WO2011093498A1 - ロキソプロフェン含有医薬組成物 - Google Patents
ロキソプロフェン含有医薬組成物 Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- loxoprofen
- hydrochloride
- loxoprofen sodium
- pharmaceutical composition
- Prior art date
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- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims abstract description 314
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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.
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