Pharmaceutical composition containing loxoprofen (land)

Abstract

To provide a pharmaceutical composition that suppresses the interaction between loxoprofen or its salt and a terpene.SOLUTION: The details of this invention are set forth in the application document.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing loxoprofen, also known as the active ingredient of Loxonin (registered trademark). [Background technology]

[0002] Loxoprofen is a type of nonsteroidal anti-inflammatory analgesic (NSAID) (Non-Patent Document 1) and is used as an active ingredient in external preparations such as gels, poultices and tapes that have anti-inflammatory and analgesic effects for diseases and symptoms such as osteoarthritis, muscle pain, and swelling and pain after trauma (Non-Patent Document 2). On the other hand, terpenes such as menthol and peppermint oil are incorporated into topical anti-inflammatory and analgesic agents for the purpose of providing a cooling sensation, and topical agents containing them together with loxoprofen are also known (Patent Documents 1 to 3). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 10-120560 [Patent Document 2] Japanese Patent Application Laid-Open No. 2001-199883 [Patent Document 3] International Publication No. 2006 / 48939 Brochure [Non-patent literature]

[0004] [Non-Patent Document 1] Commentary on the 16th revised Japanese Pharmacopoeia, Hirokawa Publishing Co., Ltd., pages C-5359-5364 [Non-patent document 2] Loxonin (registered trademark) Gel 1% Pharmaceutical Interview Form Daiichi Sankyo Co., Ltd. Revised October 2010 (3rd edition) Summary of the Invention [Problem to be solved by the invention]

[0005] However, it is not known whether or not there is an interaction between loxoprofen or a salt thereof and terpenes, including l-menthol, that affects storage stability. Therefore, the present inventors first investigated the storage stability of loxoprofen or a salt thereof and various ingredients, and unexpectedly found that when a composition containing loxoprofen or a salt thereof and terpenes including l-menthol is prepared, interactions between these ingredients may occur, resulting in stability problems.

[0006] Therefore, an object of the present invention is to provide a pharmaceutical composition in which the interaction between loxoprofen or a salt thereof and the above-mentioned terpenes is suppressed. [Means for solving the problem]

[0007] Therefore, the present inventors have conducted further studies to solve this problem, and have found that it is possible to further combine loxoprofen or a salt thereof and a terpene with either one of the following (C-1) or (C-2):

[0008] (C-1) A compound represented by the following general formula (1), which includes chlorpheniramine or a salt thereof,

[0009] [ka]

[0010] [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, and R 1 represents a hydrogen atom, a hydroxyl group, or an alkyl group, and R 2 represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom.] or a salt thereof (C-2) Polyhydric alcohol (In this specification, one or more components selected from the above (C-1) and (C-2) may be referred to as an "interaction-suppressing component.") The present inventors have found that the interaction can be suppressed by allowing the two to coexist, and have completed the present invention.

[0011] That is, the present invention provides a composition comprising the following components (A), (B) and (C): (A) Loxoprofen or a salt thereof (B) Terpenes (C) One or more selected from the group consisting of the following components (C-1) and (C-2): (C-1) The following general formula (1)

[0012] [ka]

[0013] [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, and R 1 represents a hydrogen atom, a hydroxyl group, or an alkyl group, and R 2 represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom.] or a salt thereof (C-2) Polyhydric alcohol The present invention provides a pharmaceutical composition comprising: [Effects of the Invention]

[0014] According to the present invention, the interaction between loxoprofen or a salt thereof and terpenes can be suppressed, and therefore a pharmaceutical composition containing loxoprofen or a salt thereof and terpenes, which has excellent storage stability, can be provided. Furthermore, a pharmaceutical composition containing loxoprofen or a salt thereof and terpenes, with suppressed interactions, can be provided simply and inexpensively without going through complicated processes. DETAILED DESCRIPTION OF THE INVENTION

[0015] <Component (A)> In the present invention, "loxoprofen or a salt thereof" includes not only loxoprofen itself, but also pharmaceutically acceptable salts of loxoprofen, and solvates of loxoprofen or its pharmaceutically acceptable salts with water, alcohol, etc. These are known compounds and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate dihydrate).

[0016] The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately depending on the desired anti-inflammatory and analgesic effect. In the present invention, the content of loxoprofen or a salt thereof is preferably 0.01 to 10% by mass, more preferably 0.1 to 5% by mass, and particularly preferably 0.5 to 3% by mass, calculated as anhydrous loxoprofen sodium, relative to the total mass of the pharmaceutical composition.

[0017] <Ingredient (B)> In the present invention, the "terpenes" are not particularly limited, and examples thereof include cyclic or chain monoterpenes and sesquiterpenes. Specific examples of such terpenes include isoborneol, irone, ocimene, carveol, carbotanacetone, carvomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, sylvestrene, thymol, isothujole, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampheol, pinol, piperitenone, phellandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillyl aldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, limonene, and the like. These may be used alone or in combination of two or more. When these terpenes have optical isomerism, the present invention includes any optical isomer, and may be a single optical isomer or a mixture of various optical isomers. Among these, camphor, geraniol, citronellal, terpineol, borneol, menthol, limonene, etc. are preferred, d-camphor, dl-camphor, thymol, borneol, l-menthol, and dl-menthol are more preferred, and l-menthol and dl-camphor are particularly preferred.

[0018] When the above-mentioned terpenes are contained in a pharmaceutical composition, essential oils containing the above-mentioned terpenes may be used. Such essential oils include, for example, anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayaputo oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, Japanese pepper oil, perilla oil, citriodora oil, citronella oil, ginger oil, cardamom oil, camphor oil, ginger grass oil, spearmint oil, peppermint oil, geranium oil, star anise oil, clove oil, Examples of oils that can be used include turpentine, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, chenopodium oil, bergamot oil, bois de rose oil, basil oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime oil, lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil, and these may be used alone or in combination of two or more. Among these, ylang-ylang oil, fennel oil, orange oil, chamomile oil, cinnamon oil, perilla oil, citronella oil, ginger oil, camphor oil, peppermint oil, geranium oil, clove oil, turpentine, spruce oil, neroli oil, peppermint oil, palmarosa oil, bergamot oil, eucalyptus oil, lavender oil, linaloe oil, lemon oil, rose oil, rosemary oil, Roman chamomile oil, etc. are preferred, with camphor oil, peppermint oil, turpentine, peppermint oil, and eucalyptus oil being more preferred, and peppermint oil being particularly preferred.

[0019] The content of terpenes in the pharmaceutical composition of the present invention is not particularly limited and may be determined by appropriate consideration. In the present invention, the content of terpenes is preferably 0.01 to 15% by mass, more preferably 0.1 to 10% by mass, and particularly preferably 0.5 to 7% by mass, relative to the total mass of the pharmaceutical composition. Furthermore, when the above-mentioned essential oils are used, the content of the essential oils is preferably 0.1 to 40% by mass, more preferably 0.5 to 30% by mass, and particularly preferably 1 to 20% by mass, relative to the total mass of the pharmaceutical composition.

[0020] The ratio of loxoprofen or a salt thereof to terpenes contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined by appropriate consideration, but preferably contains 0.01 to 15 parts by mass, more preferably 0.1 to 10 parts by mass, and particularly preferably 0.5 to 7 parts by mass of terpenes per part by mass of loxoprofen or a salt thereof, calculated as anhydrous loxoprofen sodium. When the above-mentioned essential oil is used, the ratio of essential oil to loxoprofen or a salt thereof, calculated as anhydrous loxoprofen sodium, is preferably 0.1 to 40 parts by mass, more preferably 0.5 to 30 parts by mass, and particularly preferably 1 to 20 parts by mass.

[0021] <Component (C-1)> In the present invention, the general formula (1)

[0022] [ka]

[0023] [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, and R 1 represents a hydrogen atom, a hydroxyl group, or an alkyl group, and R 2 represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom.] The compound represented by the formula (1) or a salt thereof includes not only the compound represented by the formula (1) itself but also pharmaceutically acceptable salts of the compound represented by the formula (1). Specific examples of the compound represented by the formula (1) or a salt thereof include the compound represented by the formula (1), inorganic acid salts or organic acid salts of the compound represented by the formula (1) (e.g., hydrochloride, maleate, fumarate, diphenyldisulfonate, teoclate, salicylate, tannate, besylate, phosphate, etc.). Furthermore, when an asymmetric carbon is present in the chemical structure of the compound represented by the formula (1), various optical isomers exist. In the present invention, any of the optical isomers is included, and the compound represented by the formula (1) or a salt thereof may be a single optical isomer or a mixture of various optical isomers. Furthermore, the compound represented by the formula (1) or a salt thereof may be in the form of a solvate, and solvates of the compound represented by the formula (1) or a salt thereof with water, alcohol, etc. are also included in the "compound represented by the formula (1) or a salt thereof."

[0024] Above R 1 In the above, the alkyl group is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, with a methyl group being preferred. Also, the above R 1 is preferably a hydrogen atom or a methyl group.

[0025] Above R 2 In the above, the "cyclic amino group" in the cyclic amino group which may have a substituent means a 5- to 7-membered alicyclic group having at least one, preferably 1 or 2, nitrogen atoms as a ring-constituting atom. Specific examples of such cyclic amino groups include a pyrrolidinyl group, a pyrazolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a homopiperidinyl group, a homopiperazinyl group, etc. Among these, a piperidinyl group, a piperazinyl group, and a homopiperazinyl group are preferred, and a piperidinyl group and a piperazinyl group are more preferred.

[0026] Furthermore, examples of the "substituent" in the cyclic amino group which may have a substituent include an alkyl group which may be substituted with one or more groups selected from an alkylbenzoyl group, a 1,3-dihydro-2H-benzimidazol-2-one-1-yl group, a carboxyalkoxy group, a carboxyl group, a carboxyalkylphenyl group, and a hydroxyl group. Among these, an alkyl group, a carboxyalkoxyalkyl group, and a carboxyalkylphenyl(hydroxy)alkyl group are preferred. Specific examples of the above-mentioned "substituent" include, for example, a methyl group, a 3-(4-tert-butylbenzoyl)propyl group, a 3-(1,3-dihydro-2H-benzimidazol-2-one-1-yl)propyl group, a 2-(carboxymethoxy)ethyl group, a 4-[4-(2-carboxypropan-2-yl)phenyl]-4-hydroxybutyl group, a 3-carboxypropyl group, and the like.

[0027] Above R 2 In the above, the "cyclic amino group which may have a substituent" is preferably a 1-methylpiperidin-4-yl group, a 4-methylhomopiperazin-1-yl group, a 1-[3-(4-tert-butylbenzoyl)propyl]piperidin-4-yl group, a 4-[3-(1,3-dihydro-2H-benzimidazol-2-one-1-yl)propyl]piperazin-1-yl group, a 4-[2-(carboxymethoxy)ethyl]piperazin-1-yl group, a 1-{4-[4-(2-carboxypropan-2-yl)phenyl]-4-hydroxybutyl}piperidin-4-yl group, or a 1-(3-carboxypropyl)piperidin-4-yl group.

[0028] Above R 2 In the above, the "aminoalkyl group" in the aminoalkyl group which may have a substituent means an alkyl group substituted with an amino group, a monoalkylamino group, a dialkylamino group, or a cyclic amino group (the "cyclic amino group" has the same meaning as the "cyclic amino group" in the above "cyclic amino group which may have a substituent"). Among these, an alkyl group substituted with a dialkylamino group or a cyclic amino group is preferred. Note that the cyclic amino group is preferably a pyrrolidinyl group. Specific examples of such aminoalkyl groups include a 2-(dimethylamino)ethyl group, a 2-(pyrrolidin-2-yl)ethyl group, a 2-[(isopropyl)(methyl)amino]ethyl group, etc. Furthermore, examples of the "substituent" in the optionally substituted aminoalkyl group include a hydroxyl group, a phenyl group, an alkyl group, etc.

[0029] Above R 2 In the above, the "aminoalkyl group which may have a substituent" is preferably a 2-(dimethylamino)ethyl group, a 2-(1-methylpyrrolidin-2-yl)ethyl group, or a 2-[(methyl)(1-phenyl-1-hydroxypropan-2-yl)amino]ethyl group.

[0030] In addition, the above R 2 In the above, the alkyl group moiety in the "alkyl group", "alkylbenzoyl group", "carboxyalkylphenyl group", "aminoalkyl group", "monoalkylamino group" and "dialkylamino group" is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group. Also, the above R 2 In the formula (I), the alkoxy group portion in the "carboxyalkoxy group" is preferably a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, and specific examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, and a hexyloxy group.

[0031] Above R 3 In the general formula (1), examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like, and in the present invention, a chlorine atom is preferred. 3 The substitution position on the phenyl group is not particularly limited, but substitution at the 4-position is preferred.

[0032] In the present invention, specific examples of the compound represented by general formula (1) or a salt thereof include ebastine or a salt thereof; oxatomide or a salt thereof; carbinoxamine or a salt thereof such as carbinoxamine diphenyldisulfonate and carbinoxamine maleate; clemastine or a salt thereof such as clemastine fumarate; chlorpheniramine or a salt thereof such as d-chlorpheniramine maleate and dl-chlorpheniramine maleate; difeterol hydrochloride, difeterol phosphate, etc. Examples of such an antihistamine include difeterol or a salt thereof; diphenylpyraline or a salt thereof, such as diphenylpyraline hydrochloride or diphenylpyraline teoclate; diphenhydramine or a salt thereof, such as diphenhydramine hydrochloride, diphenhydramine salicylate or diphenhydramine tannate; cetirizine or a salt thereof, such as cetirizine hydrochloride; fexofenadine or a salt thereof; bepotastine or a salt thereof, such as bepotastine besilate; homochlorcyclidine or a salt thereof, such as homochlorcyclidine hydrochloride. These may be used alone or in combination of two or more. The compounds represented by the above general formula (1) and salts thereof, particularly the above-mentioned compounds and salts thereof, are known and can be produced by known methods, or commercially available products can be used.

[0033] The total content of the compound represented by formula (1) or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of interaction inhibition. In the present invention, from the viewpoint of interaction inhibition, the compound represented by formula (1) or a salt thereof is preferably contained in an amount of 0.01 to 10% by mass, more preferably 0.05 to 5% by mass, and particularly preferably 0.1 to 3% by mass, based on the total mass of the pharmaceutical composition.

[0034] The content ratio of loxoprofen or a salt thereof and the compound represented by general formula (1) or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of suppressing interactions. However, from the viewpoint of the interaction-suppressing effect, the pharmaceutical composition preferably contains a total of 0.01 to 10 parts by mass, more preferably 0.05 to 5 parts by mass, and particularly preferably 0.1 to 3 parts by mass of the compound represented by general formula (1) or a salt thereof per part by mass of loxoprofen or a salt thereof calculated as anhydrous loxoprofen.

[0035] In the present invention, as the compound represented by general formula (1) or a salt thereof, it is preferable to use "chlorpheniramine or a salt thereof" or "diphenhydramine or a salt thereof," and "chlorpheniramine or a salt thereof" is particularly preferable.

[0036] In the present invention, "chlorpheniramine or a salt thereof" includes not only chlorpheniramine itself but also pharmaceutically acceptable salts of chlorpheniramine.

[0037] [ka]

[0038] It is a compound represented by the formula: Chlorpheniramine has an asymmetric carbon atom and therefore has optical isomers. In the present invention, any optical isomer is included, and it may be a single optical isomer or a mixture of various optical isomers. Of these, the d- and dl-forms are preferred in the present invention. Specific examples of chlorpheniramine or a salt thereof include chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, and dl-chlorpheniramine maleate. In the present invention, d-chlorpheniramine maleate and dl-chlorpheniramine maleate are preferred, with d-chlorpheniramine maleate being particularly preferred. These are known compounds and can be produced by known methods, or commercially available products can be used.

[0039] The content of chlorpheniramine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of suppressing drug interactions. In the present invention, from the viewpoint of drug interaction suppression, the content of chlorpheniramine or a salt thereof is preferably 0.01 to 5% by mass, more preferably 0.05 to 3% by mass, and particularly preferably 0.1 to 2% by mass, based on the total mass of the pharmaceutical composition.

[0040] The content ratio of loxoprofen or a salt thereof and chlorpheniramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of suppressing interactions. However, from the viewpoint of the interaction-suppressing effect, the content of chlorpheniramine or a salt thereof is preferably 0.01 to 5 parts by mass, more preferably 0.05 to 3 parts by mass, and particularly preferably 0.1 to 2 parts by mass, per part by mass of loxoprofen or a salt thereof, calculated as anhydrous loxoprofen sodium.

[0041] In the present invention, "diphenhydramine or a salt thereof" includes not only diphenhydramine itself but also pharmaceutically acceptable salts of diphenhydramine.

[0042] [ka]

[0043] It is a compound represented by the formula: Specific examples of diphenhydramine or a salt thereof include diphenhydramine, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, etc. In the present invention, diphenhydramine, diphenhydramine hydrochloride, and diphenhydramine salicylate are preferred, and diphenhydramine and diphenhydramine salicylate are more preferred. These are known compounds and can be produced by known methods, or commercially available products can be used.

[0044] The content of diphenhydramine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of suppressing interactions. In the present invention, from the viewpoint of the inhibitory effect on interactions, the content of diphenhydramine or a salt thereof is preferably 0.05 to 10% by mass, more preferably 0.1 to 5% by mass, and particularly preferably 0.3 to 3% by mass, based on the total mass of the pharmaceutical composition.

[0045] The content ratio of loxoprofen or a salt thereof and diphenhydramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of suppressing interactions. However, from the viewpoint of the interaction-suppressing effect, the content of diphenhydramine or a salt thereof is preferably 0.05 to 10 parts by mass, more preferably 0.1 to 5 parts by mass, and particularly preferably 0.3 to 3 parts by mass, per part by mass of loxoprofen or a salt thereof, calculated as anhydrous loxoprofen sodium.

[0046] <Component (C-2)> In the present invention, the term "polyhydric alcohol" refers to an alcohol having two or more hydroxyl groups in the same molecule, and specific examples include propylene glycol, glycerin, 1,3-butylene glycol, sorbitol, mannitol, dipropylene glycol, polyvinyl alcohol, macrogol, etc. Preferred polyhydric alcohols are glycerin, 1,3-butylene glycol, sorbitol, mannitol, dipropylene glycol, and polyvinyl alcohol.

[0047] The total content of polyhydric alcohol in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of suppressing interactions. In the present invention, from the viewpoint of the interaction suppression effect, the polyhydric alcohol is preferably contained in an amount of 5 to 80% by mass, more preferably 10 to 70% by mass, and particularly preferably 20 to 60% by mass, based on the total mass of the pharmaceutical composition.

[0048] The content ratio of loxoprofen or a salt thereof and polyhydric alcohol contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of suppressing interactions. However, from the viewpoint of the interaction-suppressing effect, the content of polyhydric alcohol is preferably 0.1 to 80 parts by mass, more preferably 0.5 to 70 parts by mass, and particularly preferably 1 to 60 parts by mass, of loxoprofen or a salt thereof, calculated as anhydrous loxoprofen.

[0049] In the present invention, the polyhydric alcohol is preferably polyvinyl alcohol. "Polyvinyl alcohol" is a polymer obtained by saponifying polyvinyl acetate, and can be produced by a known method, or a commercially available product can be used. The degree of polymerization of vinyl acetate, which is the raw material for polyvinyl alcohol, can be appropriately adjusted, and the degree of saponification can also be appropriately adjusted.

[0050] The degree of polymerization and degree of saponification of vinyl acetate are not particularly limited and may be determined by appropriate consideration. The degree of polymerization is preferably about 200 to 3500, and particularly preferably about 300 to 2200. The degree of saponification is preferably 65 mol% or more, and more preferably 78 mol% or more. Among these, those with a degree of saponification of 78 to 96 mol% (referred to as polyvinyl alcohol (partially saponified product)) and those with a degree of saponification of 97 mol% or more (referred to as polyvinyl alcohol (completely saponified product)) are more preferred, and those with a degree of saponification of 78 to 96 mol% are particularly preferred.

[0051] The content of polyvinyl alcohol in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of suppressing interactions. In the present invention, from the viewpoint of the interaction suppression effect, the content of polyvinyl alcohol is preferably 0.05 to 10% by mass, more preferably 0.1 to 7% by mass, and particularly preferably 0.2 to 5% by mass, based on the total mass of the pharmaceutical composition.

[0052] The content ratio of rofecoxib or a salt thereof and polyvinyl alcohol contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately from the viewpoint of suppressing interactions. However, from the viewpoint of the interaction-suppressing effect, the content of polyvinyl alcohol is preferably 0.05 to 10 parts by mass, more preferably 0.1 to 7 parts by mass, and particularly preferably 0.2 to 5 parts by mass, of rofecoxib or a salt thereof, calculated as anhydrous rofecoxib sodium, per 1 part by mass of rofecoxib or a salt thereof, calculated as anhydrous rofecoxib sodium.

[0053] The pharmaceutical composition of the present invention can be produced by known methods, for example, as described in the General Provisions for Preparations in the Japanese Pharmacopoeia, 16th Edition. The dosage form is not particularly limited and may be any of solid, semi-solid, and liquid forms, and may be any form commonly used in pharmaceuticals depending on the intended use. Specifically, the pharmaceutical composition may be in any dosage form described in the General Provisions for Preparations in the Japanese Pharmacopoeia, 16th Edition, such as oral administration preparations (tablets, capsules, granules, powders, oral liquid preparations, syrups, oral jellies, etc.), vaginal administration preparations (vaginal tablets, vaginal suppositories, etc.), and skin administration preparations (external solid preparations, external liquid preparations, sprays, ointments, creams, gels, patches, etc.). In the present invention, the preparation is preferably a semi-solid or liquid preparation, and particularly preferably a dosage form selected from oral liquid preparations, syrups, topical liquid preparations, sprays, ointments, creams, gels, and patches, and particularly preferably a dosage form selected from liniments, lotions, topical aerosol preparations, pump sprays, ointments, creams, gels, tapes, and poultices.

[0054] From another perspective, the pharmaceutical composition of the present invention is preferably a semi-solid or liquid composition, and more preferably a water-containing composition (more specifically, a composition containing water in an amount of 1% by mass or more, more preferably 5% by mass or more, and particularly preferably 10 to 80% by mass). As specifically disclosed in the Examples below, it has been confirmed that the interaction-inhibiting component inhibits the interaction between loxoprofen or a salt thereof and terpenes in solution.

[0055] The pharmaceutical composition of the present invention can be administered orally or parenterally, such as transdermally or vaginally. In the present invention, parenteral administration is preferred, with transdermal administration being particularly preferred.

[0056] The pharmaceutical composition of the present invention may contain, as a medicinal ingredient, one or more drugs other than loxoprofen or a salt thereof, terpenes, and interaction inhibitors, such as analgesic ingredients, anti-inflammatory ingredients, antihistamine ingredients, antiseptic ingredients, astringent / protective ingredients, blood circulation promoting ingredients, warming ingredients, local anesthetic ingredients, antitussives, noscapines, bronchodilators, expectorants, hypnotics / sedatives, vitamins, gastric mucosa protecting agents, antacids, anticholinergics, herbal medicines, and Chinese herbal prescriptions.

[0057] Examples of analgesic ingredients include aspirin, aluminum aspirin, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, sazapyrine, salicylamide, salicylic acid, ethylene glycol salicylate, glycol salicylate, sodium salicylate, methyl salicylate, tiaramide hydrochloride, and lactylphenetidine. Examples of anti-inflammatory ingredients include sodium guaiazulene sulfonate, glycyrrhizinic acid and its derivatives and salts thereof (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), glycyrrhetinic acid, seaprose, semi-alkaline proteinase, serrapeptase, proctase, pronase, bromelain, etc.

[0058] Examples of antihistamine ingredients include azelastine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, epinastine hydrochloride, emedastine fumarate, ketotifen fumarate, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, promethazine hydrochloride, promethazine methylenedisalicylate, mequitazine, methdilazine hydrochloride, and mebhydroline napadisilate.

[0059] Examples of antiseptic ingredients include benzalkonium chloride. Examples of astringent and protective ingredients include zinc oxide. Examples of blood circulation promoting ingredients include tocopherol acetate, benzyl nicotinate, heparinoids, and sodium polyethylene sulfonate. Examples of warming ingredients include nonanoic acid vanillylamide, capsaicin, and chili pepper. Examples of local anesthetic ingredients include lidocaine, clove oil, and belladonna extract.

[0060] Examples of antitussives include alloclamide hydrochloride, eprazinone hydrochloride, carbetapentane citrate, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate and the like.

[0061] Examples of noscapines include noscapine hydrochloride and noscapine. Bronchodilators include, for example, trimetoquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride, etc.

[0062] Examples of expectorants include ammonia, fennel extract, and ammonium chloride.

[0063] Examples of hypnotics and sedatives include allylisopropylacetylurea and bromvalerylurea. Vitamins include vitamin B1, vitamin B2, vitamin B5, vitamin B6, and vitamin B 12, vitamin C, hesperidin and its derivatives and salts thereof (e.g., thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, setotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, shikotiamine, thiamine disulfide, bis-ibutiamine, bis-bentiamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin sodium phosphate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

[0064] Gastric mucosa protecting agents include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride, and the like. Antacids include aminoacetic acid, magnesium aluminosilicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, magnesium alumina hydroxide, aluminum hydroxide gel, dried aluminum hydroxide gel, dried mixed gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide and sodium bicarbonate, co-precipitation product of aluminum hydroxide, calcium carbonate and magnesium carbonate, magnesium hydroxide, co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, sodium bicarbonate, precipitated calcium carbonate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, squid bone, stone jelly, and sea urchin.

[0065] Anticholinergic agents include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, tipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, and the like.

[0066] Herbal medicines include Mallotus japonicus (Mallotus japonicus), Asanonia serrata (Asian medicine), Arnica, Coriaceae (Indian ginseng), Fennel (Fennel), Turmeric (Turmeric), Corydalis chinensis (Corydalis chinensis), Scutellaria baicalensis (Scutellaria baicalensis), Phellodendron bark (Phellodendron bark), Coptis chinensis (Coptis chinensis), Onji (Philosophyllaceae), Zedoary (Zejuts rhododendron), Valerian (Valeriana japonica), Chamomile, Calonin (Carolina rhododendron), Platycodon grandiflorum (Platycodon grandiflorum), and Apricot kernel (Prunus apricot kernel). ), Lycium chinense (wolfberry berry), Lycium coccineum (lycium bark), Cinnamon bark, Cassia japonica (cassia seed), Gentian (gentian), Geranium herb (genus herb), Safflower (safflower), Kobushi (corn berry), Bezoar (bezoar), Schisandra chinensis (schizandra berry), Asarum chinense (spicy spice), Gardenia chinense (gardenia berry), Zanthoxylum pepper (Japanese pepper), Asparagus root (asparagus root), Zhikkopi (ground bone bark), Lithospermum root (safflower), Paeonia lactiflora (peony), Musk (musk), Shajin ( Shashen (Psathyrium chinense), Shazenshi (Psathyrium chinense), Shazensou (Psathyrium chinense), Animal gall (including Yutan (bear gall)), Zhang ginger, Jiryu (Earth dragon), Shini (Magnolia), Horse chestnut, Sekisan (Garlic), Senega, Cnikyu (Czech rhizome), Zenko (Chinese husk), Swertia bristlecone, Soujutsu (Atractylodes chinense), Sohakuhi (Mulberry bark), Soyou (Perilla serrata), Taisan (Garlic), Chikusetsuninjin (Bamboo joint ginseng), Chinpi (Citrus unshiu peel) Examples of herbal medicines include Angelica acutiloba (Angelica Root), Ipecac (Ipecac Root), Nandina Fruit, Ginseng, Fritillaria Root, Ophiopogon, Pinellia Root, Saffron Flower, Anemone Root, Angelica Root, Atractylodes Rhizome, Poria Cocos Root, Peony Bark, Plum Bark, Deer Antler, and other herbal medicines, as well as extracts thereof (extracts, tinctures, dried extracts, etc.).

[0067] Examples of Chinese herbal medicine prescriptions include Keishito (Keishito), Kousosan (Kousosan), Saikokeishito (Saikokeishito), Shosaikoto (Shosaikoto), Bakumondoutou (Bakumondoutou), and Hangekoubokuto (Hangekoubokuto).

[0068] The pharmaceutical composition of the present invention contains loxoprofen, an NSAID, or a salt thereof, and therefore can be used as a prescription drug or an OTC drug. Specifically, the pharmaceutical composition has efficacy or effects such as anti-inflammatory and analgesic effects for diseases and symptoms selected from osteoarthritis, muscle pain, and swelling and pain after trauma, and is useful as an analgesic and anti-inflammatory agent. [Example]

[0069] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples in any way. [Test Example 1] Study on the interaction between loxoprofen sodium hydrate and l-menthol Part 1 Each sample solution was prepared by dissolving each component listed in Table 1 in a mixture of equal amounts of Buritton-Robinson's buffer (pH 7.0) and absolute ethanol to the concentration (w / w%) listed in the table, and then adjusting the pH to 8.0 with dilute hydrochloric acid or 10% aqueous sodium hydroxide solution. 10 ml of each sample solution was filled into a glass bottle (10K standard bottle). The presence or absence of interactions was determined by visually evaluating the appearance of each sample solution immediately after preparation (1 hour after preparation). A clear appearance was marked with an O, and an X was marked with an X when insoluble matter was observed. The results are shown in Table 1.

[0070] [Table 1]

[0071] As is clear from the test results shown in Table 1, although the sample solutions containing loxoprofen sodium hydrate or l-menthol alone (Reference Examples 1 and 2) had a clear appearance, the sample solution containing both loxoprofen sodium hydrate and l-menthol (Comparative Example 1) showed the formation of insoluble matter, confirming an interaction between the two components. On the other hand, it was revealed that the sample solution of Example 1, which further contained chlorpheniramine maleate in addition to loxoprofen sodium hydrate and l-menthol, exhibited a clear appearance, similar to Reference Examples 1 and 2. The sample solution of Example 1 maintained its clear appearance even after being stored at 25°C for one week. From the above test results, it became clear that the compound represented by the above general formula (1) or its salt, including chlorpheniramine or its salt, has the effect of suppressing the interaction between rofecoxib or its salt and terpenes.

[0072] [Test Example 2] Study on the interaction between loxoprofen sodium hydrate and l-menthol Part 2 Except for replacing chlorpheniramine maleate with polyvinyl alcohol (partially saponified product: Gohsenol EG-05 (manufactured by Nippon Synthetic Chemical Industry)), the drug interaction was investigated in the same manner as in Test Example 1. The results are shown in Table 2.

[0073] [Table 2]

[0074] As is clear from the test results shown in Table 2, the sample solution of Example 2 containing polyvinyl alcohol also exhibited a clear appearance, similar to the sample solution of Example 1. The sample solution of Example 2 maintained its clear appearance even after being stored at 25°C for one week. From the above test results, it was revealed that polyhydric alcohols have the effect of suppressing the interaction between loxoprofen or a salt thereof and terpenes.

[0075] Production Example 1 (Gel) A gel containing the following ingredients per 100 mg was prepared by a conventional method. Loxoprofen sodium hydrate 1.13mg l-menthol 3mg Chlorpheniramine maleate 0.1mg Hydroxypropyl methylcellulose 1mg Carboxyvinyl polymer 1.2mg 1,3-butylene glycol 5mg Triethanolamine 1.5mg Ethanol 20mg Purified water total amount 100mg

[0076] Production Example 2 (Tape) A tape (plaster) containing the following ingredients per 100 mg was prepared by a conventional method. Loxoprofen sodium hydrate 1.13mg l-menthol 6mg Chlorpheniramine maleate 0.1mg SIS copolymer 20mg Polyisobutylene 7.5mg Hydrogenated rosin glycerin ester 25mg Liquid paraffin 36.77mg Dibutylhydroxytoluene 0.5mg Phosphate 1mg Crotamiton 2mg Purified water total amount 100mg

[0077] Production Example 3 (Gel) A gel (gel cream) containing the following ingredients per 100 mg was prepared by a conventional method. Loxoprofen sodium hydrate 1.13mg l-menthol 2mg Polyvinyl alcohol 0.2mg Salicylic acid glycol ester 2mg Carboxyvinyl polymer 1mg Glycerin 10mg Octyldodecanol 10mg Glycerin monostearate 0.5mg Polyoxyl stearate 0.5mg Isopropyl myristate 5mg Lauromacrogol 1.5mg Triethanolamine 1mg Purified water total amount 100mg

[0078] Production Example 4 (Pot) A cataplasm containing the following ingredients per 100 mg was prepared by a conventional method. Loxoprofen sodium hydrate 1.13mg l-menthol 3mg Polyvinyl alcohol 0.8mg Partially neutralized polyacrylic acid 7mg Carmellose sodium 5mg Crotamiton 2mg Concentrated glycerin 25mg Polysorbate 80 0.3mg Aluminum hydroxide gel 0.05mg Titanium oxide 1mg Talc 2mg Tartaric acid 0.6mg Disodium edetate hydrate 0.1mg Kaolin 2.5mg Sodium bisulfite 0.3mg Purified water total amount 100mg

[0079] Production Example 5 (Lotion) A lotion containing the following ingredients per 100 mg was prepared in a conventional manner. Loxoprofen sodium hydrate 1.13mg Peppermint oil 6mg Nonanoic acid vanillylamide 0.1mg Chlorpheniramine maleate 0.5mg Diisopropyl adipate 5mg Isopropanol 40mg Hydroxypropyl methylcellulose 0.1mg Polyethylene glycol 1mg Sodium bisulfite 0.2mg Purified water total amount 100mg

[0080] Production Example 6 (Tape) A tape (plaster) containing the following ingredients per 100 mg was prepared by a conventional method. Loxoprofen sodium hydrate 1.13mg l-menthol 1mg Nonanoic acid vanillylamide 0.12mg Chlorpheniramine maleate 0.5mg SIS copolymer 20mg Polyisobutylene 7.5mg Hydrogenated rosin glycerin ester 25mg Liquid paraffin 42.25mg Dibutylhydroxytoluene 0.5mg Phosphate 1mg Crotamiton 2mg Purified water total amount 100mg

[0081] Production Example 7 (Cream) A cream containing the following ingredients per 100 mg was prepared by a conventional method. Loxoprofen sodium hydrate 1.13mg dl-Camphor 4mg Nonanoic acid vanillylamide 0.12mg Polyvinyl alcohol 0.2mg Carboxyvinyl polymer 0.8mg Sodium edetate aqueous solution 1mg Sodium bisulfite 0.1mg Octyldodecyl myristate 10mg Diisopropyl adipate 5mg Glycerin monostearate 2mg Sorbitan monostearate 0.5mg Polyoxyethylene sorbitan monostearate 1mg Paraben 0.2mg Polyoxyethylene sorbitan monostearate 0.1mg Sodium hydroxide 0.1mg Purified water total amount 100mg

[0082] Production Example 8 (Pot) A cataplasm containing the following ingredients per 100 mg was prepared by a conventional method. Loxoprofen sodium hydrate 1.13mg l-menthol 3mg Nonanoic acid vanillylamide 0.1mg Polyvinyl alcohol 1mg Partially neutralized polyacrylic acid 7mg Carmellose sodium 5mg Crotamiton 2mg Concentrated glycerin 25mg Polysorbate 80 0.3mg Aluminum hydroxide gel 0.05mg Titanium oxide 1mg Talc 2mg Tartaric acid 0.6mg Disodium edetate hydrate 0.1mg Kaolin 2.5mg Sodium bisulfite 0.3mg Purified water total amount 100mg [Industrial Applicability]

[0083] According to the present invention, the interaction between loxoprofen or a salt thereof and terpenes can be suppressed. Therefore, a pharmaceutical composition containing loxoprofen or a salt thereof and terpenes, which has excellent storage stability, can be provided. Since the pharmaceutical composition of the present invention contains loxoprofen, an NSAID, it can be suitably used as a pharmaceutical composition effective for, for example, anti-inflammation and analgesia for diseases and symptoms selected from osteoarthritis, muscle pain, and swelling and pain after trauma.

Claims

1. The following components (A), (B), and (C): (A) Loxoprofen or a salt thereof (B) Menthol (C) Macrogol A semi-solid or liquid aqueous pharmaceutical composition comprising the above and having a dosage form of a lotion.

2. 2. The pharmaceutical composition of claim 1, which does not contain crotamiton.

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