Pharmaceutical composition

Abstract

To provide a technique that prevents incompatibility in a pharmaceutical composition containing loxoprofen or a salt thereof and cinnamon bark or its extract.SOLUTION: A pharmaceutical composition contains following components (A), (B) and (C): (A) loxoprofen or a salt thereof; (B) cinnamon bark or its extract; and (C) at least one selected from the group consisting of following components (C-1)-(C-3): (C-1) tranexamic acid or a salt thereof; (C-2) a xanthine derivative; and a basic compound (C-3) having an acid-neutralizing ability.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to pharmaceutical compositions, etc. [Background technology]

[0002] Loxoprofen is a type of nonsteroidal anti-inflammatory drug (NSAID) and is known to be effective in reducing inflammation, pain, and fever in conditions such as rheumatoid arthritis, osteoarthritis, lower back pain, periarthritis of the shoulder, cervicobrachial syndrome, toothache, acute upper respiratory tract infections, and post-operative, post-traumatic, and post-extraction conditions (Non-Patent Literature 1). Due to its excellent antipyretic and analgesic effects, it is expected to be incorporated into combination cold medicines and antipyretic analgesics. Cinnamon is also known to have various pharmacological effects, including antipyretic effects (Non-Patent Literature 2), and is used as an ingredient in combination cold medicines and antipyretic analgesics. Therefore, pharmaceuticals containing both loxoprofen and cinnamon are considered useful as general cold medicines, antipyretics, and analgesics. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Commentary on the 15th Revised Japanese Pharmacopoeia, Hirokawa Shoten Co., Ltd., pp. C-4790-4795. [Non-Patent Document 2] Commentary on the 17th Revised Japanese Pharmacopoeia, Hirokawa Shoten Co., Ltd., pp. D-272-277. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] However, it is completely unknown whether any interactions occur between loxoprofen or its salts and cinnamon or its extracts that would affect storage stability. The inventors investigated the storage stability between loxoprofen or its salt and cinnamon or its extract and unexpectedly found that when the two components were stored together, changes in their composition occurred, resulting in solidification and significant discoloration of the mixture.

[0005] Therefore, the object of the present invention is to provide a technology for suppressing changes in the formulation of a pharmaceutical composition containing loxoprofen or a salt thereof and cinnamon or an extract thereof. [Means for solving the problem]

[0006] Therefore, the inventors diligently investigated the above problem and, surprisingly, found that a pharmaceutical composition containing loxoprofen or a salt thereof and cinnamon or an extract thereof further contains one or more of the following components 1 to 3: 1. Tranexamic acid or its salt; 2. Xanthine derivatives, such as anhydrous caffeine; 3. Basic compounds with acid-neutralizing ability, such as magnesium carbonate, magnesium oxide, and magnesium aluminometasilicate; We have discovered that by means of including a substance, by means of housing a pharmaceutical composition containing loxoprofen or a salt thereof and cinnamon or an extract thereof in an airtight package such as a bottle or PTP package, or by means of a combination of these means, changes in the formulation can be suppressed compared to when none of these means are taken, and thus completed the present invention.

[0007] In other words, the present invention comprises the following components (A), (B), and (C): (A) Loxoprofen or a salt thereof; (B) Cinnamon or its extract; (C) One or more selected from the group consisting of the following components (C-1) to (C-3); (C-1) Tranexamic acid or its salt; (C-2) xanthine derivatives; (C-3) Basic compounds with acid neutralizing ability; This invention provides a pharmaceutical composition containing [the specified ingredient].

[0008] Further, the present invention provides a pharmaceutical product in which a pharmaceutical composition containing the following components (A) and (B): (A) Loxoprofen or a salt thereof; (B) Cinnamon or an extract thereof; is contained in an airtight package.

[0009] Furthermore, the present invention provides a pharmaceutical product in which a pharmaceutical composition containing the following components (A), (B) and (C): (A) Loxoprofen or a salt thereof; (B) Cinnamon or an extract thereof; (C) At least one selected from the group consisting of the following components (C-1) to (C-3); (C-1) Tranexamic acid or a salt thereof; (C-2) Xanthine derivative; (C-3) Basic compound having an acid-neutralizing ability; is contained in an airtight package. [Effect of the Invention]

[0010] According to the present invention, the blending change between loxoprofen or a salt thereof and cinnamon or an extract thereof can be suppressed. Therefore, it is possible to provide a pharmaceutical having excellent storage stability containing loxoprofen or a salt thereof and cinnamon or an extract thereof. [Embodiment for Carrying out the Invention]

[0011] [Component (A)] In the present invention, "loxoprofen or its salt" includes not only loxoprofen itself, but also pharmaceutically acceptable salts of loxoprofen, and further, solvates of loxoprofen or its pharmaceutically acceptable salt 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 sodium hydrate (chemical name: Monosodium 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate dihydrate) is preferred as loxoprofen or its salt.

[0012] The amount of loxoprofen or its salt contained in the pharmaceutical composition of the present invention is not particularly limited and can be determined appropriately depending on the gender, age, symptoms, etc. of the user. For example, it can contain an amount that allows for a daily dose of 10 to 300 mg, more preferably 30 to 240 mg, and most preferably 60 to 180 mg, of anhydrous loxoprofen sodium. In the present invention, it is preferable that the pharmaceutical composition contains loxoprofen or a salt thereof in an amount of 0.1 to 91% by mass, more preferably 1 to 35% by mass, and even more preferably 2 to 30% by mass, based on the total mass of loxoprofen sodium. Of these, it is even more preferable that it contains 3 to 25% by mass, even more preferably 4 to 20% by mass, and particularly preferable that it contains 5 to 15% by mass.

[0013] <Ingredient (B)> "Keihi" (cinnamon bark) is a crude drug derived from the plant Cinnamomum cassia Blume (Lauraceae), but it is preferable to use cinnamon bark or a portion of the periderm removed. The form of keihi can be adjusted as needed; it can be cut or crushed into small pieces or lumps, or ground into a powder. For example, "keihi powder" can also be used in this invention. Furthermore, considering the convenience of handling during the manufacture of the pharmaceutical composition, keihi that has undergone some kind of extraction treatment (hereinafter referred to as "keihi extract") may also be used. Furthermore, the term "cinnamon extract" as described above also includes extracts that have undergone processing such as heating, drying, and grinding in addition to extraction. Specifically, the term "cinnamon extract" of the present invention also includes liquids obtained by leaching cinnamon after cutting it to an appropriate size as needed, liquids obtained by concentrating the leaching (soft extract, tincture, etc.), and even dried versions of these (dried extract, etc.). In the present invention, cinnamon or its extract is preferably dried cinnamon extract.

[0014] The method for producing cinnamon extract is not particularly limited, and it can be produced by referring to known methods for producing plant extracts, such as those described in the sections on "extracts," "infusions / decoctions," "tinctures," and "fluid extracts" in the General Provisions of the Seventeenth Revised Japanese Pharmacopoeia. Specifically, for example, it can be produced by cutting, heating, or grinding cinnamon as necessary, and then extracting it with an appropriate extraction solvent. The obtained extract may be further concentrated or dried as necessary.

[0015] Examples of the extraction solvents mentioned above include lower monohydric alcohols such as methanol, ethanol, isopropanol, and n-butanol (preferably linear or branched aliphatic alcohols having 1 to 6 carbon atoms); lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, and glycerin; ethers such as diethyl ether; ketones such as acetone and ethyl methyl ketone; esters such as ethyl acetate; nitriles such as acetonitrile; alkanes such as pentane, hexane, cyclopentane, and cyclohexane; halogenoalkanes such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene and toluene; amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide; and water (including hot water). These may be used individually or in combination of two or more. In the present invention, the extraction solvent is preferably a solvent containing at least water or a linear or branched aliphatic alcohol having 1 to 6 carbon atoms, more preferably a solvent selected from water, a linear or branched aliphatic alcohol having 1 to 6 carbon atoms, and a mixture of water and a linear or branched aliphatic alcohol having 1 to 6 carbon atoms, and particularly preferably a solvent selected from the group consisting of water, ethanol, and a water / ethanol mixture.

[0016] The extraction procedure is not particularly limited, and known methods used for extraction from plants can be employed. Specifically, examples include immersion in an extraction solvent (cold immersion, warm immersion, percolation, etc.) and extraction using supercritical or subcritical fluids. To increase the extraction efficiency, stirring or homogenization in the extraction solvent may be performed. The extraction temperature is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but it is preferable to set it to a temperature between approximately 5°C and below the boiling point of the extraction solvent. The extraction time is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but it is preferable to use a time of approximately 1 hour to 14 days.

[0017] Furthermore, in the present invention, cinnamon or its extract may be used as an ingredient in herbal medicine prescriptions. Specific examples of such herbal medicine prescriptions include Kakkonto, Keishito, Saikokeishito, Shoseiryuto, and Maoto.

[0018] In the present invention, commercially available products can be used as cinnamon or its extract. Specific examples of commercially available products include cinnamon tincture, cinnamon tincture-N, cinnamon extract, cinnamon fluid extract, cinnamon dry extract, and Japanese Pharmacopoeia cinnamon oil (all manufactured by Nippon Powder Pharmaceutical Co., Ltd.).

[0019] The content of cinnamon or its extract in the pharmaceutical composition of the present invention is not particularly limited, but it is preferably 0.01 to 15% by mass, more preferably 0.05 to 10% by mass, even more preferably 0.1 to 9.5% by mass, and particularly preferably 1 to 4% by mass, based on the total mass of the pharmaceutical composition. Furthermore, when the content of cinnamon or its extract is converted to the amount of crude drug, it is preferable that it be contained in an amount equivalent to 0.1 to 200% by mass of the total mass of the pharmaceutical composition, more preferably 1 to 150% by mass, even more preferably 5 to 100% by mass, and particularly preferably 10 to 50% by mass.

[0020] <Ingredient (C)> (Component (C-1)) In the present invention, "tranexamic acid or its salt" includes not only tranexamic acid itself, but also pharmaceutically acceptable salts of tranexamic acid (for example, acid addition salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; acid addition salts with organic acids such as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate; alkali metal salts such as sodium salt and potassium salt; salts with Group 2 metal elements such as calcium salt and magnesium salt; organic amine salts such as phenethylamine salt; salts with amino acids such as lysine, etc.), and also solvates of tranexamic acid or its pharmaceutically acceptable salt with water, alcohol, etc., and one or more of these can be used in combination. Tranexamic acid or its salts are known to cause changes in color and properties over time when stored in combination with loxoprofen or its salts (Japanese Patent Publication No. 2016-104812). However, as described in the examples below, when both cinnamon or its extract, which causes solidification and significant discoloration when combined with loxoprofen or its salts, and tranexamic acid or its salts as described above are combined with loxoprofen or its salts, the changes in composition are surprisingly suppressed.

[0021] Tranexamic acid or its salt is preferred, and tranexamic acid listed in the 17th edition of the Japanese Pharmacopoeia is particularly preferred. Tranexamic acid or its salts are well known and can be manufactured by known methods, or commercially available products may be used. Examples of commercially available products include tranexamic acid manufactured by Daiichi Sankyo Propharma Co., Ltd.

[0022] The content of tranexamic acid or its salt in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of suppressing changes in formulation, it is preferable to contain 1 to 75% by mass of tranexamic acid as a free form relative to the total mass of the pharmaceutical composition, more preferably 5 to 70% by mass, even more preferably 10 to 65% by mass, and particularly preferably 20 to 65% by mass.

[0023] Furthermore, the mass ratio of loxoprofen or its salt to tranexamic acid or its salt in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of suppressing changes in formulation, it is preferable to contain 0.1 to 20 parts by mass of tranexamic acid or its salt, more preferably 0.5 to 15 parts by mass, even more preferably 1 to 10 parts by mass, and particularly preferably 2 to 5 parts by mass, of 1 part by mass of loxoprofen or its salt, on a free form basis.

[0024] (Component (C-2)) In the present invention, the "xanthine derivative" is preferably a compound represented by the following general formula (1). Xanthine derivatives are known to undergo changes in state over time when stored in combination with loxoprofen or its salts (Japanese Patent Publication No. 2015-227347). However, as described in the examples below, when both cinnamon or its extract, which causes solidification or significant discoloration when combined with loxoprofen or its salts, and the above-mentioned xanthine derivatives are combined with loxoprofen or its salts, the changes in composition are surprisingly suppressed.

[0025] [ka]

[0026] [In formula (1), R 1 and R 2 Each of these independently represents a hydrogen atom or a methyl group, and R 3 This represents a hydrogen atom, a methyl group, a monohydroxypropyl group, or a dihydroxypropyl group.

[0027] In formula (1), R 3 In this case, a 2-hydroxypropyl group is preferred as the monohydroxypropyl group. Furthermore, a 2,3-dihydroxypropyl group is preferred as the dihydroxypropyl group.

[0028] In the above general formula (1), (1) When R 1 is a methyl group, R 2 is a methyl group, and R 3 is a methyl group, it means caffeine. (2) When R 1 is a methyl group, R 2 is a methyl group, and R 3 is a hydrogen atom, it means theophylline. (3) When R 1 is a hydrogen atom, R 2 is a methyl group, and R 3 is a methyl group, it means theobromine. (4) When R 1 is a methyl group, R 2 is a hydrogen atom, and R 3 is a methyl group, it means paraxanthine. (5) When R 1 is a methyl group, R 2 is a methyl group, and R 3 is a 2-hydroxypropyl group, it means proxiphylline. (6) When R 1 is a methyl group, R 2 is a methyl group, and R 3 is a 2,3-dihydroxypropyl group, it means diprophylline.

[0029] The compounds of the general formula (1) are known. In the present invention, in addition to those produced by known methods, commercially available ones can also be used. In addition to the compound represented by the general formula (1) above, pharmaceutically acceptable salts thereof (for example, those forming double salts (sodium benzoate caffeine (double salt of sodium benzoate and caffeine), aminophylline (double salt of theophylline and ethylenediamine)), etc.), solvates of the compound represented by general formula (1) or its salt with water or alcohol, etc.) can also be used as xanthine derivatives, and these are also included in "xanthine derivatives," and the above-mentioned compounds (caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprophylline) also include these compounds, their salts, and their solvates. In the present invention, one or more of these xanthine derivatives can be used.

[0030] In the present invention, the xanthine derivative is preferably one or more selected from the group consisting of caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprophylline. In particular, caffeine is preferred from the viewpoint of using the pharmaceutical composition of the present invention as an antipyretic analgesic or a combination cold medicine. Suitable specific examples of caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate, of which caffeine hydrate, anhydrous caffeine, and sodium benzoate caffeine are particularly preferred.

[0031] The content of xanthine derivatives in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of suppressing changes in formulation, it is preferable to contain 0.1 to 80% by mass of the xanthine derivative as a free form relative to the total mass of the pharmaceutical composition, more preferably 0.5 to 75% by mass, even more preferably 1 to 70% by mass, and particularly preferably 3 to 65% by mass.

[0032] Furthermore, the mass ratio of loxoprofen or its salt to xanthine derivative in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of suppressing changes in formulation, it is preferable to contain 0.0001 to 15 parts by mass of xanthine derivative on a free form basis for every 1 part by mass of loxoprofen or its salt on a free form basis, more preferably 0.001 to 10 parts by mass, even more preferably 0.01 to 5 parts by mass, and particularly preferably 0.1 to 3 parts by mass.

[0033] (Component (C-3)) In this invention, "basic compound having acid neutralizing ability" means a basic compound having acid neutralizing ability. Here, "acid neutralizing ability" can be determined by performing a test according to the antacidity test method described in the General Test Methods of the 17th edition of the Japanese Pharmacopoeia. Among component (C), (C-3) basic compounds having acid neutralizing ability are preferred from the viewpoint of suppressing changes in formulation.

[0034] In the present invention, examples of basic compounds having acid neutralizing ability include basic inorganic compounds such as alkaline earth metals and / or earth metal-based basic inorganic compounds such as magnesium, aluminum, and calcium; alkali metal-based basic inorganic compounds such as sodium and potassium; and amine-based basic inorganic compounds; and basic organic compounds such as alkaline earth metals and / or earth metal-based basic organic compounds such as magnesium, aluminum, and calcium; alkali metal-based basic organic compounds such as sodium and potassium; and amine-based basic organic compounds.

[0035] Examples of basic inorganic compounds include alkaline earth metals and / or earth metal-based basic inorganic compounds such as magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, coprecipitation products of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, and crystalline cellulose, magnesium aluminum hydroxide, aluminum hydroxide gel, coprecipitation products of aluminum hydroxide and sodium bicarbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitation products of aluminum hydroxide, magnesium carbonate, and calcium carbonate, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate, as well as inorganic salts of metals selected from magnesium, aluminum, and calcium. Examples of alkali metal-based basic inorganic compounds include anhydrous sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, tetrasodium pyrophosphate, trisodium phosphate, sodium hydrogen phosphate hydrate, anhydrous sodium pyrophosphate, anhydrous monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, potassium carbonate, and other inorganic salts of metals selected from sodium and potassium.

[0036] In the present invention, preferred basic inorganic compounds having acid-neutralizing ability include magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, coprecipitation product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, synthetic aluminum silicate, hydroxypropyl starch, and crystalline cellulose, magnesium aluminum hydroxide, aluminum hydroxide gel, coprecipitation product of aluminum hydroxide and sodium bicarbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitation product of aluminum hydroxide, magnesium carbonate, and calcium carbonate, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, and sodium bicarbonate.

[0037] Furthermore, examples of alkaline earth metal and / or earth metal-based basic organic compounds in the above-mentioned basic organic compounds include aldioxa, dihydroxyaluminum aminoacetate, sucralfate hydrate, and calcium pantothenate. Examples of alkali metal-based basic organic compounds include sodium citrate hydrate, disodium succinate hexahydrate, DL-sodium tartrate, L-sodium tartrate, sodium copper chlorophyllin, sodium polyacrylate, 5'-ribonucleotide disodium, and potassium copper chlorophyllin. Examples of amine-based basic organic compounds include aminoacetic acid, L-arginine, and meglumine.

[0038] In the present invention, preferred basic organic compounds having acid-neutralizing ability include aldioxa, dihydroxyaluminum aminoacetate, and sucralfate hydrate.

[0039] In addition, in the present invention, crude drugs containing basic compounds such as squid bone, oyster shell, and oyster shell may be used as the basic compound.

[0040] In the present invention, as the basic compound having acid neutralizing ability, from the viewpoint of suppressing changes in formulation, one or more selected from the group consisting of aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried aluminum hydroxide / magnesium carbonate gel, coprecipitation product of aluminum hydroxide / sodium bicarbonate, coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, and magnesium aluminometasilicate is preferred; one or more selected from the group consisting of magnesium oxide, aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, and magnesium aluminometasilicate is more preferred; and one or more selected from the group consisting of magnesium oxide, magnesium carbonate, and magnesium aluminometasilicate is particularly preferred. Furthermore, basic compounds with acid-neutralizing ability may be used individually or in combination of two or more.

[0041] The content of the basic compound having acid-neutralizing ability in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of suppressing changes in formulation, it is preferably 5 to 80% by mass, more preferably 10 to 75% by mass, even more preferably 15 to 70% by mass, and particularly preferably 20 to 65% by mass, based on the total mass of the pharmaceutical composition.

[0042] Furthermore, the mass ratio of loxoprofen or a salt thereof to a basic compound having acid-neutralizing ability in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of suppressing changes in formulation, it is preferable to contain 0.01 to 30 parts by mass of a basic compound having acid-neutralizing ability per 1 part by mass of loxoprofen or a salt thereof on a free form basis, more preferably 0.1 to 20 parts by mass, even more preferably 0.5 to 10 parts by mass, and particularly preferably 1 to 5 parts by mass.

[0043] The pharmaceutical composition may contain, as a pharmacoactive ingredient, one or more ingredients other than those listed above, for example, one or more selected from the group consisting of antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotics and sedatives, vitamins, anti-inflammatory agents, gastric mucosal protectants, anticholinergics, and herbal medicines.

[0044] Examples of antipyretic and analgesic drugs include aspirin, aluminum aspirin, acetaminophen, ibuprofen, ethenzamide, sazapyrin, salicylamide, lactylphenetidine, and sodium salicylate. Examples of antihistamines include, specifically, azelastine hydrochloride, alimazine tartrate, isotipendyl hydrochloride, iproheptine hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, difeterol hydrochloride, difeterol phosphate, and diphenylpyraline salt. Examples include salts, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cyproheptadine hydrochloride hydrate, cetirizine hydrochloride, triprolizine hydrochloride, triperenamine hydrochloride, tondilamine hydrochloride, fexofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besilate, homochlorcyclidine hydrochloride, mequitazine, methidilazine hydrochloride, mebhydrolin napadisylate, loratadine, etc.

[0045] Examples of antitussives include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, and other codeine derivatives, as well as aloclamide hydrochloride, eprazinon hydrochloride, carbetapentanceatate, cloperastine hydrochloride, cloperastine fendizoate, dibnate sodium, dimemorphan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, and dextromethorphan phenolphthalein salt.

[0046] Examples of noscapines include noscapine hydrochloride and noscapine. Examples of bronchodilators include, specifically, trimethoquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, l-methylephedrine saccharin salt, dl-methylephedrine saccharin salt, and methoxyphenamine hydrochloride.

[0047] Examples of expectorants include ammonia fennel extract, ethylcysteine ​​hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, methylcysteine ​​hydrochloride, l-menthol, and lysozyme hydrochloride.

[0048] Examples of hypnotic sedatives include allyl isopropylacetylurea and bromovalerylurea. Examples of vitamins include, for example, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin C, hesperidin and its derivatives, and their salts (specifically, for example, thiamine, thiamine hydrochloride, thiamine nitrate, dicethiamine hydrochloride, cetothiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, shikotiamine, thiamine disulfide, bis-ibthiamine, 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.).

[0049] Examples of anti-inflammatory agents include, specifically, glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), seaprose, semi-alkaline proteinase, serrapeptase, proctases, pronase, bromelain, and the like.

[0050] Examples of gastric mucosal protective agents include, for example, gefarnate, cetraxate hydrochloride, sofalcone, teprenone, and methylmethionine sulfonium chloride.

[0051] Examples of anticholinergic agents include, specifically, oxyfencycline hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datura extract, tipepidium bromide, methylatropine bromide, methylanisotropine bromide, methylscopolamine bromide, methyl-l-hyoscyamine bromide, methylbenactydium bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, belladonna root, and total belladonna root alkaloid citrate.

[0052] Specific examples of herbal medicines include: Akamegashiwa (red oak), Asanyaku (catechu), Inyokaku (epimony), Enkyo (fennel), Engosaku (coral grass), Ogon (scutellaria), Oushoku (scutellaria), Oushoku (yellow sage), Oubaku (yellow oak), Oubai (cherry bark), Ouren (coptis), Onji (polygala), Gajutsu (turmeric), Kanokosou (valerian), Kamitsure (chamomile), Caronine (caramel), Kikyo (platycodon), Kyo Apricot kernel, Goji berry, Goji berry leaf, Schizonepeta, Cassia seed, Gentian, Geranium thunbergii, Cyperus rotundus, Ox gall, Schisandra chinensis, Asarum sieboldii, Japanese pepper, Aster tataricus, Lycium barbarum, Peony, Musk, Adenophora triphylla, Plantago seed, and Chaenomeles speciosa. Plantago asiatica, animal bile (including bear bile), ginger, earthworm, magnolia, garlic, senega, lilac, gentian, gentian bark, mulberry bark, perilla leaf, garlic, bamboo ginseng, clove, dried tangerine peel, angelica tree Examples include crude drugs such as ), Tokon (spitting root), Nandina fruit, Ginseng, Fritillaria, Ophiopogon, Pinellia, Safflower, Angelica, Atractylodes, Poria, Peony bark, Ephedra, Deer antler, etc., as well as extracts (extracts, tinctures, dried extracts, etc.) of these.

[0053] In this specification, the dosage form of a "pharmaceutical composition" is not particularly limited and may be solid, semi-solid, or liquid, and can be selected according to its intended use. Examples of dosage forms of pharmaceutical compositions include those described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia. Specifically, examples of oral dosage forms include solid preparations such as tablets (e.g., ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules (e.g., effervescent granules, etc.), powders, and pills; semi-solid preparations such as oral jellies; and liquid preparations such as oral solutions (e.g., elixirs, suspensions, emulsions, and limonades). Examples of parenteral dosage forms include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, external solid preparations, external solutions, sprays, ointments, creams, gels, and patches.

[0054] As for the dosage form of the pharmaceutical composition, solid dosage forms are preferred from the viewpoint of ease of administration and intake, and solid dosage forms selected from tablets (e.g., including regular tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules (e.g., including effervescent granules, etc.), powders, and pills are particularly preferred.

[0055] Pharmaceutical compositions can be manufactured according to their dosage form by known methods, such as those described in the 17th edition of the Japanese Pharmacopoeia, General Provisions for Pharmaceutical Preparations. In this case, pharmaceutically acceptable carriers (pharmaceutical additives) may be added to the pharmaceutical composition. Examples of such pharmaceutical additives include, but are not limited to, excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, powders, poorly water-soluble polymers, antioxidants, flavoring agents, and sweeteners. The above-mentioned component (C) may also be used as a pharmaceutical additive. Specific examples of these pharmaceutical additives include those listed in the Pharmaceutical Additives Dictionary 2016 (published by Yakuji Nippo Co., Ltd.) and Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press).

[0056] Excipients include, specifically, inorganic excipients such as aluminum silicate, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, monocalcium phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate; starch, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), and fruit Examples of organic excipients include sugars, caramel, agar, xylitol, paraffin, crystalline cellulose, sucrose, maltose, lactose, lactose monohydrate, sucrose, glucose, pullulan, polyoxyethylene hydrogenated castor oil, maltitol, reduced maltose syrup, powdered reduced maltose syrup, erythritol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, calcium citrate, and others. These can be used individually or in combination of two or more.

[0057] Examples of disintegrants include super disintegrants such as sodium carboxymethyl starch, sodium croscarmellose, and crospovidone, as well as carmellose, carmellose calcium, starch, sucrose fatty acid esters, gelatin, sodium bicarbonate, dextrin, dehydroacetic acid and its salts, povidone, and polyoxyethylene hydrogenated castor oil 60. These can be used individually or in combination of two or more.

[0058] Examples of binders include, specifically, oils and fats such as hydrogenated beef tallow, hydrogenated oil, hydrogenated vegetable oil, hydrogenated soybean oil, carnauba wax, bleached beeswax, beeswax, and Japanese wax, as well as methylcellulose, hydroxypropylcellulose, hypromellose, sodium carmellose, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), dextrin, pullulan, acacia gum, agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, and polyvinyl acetal diethylaminoacetate. These can be used individually or in combination of two or more.

[0059] Examples of lubricants include calcium stearate, magnesium stearate, sodium stearyl fumarate, and sucrose fatty acid esters. These can be used individually or in combination of two or more.

[0060] Examples of plasticizers include triethyl citrate, glycerin, sesame oil, sorbitol, castor oil, and polysorbate 80 (polyoxyethylene (20) sorbitan oleate). These can be used individually or in combination of two or more.

[0061] Examples of film-forming agents include alkylcelluloses such as methylcellulose and ethylcellulose; alginic acid or its salts such as sodium alginate; carrageenan; carboxyalkylcelluloses such as sodium carboxymethylcellulose, calcium carboxymethylcellulose, potassium carboxymethylcellulose, carboxymethylcellulose, and carboxymethylethylcellulose; xanthan gum; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hypromellose (hydroxypropylmethylcellulose); hydroxyalkylcellulose phthalates such as hydroxypropylmethylcellulose phthalate; pullulan; polyvinyl acetate; polyvinyl acetate phthalate; and polyvinylpyrrolidone. These can be used individually or in combination of two or more.

[0062] Examples of powders include organic or inorganic powders such as talc, titanium dioxide, yellow iron(III) oxide, iron(III) oxide, and legally approved dyes. These can be used individually or in combination of two or more.

[0063] Examples of poorly water-soluble polymers include carboxyvinyl polymers and aminoalkyl methacrylate copolymers. These can be used individually or in combination of two or more. Examples of antioxidants include ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, and butylhydroxyanisole. These can be used individually or in combination of two or more.

[0064] Examples of flavoring agents include terpenes such as limonene, pinene, camphene, cymene, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rodinol, borneol, isoborneol, menthone, camphor, eugenol, and synzeiranol; essential oils containing terpenes such as spruce oil, orange oil, peppermint oil, camphor oil, eucalyptus oil, turpentine oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender oil, fennel oil, chamomile oil, perilla oil, and spearmint oil; and acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid, and their salts. These can be used individually or in combination of two or more.

[0065] Examples of sweeteners include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and sodium saccharin, and one or more of these can be used in combination.

[0066] Pharmaceutical compositions can be manufactured by known methods depending on their dosage form. For example, if the pharmaceutical composition is a solid dosage form, it can be manufactured by appropriately combining unit operations such as crushing, mixing, granulation, drying, sizing, classification, filling, tableting, and coating. More specifically, for example, in the case of a pharmaceutical composition in the form of granules, powders, pills, or other granular formulations, in addition to components (A) to (B) or components (A) to (C), excipients, binders, disintegrants, lubricants, and other formulation additives may be used as needed. After mixing all or part of these components, granulation is carried out using known granulation methods such as extrusion granulation, rolling granulation, agitation granulation, fluid bed granulation, spray granulation, melt granulation, and crushing granulation to obtain granules. Further classification and sizing may be performed as needed. The obtained granules may also be coated with a coating agent or the like using known methods. Furthermore, when the dosage form of the pharmaceutical composition is tablets, in addition to components (A) to (B) or components (A) to (C), appropriate pharmaceutical additives such as excipients, binders, disintegrants, and lubricants may be used as needed, and all or part of these components are mixed to obtain a mixture, which is then directly compressed (tableted) (direct powder compression method), or the above granules are classified and sized as needed before being compressed (tableted) (semi-dry granule compression method, dry granule compression method, wet granule compression method, etc.). The resulting compressed material (tablets) can also be coated with a coating agent or the like by known methods. Furthermore, if the dosage form of the pharmaceutical composition is a capsule, the above-mentioned granules or compressed material can be filled into the capsule.

[0067] In the present invention, from the viewpoint of suppressing changes in formulation, the pharmaceutical composition may be further contained in an airtight package (hereinafter, in this specification, a pharmaceutical composition contained in an airtight package will be referred to as a "pharmaceutical product"). In the present invention, a pharmaceutical product may also be provided with packaging other than the airtight package described below, and the pharmaceutical composition may be contained directly or indirectly in the airtight package. In this specification, "airtight packaging" means packaging that can prevent the intrusion of solid or liquid foreign matter under normal handling, transportation, or storage conditions, and is a concept that encompasses "airtight containers" and "sealed containers" as defined in the General Rules of the 17th Revised Japanese Pharmacopoeia. Airtight packaging can be either fixed-shaped or irregular-shaped, and specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc. Airtight packaging may also be a combination of multiple types of these, and specific examples of such combinations include packaging a pharmaceutical composition first in PTP packaging and then further packaging it in pillow packaging. As for the airtight packaging, from the viewpoint of suppressing changes in formulation, it is preferable that it be one or more types selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging, and it is particularly preferable that it includes at least PTP packaging (PTP packaging combined with other packaging such as bottle packaging, SP packaging, pillow packaging, and stick packaging as needed).

[0068] The packaging material (material) for the airtight packaging is not particularly limited, and materials used in fields such as pharmaceuticals and food, such as glass, plastics (polyesters such as polyethylene terephthalate and polyethylene naphthalate; polyethylene (including low-density (LDPE), medium-density (MDPE), and high-density (HDPE))), polyolefins such as polypropylene; polycarbonate; polystyrene, etc.), and metals (aluminum, etc.), can be used individually or in combination of two or more as appropriate.

[0069] For example, the packaging materials used for bottle packaging are not particularly limited and include glass, plastic, and metal, and one or more of these can be combined as appropriate. Preferred materials for bottle packaging are glass, polyethylene, and polypropylene, more preferably glass, low-density polyethylene (LDPE), and high-density polyethylene (HDPE), and particularly preferably glass and high-density polyethylene (HDPE). When packaging in bottles, for example, an appropriate quantity of the pharmaceutical composition can be placed in the bottle, and then sealed with a suitable stopper or cap. The size of the bottle should be appropriately selected according to the quantity of pharmaceutical composition to be stored, and the bottle capacity is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and more preferably 24 to 350 mL.

[0070] Furthermore, the packaging materials used in SP packaging, PTP packaging, pillow packaging, stick packaging, etc., are not particularly limited. Examples include biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glycol-modified PET (PET-G), biaxially oriented nylon (ONy, PA), cellophane, paper, low-density polyethylene (LDPE), linear low-density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unoriented polypropylene (CPP, IPP), and ionomer resin (IO). Examples include resins such as ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic polyolefin (COC), unoriented nylon (CNy), polycarbonate (PC), polystyrene (PS), and rigid polyvinyl chloride (VSC), as well as metal foils such as aluminum foil (AL). One or more of these can be appropriately combined.

[0071] When producing SP packaging, PTP packaging, pillow packaging, stick packaging, etc., the packaging can be manufactured using a sheet made of one or more of the above-mentioned packaging materials by a known method, and in this case, the packaging materials can be appropriately combined to form a multilayer structure. One method for creating a multilayer structure using two or more types of packaging materials as a sheet is to produce a laminated sheet by laminating the packaging materials. Laminated sheets can be manufactured by known methods such as extrusion lamination, dry lamination, co-extrusion lamination, thermal lamination, wet lamination, non-solvent lamination, and heat lamination. In addition, commercially available sheets known to be used for SP packaging, PTP packaging, pillow packaging, and stick packaging can also be used.

[0072] In the above-mentioned sheets, single-layer sheets using one type of packaging material include PVC sheets and CPP sheets, and laminated sheets using two or more types of packaging materials include, for example, sheets laminated with PVC and PVDC (PVC / PVDC; hereinafter abbreviated similarly), PVC / PVDC / PE / PVC, PVC / PVDC / PE / PVDC / PVC, CPP / COC / CPP, PVC / PCTFE, CPP / PCTFE, PVC / AL / PA, PVC / AL, CPP / AL, CPP / CPP / CPP (the above sheets use two or more types of CPP), but are not limited to these.

[0073] One form of PTP packaging involves storing one pharmaceutical composition or one dose unit in pockets formed in a resin sheet or the like using a known method, and then sealing the package with a sheet made of metal foil such as aluminum foil as a lid material. Alternatively, a so-called double-sided aluminum PTP packaging may be used, where the sheet forming the pockets is also made of aluminum foil. In this invention, from the viewpoint of suppressing changes in formulation, it is preferable to further package the PTP packaging in pillow packaging (for example, aluminum pillow packaging). Examples of packaging methods such as SP packaging, pillow packaging, and stick packaging include packaging pharmaceutical compositions one unit or one dose unit at a time using sheets made of resin sheets or aluminum foil as constituent materials, as is known. In the present invention, it is preferable to use sheets made of aluminum foil as a constituent material from the viewpoint of suppressing changes in formulation.

[0074] In this specification, the occupancy rate (volume ratio) of the pharmaceutical composition inside the packaging of a pharmaceutical product is typically 25-90%, preferably 28-75%, and more preferably 30-50% when the packaging is a bottle. When the packaging is SP packaging, PTP packaging, pillow packaging, or stick packaging, the occupancy rate is typically 30-98%, preferably 40-95%, more preferably 45-93%, and particularly preferably 50-90%. In this case, the occupancy rate refers to the occupancy rate of the pharmaceutical composition relative to the total volume inside the packaging, and packing materials or stoppers used to prevent damage to the pharmaceutical composition stored inside the packaging are not considered when calculating the space occupancy rate.

[0075] As airtight packaging, commercially available packaging may be used as is, or commercially available packaging materials may be processed and used. Examples of commercially available bottle packaging include glass bottles (manufactured by Isoya Glass Industry Co., Ltd.), tablet bottles (manufactured by Tokyo Glass Co., Ltd.), and the Z-series (manufactured by Hanshin Chemical Industries, Ltd.). Examples of commercially available pillow packaging include Lamizip (registered trademark) (manufactured by Seisan Nipponsha Co., Ltd.). Furthermore, examples of packaging materials for SP packaging, PTP packaging, pillow packaging, and stick packaging include Sumilight VSS, Sumilight VSL, Sumilight NS, Sumilight FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), the TAS series (manufactured by Taisei Chemical Co., Ltd.), PTP vinyl foil, PTP super foil (both manufactured by Mitsubishi Plastics, Inc.), Nippaku aluminum foil (manufactured by Nippon Foil Co., Ltd.), and plain silver aluminum foil (manufactured by Yamato Chemical Industry Co., Ltd.).

[0076] The method for containing the pharmaceutical composition in an airtight package is not particularly limited and can be achieved by placing the pharmaceutical composition inside the package by appropriate means, such as introducing the pharmaceutical composition into the package. In this case, a means of introducing a desiccant (for example, cylindrical (tablet-type) or sheet-type) together with the pharmaceutical composition inside the package may also be used.

[0077] In the present invention, the pharmaceutical composition or drug contains loxoprofen or a salt thereof, which is a type of NSAID, and cinnamon or an extract thereof, which has various pharmacological effects such as antipyretic effects. For example, it has efficacy or effects such as pain relief for headaches, toothaches, post-extraction pain, sore throats, earaches, joint pain, neuralgia, lower back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain, and traumatic pain, as well as fever reduction during chills and fever, and relief of various cold symptoms (sore throat, chills, fever, headache, phlegm, joint pain, muscle pain), and is useful as a combination cold medicine or antipyretic analgesic.

[0078] The route of administration of the pharmaceutical composition is not particularly limited and can be determined as appropriate depending on the disease to be treated, the type of preparation, the gender, age, and symptoms of the user. However, oral administration is preferred from the viewpoint of ease of administration. The pharmaceutical composition can also be taken in 1 to 4 divided doses per day, such as before meals, between meals, after meals, or before bedtime.

[0079] This specification is not limited to these, but discloses, for example, the following embodiments of the invention. [1A] The following components (A), (B), and (C): (A) Loxoprofen or a salt thereof; (B) Cinnamon or its extract; (C) One or more selected from the group consisting of the following components (C-1) to (C-3); (C-1) Tranexamic acid or its salt; (C-2) xanthine derivatives; (C-3) Basic compounds with acid neutralizing ability; A pharmaceutical composition containing the following: [2A] The pharmaceutical composition according to [1A], wherein component (B) is a cinnamon extract. [3A] The pharmaceutical composition according to [2A], wherein the cinnamon extract is extracted using a solvent containing at least water or a linear or branched aliphatic alcohol having 1 to 6 carbon atoms as the extraction solvent. [4A] A pharmaceutical composition according to any one of [1A] to [3A], wherein component (B) is a cinnamon extract obtained by extracting with a solvent selected from the group consisting of water, ethanol, and a water / ethanol mixture. [5A] A pharmaceutical composition according to any one of [1A] to [4A], wherein component (C-2) is one or more selected from the group consisting of caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. [6A] A pharmaceutical composition according to any one of [1A] to [5A], wherein component (C-3) is one or more selected from the group consisting of aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried aluminum hydroxide / magnesium carbonate gel, coprecipitation product of aluminum hydroxide / sodium bicarbonate, coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, and magnesium aluminometasilicate. [7A] A pharmaceutical composition described in any of [1A] to [6A], which is a solid dosage form. [8A] A pharmaceutical composition according to any one of [1A] to [7A], wherein the dosage form is a tablet, capsule, granule, powder, or pill.

[0080] Furthermore, although this specification is not limited thereto, the following embodiments of the invention are also disclosed. [1B] The following components (A) and (B): (A) Loxoprofen or a salt thereof; (B) Cinnamon or its extract; A pharmaceutical product comprising a pharmaceutical composition containing the above, contained in an airtight package. [2B] The pharmaceutical product described in [1B], wherein ingredient (B) is a cinnamon extract. [3B] The pharmaceutical product according to [2B], wherein the cinnamon extract is obtained using a solvent containing at least water or a linear or branched aliphatic alcohol having 1 to 6 carbon atoms as the extraction solvent. [4B] A pharmaceutical product according to any one of [1B] to [3B], wherein component (B) is a cinnamon extract extracted with a solvent selected from the group consisting of water, ethanol, and a water / ethanol mixture. [5B] A pharmaceutical product according to any of [1B] to [4B], wherein the pharmaceutical composition is a solid dosage form. [6B] A pharmaceutical product according to any of [1B] to [5B], wherein the dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder, or pill. [7B] A pharmaceutical product according to any of [1B] to [6B], wherein the airtight packaging is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.

[0081] Furthermore, although this specification is not limited thereto, the following embodiments of the invention are also disclosed. [1C] The following components (A), (B), and (C): (A) Loxoprofen or a salt thereof; (B) Cinnamon or its extract; (C) One or more selected from the group consisting of the following components (C-1) to (C-3); (C-1) Tranexamic acid or its salt; (C-2) xanthine derivatives; (C-3) Basic compounds with acid neutralizing ability; A pharmaceutical product comprising a pharmaceutical composition containing the above, contained in an airtight package. [2C] The pharmaceutical product described in [1C], wherein ingredient (B) is a cinnamon extract. [3C] The pharmaceutical product according to [2C], wherein the cinnamon extract is extracted using a solvent containing at least water or a linear or branched aliphatic alcohol having 1 to 6 carbon atoms as the extraction solvent. [4C] A pharmaceutical product according to any one of [1C] to [3C], wherein component (B) is a cinnamon extract extracted with a solvent selected from the group consisting of water, ethanol, and a water / ethanol mixture. [5C] A pharmaceutical product as described in any of [1C] to [4C], wherein the component (C-2) is one or more selected from the group consisting of caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. [6C] A pharmaceutical product as described in any of [1C] to [5C], wherein component (C-3) is one or more selected from the group consisting of aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried aluminum hydroxide and magnesium carbonate gel, coprecipitation product of aluminum hydroxide and sodium bicarbonate, coprecipitation product of aluminum hydroxide, calcium carbonate and magnesium carbonate, coprecipitation product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, and magnesium aluminometasilicate. [7C] A pharmaceutical product according to any of [1C] to [6C], wherein the pharmaceutical composition is a solid dosage form. [8C] A pharmaceutical product according to any of [1C] to [7C], wherein the dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder, or pill. [9C] A pharmaceutical product according to any one of [1C] to [8C], wherein the airtight packaging comprises at least PTP packaging.

[0082] Furthermore, although this specification is not limited thereto, the following embodiments of the invention are also disclosed. [1D] The following components (A), (B), and (C): (A) Loxoprofen or a salt thereof; (B) Cinnamon or its extract; (C) One or more selected from the group consisting of the following components (C-1) to (C-3); (C-1) Tranexamic acid or its salt; (C-2) xanthine derivatives; (C-3) Basic compounds with acid neutralizing ability; A method for suppressing changes in formulation, comprising the step of incorporating into the same pharmaceutical composition. [2D] The method according to [1D], wherein component (B) is a cinnamon extract. [3D] The method according to [2D], wherein the cinnamon extract is obtained using a solvent containing at least water or a linear or branched aliphatic alcohol having 1 to 6 carbon atoms as the extraction solvent. [4D] The method according to any one of [1D] to [3D], wherein component (B) is a cinnamon extract obtained by extracting with a solvent selected from the group consisting of water, ethanol, and a water / ethanol mixture. [5D] The method described in any of [1D] to [4D], wherein component (C-2) is one or more selected from the group consisting of caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. [6D] The method according to any one of [1D] to [5D], wherein component (C-3) is one or more selected from the group consisting of aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitation product of aluminum hydroxide and sodium bicarbonate, coprecipitation product of aluminum hydroxide, calcium carbonate and magnesium carbonate, coprecipitation product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, and magnesium aluminometasilicate. [7D] The method according to any one of [1D] to [6D], wherein the pharmaceutical composition is a solid dosage form. [8D] The method according to any one of [1D] to [7D], wherein the dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder, or pill.

[0083] Furthermore, although this specification is not limited thereto, the following embodiments of the invention are also disclosed. [1E] The following components (A) and (B): (A) Loxoprofen or a salt thereof; (B) Cinnamon or its extract; A method for suppressing changes in formulation, comprising the steps of incorporating into the same pharmaceutical composition and housing the pharmaceutical composition in an airtight package. [2E] The method according to [1E], wherein component (B) is a cinnamon extract. [3E] The method according to [2E], wherein the cinnamon extract is obtained using a solvent containing at least water or a linear or branched aliphatic alcohol having 1 to 6 carbon atoms as the extraction solvent. [4E] The method according to any one of [1E] to [3E], wherein component (B) is a cinnamon extract obtained by extracting with a solvent selected from the group consisting of water, ethanol, and a water / ethanol mixture. [5E] The method according to any one of [1E] to [4E], wherein the pharmaceutical composition is a solid dosage form. [6E] The method according to any one of [1E] to [5E], wherein the dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder, or pill. [7E] The method according to any one of [1E] to [6E], wherein the airtight packaging is one or more types selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging.

[0084] Furthermore, although this specification is not limited thereto, it also discloses, for example, the following embodiments of the invention. [1F] The following components (A), (B), and (C): (A) Loxoprofen or a salt thereof; (B) Cinnamon or its extract; (C) One or more selected from the group consisting of the following components (C-1) to (C-3); (C-1) Tranexamic acid or its salt; (C-2) xanthine derivatives; (C-3) Basic compounds with acid neutralizing ability; A method for suppressing changes in formulation, comprising the steps of incorporating into the same pharmaceutical composition and housing the pharmaceutical composition in an airtight package. [2F] The method described in [1F], wherein component (B) is a cinnamon extract. [3F] The method according to [2F], wherein the cinnamon extract is obtained using a solvent containing at least water or a linear or branched aliphatic alcohol having 1 to 6 carbon atoms as the extraction solvent. [4F] The method according to any one of [1F] to [3F], wherein component (B) is a cinnamon extract obtained by extracting with a solvent selected from the group consisting of water, ethanol, and a water / ethanol mixture. [5F] The method described in any of [1F] to [4F], wherein component (C-2) is one or more selected from the group consisting of caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. [6F] The method according to any one of [1F] to [5F], wherein component (C-3) is one or more selected from the group consisting of aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried aluminum hydroxide / magnesium carbonate gel, coprecipitation product of aluminum hydroxide / sodium bicarbonate, coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, and magnesium aluminometasilicate. [7F] The method according to any one of [1F] to [6F], wherein the pharmaceutical composition is a solid dosage form. [8F] The method according to any one of [1F] to [7F], wherein the dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder, or pill. [9F] The method according to any one of [1F] to [8F], wherein the airtight packaging comprises at least PTP packaging. [Examples]

[0085] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way thereto.

[0086] [Test Example 1] Stability Test Part 1 Samples 1-4 shown below were prepared and stored in the dark for one day under conditions of 40°C and 75% relative humidity (RH). The state of the mixture in the samples was visually evaluated immediately after the start of storage and after one day to check for any changes in the composition. The results are shown in Table 1.

[0087] [Sample 1] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.) and 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and this was designated as Sample 1. [Sample 2] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.) and 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug). 3 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and sealed, and this was designated as Sample 2. The occupancy rate (volume) of the mixture inside the glass bottle was 25%.

[0088] [Sample 3] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of tranexamic acid (manufactured by Kyowa Pharma Chemical Co., Ltd., trade name: Japanese Pharmacopoeia Tranexamic Acid), and this mixture was designated as Sample 3. [Sample 4] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of tranexamic acid (manufactured by Kyowa Pharma Chemical Co., Ltd., trade name: Japanese Pharmacopoeia Tranexamic Acid). 3 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and sealed, and this was designated as Sample 4. The occupancy rate (volume) of the mixture inside the glass bottle was 25%.

[0089] [Table 1]

[0090] As shown in Table 1, the test results revealed that when loxoprofen sodium hydrate and cinnamon extract were mixed (Sample 1), a change in composition occurred one day after the start of storage, resulting in discoloration and solidification of the mixture. On the other hand, in Sample 2, which was a mixture of loxoprofen sodium hydrate and cinnamon extract and contained in an airtight package (bottle), and in Sample 3, which was a mixture of loxoprofen sodium hydrate, cinnamon extract, and tranexamic acid, it was found that the degree of discoloration was reduced and solidification was suppressed. Furthermore, in Sample 4, which was a mixture of loxoprofen sodium hydrate, cinnamon extract, and tranexamic acid and contained in an airtight package (bottle), it was found that the white powdery state was maintained even after 1 day of storage, just as it was immediately after storage began.

[0091] From the above test results, it became clear that the changes in formulation that occur in a pharmaceutical composition containing loxoprofen or its salt and cinnamon or its extract can be suppressed by means of further containing tranexamic acid or its salt in the pharmaceutical composition, means of housing the pharmaceutical composition in an airtight package, or means of further containing tranexamic acid or its salt in the pharmaceutical composition and then housing it in an airtight package. Furthermore, it became clear that the means of further containing tranexamic acid or its salt in the pharmaceutical composition and then housing it in an airtight package is remarkably superior in suppressing the changes in formulation.

[0092] [Test Example 2] Stability Test Part 2 Samples 5-8 shown below were prepared and stored in the dark for one day under conditions of 40°C and 75% relative humidity (RH). The state of the mixture in the samples was visually evaluated immediately after the start of storage and after one day to check for any changes in the composition. The results are shown in Table 2.

[0093] [Sample 5] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.) and 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and this was designated as Sample 5. [Sample 6] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.) and 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug). 3 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and sealed, and this was designated as Sample 6. The occupancy rate (volume) of the mixture inside the glass bottle was 25%.

[0094] [Sample 7] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of anhydrous caffeine (manufactured by Shizuoka Caffeine Industry Co., Ltd.), and this was designated as Sample 7. [Sample 8] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of anhydrous caffeine (manufactured by Shizuoka Caffeine Industry Co., Ltd.). 3 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and sealed, and this was designated as Sample 8. The occupancy rate (volume) of the mixture inside the glass bottle was 30%.

[0095] [Table 2]

[0096] As shown in the test results in Table 2, when loxoprofen sodium hydrate and cinnamon extract were mixed (Sample 5), a change in composition occurred one day after the start of storage, resulting in discoloration and solidification of the mixture. On the other hand, in sample 6, which was a mixture of loxoprofen sodium hydrate and cinnamon extract and contained in an airtight package (bottle), and in sample 7, which was a mixture of loxoprofen sodium hydrate, cinnamon extract, and anhydrous caffeine, it was found that the degree of discoloration was reduced and solidification was suppressed. Furthermore, in sample 8, which was a mixture of loxoprofen sodium hydrate, cinnamon extract, and anhydrous caffeine and contained in an airtight package (bottle), it was found that the white powdery state was maintained even after 1 day of storage, just as it was immediately after storage began.

[0097] From the above test results, it became clear that the changes in formulation that occur in a pharmaceutical composition containing loxoprofen or a salt thereof and cinnamon or an extract thereof can be suppressed by further including a xanthine derivative in the pharmaceutical composition, by housing the pharmaceutical composition in an airtight package, or by further including a xanthine derivative in the pharmaceutical composition and then housing it in an airtight package. Furthermore, it became clear that the method of further including a xanthine derivative in the pharmaceutical composition and then housing it in an airtight package is remarkably superior in suppressing the changes in formulation.

[0098] [Test Example 3] Stability Test Part 3 Samples 9-16 shown below were prepared and stored in the dark for one day under conditions of 40°C and 75% relative humidity (RH). The state of the mixture in the samples was visually evaluated immediately after the start of storage and after one day to check for any changes in the composition. The results are shown in Table 3.

[0099] [Sample 9] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.) and 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and this was designated as Sample 9. [Sample 10] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.) and 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug). 3 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and sealed, and this was designated as Sample 10. The occupancy rate (volume) of the mixture inside the glass bottle was 30%.

[0100] [Sample 11] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of magnesium carbonate (manufactured by Kyowa Chemical Industry Co., Ltd.), and this mixture was designated as Sample 11. [Sample 12] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of magnesium oxide (manufactured by Tomita Pharmaceutical Co., Ltd.), and this mixture was designated as Sample 12. [Sample 13] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of magnesium aluminometasilicate (manufactured by Fuji Chemical Industry Co., Ltd.) to obtain a mixture, which was designated as Sample 13.

[0101] [Sample 14] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of magnesium carbonate (manufactured by Kyowa Chemical Industry Co., Ltd.). 3 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and sealed, and this was designated as Sample 14. The occupancy rate (volume) of the mixture inside the glass bottle was 30%. [Sample 15] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of magnesium oxide (manufactured by Tomita Pharmaceutical Co., Ltd.). 3 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and sealed, and this was designated as Sample 15. The occupancy rate (volume) of the mixture inside the glass bottle was 30%. [Sample 16] A mixture was obtained by mixing 10 parts by mass of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd.), 1 part by mass of cinnamon extract (manufactured by Alps Pharmaceutical Co., Ltd.) (equivalent to 22 parts by mass of crude drug), and 20 parts by mass of magnesium aluminometasilicate (manufactured by Fuji Chemical Industry Co., Ltd.) neushilin. 3 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and sealed, and this was designated as Sample 16. The occupancy rate (volume) of the mixture inside the glass bottle was 30%.

[0102] [Table 3]

[0103] As shown in Table 3, the test results revealed that when loxoprofen sodium hydrate and cinnamon extract were mixed (Sample 9), a change in composition occurred one day after the start of storage, resulting in discoloration and solidification of the mixture. On the other hand, in sample 10, which was a mixture of loxoprofen sodium hydrate and cinnamon extract and contained in an airtight package (bottle), it was found that the degree of discoloration was reduced and solidification was suppressed. Furthermore, in various samples in which loxoprofen sodium hydrate, cinnamon extract, and additional basic compounds with acid-neutralizing ability (sample 11: magnesium carbonate, sample 12: magnesium oxide, sample 13: magnesium aluminometasilicate), and in various samples in which loxoprofen sodium hydrate, cinnamon extract, and additional basic compounds with acid-neutralizing ability (sample 14: magnesium carbonate, sample 15: magnesium oxide, sample 16: magnesium aluminometasilicate) were mixed and contained in an airtight package (bottle), it was found that the white powdery state was maintained even after 1 day of storage, just as it was immediately after storage began.

[0104] From the above test results, it became clear that the changes in formulation that occur in a pharmaceutical composition containing loxoprofen or a salt thereof and cinnamon or an extract thereof can be suppressed by means of further including a basic compound with acid-neutralizing ability in the pharmaceutical composition, means of housing the pharmaceutical composition in an airtight package, or means of including a basic compound with acid-neutralizing ability in the pharmaceutical composition and then housing it in an airtight package. Furthermore, it became clear that the means of further including a basic compound with acid-neutralizing ability in the pharmaceutical composition and the means of housing it in an airtight package are remarkably superior in suppressing the changes in formulation. [Industrial applicability]

[0105] According to the present invention, a pharmaceutical composition containing both loxoprofen and cinnamon, which have excellent pharmacological effects, and which also has excellent storage stability, can be provided, and can therefore be used, for example, in the pharmaceutical industry.

Claims

1. The following components (A), (B), and (C): (A) Loxoprofen or a salt thereof; (B) Water and / or ethanol extract of cinnamon; (C) One or more selected from the group consisting of the following components (C-1) to (C-3); (C-1) Tranexamic acid or its salt; (C-2) One or more xanthine derivatives selected from the group consisting of caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate; (C-3) One or more basic compounds having acid neutralizing ability selected from the group consisting of (C-3) aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried aluminum hydroxide / magnesium carbonate gel, coprecipitation product of aluminum hydroxide / sodium bicarbonate, coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, and magnesium aluminometasilicate; A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, which is a solid dosage form.

3. The pharmaceutical composition according to claim 1 or 2, wherein the dosage form is a tablet, capsule, granule, powder, or pill.

4. A pharmaceutical product comprising a pharmaceutical composition according to any one of claims 1 to 3, contained in an airtight package.

5. The pharmaceutical product according to claim 4, wherein the airtight packaging is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.

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