts by mass in terms of 1 part by mass in terms of loxoprofen sodium anhydride and ambroxol or a salt in terms of ambroxol hydrochloride. Those containing 0.0005 to 5 parts by mass are more preferred, and those containing 0.001 to 3 parts by mass are more preferred.
- the lysozyme or a salt thereof used in the pharmaceutical composition of the present invention includes lysozyme itself and a pharmaceutically acceptable salt of lysozyme.
- Specific examples of lysozyme or a salt thereof include lysozyme, lysozyme hydrochloride and the like, and lysozyme hydrochloride is preferable in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.
- the content of lysozyme or a salt thereof in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the sex, age, symptom, etc. of the user, but lysozyme or a salt thereof is lysozyme hydrochloride per day.
- salt titer an amount that can be taken from 5 to 450 mg (titer) is preferred, an amount that can be taken from 10 to 360 mg (titer) is more preferred, and an amount that can be taken from 15 to 270 mg (titer) is even more preferred.
- the content of lysozyme or a salt thereof is preferably 0.2 to 30% by mass (titer) in terms of titer of lysozyme hydrochloride with respect to the total mass of the pharmaceutical composition. More preferably, it is contained in an amount of ⁇ 25% by mass (titer), more preferably 0.6-20% by mass (titer). In addition, what is necessary is just to determine the content of a lysozyme or its salt according to the dose per day mentioned above.
- loxoprofen or a salt thereof and lysozyme or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above.
- loxoprofen or a salt thereof contains 0.01 to 45 parts by mass (titer) of lysozyme or a salt thereof in terms of titer of lysozyme hydrochloride with respect to 1 part by mass of loxoprofen sodium anhydride.
- Those containing 0.04 to 12 parts by mass (titer) are more preferred, and those containing 0.08 to 5 parts by mass (titer) are more preferred.
- Dextromethorphan or a salt thereof used in the pharmaceutical composition of the present invention includes dextromethorphan itself, pharmaceutically acceptable salts of dextromethorphan, and pharmaceutically acceptable dextromethorphan and dextromethorphan. And solvates of water and alcohol.
- Specific examples of dextromethorphan or a salt thereof include, for example, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenol phthaline salt, etc., and dextromethorphan hydrobromide hydrate.
- Dextromethorphan phenol phthaline salt is preferred, and dextromethorphan hydrobromide hydrate is more preferred.
- the content of dextromethorphan or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but per day, dextromethorphan or its It is preferable to take 0.1 to 270 mg of salt, more preferably 0.5 to 180 mg, and even more preferably 1 to 90 mg.
- dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate
- an amount capable of taking 6 to 60 mg of dextromethorphan hydrobromide hydrate per day is preferable, and 15 to 60 mg
- the amount that can be taken is more preferred, and the amount that can be taken 20 to 60 mg is more preferred.
- dextromethorphan or a salt thereof is dextromethorphan phenol phthaline salt
- an amount capable of taking 9 to 90 mg of dextromethorphan phenol phthalin salt per day is preferable, and an amount capable of taking 22 to 90 mg is more preferable. More preferably, the dose is 30 to 90 mg.
- the content of dextromethorphan or a salt thereof is preferably 0.004 to 20% by mass, more preferably 0.02 to 15% by mass with respect to the total mass of the pharmaceutical composition, More preferably, the content is 0.04 to 10% by mass.
- what is necessary is just to determine the content of dextromethorphan or its salt according to the dose per day mentioned above.
- the content ratio of loxoprofen or a salt thereof and dextromethorphan or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the daily dose of each component described above. It is preferable that loxoprofen or a salt thereof contains 0.0001 to 20 parts by mass of dextromethorphan or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0005 to 10 parts by mass. More preferably, the content is 0.001 to 5 parts by mass.
- “containing so as not to substantially contact each other” means containing in a pharmaceutical composition so that loxoprofen or a salt thereof, codeine, and the like do not come into contact with each other so as not to exhibit an interaction. Although it means, it is preferable to contain so that a loxoprofen or its salt, codeines, etc. may not contact.
- the dosage form of the pharmaceutical composition of the present invention is not particularly limited, but a solid preparation is preferable from the viewpoint of ease of taking.
- solid preparations include, for example, oral preparations such as capsules, pills, granules, fine granules, powders, tablets, dry syrups, jellies, troches, and parenteral administration such as suppositories. Examples include oral preparations, and oral solid preparations are preferred.
- the pharmaceutical composition of the present invention may be coated with a sugar coating or a film coating by a known method.
- the solid preparation contains (A) loxoprofen or a salt thereof, or a solid composition containing loxoprofen or a salt thereof, and (B) a codeine or the like itself, or a solid composition containing codeine or the like.
- the components constituting these solid compositions include those in which loxoprofen or a salt thereof and codeine are arranged so as not to contact each other (however, the component (A) is composed of loxoprofen or a salt thereof itself). And the component (B) is codeine or the like itself).
- These solid compositions are in the form of powder, granules, tablets, and the like.
- solid preparation As specific forms of the solid preparation, the following (a) to (h) can be exemplified, and these are described in known methods as described above, for example, the 15th revised Japanese Pharmacopoeia General Rules for Preparations, etc. According to the known methods, it can be produced and formulated using appropriate formulation additives.
- specific forms of solid preparations are exemplified by taking codeines as examples. In the case of using chlorpheniramine or a salt thereof that interacts with loxoprofen or a salt thereof instead of codeine, a solid preparation can be produced and formulated in the same manner as codeine.
- (I) Either loxoprofen or a salt thereof and codeine are granulated by an appropriate method to form a granule, and the other loxoprofen or a salt thereof or codeine is blended without granulation. Powders, granules, etc., as well as preparations in which the granules are further coated by an appropriate method.
- (B) Loxoprofen or a salt thereof and codeine are separately granulated by an appropriate method to form granules, and powders and granules produced by blending these, and the granules are further processed by an appropriate method. Coated formulation.
- the multi-layered tablet is preferably one in which loxoprofen or a salt thereof and codeine are located in different layers, and as a multi-layered tablet having three or more layers, a layer containing loxoprofen or a salt thereof and a layer containing codeine are mutually attached.
- the granular material produced in the above (i) or (b) can be used.
- One of loxoprofen or a salt thereof and codeine is arranged in a core tablet (also referred to as a core tablet or a central tablet) so that loxoprofen or a salt thereof and codeine are not substantially in contact with each other.
- the loxoprofen or a salt thereof and codeine the granular material produced in the above (i) or (b) can be used.
- a cyclodextrin such as ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin.
- Loxoprofen or a salt thereof and codeine are contained in a preparation prepared by a usual method, and are provided with a sugar coating layer or a film coating layer, and the other sugar coating layer or coating layer is provided on the other side. And a preparation prepared so that loxoprofen or a salt thereof and codeine are not substantially in contact with each other (when the dosage form is a tablet, it is called a sugar-coated tablet or a film-coated tablet).
- Granules in the above (a) and (b) are known granulations such as extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, crushed granulation, melt granulation, etc. Depending on the method, it may be prepared using appropriate formulation additives. In the present invention, all of the granular material containing loxoprofen or a salt thereof and the granular material containing codeine may be produced by the same granulation method or by different granulation methods. May be.
- the granular material containing loxoprofen or a salt thereof can be produced by granulating by an appropriate method based on a known method, but a commercially available product can be used.
- the fine granules include loxoprofen sodium hydrate, lactose hydrate, hydroxypropylcellulose, magnesium stearate, talc, silicon dioxide, iron trioxide, polysorbate 40, and 113 g of loxoprofen sodium hydrate in 1 g. .4 mg (as anhydride) 100 mg) contained), Kentan (registered trademark) fine granules 10% manufactured by Medisa Shinyaku Co., Ltd.
- the fine granules are loxoprofen sodium hydrate, light anhydrous silicic acid, iron sesquioxide, magnesium stearate, lactose hydrate Product, hydroxypropylcellulose, fumaric acid, D-mannitol, 113.4 mg of loxoprofen sodium hydrate in 1 g (100 mg as an anhydride), Ponaperto (registered trademark) fine granules manufactured by Biomedics Co., Ltd.
- the fine granules contain loxoprofen sodium hydrate, lactose hydrate, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate, iron sesquioxide, 1 g of loxoprofen sodium hydrate 113.4 mg (as anhydride) 100 mg)), 10% Lingeles (registered trademark) manufactured by Yoshindo Co., Ltd.
- the fine particles are loxoprofen sodium hydrate, lactose hydrate, crospovidone, hydroxypropylcellulose, magnesium stearate
- loxoprofen sodium hydrate hydroxypropylcellulose, low-substituted hydroxypropylcellulose, iron sesquioxide, lactose hydrate, magnesium stearate, 113.4 mg of loxoprofen sodium hydrate in 1 g (100 mg as anhydrous) ) Contained)
- Rolfue made by Nichi-Iko Namin® Fine Granules 10% (The fine granules include loxoprofen sodium hydrate, lactose hydrate, carboxymethyl starch sodium, hydroxypropyl starch, hydroxypropyl cellulose, magnesium stearate, talc, iron sesquioxide.
- loxoprofen sodium hydrate is contained in 1 g (100 mg as anhydrous). ) And the like.
- the fine granule containing 113.4 mg of loxoprofen sodium hydrate (100 mg as an anhydride) in 1 g of the left column is obtained by appropriately increasing or decreasing the content of loxoprofen sodium hydrate based on a known method. be able to.
- binder include methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl Alcohol etc. are mentioned.
- a binder having a low melting point (freezing point) that is solid at room temperature and melts or softens by heating. is preferably used.
- the melting point (freezing point) of such a binder is preferably lower than the melting point of the components according to the present invention (loxoprofen or a salt thereof, codeine, etc.).
- a binder having a melting point (freezing point) of 30 to 100 ° C. is preferable, and a binder having a temperature of 50 to 80 ° C. is more preferable.
- macrogols for example, macrogol 4000, macrogol 6000, macrogol 20000, etc.
- fats and oils for example, beef tallow oil, hydrogenated oil, hydrogenated vegetable oil, soybean hydrogenated oil, carnauba wax
- Hydrocarbons eg, paraffin, microcrystalline wax, etc.
- higher alcohols eg, cetyl alcohol, stearyl alcohol, etc.
- fatty acids eg, stearic acid
- fatty acid esters for example, acetyl glycerin fatty acid ester, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, glyceryl monostearate, etc.
- Excipients include, for example, crystalline cellulose, powdered cellulose, lactose hydrate, sucrose, glucose, mannitol, erythritol, xylitol, trehalose, maltitol, lactitol, sorbitol, wheat starch, corn starch, potato starch, phosphoric anhydride Examples thereof include calcium hydrogen, calcium carbonate, silicon dioxide and the like.
- disintegrant examples include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl ethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, hydroxypropyl starch, and the like.
- Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, and sodium stearyl fumarate.
- Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide and the like.
- Examples of the colorant include yellow ferric oxide, ferric oxide, edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible yellow No. 5, edible green No. 3, edible red No. 2, and edible red No. 3 Edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106 and the like.
- a drug other than loxoprofen or a salt thereof, and codeine such as antipyretic analgesic, antihistamine, antitussive, noscapine, bronchodilator, expectorant, hypnotic sedative
- codeine such as antipyretic analgesic, antihistamine, antitussive, noscapine, bronchodilator, expectorant, hypnotic sedative
- It may contain one or more selected from the group consisting of vitamins, anti-inflammatory agents, gastric mucosa protective agents, anticholinergics, herbal medicines, Chinese herbal formulas, caffeine, xanthine components and the like.
- antipyretic analgesics examples include aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, sazapyrine, salicylamide, sodium salicylate, thiaramide hydrochloride, lactylphenetidine, and the like.
- Antihistamines include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, ketotifen fumarate, difeterol hydrochloride, dipheterol phosphate, diphenhydramine Hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, mequitazine, methodirazine hydrochloride, mebhydrolinapadi Silates and the like can be mentioned.
- Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, dibutate sodium, dimemorphan phosphate, tipepidine citrate, And tipepidine hibenzate.
- noscapine include noscapine hydrochloride and noscapine.
- bronchodilators examples include trimethquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, ephedrines (pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride Salt, dl-methylephedrine saccharin salt), methoxyphenamine hydrochloride and the like.
- expectorants include ammonia fennel, ethyl cysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacol sulfonate, potassium cresol sulfonate, methyl cysteine hydrochloride, 1-menthol and the like.
- examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromvalerylurea.
- vitamins include vitamin B 1 , vitamin B 2 , vitamin B 5 , vitamin B 6 , vitamin B 12 , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, Thiamine nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavinline Acid ester, riboflavin butyrate, sodium riboflavin phosphate, panthenol, pantethine, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecoba Lamin, ascorbic acid, sodium ascorbate
- anti-inflammatory agent examples include glycyrrhizic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, bromelain and the like. Can be mentioned.
- gastric mucosa protective agent examples include aminoacetic acid, aldioxa, magnesium silicate, gefarnate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product , Sucralfate, cetraxate hydrochloride, sofalcone, magnesium carbonate, teprenone, copper chlorophyllin potassium, copper chlorophyllin sodium, magnesium metasilicate aluminate, methylmethionine Honiumukurorido, and the like.
- anticholinergic agent examples include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipedium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl- l-hyostiamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodopropamide iodide, diphenylpiperidinomethyldioxolane, funnel extract, funnel root, funnel Examples include root total alkaloid citrate.
- Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyokaku (horny sheep), fennel (mushrooms), turmeric (depressed gold), engosaku (yenkogong), enmeisou (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Oubak (yellow twilight), Spruce (cherry skin), Auren (yellow ream), Onji (distant), Gajutsu (we), Ganoderma (deer herb), Chamomile, Caronin (Karojin), Licorice (licorice), Kyokyo (Kikkyo), Kyonin (Kyojin), Kukoshi (Isogo), Kukoyo (Kashiwaha), Keigai (Kashiwagi), Keihi (Kinseido), Ketsumeishi (Kameko), Gentiana, Gennoshouko (current evidence),
- Examples of Kampo prescriptions include Keishi-yu, Kosou-san, Saiko-Kei-do, Sho-saiko-yu, Bakumon-fu-to, Hanka-koboku-yu, and the like.
- Examples of caffeine include sodium benzoate caffeine, caffeine hydrate, and anhydrous caffeine.
- Examples of the xanthine component include aminophylline, diprofylline, theophylline, proxyphylline and the like.
- composition of the present invention those other than the following (a) to (u) are preferable.
- the route of administration of the pharmaceutical composition of the present invention includes oral and parenteral such as rectal and vaginal, but oral administration is preferred.
- the pharmaceutical composition of the present invention can be taken 1 to 4 times per day before meals, between meals, after meals, before going to bed, etc.
- the pharmaceutical composition of the present invention may be further stored in the presence of a desiccant from the viewpoint of inhibition of interaction.
- a desiccant from the viewpoint of inhibition of interaction.
- pharmaceutical formulation what contains the pharmaceutical composition and desiccant of this invention in a container.
- the desiccant is not particularly limited.
- the desiccant include silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride and magnesium oxide. 1 type or 2 types or more are mentioned, What mixed these and activated carbon may be sufficient.
- one or more selected from silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve) and calcium chloride are more preferable, and synthetic zeolite is particularly preferable from the viewpoint of interaction suppression.
- the shape of the desiccant is not particularly limited, and examples thereof include a plate-shaped or bag-shaped sheet mold, a cylinder-shaped (tablet mold), and the like. A film-coated one may also be used.
- Various desiccants are commercially available. For example, Shiblet, MS-Tablet, MS-Serum W, Tokai Gel, Decite Kite 25, Alp sheet, Toray Chemical Co., Ltd. ) Packaged items, Dryan (registered trademark) tablets, Dryan (registered trademark) sheets, Sekawa, Allosheet, Zeosheet, Shinzo Kasei Co., Ltd., OZO Co., Ltd. OZO, IDi Co., Ltd. IDi-packing desiccant and the like.
- the content of the desiccant in the pharmaceutical preparation of the present invention may be determined by appropriate examination, but is preferably 0.05 to 35 parts by weight, preferably 0.15 to 17 parts by weight with respect to 1 part by weight of loxoprofen or a salt thereof. Part is more preferred.
- the content of the desiccant is preferably 0.001 to 1 part by weight, and 0.004 to 0.00 parts per 1 part by weight of the pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, codeine and the like. 4 parts by mass is more preferable.
- the container used for the pharmaceutical preparation of the present invention is not particularly limited as long as it can be used as a container for foods, supplements, pharmaceuticals, health foods, etc., and any of a fixed container and an amorphous container can be used and sealed. What is possible is preferred.
- Examples of the fixed container include bottles, cans, and boxes.
- Examples of the amorphous container include bags (pillow packaging, stick packaging, PTP packaging, SP packaging, etc.) and the like. Of these containers, specifically, bottles and bags are preferable.
- the forming member of the container is not particularly limited, and examples thereof include paper, glass, a resin or a resin film, or a member such as a metal or a metal film, and a composite structure or a multilayer structure in which these members are appropriately combined. It may be a thing. Moreover, it is preferable that moisture permeation prevention processing is performed about the member which has moisture permeability, such as paper.
- the container may be transparent, translucent, or opaque.
- the method of storing the pharmaceutical composition of the present invention and the desiccant in a container is not particularly limited, and any of them can be achieved by arranging them by appropriate means such as charging into the container.
- the desiccant preferably, a columnar shape (tablet shape)
- the bottle is placed in the bottle, or stored in the back side (inner cap) of the bottle lid, and stored in the container.
- the pharmaceutical composition containing loxoprofen of the present invention or a salt thereof, codeine and the like is preferably a solid preparation containing these.
- the container when the container is a bag, it can be achieved by storing the desiccant (preferably, a plate-like or bag-like sheet type) and the pharmaceutical composition of the present invention in the bag.
- the pharmaceutical composition containing loxoprofen or a salt thereof, codeine or the like of the present invention is preferably a solid preparation containing these.
- the pharmaceutical composition of the present invention may be once packaged by SP packaging, PTP packaging or a bag, and then the packaged pharmaceutical composition and desiccant may be enclosed in a bag.
- the form etc. which carry out pillow packaging of the solid formulation which carried out SP packaging or PTP packaging, and a plate-shaped or bag-shaped sheet type desiccant etc. are mentioned.
- the pillow packaging form may be stored in a box or the like.
- the pharmaceutical composition of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain ⁇ Bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain), pain relief, chills, antipyretic fever, cold symptoms (sore throat, cough, chills, fever, headache, joint pain) , Muscle pain), cough, etc., and is useful as a cold medicine, antipyretic analgesic and the like.
- Test Example 2 Examination of Interaction Regarding the composition of Example 1 below (formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (1)) and Comparative Example 1, The state in the glass bottle after 1 day, 3 days and 1 week was evaluated, and the results are shown in Table 2.
- Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and 24.3 g of corn starch (Nippon Chemical Co., Ltd .: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then passed through a No. 18 sieve to obtain a granulated product.
- loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P), corn starch 24 3 g (manufactured by Nissho Chemical Co., Ltd .: trade name corn starch ST-C) and 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”) are mixed and placed in a glass bottle (13K standard bottle) It was stored at 50 ° C. for 1 week (Comparative Example 1).
- Example 2 Formulation (2) in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact with each other Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and corn starch 24.3 g (Nippon Chemical Co., Ltd .: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then passed through a No.
- Example 3 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (3) Tablets were obtained in the same manner except that Macrogol 6000 was replaced with hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).
- Example 4 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (4)
- Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and corn starch 24.3 g (Nippon Chemical Co., Ltd .: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then passed through a No.
- Example 5 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (5) 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”), 3.4 g of macrogol 6000 (manufactured by NOF Corporation: trade name Macrogol 6000P) and 2.9 g of corn starch (manufactured by Nissho Chemical Co., Ltd.) : Product name Corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then sieved with a No.
- dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”
- macrogol 6000 manufactured by NOF Corporation: trade name Macrogol 6000P
- corn starch
- loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate), carmellose calcium 81 g (manufactured by Gotoku Pharmaceutical: trade name ECG505), lactose water 638.5 g of Japanese product (manufactured by DMV: trade name: lactose 200M) and 8.1 g of magnesium stearate (manufactured by Taihei Chemical Industry: trade name: magnesium stearate (vegetable)) were mixed, and a bowl with a diameter of 8.5 mm was attached. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) to obtain tablets each having a mass of 270 mg.
- a tableting machine manufactured by Hata Iron Works: Model HT-AP18SS
- Example 6 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate do not substantially contact (6)
- Loxoprofen sodium hydrate 68.1 g (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate), hydroxypropylcellulose 24.3 g (manufactured by Nippon Soda: trade name HPC-L), carmellose calcium 81 g (Gotoku) Made by chemicals: trade name ECG505), 620.5 g of crystalline cellulose (made by Asahi Kasei Chemicals: trade name Theolas PH-101) were put into a high-speed stirring granulator (manufactured by Paulek: model VG-05), mixed and purified water 328 .8 g was added and kneaded.
- This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type).
- Example 7 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (7) 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”), 24.3 g of hydroxypropyl cellulose (trade name: HPC-L, manufactured by Nippon Soda), 81 g of carmellose calcium (trade name, manufactured by Gotoku Yakuhin Co.
- dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”
- HPC-L hydroxypropyl cellulose
- carmellose calcium trade name, manufactured by Gotoku Yakuhin Co.
- ECG505 ECG505
- 620.5 g of crystalline cellulose product name: Asahi Kasei Chemicals: trade name: Theolas PH-101
- a high-speed stirring granulator manufactured by Paulek: VG-05 type
- 328.8 g of purified water was added. Kneaded.
- This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type).
- Example 8 Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (8)
- Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate), hydroxypropylcellulose 12.1 g (manufactured by Nippon Soda: trade name HPC-L), carmellose calcium 40.5 g (Product name: ECG505 manufactured by Gotoku Pharmaceutical Co., Ltd.), 280.2 g of crystalline cellulose (product name: Asola Chemical PH-101 manufactured by Asahi Kasei Chemicals Co., Ltd.) are charged into a high-speed stirring granulator (manufactured by Paulek: Model VG-05), mixed and purified.
- dihydrocodeine phosphate manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”
- 12.1 g of hydroxypropyl cellulose manufactured by Nippon Soda: trade name: HPC-L
- 40.5 g of carmellose calcium (Gotoku Pharmaceutical) Product: ECG505)
- 340.3 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas PH-101) were put into a high-speed agitation granulator (Paurek: Model VG-05), mixed, and purified water 164. 3 g was added and kneaded.
- This granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then sized using a granulator (Okada Seiko: ND-10 type) (Granulated product B). ). 400 g of the sized product A, 400 g of the sized product B and 8 g of magnesium stearate (manufactured by Taihei Kagaku Kogyo: trade name magnesium stearate (vegetable)) were put into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 8.5 mm diameter punch, and tablets with a mass of 270 mg were obtained.
- a tableting machine manufactured by Hata Iron Works: Model HT-AP18SS
- loxoprofen sodium hydrate 120 mg / 2 mL saline / kg was orally administered to each group of rats to induce gastric mucosal damage.
- the rats were euthanized by cervical dislocation, the cardia was ligated, and the stomach was removed. After injecting 10 mL of 1% formalin solution into the stomach from the pyloric region and ligating the pyloric region, the entire stomach was immersed in the formalin solution for about 20 minutes and fixed lightly.
- dihydrocodeine phosphate reduced gastric mucosal damage caused by loxoprofen.
- Example 5 The following Example 9 (formulation in which loxoprofen sodium and d-chlorpheniramine maleate are not substantially in contact (1)) and the composition of Comparative Example 2 were immediately after storage, 1 day, 3 days, and 7 days The condition in the glass bottle after 14 days and after 28 days was evaluated. That is, loxoprofen sodium hydrate and d-chlorpheniramine maleate were replaced by replacing 8 g of dihydrocodeine phosphate with 1.2 g of d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd., trade name: D-chlorpheniramine maleate).
- Example 9 A mixture (Example 9) in which a mixture of an acid salt (Comparative Example 2), loxoprofen sodium hydrate, and d-chlorpheniramine maleate are not substantially in contact with each other was prepared.
- the test was carried out in the same manner as in Test Example 2 except that the samples were stored for 1 day, immediately after the start of storage, and after 1 day, 3 days, 7 days, 14 days, and 28 days. The results are shown in Table 5.
- Example 9 As is clear from Table 5, the mixture of loxoprofen sodium hydrate and chlorpheniramine maleate that had been preserved only became wet after 3 days from the start of storage as a result of the interaction.
- Example 9 a granulated product obtained by granulating loxoprofen sodium hydrate and stored by simply mixing chlorpheniramine maleate maintains the same state as at the start even after 28 days, and the interaction is maintained. It was found that it can be suppressed (Example 9). As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in a pharmaceutical composition so as not to contact each other.
- Example 10 Formulation in which loxoprofen sodium and d-chlorpheniramine maleate are not substantially in contact (2)
- Example 2 except that 8 g of dihydrocodeine phosphate was replaced with 1.2 g of d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-chlorpheniramine maleate), and corn starch was replaced with 31.1 g. In the same manner, tablets were obtained.
- Example 11 Formulation in which loxoprofen sodium and d-chlorpheniramine maleate are not substantially in contact (3) Tablets were obtained in the same manner as in Example 10, except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
- Test Example 6 Loxoprofen-induced digestive tract disorder inhibitory action (2) As a test drug, d-chlorpheniramine maleate (CM) suspended in 0.5% methylcellulose (MC) solution was orally administered in a predetermined amount (5, 40 mg / 5 mL / kg). The test was carried out in the same manner as in Test Example 3, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 6.
- CM d-chlorpheniramine maleate
- MC methylcellulose
- chlorpheniramine maleate reduced gastric mucosal damage caused by loxoprofen.
- Example 12 Formulation in which loxoprofen sodium and clemastine fumarate are not in substantial contact (1)
- a tablet is obtained in the same manner as in Example 2 except that 8 g of dihydrocodeine phosphate is changed to 0.5 g of clemastine fumarate (product name: clemastine fumarate, manufactured by Daito) and corn starch is changed to 31.8 g. .
- Example 13 Formulation in which loxoprofen sodium and clemastine fumarate do not substantially contact (2) Tablets are obtained in the same manner as in Example 12 except that the macrogol 6000 is changed to hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
- Test Example 8 Loxoprofen-induced gastrointestinal tract disorder inhibitory action (3)
- a suspension of clemastine fumarate (CF) in a 0.5% methylcellulose (MC) solution was used, and a predetermined amount (1 mg / 5 mL / kg) was orally administered, as in Test Example 3.
- the test was carried out, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 8.
- Example 14 Formulation in which loxoprofen sodium and carbinoxamine maleate do not substantially contact (1)
- 8 g of dihydrocodeine phosphate was replaced with 2.5 g of carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) and corn starch was replaced with 29.8 g. Get.
- Example 15 Formulation in which loxoprofen sodium and carbinoxamine maleate do not substantially contact (2) Tablets are obtained in the same manner as in Example 14 except that Macrogol 6000 is replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
- Test Example 10 Loxoprofen-induced gastrointestinal tract disorder inhibitory action (4) As test drug, carbinoxamine maleate (CAM) suspended in 0.5% methylcellulose (MC) solution and orally administered in a predetermined amount (0.75, 75 mg / 5 mL / kg) The test was carried out in the same manner as in Test Example 3, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 10.
- CAM carbinoxamine maleate
- MC methylcellulose
- Example 12 The following Example 16 (formulation in which loxoprofen sodium and diphenylpyraline hydrochloride are not substantially in contact with each other) (1) and the composition of Comparative Example 3, immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, The state in the glass bottle after 28 days was evaluated.
- Example 17 Formulation in which loxoprofen sodium and diphenylpyraline hydrochloride are not substantially in contact (1) Tablets were obtained in the same manner as in Production Example 2 except that 8 g of dihydrocodeine phosphate was changed to 1.3 g of diphenylpyraline hydrochloride (Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) and corn starch was changed to 31 g.
- diphenylpyraline hydrochloride Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride
- Example 18 Formulation in which loxoprofen sodium and diphenylpyraline hydrochloride are not substantially in contact (2) Tablets were obtained in the same manner as in Production Example 17 except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
- diphenylpyraline hydrochloride reduced gastric mucosal damage caused by loxoprofen.
- Example 15 The following Example 19 (formulation in which loxoprofen sodium and bromhexine hydrochloride are not substantially in contact (1)) and the composition of Comparative Example 4 were used immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, 28 The state in the glass bottle after a day was evaluated.
- Example 20 Formulation in which loxoprofen sodium and bromhexine hydrochloride do not substantially contact (2) Tablets were obtained in the same manner as in Production Example 2 except that 8 g of dihydrocodeine phosphate was changed to 4 g of bromohexine hydrochloride (trade name: bromohexine hydrochloride manufactured by Sanyo Chemical Co., Ltd.) and corn starch was changed to 28.3 g.
- Example 21 Preparation in which loxoprofen sodium and bromhexine hydrochloride do not substantially contact (3) Tablets were obtained in the same manner as in Production Example 20, except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
- Example 17 The following Example 22 (formulation in which loxoprofen sodium and ambroxol hydrochloride are not substantially in contact with each other (1)) and the composition of Comparative Example 5 were immediately after the start of storage, 1 day, 3 days, 7 days, and 14 days later. The state in the glass bottle after 28 days was evaluated.
- Example 23 Formulation in which loxoprofen sodium and ambroxol hydrochloride are not substantially in contact (2) Except that 8g of dihydrocodeine phosphate is replaced with 15g of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Kogyosho: trade name ambroxol hydrochloride), Macrogol 6000 is replaced with 25.7g, and corn starch is replaced with 20.8g. In the same manner as in Example 2, tablets were obtained.
- Example 24 Formulation in which loxoprofen sodium and ambroxol hydrochloride are not substantially in contact (3) Tablets were obtained in the same manner as in Example 23 except that Macrogol 6000 was changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).
- loxoprofen sodium hydrate alone (Control Example 15) and potassium guaiacol sulfonate alone (Control Example 16) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 18.
- Example 25 Formulation (1) in which loxoprofen sodium and potassium guaiacol sulfonate are not substantially in contact with each other 8 g of dihydrocodeine phosphate is replaced with 83 g of potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name potassium guaiacol sulfonate), 292 g of macrogol 6000, 243 g of corn starch and 34. lactose hydrate. A tablet is obtained in the same manner as in Example 2 except that the amount is changed to 8 g.
- Example 26 Formulation in which loxoprofen sodium and guaiacol potassium sulfonate are not substantially in contact (2) Tablets are obtained in the same manner as in Example 25 except that Macrogol 6000 is changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).
- Example 20 The following Example 27 (formulation in which loxoprofen sodium and lysozyme hydrochloride are not substantially contacted (1)) and the composition of Comparative Example 6 were immediately after storage, 1 day, 3 days, 7 days, 14 days, 28 The state in the glass bottle after a day was evaluated.
- a mixture of loxoprofen sodium hydrate and lysozyme hydrochloride (Comparative Example 6) and loxoprofen sodium hydrate in which 8 g of dihydrocodeine phosphate is replaced with 30 g of lysozyme hydrochloride (manufactured by Eisai: trade name lysozyme chloride) And a lysozyme hydrochloride substantially free from contact with lysozyme hydrochloride (Example 27) was prepared and stored at 50 ° C. for 28 days, immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, and 28 days later. Except for the evaluation, the test was performed in the same manner as in Test Example 2. The results are shown in Table 20.
- Example 28 Formulation in which loxoprofen sodium and lysozyme hydrochloride are not substantially in contact (2)
- Example 2 except that 8 g of dihydrocodeine phosphate was changed to 30 g of lysozyme hydrochloride (manufactured by Eisai: trade name: lysozyme chloride), macrogol 6000 was changed to 25.7 g, and corn starch was changed to 20.8 g. A pill was obtained.
- Example 29 Formulation in which loxoprofen sodium and lysozyme hydrochloride are not substantially in contact (3) Tablets were obtained in the same manner as in Example 68 except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
- Example 30 Formulation in which loxoprofen sodium and dl-methylephedrine hydrochloride do not substantially contact (1) 8 g of dihydrocodeine phosphate was replaced with 20 g of dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia, dl-methylephedrine hydrochloride powder), Macrogol 6000 was changed to 23.2 g, and corn starch was 18.3 g. A tablet is obtained in the same manner as in Example 2 except that.
- Example 31 Formulation in which loxoprofen sodium and dl-methylephedrine hydrochloride are not substantially in contact (2) Tablets are obtained in the same manner as in Example 30, except that Macrogol 6000 is changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).
- Test Example 22 Loxoprofen-induced gastrointestinal tract disorder inhibitory action (6) As a test drug, dl-methylephedrine hydrochloride (ME) suspended in 0.5% methylcellulose (MC) solution was orally administered in a predetermined amount (20, 60, 180 mg / 5 mL / kg). The test was conducted in the same manner as in Test Example 3, the ulcer suppression rate (%) in the administration of the test drug was calculated, and the results are shown in Table 22.
- ME dl-methylephedrine hydrochloride
- MC methylcellulose
- Example 24 For the composition of Example 32 (formulation (1) in which loxoprofen sodium and dextromethorphan hydrobromide hydrate are not substantially in contact with each other) and the composition of Comparative Example 7, The state in the glass bottle after 7 days, 14 days, and 28 days was evaluated. That is, loxoprofen sodium hydrate and dextromethorphan hydrobromide water are used by replacing 8 g of dihydrocodeine phosphate with 16 g of dextromethorphan hydrobromide hydrate (product name: Dextromethorphan HBR manufactured by Daiichi Fine Chemical).
- Example 32 A preparation (Example 32) in which a mixture of a Japanese product (Comparative Example 7), loxoprofen sodium hydrate, and dextromethorphan hydrobromide hydrate are substantially not in contact is produced,
- the test was carried out in the same manner as in Test Example 2 except that the evaluation was performed immediately after the start of storage, after 1 day, after 3 days, after 7 days, after 14 days, and after 28 days. The results are shown in Table 24.
- Example 33 Formulation in which loxoprofen sodium and dextromethorphan hydrobromide hydrate are not substantially in contact (2) 8 g of dihydrocodeine phosphate was replaced with 16 g of dextromethorphan hydrobromide hydrate (product name: Dextromethorphan HBR manufactured by Daiichi Fine Chemical Co., Ltd.). Macrogol 6000 was changed to 25.2 g and corn starch was changed to 20.3 g. A tablet is obtained in the same manner as in Example 2 except for changing.
- Example 34 Formulation in which loxoprofen sodium and dextromethorphan hydrobromide hydrate are not substantially in contact (3) Tablets are obtained in the same manner as in Example 33 except that Macrogol 6000 is replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
- Example 35 Formulation in which loxoprofen sodium and guaifenesin are not substantially in contact (1)
- Example 2 except that 8 g of dihydrocodeine phosphate was replaced with 83 g of guaifenesin (manufactured by Alps Pharmaceuticals: trade name Guaifenesin), macrogol 6000 was replaced with 292 g, corn starch was replaced with 243 g, and lactose hydrate was replaced with 34.8 g. In the same manner, a tablet is obtained.
- Example 36 Formulation in which loxoprofen sodium and guaifenesin are not substantially in contact (2) Tablets are obtained in the same manner as in Example 35 except that Macrogol 6000 is replaced with hydrogenated oil (product name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
- a storage-stable pharmaceutical composition can be provided by containing loxoprofen or a salt thereof and codeine or the like in the pharmaceutical composition so that they do not substantially contact each other. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and codeine, which is excellent in storage stability and reduces or suppresses gastrointestinal disorders caused by loxoprofen.
Abstract
Description
また、ロキソプロフェンをブロムヘキシン塩酸塩やアンブロキソール塩酸塩と組み合わせることによる、咳嗽症状に対する効果の増強作用(特許文献4)及び杯細胞過形成抑制作用(特許文献5)並びにロキソプロフェンをブロムヘキシン塩酸塩と組み合わせることによる消炎・鎮痛・解熱効果の増強作用(特許文献6)等が知られている。 Loxoprofen has been studied for combining with various drugs because of its excellent pharmacological action. Examples of the action obtained by the combination include enhancement of anti-inflammatory, analgesic and antipyretic effects by combining with caffeine, ethenamide and acetaminophen (Patent Document 1), carbinoxamine maleate, chlorpheniramine malee Of nasal congestion by combining with acid salt, ketotifen fumarate, mequitazine and epinastine hydrochloride (Patent Document 2), inhibitory effect on goblet cell hyperplasia by combining with azelastine hydrochloride and mequitazine (Patent Document 3), etc. Is mentioned.
Further, combining loxoprofen with bromhexine hydrochloride or ambroxol hydrochloride enhances the effect on cough symptoms (Patent Document 4) and suppresses goblet cell hyperplasia (Patent Document 5), and combines loxoprofen with bromhexine hydrochloride. There are known anti-inflammatory, analgesic and antipyretic effects (Patent Document 6).
また、前記のロキソプロフェンとコデイン類との組み合せは幾つか知られている。例えば、ロキソプロフェンとジヒドロコデイン塩酸塩を組み合わせることにより、抗炎症作用が増強すること(特許文献6)、ロキソプロフェンとコデインリン酸塩を組み合わせると、気道杯細胞過形成抑制作用を示すこと(特許文献8)が知られている。
また、ロキソプロフェンとコデイン類を含む製剤については、細粒剤、カプセル剤、錠剤(特許文献2、4、6及び8)が知られている。
しかしながら、製剤中における、ロキソプロフェン又はその塩とコデイン類との間に、これら化合物の保存安定性等に影響を与えるような相互作用が生じるか否かについては、知られていない。 On the other hand, codeines are known to be narcotic antitussive components having an antitussive action by suppressing the function of the cough center. And based on this action, it is a drug used as a general cold medicine and antitussive expectorant as an antitussive component (Non-patent Document 2 and others).
Some combinations of loxoprofen and codeines are known. For example, the combination of loxoprofen and dihydrocodeine hydrochloride enhances the anti-inflammatory effect (Patent Document 6), and the combination of loxoprofen and codeine phosphate exhibits an airway goblet cell hyperplasia inhibitory effect (Patent Document 8). Are known.
In addition, fine granules, capsules, and tablets (Patent Documents 2, 4, 6, and 8) are known for preparations containing loxoprofen and codeine.
However, it is not known whether or not an interaction that affects the storage stability of these compounds occurs between loxoprofen or a salt thereof and codeines in the preparation.
従って、本発明の課題は、コデイン類、カルビノキサミン又はその塩、クレマスチン又はその塩、クロルフェニラミン又はその塩、ジフェニルピラリン又はその塩、ブロムヘキシン又はその塩、アンブロキソール又はその塩、リゾチーム又はその塩及びデキストロメトルファン又はその塩からなる群より選ばれる1種以上と、ロキソプロフェン又はその塩とを含有する安定な医薬組成物の提供である。 The present inventors first of all, codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof In order to develop a pharmaceutical composition containing at least one selected from the group consisting of dextromethorphan and salts thereof (hereinafter also referred to as codeines) and loxoprofen or a salt thereof, the storage stability thereof is examined. As a result, it has been found that when the above codeines and the like and loxoprofen or a salt thereof are mixed and stored, solidification, discoloration, etc. occur unexpectedly, resulting in problems in storage stability.
Accordingly, the object of the present invention is to provide codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof. And a stable pharmaceutical composition comprising at least one member selected from the group consisting of dextromethorphan or a salt thereof and loxoprofen or a salt thereof.
そこで、本発明者らは、上記コデイン類等と、ロキソプロフェン又はその塩とが実質的に接触しないように医薬組成物中に含有せしめることにより、上記相互作用を抑制することができることを見出した。 First, the present inventors have further studied to solve the above storage stability problem, and the interaction caused by the contact between the codeines and loxoprofen or a salt thereof is the cause of the storage stability problem. It revealed that.
Therefore, the present inventors have found that the above-mentioned interaction can be suppressed by incorporating the above-mentioned codeine or the like and loxoprofen or a salt thereof in the pharmaceutical composition so as not to substantially contact.
また、本発明者らは、上記コデイン類等が、ロキソプロフェンに起因する消化管障害を軽減又は抑制することを見出している。
したがって、本発明によれば、保存安定性に優れるとともに、ロキソプロフェンに起因する消化管障害が軽減又は抑制された医薬組成物を提供できる。 The pharmaceutical composition of the present invention has excellent storage stability.
In addition, the present inventors have found that the above codeines and the like reduce or suppress gastrointestinal disorders caused by loxoprofen.
Therefore, according to the present invention, it is possible to provide a pharmaceutical composition having excellent storage stability and reducing or suppressing gastrointestinal disorders caused by loxoprofen.
まず、本発明で用いるロキソプロフェン又はその塩について説明する。 The pharmaceutical composition of the present invention comprises codeines, carbinoxamine or a salt thereof, clemastine or a salt thereof, chlorpheniramine or a salt thereof, diphenylpyraline or a salt thereof, bromhexine or a salt thereof, ambroxol or a salt thereof, lysozyme or a salt thereof And at least one member selected from the group consisting of dextromethorphan or a salt thereof and loxoprofen or a salt thereof so as not to substantially contact each other.
First, loxoprofen or a salt thereof used in the present invention will be described.
本発明においては、上述の1日あたりの服用量に応じて、適宜検討して決定すればよいが、ロキソプロフェン又はその塩を医薬組成物全質量に対して、ロキソプロフェンナトリウム無水物換算で、0.4~90質量%含有するのが好ましく、0.4~50質量%含有するのがより好ましく、1.2~30質量%含有するのがさらに好ましく、1.2~25質量%含有するのが特に好ましい。 The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but 10 per day in terms of loxoprofen sodium anhydride. An amount that can be taken in an amount of ˜300 mg is preferred, an amount that can be taken in an amount of 30 to 240 mg is more preferred, and an amount that can be taken in an amount of 60 to 180 mg is more preferred.
In the present invention, it may be determined by appropriate examination according to the above-mentioned daily dose. However, loxoprofen or a salt thereof is 0. 0 in terms of loxoprofen sodium anhydride relative to the total mass of the pharmaceutical composition. It is preferably contained in an amount of 4 to 90% by mass, more preferably 0.4 to 50% by mass, further preferably 1.2 to 30% by mass, and more preferably 1.2 to 25% by mass. Particularly preferred.
コデイン類の好適な具体例としては、本発明の医薬組成物を総合感冒薬等として利用した場合の観点から、コデイン、ジヒドロコデイン、コデインリン酸塩水和物、ジヒドロコデインリン酸塩等が挙げられるが、コデインリン酸塩水和物、ジヒドロコデインリン酸塩が好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 The codeines used in the pharmaceutical composition of the present invention mean one or more selected from the group consisting of codeine, dihydrocodeine or salts thereof, and solvates thereof. That is, codeines include not only codeine and dihydrocodeine itself, but also pharmaceutically acceptable salts of codeine and dihydrocodeine and solvates thereof.
Specific examples of codeines include codeine, dihydrocodeine, codeine phosphate hydrate, dihydrocodeine phosphate and the like from the viewpoint of using the pharmaceutical composition of the present invention as a general cold medicine. Acid salt hydrate and dihydrocodeine phosphate are preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
本発明の医薬組成物におけるコデイン類の含有量は、服用者の性別、年齢、症状や目したロキソプロフェン起因の消化管障害軽減・抑制効果等に応じて、適宜検討して決定すればよいが、1日あたり、2~60mg服用できる量が好ましく、4~48mg服用できる量がより好ましく、6~26mg服用できる量がさらに好ましい。
なお、コデイン類として、コデインリン酸塩水和物を用いる場合は、1日当り、4~60mg服用できる量が好ましく、8~48mg服用できる量がより好ましく、12~36mg服用できる量がさらに好ましい。また、ジヒドロコデインリン酸塩を用いる場合は、1日あたり、2~30mg服用できる量が好ましく、4~24mg服用できる量がより好ましく、6~24mg服用できる量がさらに好ましい。本発明においては、コデイン類を医薬組成物全質量に対して、0.08~4質量%含有するのが好ましい。また、コデイン類がコデインリン酸塩水和物である場合、医薬組成物全質量に対して、0.15~4質量%含有するのが好ましく、0.3~3質量%含有するのがより好ましく、0.5~2.5質量%含有するのがさらに好ましい。さらに、コデイン類がジヒドロコデインリン酸である場合、医薬組成物全質量に対して、0.08~2質量%含有するのが好ましく、0.16~1.5質量%含有するのがより好ましく、0.24~1.5質量%含有するのがさらに好ましい。 Next, the codeines used in the present invention will be described in detail.
The content of codeine in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the gender, age, symptom of the user, and the effect of reducing or suppressing the gastrointestinal tract disorder caused by the observed loxoprofen, The amount that can be taken 2 to 60 mg per day is preferred, the amount that can be taken 4 to 48 mg is more preferred, and the amount that can be taken 6 to 26 mg is more preferred.
When codeine phosphate hydrate is used as the codeine, the amount that can be taken 4 to 60 mg per day is preferable, the amount that can be taken 8 to 48 mg is more preferable, and the amount that can be taken 12 to 36 mg is more preferable. When dihydrocodeine phosphate is used, the amount that can be taken 2 to 30 mg per day is preferred, the amount that can be taken 4 to 24 mg is more preferred, and the amount that can be taken 6 to 24 mg is more preferred. In the present invention, the codeine is preferably contained in an amount of 0.08 to 4% by mass based on the total mass of the pharmaceutical composition. When the codeine is codeine phosphate hydrate, it is preferably contained in an amount of 0.15 to 4% by mass, more preferably 0.3 to 3% by mass, based on the total mass of the pharmaceutical composition. More preferably, the content is 0.5 to 2.5% by mass. Further, when the codeine is dihydrocodeine phosphate, the content is preferably 0.08 to 2% by mass, more preferably 0.16 to 1.5% by mass, based on the total mass of the pharmaceutical composition, More preferably, the content is 0.24 to 1.5% by mass.
本発明においては、カルビノキサミン又はその塩を医薬組成物全質量に対して0.004~4質量%含有するのが好ましく、0.02~2質量%含有するのがより好ましく、0.04~1質量%含有するのが特に好ましい。なお、カルビノキサミン又はその塩の含有量は、上述した1日あたりの服用量に応じて決定すればよい。 The content of carbinoxamine or a salt thereof in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the sex, age, symptoms, etc. of the user, but can be taken 0.1 to 60 mg per day. The amount is preferably, more preferably 0.5 to 30 mg, more preferably 1 to 16 mg.
In the present invention, the carbinoxamine or a salt thereof is preferably contained in an amount of 0.004 to 4% by mass, more preferably 0.02 to 2% by mass, more preferably 0.04 to 1%, based on the total mass of the pharmaceutical composition. The content by mass is particularly preferred. The content of carbinoxamine or a salt thereof may be determined according to the above-mentioned daily dose.
本発明において、クレマスチン又はその塩を医薬組成物全質量に対してクレマスチンのフリー体換算で0.008~0.4質量%含有するのが好ましく、0.01~0.2質量%含有するのがより好ましく、0.015~0.15質量%含有するのが特に好ましい。なお、クレマスチン又はその塩の含有量は、上述した1日あたりの服用量に応じて決定すればよい。 The content of clemastine or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but per day, in terms of clemastine free body, The amount that can be taken 0.01 to 5 mg is preferred, the amount that can be taken 0.05 to 3 mg is more preferred, and the amount that can be taken 0.1 to 2 mg is even more preferred. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
In the present invention, clemastine or a salt thereof is preferably contained in an amount of 0.008 to 0.4% by mass in terms of a free form of clemastine, preferably 0.01 to 0.2% by mass, based on the total mass of the pharmaceutical composition. Is more preferable, and 0.015 to 0.15% by mass is particularly preferable. In addition, what is necessary is just to determine the content of a clemastine or its salt according to the dose per day mentioned above.
クロルフェニラミンには不斉炭素が存するため、光学異性体を有するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。これらのうち、本発明においては、d-体、dl-体が好ましい。当該クロルフェニラミン又はその塩の具体例としては例えば、クロルフェニラミン、クロルフェニラミンマレイン酸塩、d-クロルフェニラミンマレイン酸塩、dl-クロルフェニラミンマレイン酸塩等が挙げられる。本発明においては、d-クロルフェニラミンマレイン酸塩、dl-クロルフェニラミンマレイン酸塩が好ましく、d-クロルフェニラミンマレイン酸塩が特に好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 The chlorpheniramine or a salt thereof used in the pharmaceutical composition of the present invention includes chlorpheniramine itself and a pharmaceutically acceptable salt of chlorpheniramine.
Since chlorpheniramine has an asymmetric carbon, it has an optical isomer, but in the present invention, any optical isomer may be included, which may be a single optical isomer or a mixture of various optical isomers. . Of these, d-form and dl-form are preferred in the present invention. Specific examples of the chlorpheniramine or a salt thereof include chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate and the like. In the present invention, d-chlorpheniramine maleate and dl-chlorpheniramine maleate are preferable, and d-chlorpheniramine maleate is particularly preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.
本発明において、ジフェニルピラリン又はその塩の含有量は、医薬組成物全質量に対して0.004~1.5質量%含有するのが好ましく、0.004~1質量%含有するのがより好ましい。このうち、0.04~0.5質量%含有するのが好ましく、0.04~0.3質量%含有するのがより好ましく、0.06~0.25質量%含有するのが特に好ましい。なお、ジフェニルピラリン又はその塩の含有量は、上述した1日あたりの服用量に応じて決定すればよい。 The content of diphenylpyralin or a salt thereof in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the sex, age, symptom, etc. of the user, but from 0.1 to 13 per day. The amount that can be taken 5 mg is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred. When diphenylpyraline hydrochloride is used as diphenylpyraline or a salt thereof, the amount that can be taken 0.1 to 12 mg per day is preferable, and the amount that can be taken 1 to 4 mg is more preferable. When using diphenylpyraline theocuroate, the amount that can be taken 0.1 to 13.5 mg per day is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred.
In the present invention, the content of diphenylpyralin or a salt thereof is preferably 0.004 to 1.5% by mass, more preferably 0.004 to 1% by mass, based on the total mass of the pharmaceutical composition. . Of these, 0.04 to 0.5% by mass is preferable, 0.04 to 0.3% by mass is more preferable, and 0.06 to 0.25% by mass is particularly preferable. In addition, what is necessary is just to determine the content of diphenyl pyralin or its salt according to the dose per day mentioned above.
本発明において、アンブロキソール又はその塩の含有量は、医薬組成物全質量に対してアンブロキソール塩酸塩に換算して0.004~10質量%含有するのが好ましく、0.02~7質量%含有するのがより好ましく、0.04~5質量%含有するのがさらに好ましい。なお、アンブロキソール又はその塩の含有量は、上述した1日あたりの服用量に応じて決定すればよい。 The content of ambroxol or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but per day, ambroxol or a salt thereof The amount that can be taken 0.1 to 150 mg in terms of ambroxol hydrochloride is preferred, the amount that can be taken 0.5 to 100 mg is more preferred, and the amount that can be taken 1 to 50 mg is more preferred.
In the present invention, the content of ambroxol or a salt thereof is preferably 0.004 to 10% by mass in terms of ambroxol hydrochloride relative to the total mass of the pharmaceutical composition, and preferably 0.02 to 7%. More preferably, it is contained in an amount of 0.04 to 5% by mass. The content of ambroxol or a salt thereof may be determined according to the above-mentioned daily dose.
本発明において、デキストロメトルファン又はその塩の含有量は、医薬組成物全質量に対して0.004~20質量%含有するのが好ましく、0.02~15質量%含有するのがより好ましく、0.04~10質量%含有するのがさらに好ましい。なお、デキストロメトルファン又はその塩の含有量は、上述した1日あたりの服用量に応じて決定すればよい。 The content of dextromethorphan or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but per day, dextromethorphan or its It is preferable to take 0.1 to 270 mg of salt, more preferably 0.5 to 180 mg, and even more preferably 1 to 90 mg. When dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate, an amount capable of taking 6 to 60 mg of dextromethorphan hydrobromide hydrate per day is preferable, and 15 to 60 mg The amount that can be taken is more preferred, and the amount that can be taken 20 to 60 mg is more preferred. In addition, when dextromethorphan or a salt thereof is dextromethorphan phenol phthaline salt, an amount capable of taking 9 to 90 mg of dextromethorphan phenol phthalin salt per day is preferable, and an amount capable of taking 22 to 90 mg is more preferable. More preferably, the dose is 30 to 90 mg.
In the present invention, the content of dextromethorphan or a salt thereof is preferably 0.004 to 20% by mass, more preferably 0.02 to 15% by mass with respect to the total mass of the pharmaceutical composition, More preferably, the content is 0.04 to 10% by mass. In addition, what is necessary is just to determine the content of dextromethorphan or its salt according to the dose per day mentioned above.
また、本発明の医薬組成物の剤形は、特に限定されるべきものではないが、服用のしやすさ等の観点から、固形製剤が好ましい。 Further, in the present invention, “containing so as not to substantially contact each other” means containing in a pharmaceutical composition so that loxoprofen or a salt thereof, codeine, and the like do not come into contact with each other so as not to exhibit an interaction. Although it means, it is preferable to contain so that a loxoprofen or its salt, codeines, etc. may not contact.
The dosage form of the pharmaceutical composition of the present invention is not particularly limited, but a solid preparation is preferable from the viewpoint of ease of taking.
(ロ)ロキソプロフェン又はその塩、及びコデイン類をそれぞれ適当な方法で別個に造粒して粒状物とし、これらを配合して製した散剤や顆粒剤等、並びに当該粒状物を更に適当な方法で被覆した製剤。
(ハ)上記(イ)又は(ロ)で製した散剤や顆粒剤等をカプセルに充填したカプセル剤。
(ニ)上記(イ)又は(ロ)で製した粒状物等を適当な方法で製錠して得た錠剤。製錠は、圧縮法のほか、適当な方法により一定の形状に成形することでも達成できる。
(ホ)ロキソプロフェン又はその塩、及びコデイン類が実質的に互いに接触しないように製した多層錠、並びに当該多層錠を更に適当な方法で被覆した製剤。当該多層錠としては、ロキソプロフェン又はその塩、及びコデイン類を、互いに異なる層に位置させたものが好ましく、三層以上の多層錠として、ロキソプロフェン又はその塩を含む層とコデイン類を含む層が互いに接しないように位置させたものがより好ましい。なお、ロキソプロフェン又はその塩、及びコデイン類として、上記(イ)や(ロ)で製した粒状物を用いることができる。
(ヘ)ロキソプロフェン又はその塩、及びコデイン類のいずれか一方を核錠(芯錠、中心錠ともいう)に配置し、ロキソプロフェン又はその塩、及びコデイン類が実質的に互いに接触しないように製した有核錠、並びに当該有核錠を更に適当な方法で被覆した製剤。なお、ロキソプロフェン又はその塩、及びコデイン類として、上記(イ)や(ロ)で製した粒状物を用いることができる。
(ト)上記(イ)又は(ロ)の粒状物に換えて、ロキソプロフェン又はその塩、及びコデイン類のいずれか一方又は両方をα-シクロデキストリン、β-シクロデキストリンやγ-シクロデキストリン等のシクロデキストリン類等で包接した包接化合物を用いた製剤。
(チ)ロキソプロフェン又はその塩、及びコデイン類のいずれか一方を通常の方法で製した製剤中に含有し、糖衣層やフィルムコーティング層を設けた製剤であって、当該糖衣層やコーティング層に他方を含有し、ロキソプロフェン又はその塩、及びコデイン類が実質的に互いに接しないように製した製剤(剤形が錠剤である場合、糖衣錠やフィルムコーティング錠と称される。)。 (I) Either loxoprofen or a salt thereof and codeine are granulated by an appropriate method to form a granule, and the other loxoprofen or a salt thereof or codeine is blended without granulation. Powders, granules, etc., as well as preparations in which the granules are further coated by an appropriate method.
(B) Loxoprofen or a salt thereof and codeine are separately granulated by an appropriate method to form granules, and powders and granules produced by blending these, and the granules are further processed by an appropriate method. Coated formulation.
(C) A capsule filled with the powder or granule prepared in (i) or (b) above.
(D) Tablets obtained by tableting the granular material produced in (i) or (b) above by an appropriate method. Tableting can be achieved not only by the compression method but also by molding into a certain shape by an appropriate method.
(E) A multilayer tablet prepared so that loxoprofen or a salt thereof and codeine are not substantially in contact with each other, and a preparation in which the multilayer tablet is further coated by an appropriate method. The multi-layered tablet is preferably one in which loxoprofen or a salt thereof and codeine are located in different layers, and as a multi-layered tablet having three or more layers, a layer containing loxoprofen or a salt thereof and a layer containing codeine are mutually attached. What was located so that it may not contact | connect is more preferable. In addition, as the loxoprofen or a salt thereof and codeine, the granular material produced in the above (i) or (b) can be used.
(F) One of loxoprofen or a salt thereof and codeine is arranged in a core tablet (also referred to as a core tablet or a central tablet) so that loxoprofen or a salt thereof and codeine are not substantially in contact with each other. Nucleated tablets, and preparations obtained by coating the nucleated tablets with an appropriate method. In addition, as the loxoprofen or a salt thereof and codeine, the granular material produced in the above (i) or (b) can be used.
(G) In place of the above-mentioned particulate matter (a) or (b), either or both of loxoprofen or a salt thereof and codeine is added to a cyclodextrin such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. A preparation using an inclusion compound included in dextrins.
(H) Loxoprofen or a salt thereof and codeine are contained in a preparation prepared by a usual method, and are provided with a sugar coating layer or a film coating layer, and the other sugar coating layer or coating layer is provided on the other side. And a preparation prepared so that loxoprofen or a salt thereof and codeine are not substantially in contact with each other (when the dosage form is a tablet, it is called a sugar-coated tablet or a film-coated tablet).
結合剤としては、例えば、メチルセルロース、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、ヒプロメロース、カルメロースナトリウム、デキストリン、部分アルファー化デンプン、プルラン、アラビアゴム、カンテン、ゼラチン、トラガント、アルギン酸ナトリウム、ポビドン、ポリビニルアルコール等が挙げられる。なお、上記(イ)及び(ロ)等における粒状物を製する際に溶融造粒を用いる場合は、常温時に固体であって、加熱により溶融又は軟化するような融点(凝固点)が低い結合剤を用いることが好ましい。このような結合剤の融点(凝固点)としては、本発明に係る成分(ロキソプロフェン又はその塩、及びコデイン類等)の融点よりも低いものが好ましい。具体的には、融点(凝固点)が30~100℃の結合剤が好ましく、50~80℃のものがより好ましい。このようなものとしては、例えば、マクロゴール類(例えば、マクロゴール4000、マクロゴール6000、マクロゴール20000等);油脂類(例えば、牛脂硬化油、硬化油、水素添加植物油、ダイズ硬化油、カルナウバロウ、サラシミツロウ、ミツロウ、モクロウ等);炭化水素類(例えば、パラフィン、マイクロクリスタリンワックス等);高級アルコール類(例えば、セチルアルコール、ステアリルアルコール等);脂肪酸類(例えば、ステアリン酸等);脂肪酸エステル類(例えば、アセチルグリセリン脂肪酸エステル、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、モノステアリン酸グリセリン等)等が挙げられる。 Examples of formulation additives that can be used in producing the pharmaceutical composition of the present invention include binders, excipients, disintegrants, lubricants, fluidizing agents, and coloring agents.
Examples of the binder include methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl Alcohol etc. are mentioned. In addition, when melt granulation is used when producing the granular materials in the above (a) and (b), etc., a binder having a low melting point (freezing point) that is solid at room temperature and melts or softens by heating. Is preferably used. The melting point (freezing point) of such a binder is preferably lower than the melting point of the components according to the present invention (loxoprofen or a salt thereof, codeine, etc.). Specifically, a binder having a melting point (freezing point) of 30 to 100 ° C. is preferable, and a binder having a temperature of 50 to 80 ° C. is more preferable. Examples of such materials include macrogols (for example, macrogol 4000, macrogol 6000, macrogol 20000, etc.); fats and oils (for example, beef tallow oil, hydrogenated oil, hydrogenated vegetable oil, soybean hydrogenated oil, carnauba wax) Hydrocarbons (eg, paraffin, microcrystalline wax, etc.); higher alcohols (eg, cetyl alcohol, stearyl alcohol, etc.); fatty acids (eg, stearic acid); fatty acid esters (For example, acetyl glycerin fatty acid ester, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, glyceryl monostearate, etc.) and the like.
流動化剤としては、例えば、含水二酸化ケイ素、軽質無水ケイ酸、酸化チタン等が挙げられる。
着色剤としては、例えば、黄色三二酸化鉄、三二酸化鉄、食用青色1号、食用青色2号、食用黄色4号、食用黄色5号、食用緑色3号、食用赤色2号、食用赤色3号、食用赤色102号、食用赤色104号、食用赤色105号、食用赤色106号等が挙げられる。 Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, and sodium stearyl fumarate.
Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide and the like.
Examples of the colorant include yellow ferric oxide, ferric oxide, edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible yellow No. 5, edible green No. 3, edible red No. 2, and edible red No. 3 Edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106 and the like.
ノスカピン類としては、例えば、ノスカピン塩酸塩、ノスカピン等が挙げられる。 Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, dibutate sodium, dimemorphan phosphate, tipepidine citrate, And tipepidine hibenzate.
Examples of noscapine include noscapine hydrochloride and noscapine.
催眠鎮静剤としては、例えば、アリルイソプロピルアセチル尿素やブロムワレリル尿素等が挙げられる。 Examples of expectorants include ammonia fennel, ethyl cysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacol sulfonate, potassium cresol sulfonate, methyl cysteine hydrochloride, 1-menthol and the like.
Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromvalerylurea.
カフェイン類としては、例えば、安息香酸ナトリウムカフェイン、カフェイン水和物、無水カフェイン等が挙げられる。
キサンチン系成分としては、例えば、アミノフィリン、ジプロフィリン、テオフィリン、プロキシフィリン等が挙げられる。 Examples of Kampo prescriptions include Keishi-yu, Kosou-san, Saiko-Kei-do, Sho-saiko-yu, Bakumon-fu-to, Hanka-koboku-yu, and the like.
Examples of caffeine include sodium benzoate caffeine, caffeine hydrate, and anhydrous caffeine.
Examples of the xanthine component include aminophylline, diprofylline, theophylline, proxyphylline and the like.
(b)ロキソプロフェンナトリウム水和物 180mg、ジヒドロコデインリン酸塩 20mg、結晶セルロース 140mg、ヒドロキシプロピルセルロース 100mg、ステアリン酸マグネシウム 10mg、D-マンニトール 190mg及び乳糖 適量を含有する細粒剤(3包中)、
(c)ロキソプロフェンナトリウム水和物 180mg、コデインリン酸塩 45mg、ステアリン酸マグネシウム 10mg、ポリソルベート50mg、トウモロコシデンプン170mg及び乳糖 適量を含有するカプセル剤(6カプセル中)、 (A) Loxoprofen sodium hydrate 180 mg, codeine phosphate 45 mg, crystalline cellulose 110 mg, hydroxypropylcellulose 40 mg, magnesium stearate 10 mg, lactose tablets (in 6 tablets) containing appropriate amounts,
(B) Loxoprofen sodium hydrate 180 mg, dihydrocodeine phosphate 20 mg, crystalline cellulose 140 mg, hydroxypropylcellulose 100 mg, magnesium stearate 10 mg, D-mannitol 190 mg and lactose in appropriate amounts (in 3 capsules),
(C) Loxoprofen sodium hydrate 180 mg, codeine phosphate 45 mg, magnesium stearate 10 mg, polysorbate 50 mg, corn starch 170 mg and lactose in appropriate amounts (in 6 capsules),
(e)ロキソプロフェンナトリウム水和物 60mg(無水物換算)、ジヒドロコデインリン酸塩 10mg、セラペプターゼ 10mg、ブロムヘキシン塩酸塩 4mg、ステアリン酸マグネシウム 7mg、結晶セルロース 60mg、デンプン 186mg及び乳糖 13mgを含有する錠剤(1錠350mg)、
(f)ロキソプロフェンナトリウム2水和物 60mg(無水物換算)、マレイン酸カルビノキサミン 4mg、dl-塩酸メチルエフェドリン 20mg、セラペプターゼ 10mg、ステアリン酸マグネシウム 7mg、結晶セルロース 60mg、デンプン 176mg及び乳糖 13mgを含有するハードカプセル剤(1カプセル350mg)、 (D) Loxoprofen sodium hydrate 60 mg (anhydrous equivalent), dihydrocodeine phosphate 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 200 mg and lactose 13 mg (one tablet 350 mg),
(E) Loxoprofen sodium hydrate 60 mg (anhydrous equivalent), dihydrocodeine phosphate 10 mg, serrapeptase 10 mg, bromhexine hydrochloride 4 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 186 mg and lactose 13 mg (1 tablet) 350 mg),
(f) Hard capsule containing 60 mg of loxoprofen sodium dihydrate (anhydrous equivalent), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 176 mg and lactose 13 mg (1 capsule 350mg),
(h)ロキソプロフェンナトリウム2水和物 60mg(無水物換算)、マレイン酸カルビノキサミン 4mg、ステアリン酸マグネシウム 7mg、結晶セルロース 60mg、デンプン 206mg及び乳糖 13mgを含有する錠剤(1錠中350mg)、
(i)ロキソプロフェンナトリウム2水和物 60mg(無水物換算)、マレイン酸カルビノキサミン 4mg、塩化リゾチーム 50mg、ステアリン酸マグネシウム 7mg、結晶セルロース 60mg、デンプン 156mg及び乳糖 13mgを含有する錠剤(1錠中350mg)、 (g) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 176 mg and lactose 13 mg ( 350mg in a tablet)
(h) Loxoprofen sodium dihydrate 60 mg (in terms of anhydride), carbinoxamine maleate 4 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 206 mg and lactose 13 mg (350 mg in one tablet),
(i) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), carbinoxamine maleate 4 mg, lysozyme chloride 50 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 156 mg and lactose 13 mg (350 mg in one tablet),
(k)ロキソプロフェンナトリウム2水和物 60mg(無水物換算)、マレイン酸カルビノキサミン 4mg、dl-塩酸メチルエフェドリン 20mg、セラペプターゼ 10mg、β-シクロデキストリン 300mg、アスパルテーム 30mg、マンニトール 262mg及びステアリン酸マグネシウム 14mgを含有する速溶錠又はチュアブル錠(1錠中700mg)、
(l)ロキソプロフェンナトリウム2水和物 60mg(無水物換算)、フマル酸クレマスチン 5mg、ステアリン酸マグネシウム 7mg、結晶セルロース 60mg、デンプン 205mg及び乳糖 13mgを含有する錠剤(1錠中350mg)、 (j) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, β-cyclodextrin 254 mg, aspartame 30 mg, citric acid 965 mg, sodium bicarbonate 813 mg, lactose Effervescent tablets (2400 mg in one tablet) containing 194 mg and 50 mg magnesium stearate,
(K) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, β-cyclodextrin 300 mg, aspartame 30 mg, mannitol 262 mg and magnesium stearate 14 mg Fast dissolving tablets or chewable tablets (700mg in each tablet),
(L) Loxoprofen sodium dihydrate 60 mg (anhydrous equivalent), clemastine fumarate 5 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 205 mg and lactose 13 mg (350 mg in one tablet),
(n)ロキソプロフェンナトリウム 180mg、塩酸ブロムヘキシン 12mg、結晶セルロース 100mg、ヒドロキシプロピルセルロース 40mg、ステアリン酸マグネシウム 10mg及び乳糖 適量を含有する錠剤(6錠中)、
(o)ロキソプロフェンナトリウム 180mg、塩酸アンブロキソール 15mg、塩酸ブロムヘキシン 8mg、ベラドンナ(総)アルカロイド 0.2mg、結晶セルロース 100mg、ヒドロキシプロピルセルロース 40mg、ステアリン酸マグネシウム 10mg及び乳糖 適量を含有する錠剤(6錠中)、 (M) Loxoprofen sodium 180 mg, ambroxol hydrochloride 45 mg, crystalline cellulose 100 mg, hydroxypropylcellulose 40 mg, magnesium stearate 10 mg and lactose in appropriate amounts (in 6 tablets),
(N) Loxoprofen sodium 180 mg, bromhexine hydrochloride 12 mg, crystalline cellulose 100 mg, hydroxypropylcellulose 40 mg, magnesium stearate 10 mg and lactose in appropriate amounts (in 6 tablets),
(O) Loxoprofen sodium 180 mg, ambroxol hydrochloride 15 mg, bromhexine hydrochloride 8 mg, belladonna (total) alkaloid 0.2 mg, crystalline cellulose 100 mg, hydroxypropylcellulose 40 mg, magnesium stearate 10 mg and lactose ),
(q)ロキソプロフェンナトリウム 180mg、塩酸ブロムヘキシン 12mg、結晶セルロース 130mg、ヒドロキシプロピルセルロース 100mg、ステアリン酸マグネシウム 10mg、D-マンニトール 290mg及び乳糖 適量を含有する細粒剤(3包中)、
(r)ロキソプロフェンナトリウム 180mg、塩酸アンブロキソール 15mg、塩酸ブロムヘキシン 8mg、ベラドンナ(総)アルカロイド 0.2mg、結晶セルロース 130mg、ヒドロキシプロピルセルロース 100mg、ステアリン酸マグネシウム 10mg、D-マンニトール 290mg及び乳糖 適量を含有する細粒剤(3包中)、 (P) Loxoprofen sodium 180 mg, ambroxol hydrochloride 45 mg, crystalline cellulose 130 mg, hydroxypropylcellulose 100 mg, magnesium stearate 10 mg, D-mannitol 290 mg and lactose in appropriate amounts (in 3 packages),
(Q) loxoprofen sodium 180 mg, bromhexine hydrochloride 12 mg, crystalline cellulose 130 mg, hydroxypropylcellulose 100 mg, magnesium stearate 10 mg, D-mannitol 290 mg and lactose in appropriate amounts (in 3 capsules),
(R) Loxoprofen sodium 180 mg, ambroxol hydrochloride 15 mg, bromhexine hydrochloride 8 mg, belladonna (total) alkaloid 0.2 mg, crystalline cellulose 130 mg, hydroxypropylcellulose 100 mg, magnesium stearate 10 mg, D-mannitol 290 mg and lactose in appropriate amounts Fine granules (in 3 packages),
(t)ロキソプロフェンナトリウム 180mg、塩酸ブロムヘキシン 12mg、ステアリン酸マグネシウム 10mg、ポリソルベート 50mg、トウモロコシデンプン 200mg及び乳糖 適量を含有するカプセル剤(6カプセル中)、並びに
(u)ロキソプロフェンナトリウム 180mg、塩酸アンブロキソール 15mg、塩酸ブロムヘキシン 8mg、ベラドンナ(総)アルカロイド 0.2mg、ステアリン酸マグネシウム 10mg、ポリソルベート 50mg、トウモロコシデンプン 190mg及び乳糖 適量を含有する細粒剤を充填したカプセル剤(6カプセル中)。 (S) Loxoprofen sodium 180 mg, ambroxol hydrochloride 45 mg, magnesium stearate 10 mg, polysorbate 50 mg, corn starch 180 mg and lactose in appropriate amounts (in 6 capsules),
(T) Loxoprofen sodium 180 mg, bromhexine hydrochloride 12 mg, magnesium stearate 10 mg, polysorbate 50 mg, corn starch 200 mg and lactose in appropriate capsules (in 6 capsules), and (u) loxoprofen sodium 180 mg, ambroxol hydrochloride 15 mg, Capsules filled with fine granules containing 8 mg of bromhexine hydrochloride, 0.2 mg of belladonna (total) alkaloids, 10 mg of magnesium stearate, 50 mg of polysorbate, 190 mg of corn starch and lactose (in 6 capsules).
また、乾燥剤の形状も特に限定されるものではなく、例えば、板状や袋状のシート型、円柱状(錠剤型)に成形されたもの等が挙げられ、円柱状のものにペーパーラッピングやフィルムコーティングを施したものでもよい。 In the present invention, the desiccant is not particularly limited. Examples of the desiccant include silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride and magnesium oxide. 1 type or 2 types or more are mentioned, What mixed these and activated carbon may be sufficient. Among these, one or more selected from silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve) and calcium chloride are more preferable, and synthetic zeolite is particularly preferable from the viewpoint of interaction suppression.
In addition, the shape of the desiccant is not particularly limited, and examples thereof include a plate-shaped or bag-shaped sheet mold, a cylinder-shaped (tablet mold), and the like. A film-coated one may also be used.
また、乾燥剤の含有量は、ロキソプロフェン又はその塩、及びコデイン類等を含有する本発明の医薬組成物1質量部に対して、0.001~1質量部が好ましく、0.004~0.4質量部がより好ましい。 The content of the desiccant in the pharmaceutical preparation of the present invention may be determined by appropriate examination, but is preferably 0.05 to 35 parts by weight, preferably 0.15 to 17 parts by weight with respect to 1 part by weight of loxoprofen or a salt thereof. Part is more preferred.
In addition, the content of the desiccant is preferably 0.001 to 1 part by weight, and 0.004 to 0.00 parts per 1 part by weight of the pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, codeine and the like. 4 parts by mass is more preferable.
当該容器は透明、半透明、不透明のいずれでもよい。 The forming member of the container is not particularly limited, and examples thereof include paper, glass, a resin or a resin film, or a member such as a metal or a metal film, and a composite structure or a multilayer structure in which these members are appropriately combined. It may be a thing. Moreover, it is preferable that moisture permeation prevention processing is performed about the member which has moisture permeability, such as paper.
The container may be transparent, translucent, or opaque.
また、本発明の医薬組成物に用いられるコデイン類等は、後記実施例からも明らかなように、ロキソプロフェンに起因する消化管障害を抑制・軽減する。従って、消化性潰瘍の罹患者や既往歴のある患者も、ロキソプロフェンに起因する消化管障害の虞なく、ロキソプロフェン又はその塩を服用することができる。 Since the pharmaceutical composition of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain・ Bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain), pain relief, chills, antipyretic fever, cold symptoms (sore throat, cough, chills, fever, headache, joint pain) , Muscle pain), cough, etc., and is useful as a cold medicine, antipyretic analgesic and the like.
Moreover, the codeines etc. which are used for the pharmaceutical composition of this invention suppress / reduce the digestive tract disorder | damage | failure resulting from a loxoprofen as evident also from a postscript Example. Therefore, patients suffering from peptic ulcer and patients with a history of history can also take loxoprofen or a salt thereof without fear of gastrointestinal tract disorders caused by loxoprofen.
ロキソプロフェンナトリウム水和物500mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びジヒドロコデインリン酸塩60mg(塩野義製薬製:商品名 リン酸ジヒドロコデイン「シオノギ」)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例1)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例1)、ジヒドロコデインリン酸塩単独(対照例2)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表1に示した。 [Test Example 1] Examination of interaction Loxoprofen sodium hydrate 500 mg (manufactured by Daiwa Pharmaceutical, trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and dihydrocodeine phosphate 60 mg (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate Shionogi ") was mixed, placed in a glass bottle (3K standard bottle), and stored at 60 ° C for 1 week (Reference Example 1). As comparative controls, loxoprofen sodium hydrate alone (Control Example 1) and dihydrocodeine phosphate alone (Control Example 2) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 1.
下記の実施例1(ロキソプロフェンナトリウム水和物とジヒドロコデインリン酸塩とが実質的に接しない製剤(1))と比較例1の組成物につき、保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表2に示した。
ロキソプロフェンナトリウム水和物68.1g(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)、29.2gのマクロゴール6000(日本油脂製:商品名 マクロゴール6000P)及びトウモロコシデンプン24.3g(日澱化学製:商品名 トウモロコシデンプンST-C)を65℃湯浴上のガラスビーカー中にて撹拌し、次いで冷却した後、18号篩で篩過して、造粒物を得た。得られた造粒物にジヒドロコデインリン酸塩8g(塩野義製薬製:商品名 リン酸ジヒドロコデイン「シオノギ」)を混合し、ガラス瓶(13K規格瓶)に入れ、50℃で1週間保存した(実施例1)。
一方、ロキソプロフェンナトリウム水和物68.1g(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)、29.2gのマクロゴール6000(日本油脂製:商品名 マクロゴール6000P)、トウモロコシデンプン24.3g(日澱化学製:商品名 トウモロコシデンプンST-C)及びジヒドロコデインリン酸塩8g(塩野義製薬製:商品名 リン酸ジヒドロコデイン「シオノギ」)を混合し、ガラス瓶(13K規格瓶)に入れ、50℃で1週間保存した(比較例1)。 Test Example 2 Examination of Interaction Regarding the composition of Example 1 below (formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (1)) and Comparative Example 1, The state in the glass bottle after 1 day, 3 days and 1 week was evaluated, and the results are shown in Table 2.
Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and 24.3 g of corn starch (Nippon Chemical Co., Ltd .: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then passed through a No. 18 sieve to obtain a granulated product. 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) was mixed with the obtained granulated product, placed in a glass bottle (13K standard bottle), and stored at 50 ° C. for 1 week (Example) 1).
Meanwhile, loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P), corn starch 24 3 g (manufactured by Nissho Chemical Co., Ltd .: trade name corn starch ST-C) and 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”) are mixed and placed in a glass bottle (13K standard bottle) It was stored at 50 ° C. for 1 week (Comparative Example 1).
一方、ロキソプロフェンナトリウム水和物を造粒して得た粒状物にジヒドロコデインリン酸塩を混合して製した粒状製剤を保存したものは、開始時と同じ状態を保ち、当該相互作用を抑制できることが判明した(実施例1)。 As is apparent from Table 2, the mixture of loxoprofen sodium hydrate and dihydrocodeine phosphate which had been preserved by mixing had solidified after 1 day from the start of storage as a result of the interaction (Comparative Example 1). ).
On the other hand, a granule prepared by mixing loxoprofen sodium hydrate with a granule prepared by mixing dihydrocodeine phosphate can maintain the same state as the start and suppress the interaction. (Example 1).
ロキソプロフェンナトリウム水和物68.1g(大和薬品工業製:商品名 日本薬局方ロキソプロフェンナトリウム水和物)、29.2gのマクロゴール6000(日本油脂製:商品名 マクロゴール6000P)及びトウモロコシデンプン24.3g(日澱化学製:商品名 トウモロコシデンプンST-C)を65℃湯浴上のガラスビーカー中にて撹拌し、次いで冷却した後、18号篩で篩過して、造粒物を得た。得られた造粒物にジヒドロコデインリン酸塩8g(塩野義製薬製:商品名 リン酸ジヒドロコデイン「シオノギ」)、カルメロースカルシウム81g(五徳薬品製:商品名 ECG505)、乳糖水和物591.3g(DMV製:商品名 乳糖200M)及びステアリン酸マグネシウム8.1g(太平化学工業製:商品名 ステアリン酸マグネシウム(植物性))を混合した後、直径8.5mmの杵を取り付けた打錠機(畑鉄工所製:HT-AP18SS型)を用いて打錠し、1錠の質量が270mgの錠剤を得た。 [Example 2] Formulation (2) in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact with each other
Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and corn starch 24.3 g (Nippon Chemical Co., Ltd .: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then passed through a No. 18 sieve to obtain a granulated product. The obtained granulated product was mixed with 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”), 81 g of carmellose calcium (trade name: ECG505 by Gotoku Pharmaceutical), 591.3 g of lactose hydrate ( Made by DMV: trade name: lactose 200M) and magnesium stearate 8.1 g (produced by Taihei Chemical Industry: trade name: magnesium stearate (vegetable)), and then a tableting machine with a 8.5 mm diameter punch (field) Tableting was performed using a steelworks manufactured by HT-AP18SS type, and tablets having a mass of 270 mg were obtained.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は同様にして、錠剤を得た。 [Example 3] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (3)
Tablets were obtained in the same manner except that Macrogol 6000 was replaced with hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).
ロキソプロフェンナトリウム水和物68.1g(大和薬品工業製:商品名 日本薬局方ロキソプロフェンナトリウム水和物)、29.2gのマクロゴール6000(日本油脂製:商品名 マクロゴール6000P)及びトウモロコシデンプン24.3g(日澱化学製:商品名 トウモロコシデンプンST-C)を65℃湯浴上のガラスビーカー中にて撹拌し、次いで冷却した後、18号篩で篩過して、造粒物を得た。得られた造粒物にジヒドロコデインリン酸塩8g(塩野義製薬製:商品名 リン酸ジヒドロコデイン「シオノギ」)、カルメロースカルシウム81g(五徳薬品製:商品名 ECG505)、乳糖水和物295.7g(DMV製:商品名 乳糖200M)、結晶セルロース295.6g(旭化成ケミカルズ製:商品名 セオラスPH-101)及びステアリン酸マグネシウム8.1g(太平化学工業製:商品名 ステアリン酸マグネシウム(植物性))を混合した後、直径8.5mmの杵を取り付けた打錠機(畑鉄工所製:HT-AP18SS型)を用いて打錠し、1錠の質量が270mgの錠剤を得た。 [Example 4] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (4)
Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), 29.2 g of macrogol 6000 (manufactured by Nippon Oil & Fats: trade name: Macrogol 6000P) and corn starch 24.3 g (Nippon Chemical Co., Ltd .: trade name corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then passed through a No. 18 sieve to obtain a granulated product. The obtained granulated product was mixed with 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., trade name: dihydrocodeine phosphate “Shionogi”), 81 g of carmellose calcium (trade name: ECG505 by Gotoku Pharmaceutical), and 295.7 g of lactose hydrate ( Made by DMV: Trade name Lactose 200M), 295.6 g of crystalline cellulose (made by Asahi Kasei Chemicals: trade name Theolas PH-101) and 8.1 g magnesium stearate (made by Taihei Chemical Industry: trade name magnesium stearate (vegetable)) After mixing, tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a punch with a diameter of 8.5 mm to obtain a tablet having a mass of 270 mg.
ジヒドロコデインリン酸塩8g(塩野義製薬製:商品名 リン酸ジヒドロコデイン「シオノギ」)、3.4gのマクロゴール6000(日本油脂製:商品名 マクロゴール6000P)及びトウモロコシデンプン2.9g(日澱化学製:商品名 トウモロコシデンプンST-C)を65℃湯浴上のガラスビーカー中にて撹拌し、次いで冷却した後、18号篩で篩過して、造粒物を得た。得られた造粒物に、ロキソプロフェンナトリウム水和物68.1g(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)、カルメロースカルシウム81g(五徳薬品製:商品名 ECG505)、乳糖水和物638.5g(DMV製:商品名 乳糖200M)及びステアリン酸マグネシウム8.1g(太平化学工業製:商品名 ステアリン酸マグネシウム(植物性))を混合した後、直径8.5mmの杵を取り付けた打錠機(畑鉄工所製:HT-AP18SS型)を用いて打錠し、1錠の質量が270mgの錠剤を得た。 [Example 5] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (5)
8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd .: trade name dihydrocodeine phosphate “Shionogi”), 3.4 g of macrogol 6000 (manufactured by NOF Corporation: trade name Macrogol 6000P) and 2.9 g of corn starch (manufactured by Nissho Chemical Co., Ltd.) : Product name Corn starch ST-C) was stirred in a glass beaker on a 65 ° C. hot water bath, then cooled, and then sieved with a No. 18 sieve to obtain a granulated product. To the obtained granulated product, loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate), carmellose calcium 81 g (manufactured by Gotoku Pharmaceutical: trade name ECG505), lactose water 638.5 g of Japanese product (manufactured by DMV: trade name: lactose 200M) and 8.1 g of magnesium stearate (manufactured by Taihei Chemical Industry: trade name: magnesium stearate (vegetable)) were mixed, and a bowl with a diameter of 8.5 mm was attached. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) to obtain tablets each having a mass of 270 mg.
ロキソプロフェンナトリウム水和物68.1g(大和薬品工業製:商品名 日本薬局方ロキソプロフェンナトリウム水和物)、ヒドロキシプロピルセルロース24.3g(日本曹達製:商品名 HPC-L)、カルメロースカルシウム81g(五徳薬品製:商品名 ECG505)、結晶セルロース620.5g(旭化成ケミカルズ製:商品名 セオラスPH-101)を高速攪拌造粒機(パウレック製:VG-05型)に投入して混合後、精製水328.8gを添加して練合した。この造粒物を流動層乾燥機(フロイント産業製:FLO-5型)に投入して乾燥後、整粒機(岡田精工製:ND-10型)を用いて整粒した。この整粒物793.9g、ジヒドロコデインリン酸塩8g(塩野義製薬製:商品名 リン酸ジヒドロコデイン「シオノギ」)及びステアリン酸マグネシウム8.1g(太平化学工業製:商品名 ステアリン酸マグネシウム(植物性))を混合機(コトブキ製:PM50型)に投入して混合した後、直径8.5mmの杵を取り付けた打錠機(畑鉄工所製:HT-AP18SS型)を用いて打錠し、1錠の質量が270mgの錠剤を得た。 [Example 6] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate do not substantially contact (6)
Loxoprofen sodium hydrate 68.1 g (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate), hydroxypropylcellulose 24.3 g (manufactured by Nippon Soda: trade name HPC-L), carmellose calcium 81 g (Gotoku) Made by chemicals: trade name ECG505), 620.5 g of crystalline cellulose (made by Asahi Kasei Chemicals: trade name Theolas PH-101) were put into a high-speed stirring granulator (manufactured by Paulek: model VG-05), mixed and purified water 328 .8 g was added and kneaded. This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 793.9 g of this sized product, 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) and magnesium stearate 8.1 g (manufactured by Taihei Chemical Industry: trade name: magnesium stearate (vegetable)) ) Into a blender (Kotobuki: PM50 type) and mixed, and then tableted using a tableting machine (Hatetsu Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch. A tablet having a tablet mass of 270 mg was obtained.
ジヒドロコデインリン酸塩8g(塩野義製薬製:商品名 リン酸ジヒドロコデイン「シオノギ」)、ヒドロキシプロピルセルロース24.3g(日本曹達製:商品名 HPC-L)、カルメロースカルシウム81g(五徳薬品製:商品名 ECG505)、結晶セルロース620.5g(旭化成ケミカルズ製:商品名 セオラスPH-101)を高速攪拌造粒機(パウレック製:VG-05型)に投入して混合後、精製水328.8gを添加して練合した。この造粒物を流動層乾燥機(フロイント産業製:FLO-5型)に投入して乾燥後、整粒機(岡田精工製:ND-10型)を用いて整粒した。この整粒物733.8g、ロキソプロフェンナトリウム水和物68.1g(大和薬品工業製:商品名 日本薬局方ロキソプロフェンナトリウム水和物)及びステアリン酸マグネシウム8.1g(太平化学工業製:商品名 ステアリン酸マグネシウム(植物性))を混合機(コトブキ製:PM50型)に投入して混合した後、直径8.5mmの杵を取り付けた打錠機(畑鉄工所製:HT-AP18SS型)を用いて打錠し、1錠の質量が270mgの錠剤を得た。 [Example 7] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (7)
8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”), 24.3 g of hydroxypropyl cellulose (trade name: HPC-L, manufactured by Nippon Soda), 81 g of carmellose calcium (trade name, manufactured by Gotoku Yakuhin Co. ECG505), 620.5 g of crystalline cellulose (product name: Asahi Kasei Chemicals: trade name: Theolas PH-101) were charged into a high-speed stirring granulator (manufactured by Paulek: VG-05 type) and mixed, and then 328.8 g of purified water was added. Kneaded. This granulated product was put into a fluidized bed dryer (Freund Sangyo Co., Ltd .: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko Co., Ltd .: ND-10 type). 733.8 g of this sized product, 68.1 g of loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) and 8.1 g of magnesium stearate (manufactured by Taihei Chemical Industry: trade name, stearic acid) Magnesium (vegetable)) was put into a mixer (Kotobuki: PM50 type) and mixed, and then used with a tableting machine (Hatetsu Works: HT-AP18SS type) equipped with a 8.5 mm diameter punch. Tableting was performed to obtain a tablet having a mass of 270 mg.
ロキソプロフェンナトリウム水和物68.1g(大和薬品工業製:商品名 日本薬局方ロキソプロフェンナトリウム水和物)、ヒドロキシプロピルセルロース12.1g(日本曹達製:商品名 HPC-L)、カルメロースカルシウム40.5g(五徳薬品製:商品名 ECG505)、結晶セルロース280.2g(旭化成ケミカルズ製:商品名 セオラスPH-101)を高速攪拌造粒機(パウレック製:VG-05型)に投入して混合後、精製水164.3gを添加して練合した。この造粒物を流動層乾燥機(フロイント産業製:FLO-5型)に投入して乾燥後、整粒機(岡田精工製:ND-10型)を用いて整粒した(整粒物A)。また、ジヒドロコデインリン酸塩8g(塩野義製薬製:商品名 リン酸ジヒドロコデイン「シオノギ」)、ヒドロキシプロピルセルロース12.1g(日本曹達製:商品名 HPC-L)、カルメロースカルシウム40.5g(五徳薬品製:商品名 ECG505)、結晶セルロース340.3g(旭化成ケミカルズ製:商品名 セオラスPH-101)を高速攪拌造粒機(パウレック製:VG-05型)に投入して混合後、精製水164.3gを添加して練合した。この造粒物を流動層乾燥機(フロイント産業製:FLO-5型)に投入して乾燥後、整粒機(岡田精工製:ND-10型)を用いて整粒した(整粒物B)。整粒物A 400g、整粒物B 400g及びステアリン酸マグネシウム8g(太平化学工業製:商品名 ステアリン酸マグネシウム(植物性))を混合機(コトブキ製:PM50型)に投入して混合した後、直径8.5mmの杵を取り付けた打錠機(畑鉄工所製:HT-AP18SS型)を用いて打錠し、1錠の質量が270mgの錠剤を得た。 [Example 8] Formulation in which loxoprofen sodium hydrate and dihydrocodeine phosphate are not substantially in contact (8)
Loxoprofen sodium hydrate 68.1 g (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate), hydroxypropylcellulose 12.1 g (manufactured by Nippon Soda: trade name HPC-L), carmellose calcium 40.5 g (Product name: ECG505 manufactured by Gotoku Pharmaceutical Co., Ltd.), 280.2 g of crystalline cellulose (product name: Asola Chemical PH-101 manufactured by Asahi Kasei Chemicals Co., Ltd.) are charged into a high-speed stirring granulator (manufactured by Paulek: Model VG-05), mixed and purified. 164.3 g of water was added and kneaded. This granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried and then sized using a granulator (Okada Seiko: ND-10 type) (Granulated product A). ). In addition, 8 g of dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”), 12.1 g of hydroxypropyl cellulose (manufactured by Nippon Soda: trade name: HPC-L), 40.5 g of carmellose calcium (Gotoku Pharmaceutical) Product: ECG505), 340.3 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas PH-101) were put into a high-speed agitation granulator (Paurek: Model VG-05), mixed, and purified water 164. 3 g was added and kneaded. This granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then sized using a granulator (Okada Seiko: ND-10 type) (Granulated product B). ). 400 g of the sized product A, 400 g of the sized product B and 8 g of magnesium stearate (manufactured by Taihei Kagaku Kogyo: trade name magnesium stearate (vegetable)) were put into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: Model HT-AP18SS) equipped with a 8.5 mm diameter punch, and tablets with a mass of 270 mg were obtained.
Wistar系ラット(Std:Wistar/ST、雄、8週齢、体重188.9~227.9g)を用い、1群6匹として試験を実施した。ラットは、試験開始前日(16時間以上)より絶食とした。水の摂取は試験開始前1時間までは自由摂取とし、以後絶水とした。
被験薬物として、ジヒドロコデインリン酸塩(DP)を0.5%メチルセルロース(MC)溶液に懸濁し、所定量(8、24、72mg/5mL/kg)経口投与した。
なお、対照群には溶媒(0.5%MC)のみをそれぞれ同容量(5mL/kg)経口投与した。
被験薬物投与1時間後に、ロキソプロフェンナトリウム水和物120mg/2mL生理食塩水/kgを各群のラットに経口投与し、胃粘膜障害を誘発した。ロキソプロフェンナトリウム水和物の投与5時間後、ラットを頚椎脱臼により安楽死させ、噴門部を結紮し胃を摘出した。幽門部から胃内に1%ホルマリン溶液10mLを注入し、幽門部を結紮後、胃全体を同ホルマリン溶液中に約20分間浸漬して軽度に固定した。
胃粘膜障害の程度の評価は、胃を大弯に沿って切開した後、実体顕微鏡下にて腺胃部に発生した個々の損傷(びらん)の長さ(mm)を測定することにより行い、ラット1匹当たりの損傷の総和を潰瘍指数として算出した。次式に従い、被験薬物における潰瘍抑制率(%)を算出し、結果を表3に示した。
潰瘍抑制率(%)=(1-被験薬物の潰瘍指数/対照群の潰瘍指数)×100 [Test Example 3] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (1)
The test was carried out using 6 Wistar rats (Std: Wistar / ST, male, 8 weeks old, body weight 188.9 to 227.9 g). Rats were fasted from the day before the test (16 hours or longer). Water intake was free up to 1 hour before the start of the test, and then water was stopped.
As a test drug, dihydrocodeine phosphate (DP) was suspended in a 0.5% methylcellulose (MC) solution and orally administered in predetermined amounts (8, 24, 72 mg / 5 mL / kg).
In the control group, only the solvent (0.5% MC) was orally administered in the same volume (5 mL / kg).
One hour after administration of the test drug, loxoprofen sodium hydrate 120 mg / 2 mL saline / kg was orally administered to each group of rats to induce gastric mucosal damage. Five hours after administration of loxoprofen sodium hydrate, the rats were euthanized by cervical dislocation, the cardia was ligated, and the stomach was removed. After injecting 10 mL of 1% formalin solution into the stomach from the pyloric region and ligating the pyloric region, the entire stomach was immersed in the formalin solution for about 20 minutes and fixed lightly.
Evaluation of the degree of gastric mucosal damage is performed by measuring the length (mm) of individual damage (erosion) occurring in the glandular stomach portion under a stereomicroscope after incising the stomach along the large curvature. The total damage per rat was calculated as the ulcer index. According to the following formula, the ulcer suppression rate (%) in the test drug was calculated, and the results are shown in Table 3.
Ulcer inhibition rate (%) = (1−ulcer index of test drug / ulcer index of control group) × 100
ロキソプロフェンナトリウム水和物584mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びd-クロルフェニラミンマレイン酸塩10mg(金剛化学製:商品名 D-マレイン酸クロルフェニラミン)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例2)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例3)、d-クロルフェニラミンマレイン酸塩単独(対照例4)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表4に示した。 [Experiment 4] Examination of interaction 584 mg of loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) and 10 mg of d-chlorpheniramine maleate (trade name, manufactured by Kongo Chemical Co., Ltd.) -Chlorpheniramine maleate) was mixed and placed in a glass bottle (3K standard bottle) and stored at 60 ° C for 1 week (Reference Example 2). As comparative controls, loxoprofen sodium hydrate alone (Control Example 3) and d-chlorpheniramine maleate alone (Control Example 4) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 4.
下記の実施例9(ロキソプロフェンナトリウムとd-クロルフェニラミンマレイン酸塩とが実質的に接しない製剤(1))と比較例2の組成物につき、保存開始直後、1日後、3日後、7日後、14日後、28日後のガラス瓶内の状態を評価した。
すなわち、ジヒドロコデインリン酸塩8gをd-クロルフェニラミンマレイン酸塩1.2g(金剛化学製:商品名 D-マレイン酸クロルフェニラミン)に換えて、ロキソプロフェンナトリウム水和物とd-クロルフェニラミンマレイン酸塩とを混合したもの(比較例2)とロキソプロフェンナトリウム水和物とd-クロルフェニラミンマレイン酸塩とが実質的に接しない製剤(実施例9)を製し、また、50℃で28日間保存し、保存開始直後、1日後、3日後、7日後、14日後、28日後に評価した以外は、試験例2と同様に試験を実施した。結果を表5に示した。 [Test Example 5]
The following Example 9 (formulation in which loxoprofen sodium and d-chlorpheniramine maleate are not substantially in contact (1)) and the composition of Comparative Example 2 were immediately after storage, 1 day, 3 days, and 7 days The condition in the glass bottle after 14 days and after 28 days was evaluated.
That is, loxoprofen sodium hydrate and d-chlorpheniramine maleate were replaced by replacing 8 g of dihydrocodeine phosphate with 1.2 g of d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd., trade name: D-chlorpheniramine maleate). A mixture (Example 9) in which a mixture of an acid salt (Comparative Example 2), loxoprofen sodium hydrate, and d-chlorpheniramine maleate are not substantially in contact with each other was prepared. The test was carried out in the same manner as in Test Example 2 except that the samples were stored for 1 day, immediately after the start of storage, and after 1 day, 3 days, 7 days, 14 days, and 28 days. The results are shown in Table 5.
一方、ロキソプロフェンナトリウム水和物を造粒して得た粒状物にクロルフェニラミンマレイン酸塩を混合しただけで保存したものは、28日経っても開始時と同じ状態を保ち、当該相互作用を抑制できることが判明した(実施例9)。
この結果、ロキソプロフェン又はその塩とクロルフェニラミン又はその塩とを、実施的に互いに接しないように医薬組成物に含有せしめることにより、相互作用を抑制できることが判明した。 As is clear from Table 5, the mixture of loxoprofen sodium hydrate and chlorpheniramine maleate that had been preserved only became wet after 3 days from the start of storage as a result of the interaction. Example 2).
On the other hand, a granulated product obtained by granulating loxoprofen sodium hydrate and stored by simply mixing chlorpheniramine maleate maintains the same state as at the start even after 28 days, and the interaction is maintained. It was found that it can be suppressed (Example 9).
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in a pharmaceutical composition so as not to contact each other.
ジヒドロコデインリン酸塩8gをd-クロルフェニラミンマレイン酸塩1.2g(金剛化学製:商品名 D-マレイン酸クロルフェニラミン)に換えて、トウモロコシデンプンを31.1gに換える以外は、実施例2と同様にして、錠剤を得た。 [Example 10] Formulation in which loxoprofen sodium and d-chlorpheniramine maleate are not substantially in contact (2)
Example 2 except that 8 g of dihydrocodeine phosphate was replaced with 1.2 g of d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-chlorpheniramine maleate), and corn starch was replaced with 31.1 g. In the same manner, tablets were obtained.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は実施例10と同様にして、錠剤を得た。 [Example 11] Formulation in which loxoprofen sodium and d-chlorpheniramine maleate are not substantially in contact (3)
Tablets were obtained in the same manner as in Example 10, except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
被験薬物として、d-クロルフェニラミンマレイン酸塩(CM)を0.5%メチルセルロース(MC)溶液に懸濁したものを用い、所定量(5、40mg/5mL/kg)を経口投与することにより、試験例3と同様に試験を実施し、被験薬物投与における潰瘍抑制率(%)を算出し、結果を表6に示した。 [Test Example 6] Loxoprofen-induced digestive tract disorder inhibitory action (2)
As a test drug, d-chlorpheniramine maleate (CM) suspended in 0.5% methylcellulose (MC) solution was orally administered in a predetermined amount (5, 40 mg / 5 mL / kg). The test was carried out in the same manner as in Test Example 3, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 6.
ロキソプロフェンナトリウム水和物381mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びクレマスチンフマル酸塩2.5mg(ダイト製:商品名 クレマスチンフマル酸塩)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例3)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例5)、クレマスチンフマル酸塩単独(対照例6)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表7に示した。 [Test Example 7] Examination of interaction 381 mg of loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical, trade name: Japanese Pharmacopoeia, loxoprofen sodium hydrate) and 2.5 mg of clemastine fumarate (trade name: clemastine fumarate, manufactured by Daito) ) Were mixed, placed in a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 3). As comparative controls, loxoprofen sodium hydrate alone (Control Example 5) and clemastine fumarate salt alone (Control Example 6) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the state in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 7.
この結果、ロキソプロフェン又はその塩とクレマスチン又はその塩とを、実施的に互いに接しないように医薬組成物に含有せしめることにより、相互作用を抑制できることが判明した。 As is apparent from Table 7, when the mixture of loxoprofen sodium hydrate and clemastine fumarate was stored, the mixture became wet and further discolored (Reference Example 3). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and clemastine fumarate alone (control examples 5 and 6). From this, it was found that the state change of the mixture was a result of interaction between loxoprofen sodium hydrate and clemastine fumarate.
As a result, it was found that the interaction can be suppressed by incorporating loxoprofen or a salt thereof and clemastine or a salt thereof in the pharmaceutical composition so as not to contact each other.
ジヒドロコデインリン酸塩8gをクレマスチンフマル酸塩0.5g(ダイト製:商品名 クレマスチンフマル酸塩)に換えて、トウモロコシデンプンを31.8gに換える以外は、実施例2と同様にして、錠剤を得る。 [Example 12] Formulation in which loxoprofen sodium and clemastine fumarate are not in substantial contact (1)
A tablet is obtained in the same manner as in Example 2 except that 8 g of dihydrocodeine phosphate is changed to 0.5 g of clemastine fumarate (product name: clemastine fumarate, manufactured by Daito) and corn starch is changed to 31.8 g. .
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は実施例12と同様にして、錠剤を得る。 [Example 13] Formulation in which loxoprofen sodium and clemastine fumarate do not substantially contact (2)
Tablets are obtained in the same manner as in Example 12 except that the macrogol 6000 is changed to hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
被験薬物として、クレマスチンフマル酸塩(CF)を0.5%メチルセルロース(MC)溶液に懸濁したものを用い、所定量(1mg/5mL/kg)を経口投与することにより、試験例3と同様に試験を実施し、被験薬物投与における潰瘍抑制率(%)を算出し、結果を表8に示した。 [Test Example 8] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (3)
As a test drug, a suspension of clemastine fumarate (CF) in a 0.5% methylcellulose (MC) solution was used, and a predetermined amount (1 mg / 5 mL / kg) was orally administered, as in Test Example 3. The test was carried out, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 8.
ロキソプロフェンナトリウム水和物482.3mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びカルビノキサミンマレイン酸塩17.7mg(金剛化学製:商品名 マレイン酸カルビノキサミン)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例4)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例7)、カルビノキサミンマレイン酸塩単独(対照例8)を同様に60℃で1週間保存した。保存開始直後、1日後、2日後、1週間後のガラス瓶内の状態を評価し、結果を表9に示した。 [Test Example 9] Investigation of interaction Loxoprofen sodium hydrate 482.3 mg (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and carbinoxamine maleate 17.7 mg (Kongo Chemical: product) Name Carbinoxamine maleate) was mixed and placed in a glass bottle (3K standard bottle) and stored at 60 ° C. for 1 week (Reference Example 4). As comparative controls, loxoprofen sodium hydrate alone (Control Example 7) and carbinoxamine maleate salt alone (Control Example 8) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 2 days, and 1 week was evaluated, and the results are shown in Table 9.
この結果、ロキソプロフェン又はその塩とカルビノキサミン又はその塩とを、実施的に互いに接しないように医薬組成物に含有せしめることにより、相互作用を抑制できることが判明した。 As is apparent from Table 9, when the mixture of loxoprofen sodium hydrate and carbinoxamine maleate was stored, the mixture solidified and further discolored (Reference Example 4). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and carbinoxamine maleate alone (control examples 7 and 8). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and carbinoxamine maleate.
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and carbinoxamine or a salt thereof in a pharmaceutical composition so as not to contact each other.
ジヒドロコデインリン酸塩8gをカルビノキサミンマレイン酸塩2.5g(金剛化学製:商品名 マレイン酸カルビノキサミン)に換えて、トウモロコシデンプンを29.8gに換える以外は、実施例2と同様にして、錠剤を得る。 [Example 14] Formulation in which loxoprofen sodium and carbinoxamine maleate do not substantially contact (1)
In the same manner as in Example 2, except that 8 g of dihydrocodeine phosphate was replaced with 2.5 g of carbinoxamine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name carbinoxamine maleate) and corn starch was replaced with 29.8 g. Get.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は実施例14と同様にして、錠剤を得る。 [Example 15] Formulation in which loxoprofen sodium and carbinoxamine maleate do not substantially contact (2)
Tablets are obtained in the same manner as in Example 14 except that Macrogol 6000 is replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
被験薬物として、カルビノキサミンマレイン酸塩(CAM)を0.5%メチルセルロース(MC)溶液に懸濁したものを用い、所定量(0.75、75mg/5mL/kg)を経口投与することにより、試験例3と同様に試験を実施し、被験薬物投与における潰瘍抑制率(%)を算出し、結果を表10に示した。 [Test Example 10] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (4)
As test drug, carbinoxamine maleate (CAM) suspended in 0.5% methylcellulose (MC) solution and orally administered in a predetermined amount (0.75, 75 mg / 5 mL / kg) The test was carried out in the same manner as in Test Example 3, the ulcer suppression rate (%) in the test drug administration was calculated, and the results are shown in Table 10.
ロキソプロフェンナトリウム水和物490.4mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びジフェニルピラリン塩酸塩9.6mg(金剛化学製:商品名 塩酸ジフェニルピラリン)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例5)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例9)、ジフェニルピラリン塩酸塩単独(対照例10)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表11に示した。 [Test Example 11] Examination of interaction Loxoprofen sodium hydrate 490.4 mg (manufactured by Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and diphenylpyraline hydrochloride 9.6 mg (manufactured by Kongo Chemical: trade name: hydrochloric acid) Diphenylpyralin) was mixed, placed in a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 5). As comparative controls, loxoprofen sodium hydrate alone (Control Example 9) and diphenylpyraline hydrochloride alone (Control Example 10) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 11.
この結果、ロキソプロフェン又はその塩とジフェニルピラリン又はその塩とを、実施的に互いに接しないように医薬組成物に含有せしめることにより、相互作用を抑制できることが判明した。 As is apparent from Table 11, when the mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochloride was stored, the mixture became wet and further discolored (Reference Example 5). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and diphenylpyraline hydrochloride alone (control examples 9 and 10). From this, it was found that the state change of the mixture was the result of interaction between loxoprofen sodium hydrate and diphenylpyraline hydrochloride.
As a result, it was found that the interaction can be suppressed by incorporating loxoprofen or a salt thereof and diphenylpyraline or a salt thereof in a pharmaceutical composition so as not to contact each other.
下記の実施例16(ロキソプロフェンナトリウムとジフェニルピラリン塩酸塩とが実質的に接しない製剤(1))と比較例3の組成物につき、保存開始直後、1日後、3日後、7日後、14日後、28日後のガラス瓶内の状態を評価した。
すなわち、ジヒドロコデインリン酸塩8gをジフェニルピラリン塩酸塩1.3g(金剛化学製:商品名 塩酸ジフェニルピラリン)に換えて、ロキソプロフェンナトリウム水和物とジフェニルピラリン塩酸塩とを混合したもの(比較例3)とロキソプロフェンナトリウム水和物とジフェニルピラリン塩酸塩とが実質的に接しない製剤(実施例16)を製し、また、50℃で28日間保存し、保存開始直後、1日後、3日後、7日後、14日後、28日後に評価した以外は、試験例2と同様に試験を実施した。結果を表12に示した。 [Test Example 12]
The following Example 16 (formulation in which loxoprofen sodium and diphenylpyraline hydrochloride are not substantially in contact with each other) (1) and the composition of Comparative Example 3, immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, The state in the glass bottle after 28 days was evaluated.
That is, a mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochloride in place of 8 g of dihydrocodeine phosphate 1.3 g (manufactured by Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) (Comparative Example 3) , Loxoprofen sodium hydrate, and diphenylpyraline hydrochloride (Example 16) were prepared, and stored at 50 ° C. for 28 days. Immediately after the start of storage, 1 day, 3 days, and 7 days later The test was conducted in the same manner as in Test Example 2 except that the evaluation was made after 14 days and 28 days. The results are shown in Table 12.
一方、ロキソプロフェンナトリウム水和物を造粒して得た粒状物にジフェニルピラリン塩酸塩を混合しただけで保存したものは、28日経っても開始時と同じ状態を保ち、当該相互作用を抑制できることが判明した(実施例16)。
この結果、ロキソプロフェン又はその塩とジフェニルピラリン又はその塩とを、実施的に互いに接しないように医薬組成物に含有せしめることにより、相互作用を抑制できることが判明した。 As is apparent from Table 12, the mixture of loxoprofen sodium hydrate and diphenylpyraline hydrochloride which had been preserved only became wet as a result of the interaction, resulting in the mixture becoming wet after 3 days from the start of storage (Comparative Example 3). ).
On the other hand, a granulated product obtained by granulating loxoprofen sodium hydrate, which is preserved just by mixing diphenylpyraline hydrochloride, can maintain the same state as at the beginning even after 28 days and can suppress the interaction Was found (Example 16).
As a result, it was found that the interaction can be suppressed by incorporating loxoprofen or a salt thereof and diphenylpyraline or a salt thereof in a pharmaceutical composition so as not to contact each other.
ジヒドロコデインリン酸塩8gをジフェニルピラリン塩酸塩1.3g(金剛化学製:商品名 塩酸ジフェニルピラリン)に換えて、トウモロコシデンプンを31gに換える以外は、製造例2と同様にして、錠剤を得た。 [Example 17] Formulation in which loxoprofen sodium and diphenylpyraline hydrochloride are not substantially in contact (1)
Tablets were obtained in the same manner as in Production Example 2 except that 8 g of dihydrocodeine phosphate was changed to 1.3 g of diphenylpyraline hydrochloride (Kongo Chemical Co., Ltd .: trade name diphenylpyraline hydrochloride) and corn starch was changed to 31 g.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は製造例17と同様にして、錠剤を得た。 [Example 18] Formulation in which loxoprofen sodium and diphenylpyraline hydrochloride are not substantially in contact (2)
Tablets were obtained in the same manner as in Production Example 17 except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
被験薬物として、ジフェニルピラリン塩酸塩(PP)を0.5%メチルセルロース(MC)溶液に懸濁したものを用い、所定量(3、10mg/5mL/kg)を経口投与することにより、試験例3と同様に試験を実施し、被験薬物投与における潰瘍抑制率(%)を算出し、結果を表13に示した。 [Test Example 13] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (5)
As a test drug, a suspension of diphenylpyraline hydrochloride (PP) in a 0.5% methylcellulose (MC) solution was used, and a predetermined amount (3, 10 mg / 5 mL / kg) was orally administered. The test was carried out in the same manner as described above, and the ulcer suppression rate (%) in the test drug administration was calculated. The results are shown in Table 13.
ロキソプロフェンナトリウム水和物170mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びブロムヘキシン塩酸塩10mg(山洋化学製:商品名 ブロムヘキシン塩酸塩)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例6)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例11)、ブロムヘキシン塩酸塩単独(対照例12)を同様に60℃で1週間保存した。保存開始直後、1日後、2日後、1週間後のガラス瓶内の状態を評価し、結果を表14に示した。 [Test Example 14] Examination of interaction 170 mg of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) and 10 mg of bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name: bromhexine hydrochloride) They were mixed, put in a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 6). As comparative controls, loxoprofen sodium hydrate alone (Control Example 11) and bromhexine hydrochloride alone (Control Example 12) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 2 days, and 1 week was evaluated, and the results are shown in Table 14.
この結果、ロキソプロフェン又はその塩とブロムヘキシン又はその塩とを実質的に接触させないことによって、相互作用を抑制できることが判明した。 As is clear from Table 14, when the mixture of loxoprofen sodium hydrate and bromhexine hydrochloride was stored, the mixture solidified and further discolored (Reference Example 6). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and bromhexine hydrochloride alone (Control Examples 11 and 12). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and bromhexine hydrochloride.
As a result, it has been found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and bromhexine or a salt thereof into contact with each other.
下記の実施例19(ロキソプロフェンナトリウムとブロムヘキシン塩酸塩とが実質的に接しない製剤(1))と比較例4の組成物につき、保存開始直後、1日後、3日後、7日後、14日後、28日後のガラス瓶内の状態を評価した。
すなわち、ジヒドロコデインリン酸塩8gをブロムヘキシン塩酸塩4g(山洋化学製:商品名 ブロムヘキシン塩酸塩)に換えて、ロキソプロフェンナトリウム水和物とブロムヘキシン塩酸塩とを混合したもの(比較例4)とロキソプロフェンナトリウム水和物とブロムヘキシン塩酸塩とが実質的に接しない製剤(実施例19)を製し、また、50℃で28日間保存し、保存開始直後、1日後、3日後、7日後、14日後、28日後に評価した以外は、試験例2と同様に試験を実施した。結果を表15に示した。 [Test Example 15]
The following Example 19 (formulation in which loxoprofen sodium and bromhexine hydrochloride are not substantially in contact (1)) and the composition of Comparative Example 4 were used immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, 28 The state in the glass bottle after a day was evaluated.
That is, 8 g of dihydrocodeine phosphate is replaced with 4 g of bromhexine hydrochloride (manufactured by Sanyo Chemical Co., Ltd .: trade name bromhexine hydrochloride), and a mixture of loxoprofen sodium hydrate and bromhexine hydrochloride (Comparative Example 4) and loxoprofen sodium A preparation in which hydrate and bromhexine hydrochloride are not substantially in contact with each other (Example 19) was prepared, and stored at 50 ° C. for 28 days. Immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, The test was performed in the same manner as in Test Example 2 except that the evaluation was made after 28 days. The results are shown in Table 15.
一方、ロキソプロフェンナトリウム水和物を造粒して得た粒状物にブロムヘキシン塩酸塩を混合しただけで保存したものは、28日経っても開始時と同じ状態を保ち、当該相互作用を抑制できることが判明した(実施例19)。
この結果、ロキソプロフェン又はその塩とブロムヘキシン又はその塩とを、実施的に互いに接しないように医薬組成物に含有せしめることにより、相互作用を抑制できることが判明した。 As is apparent from Table 15, in the case where loxoprofen sodium hydrate and bromhexine hydrochloride were stored, the mixture was wetted after 1 day from the start of storage as a result of the interaction (Comparative Example 4). .
On the other hand, a granule obtained by granulating loxoprofen sodium hydrate and stored by simply mixing bromhexine hydrochloride can maintain the same state as at the start even after 28 days and can suppress the interaction. Was found (Example 19).
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and bromhexine or a salt thereof in a pharmaceutical composition so as not to contact each other.
ジヒドロコデインリン酸塩8gをブロムヘキシン塩酸塩4g(山洋化学製:商品名 ブロムヘキシン塩酸塩)に換えて、トウモロコシデンプンを28.3gに換える以外は、製造例2と同様にして、錠剤を得た。 [Example 20] Formulation in which loxoprofen sodium and bromhexine hydrochloride do not substantially contact (2)
Tablets were obtained in the same manner as in Production Example 2 except that 8 g of dihydrocodeine phosphate was changed to 4 g of bromohexine hydrochloride (trade name: bromohexine hydrochloride manufactured by Sanyo Chemical Co., Ltd.) and corn starch was changed to 28.3 g.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は製造例20と同様にして、錠剤を得た。 [Example 21] Preparation in which loxoprofen sodium and bromhexine hydrochloride do not substantially contact (3)
Tablets were obtained in the same manner as in Production Example 20, except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
ロキソプロフェンナトリウム水和物500mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びアンブロキソール塩酸塩500mg(静岡カフェイン工業所製:商品名 塩酸アンブロキソール)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例7)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例13)、アンブロキソール塩酸塩単独(対照例14)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表16に示した。 [Test Example 16] Examination of interaction Loxoprofen sodium hydrate 500 mg (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and Ambroxol hydrochloride 500 mg (Shizuoka Caffeine Industry: trade name: Hydrochloric acid Ambroxol) was mixed, placed in a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 7). As comparative controls, loxoprofen sodium hydrate alone (Control Example 13) and ambroxol hydrochloride alone (Control Example 14) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 16.
この結果、ロキソプロフェン又はその塩とアンブロキソール又はその塩とを実質的に接触させないことによって、相互作用を抑制できることが判明した。 As is apparent from Table 16, when the mixture of loxoprofen sodium hydrate and ambroxol hydrochloride was stored, the mixture solidified and further discolored (Reference Example 7). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and ambroxol hydrochloride alone (control examples 13 and 14). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and ambroxol hydrochloride.
As a result, it was found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and ambroxol or a salt thereof into contact with each other.
下記の実施例22(ロキソプロフェンナトリウムとアンブロキソール塩酸塩とが実質的に接しない製剤(1))と比較例5の組成物につき、保存開始直後、1日後、3日後、7日後、14日後、28日後のガラス瓶内の状態を評価した。
すなわち、ジヒドロコデインリン酸塩8gをアンブロキソール塩酸塩15g(静岡カフェイン工業所製:商品名 塩酸アンブロキソール)に換えて、ロキソプロフェンナトリウム水和物とアンブロキソール塩酸塩とを混合したもの(比較例5)とロキソプロフェンナトリウム水和物とアンブロキソール塩酸塩とが実質的に接しない製剤(実施例22)を製し、また、50℃で28日間保存し、保存開始直後、1日後、3日後、7日後、14日後、28日後に評価した以外は、試験例2と同様に試験を実施した。結果を表17に示した。 [Test Example 17]
The following Example 22 (formulation in which loxoprofen sodium and ambroxol hydrochloride are not substantially in contact with each other (1)) and the composition of Comparative Example 5 were immediately after the start of storage, 1 day, 3 days, 7 days, and 14 days later. The state in the glass bottle after 28 days was evaluated.
That is, 8 g of dihydrocodeine phosphate was replaced with 15 g of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Industry: trade name: ambroxol hydrochloride), and a mixture of loxoprofen sodium hydrate and ambroxol hydrochloride ( Comparative Example 5), a preparation (Example 22) in which loxoprofen sodium hydrate and ambroxol hydrochloride are not substantially in contact with each other was prepared and stored at 50 ° C. for 28 days. The test was conducted in the same manner as in Test Example 2 except that the evaluation was made after 3 days, 7 days, 14 days, and 28 days. The results are shown in Table 17.
一方、ロキソプロフェンナトリウム水和物を造粒して得た粒状物にアンブロキソール塩酸塩を混合しただけで保存したものは、28日経っても開始時と同じ状態を保ち、当該相互作用を抑制できることが判明した(実施例22)。
この結果、ロキソプロフェン又はその塩とアンブロキソール又はその塩とを、実施的に互いに接しないように医薬組成物に含有せしめることにより、相互作用を抑制できることが判明した。 As is apparent from Table 17, the mixture of loxoprofen sodium hydrate and ambroxol hydrochloride which had been stored was solidified after 1 day from the start of storage as a result of interaction. 5).
On the other hand, the granule obtained by granulating loxoprofen sodium hydrate and stored by simply mixing ambroxol hydrochloride maintains the same state as the start even after 28 days and suppresses the interaction It was found that this was possible (Example 22).
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and ambroxol or a salt thereof in a pharmaceutical composition so as not to contact each other.
ジヒドロコデインリン酸塩8gをアンブロキソール塩酸塩15g(静岡カフェイン工業所製:商品名 塩酸アンブロキソール)に換えて、マクロゴール6000を25.7gに、トウモロコシデンプンを20.8gに換える以外は、実施例2と同様にして、錠剤を得た。 [Example 23] Formulation in which loxoprofen sodium and ambroxol hydrochloride are not substantially in contact (2)
Except that 8g of dihydrocodeine phosphate is replaced with 15g of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Kogyosho: trade name ambroxol hydrochloride), Macrogol 6000 is replaced with 25.7g, and corn starch is replaced with 20.8g. In the same manner as in Example 2, tablets were obtained.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は実施例23と同様にして、錠剤を得た。 [Example 24] Formulation in which loxoprofen sodium and ambroxol hydrochloride are not substantially in contact (3)
Tablets were obtained in the same manner as in Example 23 except that Macrogol 6000 was changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).
ロキソプロフェンナトリウム水和物224.9mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びグアヤコールスルホン酸カリウム275.1mg(米沢浜理薬品工業製:商品名 グアヤコールスルホン酸カリウム)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例8)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例15)、グアヤコールスルホン酸カリウム単独(対照例16)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表18に示した。 [Test Example 18] Examination of interaction Loxoprofen sodium hydrate 224.9 mg (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) and 275.1 mg potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: Trade name: Potassium guaiacol sulfonate) was mixed, put into a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 8). As comparative controls, loxoprofen sodium hydrate alone (Control Example 15) and potassium guaiacol sulfonate alone (Control Example 16) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 18.
この結果、ロキソプロフェン又はその塩とグアヤコールスルホン酸又はその塩とを実質的に接触させないことによって、相互作用を抑制できることが判明した。 As is clear from Table 18, when the mixture of loxoprofen sodium hydrate and potassium guaiacol sulfonate was stored, the mixture became wet (Reference Example 8). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and potassium guaiacol sulfonate alone (Control Examples 15 and 16). From this, it was found that the state change of the mixture was a result of interaction between loxoprofen sodium hydrate and potassium guaiacol sulfonate.
As a result, it was found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and guaiacol sulfonic acid or a salt thereof into contact with each other.
ジヒドロコデインリン酸塩8gをグアヤコールスルホン酸カリウム83g(米沢浜理薬品工業製:商品名 グアヤコールスルホン酸カリウム)に換えて、マクロゴール6000を292gに、トウモロコシデンプンを243gに、乳糖水和物を34.8gに換える以外は、実施例2と同様にして、錠剤を得る。 [Example 25] Formulation (1) in which loxoprofen sodium and potassium guaiacol sulfonate are not substantially in contact with each other
8 g of dihydrocodeine phosphate is replaced with 83 g of potassium guaiacol sulfonate (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd .: trade name potassium guaiacol sulfonate), 292 g of macrogol 6000, 243 g of corn starch and 34. lactose hydrate. A tablet is obtained in the same manner as in Example 2 except that the amount is changed to 8 g.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は実施例25と同様にして、錠剤を得る。 [Example 26] Formulation in which loxoprofen sodium and guaiacol potassium sulfonate are not substantially in contact (2)
Tablets are obtained in the same manner as in Example 25 except that Macrogol 6000 is changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).
ロキソプロフェンナトリウム水和物347.1mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びリゾチーム塩酸塩152.9mg(エーザイ製:商品名 塩化リゾチーム)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例9)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例17)、リゾチーム塩酸塩単独(対照例18)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表19に示した。 [Test Example 19] Examination of interaction Loxoprofen sodium hydrate 347.1 mg (manufactured by Daiwa Pharmaceutical, trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and lysozyme hydrochloride 152.9 mg (manufactured by Eisai: trade name, lysozyme chloride) Were put in a glass bottle (3K standard bottle) and stored at 60 ° C. for 1 week (Reference Example 9). As comparative controls, loxoprofen sodium hydrate alone (Control Example 17) and lysozyme hydrochloride alone (Control Example 18) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 19.
この結果、ロキソプロフェン又はその塩とリゾチーム又はその塩とを実質的に接触させないことによって、相互作用を抑制できることが判明した。 As is apparent from Table 19, when the mixture of loxoprofen sodium hydrate and lysozyme hydrochloride was stored, the mixture became wet and further solidified (Reference Example 9). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and lysozyme hydrochloride alone (control examples 17 and 18). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and lysozyme hydrochloride.
As a result, it was found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and lysozyme or a salt thereof into contact with each other.
下記の実施例27(ロキソプロフェンナトリウムとリゾチーム塩酸塩とが実質的に接しない製剤(1))と比較例6の組成物につき、保存開始直後、1日後、3日後、7日後、14日後、28日後のガラス瓶内の状態を評価した。
すなわち、ジヒドロコデインリン酸塩8gをリゾチーム塩酸塩30g(エーザイ製:商品名 塩化リゾチーム)に換えて、ロキソプロフェンナトリウム水和物とリゾチーム塩酸塩とを混合したもの(比較例6)とロキソプロフェンナトリウム水和物とリゾチーム塩酸塩とが実質的に接しない製剤(実施例27)を製し、また、50℃で28日間保存し、保存開始直後、1日後、3日後、7日後、14日後、28日後に評価した以外は、試験例2と同様に試験を実施した。結果を表20に示した。 [Test Example 20]
The following Example 27 (formulation in which loxoprofen sodium and lysozyme hydrochloride are not substantially contacted (1)) and the composition of Comparative Example 6 were immediately after storage, 1 day, 3 days, 7 days, 14 days, 28 The state in the glass bottle after a day was evaluated.
That is, a mixture of loxoprofen sodium hydrate and lysozyme hydrochloride (Comparative Example 6) and loxoprofen sodium hydrate in which 8 g of dihydrocodeine phosphate is replaced with 30 g of lysozyme hydrochloride (manufactured by Eisai: trade name lysozyme chloride) And a lysozyme hydrochloride substantially free from contact with lysozyme hydrochloride (Example 27) was prepared and stored at 50 ° C. for 28 days, immediately after the start of storage, 1 day, 3 days, 7 days, 14 days, and 28 days later. Except for the evaluation, the test was performed in the same manner as in Test Example 2. The results are shown in Table 20.
一方、ロキソプロフェンナトリウム水和物を造粒して得た粒状物にリゾチーム塩酸塩を混合しただけで保存したものは、28日経っても開始時と同じ状態を保ち、当該相互作用を抑制できることが判明した(実施例27)。
この結果、ロキソプロフェン又はその塩とリゾチーム又はその塩とを、実施的に互いに接しないように医薬組成物に含有せしめることにより、相互作用を抑制できることが判明した。 As is apparent from Table 20, in the case where the mixture of loxoprofen sodium hydrate and lysozyme hydrochloride was stored, the mixture became wet after 3 days from the start of storage as a result of the interaction (Comparative Example 6). .
On the other hand, a granulated product obtained by granulating loxoprofen sodium hydrate, which is preserved by simply mixing lysozyme hydrochloride, can maintain the same state as at the beginning even after 28 days and can suppress the interaction. (Example 27).
As a result, it was found that the interaction can be suppressed by incorporating loxoprofen or a salt thereof and lysozyme or a salt thereof in a pharmaceutical composition so as not to contact each other.
ジヒドロコデインリン酸塩8gをリゾチーム塩酸塩30g(エーザイ製:商品名 塩化リゾチーム)に換えて、マクロゴール6000を25.7gに、トウモロコシデンプンを20.8gに換える以外は、実施例2と同様にして、錠剤を得た。 [Example 28] Formulation in which loxoprofen sodium and lysozyme hydrochloride are not substantially in contact (2)
Example 2 except that 8 g of dihydrocodeine phosphate was changed to 30 g of lysozyme hydrochloride (manufactured by Eisai: trade name: lysozyme chloride), macrogol 6000 was changed to 25.7 g, and corn starch was changed to 20.8 g. A pill was obtained.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は実施例68と同様にして、錠剤を得た。 [Example 29] Formulation in which loxoprofen sodium and lysozyme hydrochloride are not substantially in contact (3)
Tablets were obtained in the same manner as in Example 68 except that Macrogol 6000 was replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
ロキソプロフェンナトリウム水和物500mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びdl-メチルエフェドリン塩酸塩150mg(アルプス薬品工業製:商品名 日本薬局方 dl-塩酸メチルエフェドリン末)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例10)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例19)、dl-メチルエフェドリン塩酸塩単独(対照例20)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表21に示した。 [Test Example 21] Examination of interaction Loxoprofen sodium hydrate 500 mg (Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and dl-methylephedrine hydrochloride 150 mg (Alps Pharmaceutical Industries, Ltd .: trade name Japan Pharmacy) Dl-methylephedrine hydrochloride powder) was mixed and placed in a glass bottle (3K standard bottle) and stored at 60 ° C. for 1 week (Reference Example 10). As comparative controls, loxoprofen sodium hydrate alone (Control Example 19) and dl-methylephedrine hydrochloride alone (Control Example 20) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated. The results are shown in Table 21.
この結果、ロキソプロフェン又はその塩とエフェドリン類とを実質的に接触させないことによって、相互作用を抑制できることが判明した。 As is apparent from Table 21, when the mixture of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride was stored, the mixture became wet and further discolored (Reference Example 10). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride alone (Control Examples 19 and 20). From this, it was found that the state change of the mixture was the result of interaction between loxoprofen sodium hydrate and dl-methylephedrine hydrochloride.
As a result, it was found that the interaction can be suppressed by substantially not bringing loxoprofen or a salt thereof and ephedrine into contact with each other.
ジヒドロコデインリン酸塩8gをdl-メチルエフェドリン塩酸塩20g(アルプス薬品工業製:商品名 日本薬局方 dl-塩酸メチルエフェドリン末)に換えて、マクロゴール6000を23.2gに、トウモロコシデンプンを18.3gに換える以外は、実施例2と同様にして、錠剤を得る。 [Example 30] Formulation in which loxoprofen sodium and dl-methylephedrine hydrochloride do not substantially contact (1)
8 g of dihydrocodeine phosphate was replaced with 20 g of dl-methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia, dl-methylephedrine hydrochloride powder), Macrogol 6000 was changed to 23.2 g, and corn starch was 18.3 g. A tablet is obtained in the same manner as in Example 2 except that.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は実施例30と同様にして、錠剤を得る。 [Example 31] Formulation in which loxoprofen sodium and dl-methylephedrine hydrochloride are not substantially in contact (2)
Tablets are obtained in the same manner as in Example 30, except that Macrogol 6000 is changed to hydrogenated oil (manufactured by Kawaken Fine Chemicals: trade name K-3 Wax-200).
被験薬物として、dl-メチルエフェドリン塩酸塩(ME)を0.5%メチルセルロース(MC)溶液に懸濁したものを用い、所定量(20、60、180mg/5mL/kg)を経口投与することにより、試験例3と同様に試験を実施し、被験薬物投与における潰瘍抑制率(%)を算出し、結果を表22に示した。 [Test Example 22] Loxoprofen-induced gastrointestinal tract disorder inhibitory action (6)
As a test drug, dl-methylephedrine hydrochloride (ME) suspended in 0.5% methylcellulose (MC) solution was orally administered in a predetermined amount (20, 60, 180 mg / 5 mL / kg). The test was conducted in the same manner as in Test Example 3, the ulcer suppression rate (%) in the administration of the test drug was calculated, and the results are shown in Table 22.
ロキソプロフェンナトリウム水和物404.9mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びデキストロメトルファン臭化水素酸塩水和物95.1mg(第一ファインケミカル製:商品名 デキストロメトルファン HBR)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例11)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例21)、デキストロメトルファン臭化水素酸塩水和物単独(対照例22)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表23に示した。 [Test Example 23] Examination of interaction Loxoprofen sodium hydrate 404.9 mg (manufactured by Yamato Pharmaceutical Co., Ltd .: Japanese Pharmacopoeia Loxoprofen sodium hydrate) and dextromethorphan hydrobromide hydrate 95.1 mg (No. 1) One fine chemical product: trade name: Dextromethorphan HBR) was mixed, put into a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week (Reference Example 11). As comparative controls, loxoprofen sodium hydrate alone (Control Example 21) and dextromethorphan hydrobromide hydrate alone (Control Example 22) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the condition in the glass bottle after 1 day, 3 days, and 1 week was evaluated. The results are shown in Table 23.
この結果、ロキソプロフェン又はその塩とデキストロメトルファン又はその塩とを実質的に接触させないことによって、相互作用を抑制できることが判明した。 As is apparent from Table 23, when the mixture of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate was stored, the mixture became wet (Reference Example 11). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate alone (Control Examples 21 and 22). From this, it was found that the state change of the mixture was the result of interaction between loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate.
As a result, it has been found that the interaction can be suppressed by not substantially contacting loxoprofen or a salt thereof and dextromethorphan or a salt thereof.
下記の実施例32(ロキソプロフェンナトリウムとデキストロメトルファン臭化水素酸塩水和物とが実質的に接しない製剤(1))と比較例7の組成物につき、保存開始直後、1日後、3日後、7日後、14日後、28日後のガラス瓶内の状態を評価した。
すなわち、ジヒドロコデインリン酸塩8gをデキストロメトルファン臭化水素酸塩水和物16g(第一ファインケミカル製:商品名 デキストロメトルファン HBR)に換えて、ロキソプロフェンナトリウム水和物とデキストロメトルファン臭化水素酸塩水和物とを混合したもの(比較例7)とロキソプロフェンナトリウム水和物とデキストロメトルファン臭化水素酸塩水和物とが実質的に接しない製剤(実施例32)を製し、また、50℃で28日間保存し、保存開始直後、1日後、3日後、7日後、14日後、28日後に評価した以外は、試験例2と同様に試験を実施した。結果を表24に示した。 [Test Example 24]
For the composition of Example 32 (formulation (1) in which loxoprofen sodium and dextromethorphan hydrobromide hydrate are not substantially in contact with each other) and the composition of Comparative Example 7, The state in the glass bottle after 7 days, 14 days, and 28 days was evaluated.
That is, loxoprofen sodium hydrate and dextromethorphan hydrobromide water are used by replacing 8 g of dihydrocodeine phosphate with 16 g of dextromethorphan hydrobromide hydrate (product name: Dextromethorphan HBR manufactured by Daiichi Fine Chemical). A preparation (Example 32) in which a mixture of a Japanese product (Comparative Example 7), loxoprofen sodium hydrate, and dextromethorphan hydrobromide hydrate are substantially not in contact is produced, The test was carried out in the same manner as in Test Example 2 except that the evaluation was performed immediately after the start of storage, after 1 day, after 3 days, after 7 days, after 14 days, and after 28 days. The results are shown in Table 24.
一方、ロキソプロフェンナトリウム水和物を造粒して得た粒状物にデキストロメトルファン臭化水素酸塩水和物を混合しただけで保存したものは、28日経っても開始時と同じ状態を保ち、当該相互作用を抑制できることが判明した(実施例32)。
この結果、ロキソプロフェン又はその塩とデキストロメトルファン又はその塩とを、実施的に互いに接しないように医薬組成物に含有せしめることにより、相互作用を抑制できることが判明した。 As can be seen from Table 24, the mixture of loxoprofen sodium hydrate and dextromethorphan hydrobromide hydrate which had been preserved by mixing had an interaction. Wet (Comparative Example 7).
On the other hand, what was preserved by simply mixing dextromethorphan hydrobromide hydrate with granulate obtained by granulating loxoprofen sodium hydrate, kept the same state as the start even after 28 days, It was found that this interaction can be suppressed (Example 32).
As a result, it was found that the interaction can be suppressed by including loxoprofen or a salt thereof and dextromethorphan or a salt thereof in a pharmaceutical composition so as not to contact each other.
ジヒドロコデインリン酸塩8gをデキストロメトルファン臭化水素酸塩水和物16g(第一ファインケミカル製:商品名 デキストロメトルファン HBR)に換えて、マクロゴール6000を25.2gに、トウモロコシデンプンを20.3gに換える以外は、実施例2と同様にして、錠剤を得る。 [Example 33] Formulation in which loxoprofen sodium and dextromethorphan hydrobromide hydrate are not substantially in contact (2)
8 g of dihydrocodeine phosphate was replaced with 16 g of dextromethorphan hydrobromide hydrate (product name: Dextromethorphan HBR manufactured by Daiichi Fine Chemical Co., Ltd.). Macrogol 6000 was changed to 25.2 g and corn starch was changed to 20.3 g. A tablet is obtained in the same manner as in Example 2 except for changing.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は実施例33と同様にして、錠剤を得る。 [Example 34] Formulation in which loxoprofen sodium and dextromethorphan hydrobromide hydrate are not substantially in contact (3)
Tablets are obtained in the same manner as in Example 33 except that Macrogol 6000 is replaced with hydrogenated oil (trade name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
ロキソプロフェンナトリウム水和物224.9mg(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物)及びグアイフェネシン224.9mg(アルプス薬品製:商品名 グアイフェネシン)を混合し、ガラス瓶(3K規格瓶)に入れ、60℃で1週間保存した(参考例12)。比較対照として、ロキソプロフェンナトリウム水和物単独(対照例23)、グアイフェネシン単独(対照例24)を同様に60℃で1週間保存した。保存開始直後、1日後、3日後、1週間後のガラス瓶内の状態を評価し、結果を表25に示した。 [Test Example 25] Examination of interaction Mixing 224.9 mg of loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia, loxoprofen sodium hydrate) and 224.9 mg of guaifenesin (trade name: guaifenesin, manufactured by Alps) And stored in a glass bottle (3K standard bottle) at 60 ° C. for 1 week (Reference Example 12). As comparative controls, loxoprofen sodium hydrate alone (Control Example 23) and guaifenesin alone (Control Example 24) were similarly stored at 60 ° C. for 1 week. Immediately after the start of storage, the state in the glass bottle after 1 day, 3 days, and 1 week was evaluated, and the results are shown in Table 25.
この結果、ロキソプロフェン又はその塩とグアイフェネシンとを実質的に接触させないことによって、相互作用を抑制できることが判明した。 As is clear from Table 25, when the mixture of loxoprofen sodium hydrate and guaifenesin was stored, the mixture turned into a clear liquid (Reference Example 12). On the other hand, there was no change in the storage of loxoprofen sodium hydrate and guaifenesin alone (Control Examples 23 and 24). From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen sodium hydrate and guaifenesin.
As a result, it has been found that the interaction can be suppressed by not substantially contacting loxoprofen or a salt thereof and guaifenesin.
ジヒドロコデインリン酸塩8gをグアイフェネシン83g(アルプス薬品製:商品名 グアイフェネシン)に換えて、マクロゴール6000を292gに、トウモロコシデンプンを243gに、乳糖水和物を34.8gに換える以外は、実施例2と同様にして、錠剤を得る。 [Example 35] Formulation in which loxoprofen sodium and guaifenesin are not substantially in contact (1)
Example 2 except that 8 g of dihydrocodeine phosphate was replaced with 83 g of guaifenesin (manufactured by Alps Pharmaceuticals: trade name Guaifenesin), macrogol 6000 was replaced with 292 g, corn starch was replaced with 243 g, and lactose hydrate was replaced with 34.8 g. In the same manner, a tablet is obtained.
マクロゴール6000を硬化油(川研ファインケミカル製:商品名 K-3ワックス-200)に換える以外は実施例35と同様にして、錠剤を得る。 [Example 36] Formulation in which loxoprofen sodium and guaifenesin are not substantially in contact (2)
Tablets are obtained in the same manner as in Example 35 except that Macrogol 6000 is replaced with hydrogenated oil (product name: K-3 Wax-200, manufactured by Kawaken Fine Chemicals).
従って、本発明によれば、保存安定性が優れ、またロキソプロフェンに起因する消化管障害が軽減又は抑制された、ロキソプロフェン又はその塩、及びコデイン類を含有する医薬組成物を提供することができる。 According to the present invention, a storage-stable pharmaceutical composition can be provided by containing loxoprofen or a salt thereof and codeine or the like in the pharmaceutical composition so that they do not substantially contact each other.
Therefore, according to the present invention, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and codeine, which is excellent in storage stability and reduces or suppresses gastrointestinal disorders caused by loxoprofen.
Claims (11)
- コデイン類、カルビノキサミン又はその塩、クレマスチン又はその塩、クロルフェニラミン又はその塩、ジフェニルピラリン又はその塩、ブロムヘキシン又はその塩、アンブロキソール又はその塩、リゾチーム又はその塩及びデキストロメトルファン又はその塩からなる群より選ばれる1種以上と、ロキソプロフェン又はその塩とを実質的に互いに接しないように含有する医薬組成物。 Codeine, carbinoxamine or salt thereof, clemastine or salt thereof, chlorpheniramine or salt thereof, diphenylpyraline or salt thereof, bromhexine or salt thereof, ambroxol or salt thereof, lysozyme or salt thereof, and dextromethorphan or salt thereof A pharmaceutical composition comprising at least one selected from the group consisting of and loxoprofen or a salt thereof so as not to substantially contact each other.
- コデイン類、及びロキソプロフェン又はその塩を実質的に互いに接しないように含有する医薬組成物。 A pharmaceutical composition containing codeine and loxoprofen or a salt thereof so as not to substantially contact each other.
- ロキソプロフェン又はその塩が、ロキソプロフェンナトリウム水和物である請求項1又は2記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein loxoprofen or a salt thereof is loxoprofen sodium hydrate.
- ロキソプロフェンナトリウム水和物を、ロキソプロフェンナトリウム無水物換算で、10~300mgを1日量として含有する請求項3記載の医薬組成物。 The pharmaceutical composition according to claim 3, comprising loxoprofen sodium hydrate in an amount of 10 to 300 mg per day in terms of loxoprofen sodium anhydride.
- コデイン類が、コデインリン酸塩水和物及びジヒドロコデインリン酸塩から選ばれるものである請求項1~4いずれか1項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the codeines are selected from codeine phosphate hydrate and dihydrocodeine phosphate.
- コデインリン酸塩水和物を、4~60mgを1日量として含有する請求項5記載の医薬組成物。 The pharmaceutical composition according to claim 5, comprising 4-60 mg of codeine phosphate hydrate as a daily dose.
- ジヒドロコデインリン酸塩を、2~30mgを1日量として含有する請求項5記載の医薬組成物。 The pharmaceutical composition according to claim 5, comprising 2 to 30 mg of dihydrocodeine phosphate as a daily dose.
- ロキソプロフェン又はその塩が、ロキソプロフェン又はその塩を含有する粒状物である請求項1~7いずれか1項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 7, wherein the loxoprofen or a salt thereof is a granular material containing loxoprofen or a salt thereof.
- コデイン類が、コデイン類を含有する粒状物である請求項1~8いずれか1項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 8, wherein the codeine is a granular material containing codeine.
- 固形製剤である請求項1~9いずれか1項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, which is a solid preparation.
- 剤形が、カプセル剤、丸剤、顆粒剤、細粒剤、散剤又は錠剤である請求項1~10いずれか1項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 10, wherein the dosage form is a capsule, pill, granule, fine granule, powder or tablet.
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