Pharmaceutical preparations containing loxoprofen (5)

Abstract

The present invention provides a means for suppressing discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during high-temperature storage. The present invention relates to a composition comprising the following components (A) and (B): (A) loxoprofen or a salt thereof; (B) The following component (B-1); (B-1) A menthol content of 1 to 8% by mass based on the total mass of the composition A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container.

Description

[Technical Field]

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

[0002] Loxoprofen is a type of phenylpropionic acid-based nonsteroidal anti-inflammatory drug (NSAID) (Non-Patent Document 1), and exhibits excellent anti-inflammatory and analgesic effects. For this reason, it is widely used as an active ingredient in topical anti-inflammatory and analgesic agents, and topical patches (cataplasms, tapes, etc.) and topical liniments (gels, etc.) have been developed and marketed to date, with the efficacy of anti-inflammation and analgesia for diseases and symptoms such as osteoarthritis, muscle pain, and swelling and pain after trauma (Non-Patent Document 2).

[0003] Incidentally, terpenes such as menthol are blended in topical anti-inflammatory analgesics and the like for the purpose of providing a cooling sensation, and topical preparations in which they are blended together with loxoprofen are already known (for example, Patent Documents 1 to 5). Furthermore, plants of the Asteraceae family, such as Arnica, and extracts thereof are said to have anti-inflammatory effects, and topical preparations containing them in combination with loxoprofen are already known (for example, Patent Document 6). Furthermore, polyhydric alcohols such as 1,3-butylene glycol are incorporated into topical anti-inflammatory analgesics and the like, and topical preparations containing loxoprofen are already known (for example, Patent Documents 5 and 7). Furthermore, celluloses such as hydroxypropylmethylcellulose are incorporated into topical anti-inflammatory analgesics and the like, and topical preparations containing loxoprofen are already known (for example, Patent Documents 4 and 8). Furthermore, licorice and glycyrrhetinic acids such as glycyrrhetinic acid are incorporated into topical anti-inflammatory analgesics and the like, and topical preparations containing them together with loxoprofen are already known (for example, Patent Document 8). In addition, antihistamines such as chlorpheniramine maleate and diphenhydramine hydrochloride are incorporated into topical anti-inflammatory analgesics and the like, and topical preparations containing loxoprofen are already known (for example, Patent Documents 5 and 7). In addition, chili peppers, chili peppers such as nonanoic acid vanillylamide (nonylic acid vanillylamide), or their extracts are incorporated into topical anti-inflammatory and analgesic agents, and topical preparations incorporating them together with loxoprofen are already known (e.g., Patent Documents 7 and 8). Furthermore, organic amines such as diisopropanolamine are incorporated into topical anti-inflammatory analgesics and the like, and topical preparations containing loxoprofen are already known (for example, Patent Document 9). [Prior art documents] [Patent documents]

[0004] [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 [Patent Document 4] International Publication No. 2013 / 191293 Brochure [Patent Document 5] Japanese Patent Application Laid-Open No. 2014-185132 [Patent Document 6] Japanese Patent Application Laid-Open No. 2015-110557 [Patent Document 7] Japanese Patent Application Laid-Open No. 2015-98469 [Patent Document 8] International Publication No. 2014 / 002599 Brochure [Patent Document 9] International Publication No. 2010 / 103844 Brochure [Non-patent literature]

[0005] [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]

[0006] When using loxoprofen as an active ingredient in topical preparations, it is preferable to apply it to the affected area as a liquid or semi-solid composition, such as a topical application agent such as a lotion, gel, or cream, from the viewpoint of flexibly administering only the required amount depending on the location, shape, and area of ​​the affected area. Furthermore, if a technology for stably incorporating loxoprofen into a liquid or semi-solid composition can be established, it will be possible to apply it not only to topical preparations but also to oral medications (oral liquids, etc.). Therefore, in order to establish a technology for stably incorporating rofecoxib into liquid or semi-solid compositions, the present inventors prepared liquid or semi-solid compositions containing rofecoxib or a salt thereof and evaluated their storage stability. Surprisingly, they found that discoloration may occur over time when stored under high temperature conditions.

[0007] Therefore, an object of the present invention is to provide a means for suppressing discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during storage at high temperatures. [Means for solving the problem]

[0008] Therefore, the present inventors have conducted further studies to solve this problem and have found that a liquid or semi-solid composition containing loxoprofen or a salt thereof further contains any one of the following ingredients 1 to 9: (Component 1) Terpenes such as menthol, camphor, and thymol (Ingredient 2) Plants of the genus Arnica, such as arnica tincture, or their extracts (Component 3) Polyhydric alcohols such as 1,3-butylene glycol (Component 4) Celluloses such as hypromellose (Component 5) Tocopherols, such as dl-α-tocopherol acetate (Ingredient 6) Glycyrrhetinic acid, represented by glycyrrhetinic acid (Component 7) A compound represented by the following general formula (1), such as chlorpheniramine or a salt thereof, or diphenhydramine 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.]

[0011] or a salt thereof (Ingredient 8) Capsicum annuum extract, capsicum annuum extract, or its extract, represented by nonanoic acid vanillylamide (Component 9) Organic amines, such as triethanolamine The present inventors have found that discoloration during high-temperature storage can be suppressed by incorporating the above-mentioned compound and storing the compound in a container made of a polyolefin resin, typically polyethylene or polypropylene, and have completed the present invention.

[0012] That is, the present invention provides a composition comprising the following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Any of the following components (B-1) to (B-9); (B-1) Terpenes (B-2) A plant of the genus Lacertilia or its extract (B-3) Polyhydric alcohol (B-4) Cellulose (B-5) Tocopherols (B-6) Glycyrrhetinic acid (B-7) The following general formula (1)

[0013] [ka]

[0014] [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 (B-8) Capsicum or its extract (B-9) Organic amines The present invention provides a pharmaceutical preparation in which a liquid or semi-solid composition containing the above is contained in a polyolefin resin container. The present invention also provides a composition comprising the following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Any of the following components (B-1) to (B-9); (B-1) Terpenes (B-2) A plant of the genus Lacertilia or its extract (B-3) Polyhydric alcohol (B-4) Cellulose (B-5) Tocopherols (B-6) Glycyrrhetinic acid (B-7) A compound represented by the above general formula (1) or a salt thereof (B-8) Capsicum or its extract (B-9) Organic amines The present invention provides a method for suppressing discoloration of a composition, the method comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [Effects of the Invention]

[0015] According to the present invention, discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during high-temperature storage can be suppressed, and therefore a medicine containing loxoprofen or a salt thereof with excellent storage stability can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0016] First, the invention in the form of a "pharmaceutical preparation" will be explained below. <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).

[0017] In the present invention, the content of loxoprofen or a salt thereof in the liquid or semi-solid composition 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 composition.

[0018] <Component (B-1)> In the present invention, "terpenes" is a general term (terpenoid) that includes terpene hydrocarbons as well as terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc., and the structure is not particularly limited, and examples include monoterpenes, sesquiterpenes, and derivatives thereof. In addition, the terpenes may be cyclic or chain-like. 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, silvestrene, thymol, isothujol, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampheol, pinol, piperitenone, phellandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, limonene, and the like. These may be used alone or in combination of two or more. In addition, when optical isomers exist in these terpenes, all isomers are included unless otherwise specified. In other words, in the present invention, unless a specific optical isomer is specified as the component name of a terpene, the component name includes all of the various optical isomers alone and mixtures of these in any ratio, and may be a single optical isomer or a mixture of various optical isomers in any ratio (for example, the term "menthol" includes both dl-menthol and d-menthol).

[0019] Among the above-mentioned terpenes, from the viewpoint of the discoloration inhibiting effect, cyclic terpenoids are preferred, cyclic monoterpenoids are more preferred, and monocyclic or bicyclic monoterpenoids are even more preferred, and examples thereof include monoterpenoids having a p-menthane skeleton (for example, unsaturated derivatives of p-menthane such as cymene, thymol, terpinene, terpinolene, phellandrene, and limonene; monoterpene alcohols having a p-menthane skeleton such as carveol, terpineol, and menthol; monoterpene ketones having a p-menthane skeleton such as carvone and menthone; monoterpene aldehydes having a p-menthane skeleton such as perillaldehyde; and monoterpene ethers having a p-menthane skeleton such as cineole) or monoterpenoids having a bornane skeleton (for example, Monoterpene alcohols having a bornane skeleton such as borneol; monoterpene ketones having a bornane skeleton such as camphor, etc. are even more preferred, one or more selected from the group consisting of cineole, thymol, terpineol, menthol, limonene, camphor and borneol are even more preferred, one or more selected from the group consisting of cineole, camphor, thymol, borneol and menthol are even more preferred, one or more selected from the group consisting of cineole, d-camphor, dl-camphor, thymol, d-borneol, l-menthol and dl-menthol are even more preferred, and one or more selected from the group consisting of cineole, d-camphor, dl-camphor, thymol, l-menthol and dl-menthol are particularly preferred.

[0020] When terpenes are contained in a liquid or semi-solid composition, the terpenes may be used as they are, or essential oils containing 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, hosho 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 and eucalyptus oil being particularly preferred.

[0021] In the present invention, the content of terpenes in the liquid or semi-solid composition is not particularly limited and may be determined by appropriate consideration. However, from the viewpoint of the discoloration suppression effect, 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 8% by mass, of the total mass of the composition. Among these, when camphor is used as the terpene, from the viewpoint of the discoloration suppression effect, the camphor content is preferably 0.4 to 15% by mass, more preferably 1 to 10% by mass, and particularly preferably 3 to 7% by mass, relative to the total mass of the composition. Furthermore, when thymol is used as the terpene, from the viewpoint of the discoloration suppression effect, the thymol content is preferably 0.2 to 3% by mass, more preferably 0.4 to 2% by mass, and particularly preferably 0.6 to 1% by mass, relative to the total mass of the composition. Furthermore, when menthol is used as the terpene, from the viewpoint of the discoloration suppression effect, the menthol content is preferably 0.3 to 10% by mass, more preferably 1 to 8% by mass, and particularly preferably 3 to 6% by mass, relative to the total mass of the composition.

[0022] Furthermore, in the present invention, the content ratio of rofecoxib or its salt to terpenes contained in the liquid or semi-solid composition is not particularly limited and may be determined by appropriate consideration. However, from the viewpoint of the discoloration suppression effect, it is preferable to contain 0.01 to 15 parts by mass of terpenes per 1 part by mass of rofecoxib or its salt, calculated as anhydrous rofecoxib sodium, more preferably 0.1 to 10 parts by mass, and particularly preferably 0.5 to 7 parts by mass. Among these, when camphor is used as the terpene, from the viewpoint of the discoloration suppression effect, the content of camphor is preferably 0.2 to 13 parts by mass, more preferably 0.3 to 8 parts by mass, and particularly preferably 0.4 to 7 parts by mass, per part by mass of loxoprofen or a salt thereof, calculated as loxoprofen sodium anhydrous. When thymol is used as the terpene, from the viewpoint of the discoloration suppression effect, the content of thymol is preferably 0.1 to 2 parts by mass, more preferably 0.3 to 1 part by mass, and particularly preferably 0.4 to 0.8 parts by mass, per part by mass of loxoprofen or a salt thereof, calculated as loxoprofen sodium anhydrous. Furthermore, when menthol is used as the terpene, from the viewpoint of the discoloration suppression effect, the content of menthol is preferably 0.2 to 11 parts by mass, more preferably 1 to 7 parts by mass, and particularly preferably 2 to 5 parts by mass, per part by mass of loxoprofen or a salt thereof, calculated as loxoprofen sodium anhydrous.

[0023] <Component (B-2)> In the present invention, "plants of the genus Arnica" refers to plants belonging to the genus Arnica (Arnica genus) of the Asteraceae family. The specific species is not particularly limited as long as it belongs to the genus, and examples thereof include plants with the following scientific names: Arnica montana, Arnica chamissonis, Arnica fulgens, Arnica cordifolia, Arnica latifolia, Arnica longifolia, and Arnica sachalinensis. In the present invention, a single species of Arnica may be used, or multiple different species of Arnica may be used in combination. In the present invention, Arnica montana is preferred from the viewpoint of its anti-discoloration effect. Furthermore, in the present invention, the parts of the Arnica plant used are not particularly limited, and the whole plant or parts (flowers, inflorescences, spikes, buds, leaves, branches, roots, etc.) or a combination of two or more thereof may be used.

[0024] The form of the Lagarcia plant can be adjusted as needed, and it can be cut or crushed into small pieces or chunks, or crushed into powder. Furthermore, for ease of handling during the manufacture of compositions and pharmaceutical preparations, Lagarcia plants that have been subjected to some kind of extraction treatment (referred to as "extracts of Lagarcia plants" in this specification) may also be used. The term "extract of a plant of the genus Lagarcia" also encompasses those that have been subjected to processing such as heating, drying, pulverization, etc. in addition to extraction. Specifically, the "extract of a plant of the genus Lagarcia" of the present invention includes a liquid obtained by cutting a plant of the genus Lagarcia into an appropriate size as needed and then adding an appropriate infusion (extraction solvent), a liquid obtained by concentrating the infusion (soft extract, tincture, etc.), and further a liquid obtained by drying these (dried extract, etc.).

[0025] The method for producing an extract of a plant of the genus Lagerstroemia is not particularly limited, and it can be produced by referring to known methods for producing plant extracts, such as those described in the "Extracts," "Infusions / Decoctions," "Tinctures," and "Liquid Extracts" sections of the General Provisions for Preparations in the Sixteenth Edition of the Japanese Pharmacopoeia. Specifically, for example, the extract can be produced by cutting, heating, drying, or pulverizing a plant of the genus Lagerstroemia as needed, and then adding an appropriate extraction solvent to carry out extraction. The resulting extract may be further concentrated, dried, or the like, as needed.

[0026] Examples of the extraction solvent include lower monohydric alcohols such as methanol, ethanol, isopropanol, and n-butanol; 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; dimethylformamide; dimethyl sulfoxide; and water (including hot water). These may be used alone or in combination. In the present invention, water, ethanol, propylene glycol, 1,3-butylene glycol, or a mixture of two or more of these is preferred. The extraction procedure is not particularly limited, and any known method used for extraction from plants can be appropriately adopted, specifically, for example, immersion in an extraction solvent (cold immersion, hot immersion, percolation, etc.), extraction using a supercritical fluid or subcritical fluid, etc. In order 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 is preferably from about 5°C to a temperature 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 is preferably about 1 hour to 14 days.

[0027] In the present invention, the "plant of the genus Lacertilia or an extract thereof" is preferably arnica (Arnica montana) or an extract thereof. Examples of the extract of arnica include arnica tincture and arnica extract. As the plant of the genus Lacertilia or an extract thereof, one or more arnica extracts selected from arnica tincture and arnica extract (soft extract, dry extract) are more preferred, arnica tincture and arnica extract listed in the 2006 Standards for Quasi-drug Ingredients are even more preferred, and arnica tincture is particularly preferred.

[0028] In the present invention, commercially available products can be used as plants of the genus Lacertilia or extracts thereof, and specific commercially available products include, for example, Arnica Tincture (Alps Pharmaceutical Co., Ltd.), Arnica Extract (Maruzen Pharmaceutical Co., Ltd.), Falcorex Arnica (Ichimaru Pharcos Co., Ltd.), Arnica Extract, Arnica Tincture (all Nippon Powder Pharmaceutical Co., Ltd.), etc.

[0029] In the present invention, the content of a plant of the genus Lagerstroemia or an extract thereof in a liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration inhibitory effect, the plant of the genus Lagerstroemia or an extract thereof is preferably contained in an amount of 0.00001 to 5% by mass, more preferably 0.00005 to 2% by mass, and particularly preferably 0.0007 to 0.7% by mass, based on the total mass of the composition, in terms of the amount of the plant of the genus Lagerstroemia, in terms of the amount of the plant of the genus Lagerstroemia, in terms of the amount of the plant of the genus Lagerstroemia, in terms of the amount of the plant of the genus Lagerstroemia, in terms of the amount of the plant of the genus Lagerstroemia, is preferably contained in an amount of 0.0001 to 3% by mass, more preferably 0.0005 to 1% by mass, and particularly preferably 0.001 to 0.5% by mass, based on the total mass of the composition, in terms of the amount of the plant of the genus Lagerstroemia ... is preferably contained in an amount of 0.0001 to 3% by mass, more preferably 0.0005 to 1% by mass, and particularly preferably 0.001 to 0.5% by mass. Furthermore, in the present invention, the content ratio of rofecoxib or a salt thereof to a plant of the genus Lagocera or an extract thereof in a liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration inhibitory effect. However, from the viewpoint of the discoloration inhibitory effect, it is preferable that the content of a plant of the genus Lagocera or an extract thereof is 0.00001 to 5 parts by mass, more preferably 0.00005 to 2 parts by mass, and particularly preferably 0.0007 to 0.7 parts by mass, in terms of the amount of herbal medicine per part by mass of rofecoxib or a salt thereof in terms of anhydrous rofecoxib. In particular, when arnica is used as the plant of the genus Lagenaria, from the viewpoint of the discoloration inhibitory effect, it is preferable to contain 0.0001 to 3 parts by mass of arnica or its extract in terms of the amount of crude drug per 1 part by mass of rofecoxib or its salt in terms of rofecoxib anhydrous, more preferably 0.0005 to 1 part by mass, and particularly preferably 0.001 to 0.5 parts by mass.

[0030] <Component (B-3)> 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 thereof include lower polyhydric alcohols (more specifically, lower polyhydric alcohols having 1 to 6 carbon atoms) such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, glycerin, diglycerin, 3-methyl-1,3-butanediol, butylene glycol, erythritol, xylitol, sorbitol, mannitol, and hexanetriol; and higher polyhydric alcohols (more specifically, higher polyhydric alcohols having 7 or more carbon atoms) such as polyvinyl alcohol, polyethylene glycol, polyglycerin, and polypropylene glycol. These may be used alone or in combination of two or more. In the present invention, from the viewpoint of the discoloration suppression effect, the polyhydric alcohol is preferably one or more polyhydric alcohols selected from the group consisting of ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, glycerin, 1,3-butylene glycol, erythritol, xylitol, sorbitol, mannitol, 1,2,6-hexanetriol, polyvinyl alcohol, polyethylene glycol, and polypropylene glycol, more preferably one or more polyhydric alcohols selected from the group consisting of 1,3-butylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, and polyethylene glycol 20000, and 1,3-butylene glycol is particularly preferred.

[0031] In the present invention, the content of polyhydric alcohol in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration suppression effect, the polyhydric alcohol is preferably contained in an amount of 0.1 to 70 mass %, more preferably 0.5 to 50 mass %, and particularly preferably 1 to 30 mass %, relative to the total mass of the composition.

[0032] In the present invention, the content ratio of rofecoxib or a salt thereof to a polyhydric alcohol in a liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration inhibitory effect. However, from the viewpoint of the discoloration inhibitory effect, it is preferable that the polyhydric alcohol is contained in an amount of 1 to 60 parts by mass, more preferably 3 to 40 parts by mass, and particularly preferably 5 to 20 parts by mass, of rofecoxib or a salt thereof, calculated as anhydrous rofecoxib.

[0033] <Component (B-4)> In the present invention, the term "celluloses" refers to cellulose or a salt thereof itself, as well as derivatives or salts thereof in which all or some of the hydroxy groups of cellulose form ether bonds (hereinafter referred to as "cellulose ether derivatives or salts thereof." Note that the cellulose ether derivatives or salts thereof may be further modified, as necessary, by esterification, crosslinking, or the like, in addition to the ether bonds.) The salts are not particularly limited, and specific examples include alkali metal salts such as sodium salts and potassium salts; and alkaline earth metal salts such as calcium salts and magnesium salts.

[0034] Among the celluloses, specific examples of cellulose or salts thereof include crystalline cellulose and powdered cellulose. Specific examples of cellulose ether derivatives or salts thereof include alkyl celluloses or salts thereof, such as methyl cellulose and ethyl cellulose; hydroxyalkyl celluloses or salts thereof, such as hydroxyethyl cellulose and hydroxypropyl cellulose; alkyl (hydroxyalkyl) celluloses or salts thereof, such as hydroxyethyl methyl cellulose and hypromellose; alkyl (hydroxyalkyl) cellulose derivatives or salts thereof, such as hypromellose acetate succinate and hypromellose phthalate; carboxyalkyl celluloses or salts thereof, such as carboxymethyl cellulose, carmellose potassium, carmellose calcium, and carmellose sodium; and carboxyalkyl cellulose derivatives or salts thereof, such as croscarmellose sodium. The alkyl group in the cellulose ether derivative is not particularly limited, but a linear or branched alkyl group having 1 to 6 carbon atoms is preferred. The etherification rate (substitution rate of substituents forming ether bonds, such as alkyl groups and hydroxyalkyl groups, in %) in the cellulose ether derivative is not particularly limited, but is preferably 10 to 90%, particularly preferably 20 to 80%, from the viewpoint of solubility in solvents. The etherification rate (%) is measured for each cellulose ether derivative by the method described in the 16th edition of the Japanese Pharmacopoeia or a method conforming thereto. These celluloses are all known compounds and can be produced by known methods, or commercially available products may be used.

[0035] In the present invention, from the viewpoint of discoloration inhibition effect, the cellulose is preferably a cellulose ether derivative or a salt thereof, more preferably one or more selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose, and salts thereof, even more preferably one or more selected from the group consisting of C1-C6 alkyl cellulose, hydroxy C1-C6 alkyl cellulose, C1-C6 alkyl (hydroxy C1-C6 alkyl) cellulose, carboxy C1-C6 alkyl cellulose, and salts thereof, even more preferably one or more selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, and salts thereof, and even more preferably hypromellose, with hypromellose having a degree of substitution of 2910 as specified in the 16th Edition of the Japanese Pharmacopoeia being particularly preferred.

[0036] In the present invention, the content of cellulose in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration suppression effect, it is preferably contained in an amount of 0.01 to 5 mass % relative to the total mass of the composition, more preferably 0.05 to 3 mass %, and particularly preferably 0.1 to 2 mass %.

[0037] In the present invention, the content ratio of loxoprofen or a salt thereof to cellulose in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration inhibitory effect. However, from the viewpoint of the discoloration inhibitory effect, it is preferable to contain 0.02 to 4 parts by mass of cellulose per 1 part by mass of loxoprofen or a salt thereof, calculated as anhydrous loxoprofen, more preferably 0.2 to 1.5 parts by mass, and particularly preferably 0.3 to 1 part by mass.

[0038] <Component (B-5)> In the present invention, "tocopherols" refers to one or more compounds selected from tocopherol, tocotrienol, and derivatives thereof (e.g., esterified derivatives such as acetate, succinate, and nicotinate), and salts thereof (e.g., alkaline earth metal salts such as calcium and magnesium salts). The tocopherol may be any of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, with α-tocopherol being preferred. The tocotrienol may be any of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, with α-tocotrienol being preferred. In the present invention, from the viewpoint of discoloration-inhibiting activity, one or more compounds selected from the group consisting of α-tocopherol, its acetate, its succinate, and its nicotinate, and salts thereof, are preferred. Tocopherols and tocotrienols may have optical isomers, and unless otherwise specified, all isomers are included in the present invention. In other words, unless a specific optical isomer is specified as the component name of a tocopherol in the present invention, the component name encompasses all of the various optical isomers alone and mixtures of these optical isomers in any ratio, and may be a single optical isomer or a mixture of various optical isomers in any ratio (for example, the term "acetate ester of α-tocopherol" encompasses both acetate ester of dl-α-tocopherol and acetate ester of d-α-tocopherol). Furthermore, tocopherols that can be suitably used in the present invention include "tocopherol," "tocopherol succinate calcium," "tocopherol acetate," "tocopherol nicotinate," and the like, which are listed in the 16th edition of the Japanese Pharmacopoeia.

[0039] In the present invention, from the viewpoint of the discoloration-inhibiting effect, the tocopherols are preferably one or more selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof, more preferably one or more selected from the group consisting of tocopherol, tocopherol succinate calcium, tocopherol acetate, and tocopherol nicotinate, even more preferably one or more selected from the group consisting of dl-α-tocopherol, dl-α-tocopherol succinate calcium, dl-α-tocopherol acetate, and dl-α-tocopherol nicotinate, and particularly preferably dl-α-tocopherol acetate.

[0040] In the present invention, the content of tocopherols in the liquid or semi-solid composition is not particularly limited. From the viewpoint of the discoloration suppression effect, the tocopherol content is preferably 0.01 to 8 mass %, more preferably 0.05 to 4 mass %, and particularly preferably 0.1 to 2 mass %, relative to the total mass of the composition.

[0041] In the present invention, the content ratio of loxoprofen or a salt thereof to tocopherols in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration inhibitory effect. However, from the viewpoint of the discoloration inhibitory effect, the tocopherols are preferably contained in an amount of 0.01 to 5 parts by mass, more preferably 0.05 to 3 parts by mass, and particularly preferably 0.1 to 1 part by mass, of loxoprofen or a salt thereof, calculated as anhydrous loxoprofen.

[0042] <Component (B-6)> In the present invention, "glycyrrhetinic acids" means one or more selected from glycyrrhetinic acid and its derivatives (e.g., sugar-added derivatives of glycyrrhetinic acid such as glycyrrhizinic acid) and salts thereof (e.g., alkali metal salts such as potassium salts and sodium salts; ammonium salts, etc.). In the present invention, from the viewpoint of the discoloration inhibiting effect, the glycyrrhetinic acid is preferably one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, and salts thereof, more preferably one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate, and trisodium glycyrrhizinate, still more preferably one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, and dipotassium glycyrrhizinate, and particularly preferably glycyrrhetinic acid.

[0043] When glycyrrhetinic acids are incorporated into a liquid or semi-solid composition, glycyrrhetinic acids may be used as they are, or licorice (liquorice) or an extract thereof containing glycyrrhetinic acids may be used. Here, "licorice" (liquorice) refers to the roots and stolons of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linne (Leguminosae), and also encompasses the roots and stolons from which the periderm has been removed (peeled licorice) (Japanese Pharmacopoeia, 16th Edition). The form of licorice can be adjusted as needed, for example, by cutting or crushing into small pieces or chunks, or by grinding into powder. For example, "licorice powder," which is licorice powder, can also be used. Furthermore, for ease of handling during the manufacture of pharmaceutical compositions, "licorice extracts" obtained by subjecting licorice to some extraction treatment may also be used. Here, the "licorice extract" also encompasses those that have been subjected to processing such as heating, drying, or crushing in addition to extraction. Specifically, "licorice extract" includes the liquid obtained by cutting licorice to an appropriate size as needed, adding an appropriate infusion (extraction solvent), and infusing the infusion, as well as concentrated liquids (soft extracts, tinctures, etc.) from the infusion, and further drying these (dried extracts, etc.). In the present invention, the licorice or extract thereof is preferably the licorice, licorice powder, licorice extract, or crude licorice extract described in the 16th Edition of the Japanese Pharmacopoeia.

[0044] The method for producing a licorice extract is not particularly limited, and the extract can be produced by referring to known methods for producing plant extracts, such as those described in the "Extracts," "Infusions / Decoctions," "Tinctures," and "Liquid Extracts" sections of the General Provisions for Preparations in the Sixteenth Edition of the Japanese Pharmacopoeia. Specifically, the extract can be produced by, for example, cutting, heating, drying, or pulverizing licorice as needed, and then adding an appropriate extraction solvent to carry out extraction. The resulting extract may be further concentrated, dried, or the like, as needed.

[0045] Examples of the extraction solvent include lower monohydric alcohols such as methanol, ethanol, isopropanol, and n-butanol; 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; dimethylformamide; dimethyl sulfoxide; and water (including hot water). These may be used alone or in combination. In the present invention, water, ethanol, or a water / ethanol mixture is preferred. The extraction procedure is not particularly limited, and any known method used for plant extraction can be employed, including, for example, immersion in an extraction solvent (cold immersion, hot immersion, percolation, etc.), extraction using a supercritical fluid or subcritical fluid, etc. 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 is preferably from about 5°C to a temperature 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 is preferably about 1 hour to 14 days.

[0046] In the present invention, the content of glycyrrhetinic acids in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration suppression effect, the content of glycyrrhetinic acids is preferably 0.01 to 1 mass %, more preferably 0.03 to 0.5 mass %, and particularly preferably 0.05 to 0.3 mass %, calculated as the free form, relative to the total mass of the composition.

[0047] In the present invention, the content ratio of loxoprofen or a salt thereof to glycyrrhetinic acids in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration inhibitory effect. However, from the viewpoint of the discoloration inhibitory effect, the content of glycyrrhetinic acids is preferably 0.02 to 0.8 parts by mass, more preferably 0.03 to 0.4 parts by mass, and particularly preferably 0.04 to 0.25 parts by mass, calculated as free form, per part by mass of loxoprofen or a salt thereof calculated as anhydrous loxoprofen.

[0048] <Component (B-7)> In the present invention, "general formula (1)

[0049] [ka]

[0050] [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.]

[0051] The term "compound represented by general formula (1) or a salt thereof" includes not only the compound represented by general formula (1) itself but also pharmaceutically acceptable salts of the compound represented by general formula (1). Specific examples of the compound represented by general formula (1) or a salt thereof include the compound represented by general formula (1), inorganic acid salts or organic acid salts of the compound represented by general 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 general formula (1), various optical isomers exist. In the present invention, any of the optical isomers is included, and the compound represented by general formula (1) or a salt thereof may be a single optical isomer or a mixture of various optical isomers. Furthermore, the compound represented by general formula (1) or a salt thereof may be in the form of a solvate, and solvates of the compound represented by general formula (1) or a salt thereof with water, alcohol, etc. are also included in the term "compound represented by general formula (1) or a salt thereof."

[0052] 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. In addition, the R 1 is preferably a hydrogen atom or a methyl group.

[0053] 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.

[0054] 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 "substituent" include 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, and a 3-carboxypropyl group.

[0055] 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.

[0056] 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-mentioned "cyclic amino group which may have a substituent"). Among them, 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.

[0057] 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.

[0058] 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. In addition, the 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.

[0059] 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.

[0060] 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, carbinoxamine maleate, etc.; clemastine or a salt thereof such as clemastine fumarate, etc.; chlorpheniramine or a salt thereof such as d-chlorpheniramine maleate, dl-chlorpheniramine maleate, etc.; difeterol hydrochloride, difeterol phosphate, etc. difeterol or a salt thereof; diphenylpyraline or a salt thereof such as diphenylpyraline hydrochloride, diphenylpyraline teoclate, etc.; diphenhydramine or a salt thereof such as diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, etc.; cetirizine or a salt thereof such as cetirizine hydrochloride; fexofenadine or a salt thereof; bepotastine or a salt thereof such as bepotastine besilate, etc.; homochlorcyclidine or a salt thereof such as homochlorcyclidine hydrochloride, etc. These may be used alone or in combination of two or more. The compounds represented by the general formula (1) and salts thereof, particularly the compounds and salts thereof described above, are known and can be produced by known methods, or commercially available products can be used.

[0061] In the present invention, the total content of the compound represented by general formula (1) or a salt thereof in the liquid or semi-solid composition is not particularly limited. From the viewpoint of the discoloration suppression effect, the compound represented by general formula (1) or a salt thereof is preferably contained in an amount of 0.01 to 10 mass %, more preferably 0.05 to 5 mass %, and particularly preferably 0.1 to 3 mass %, relative to the total mass of the composition.

[0062] In the present invention, the content ratio of loxoprofen or a salt thereof and the compound represented by general formula (1) or a salt thereof in the liquid or semi-solid composition is not particularly limited. However, from the viewpoint of the discoloration suppression effect, the compound represented by general formula (1) or a salt thereof is preferably contained in a total amount 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, per part by mass of loxoprofen or a salt thereof, calculated as anhydrous loxoprofen.

[0063] In the present invention, it is preferable to use "chlorpheniramine or a salt thereof" or "diphenhydramine or a salt thereof" as the compound represented by general formula (1) or a salt thereof.

[0064] In the present invention, "chlorpheniramine or a salt thereof" includes not only chlorpheniramine itself but also pharmaceutically acceptable salts of chlorpheniramine.

[0065] [ka]

[0066] 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, chlorpheniramine maleate is preferred, with d-chlorpheniramine maleate and dl-chlorpheniramine maleate being more preferred, and d-chlorpheniramine maleate being particularly preferred. These are known compounds and can be produced by known methods, or commercially available products can be used.

[0067] When chlorpheniramine or a salt thereof is used, the content of chlorpheniramine or a salt thereof in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration inhibitory effect, the content of chlorpheniramine or a salt thereof is preferably 0.01 to 5 mass %, more preferably 0.05 to 3 mass %, and particularly preferably 0.1 to 2 mass %, relative to the total mass of the composition.

[0068] When chlorpheniramine or a salt thereof is used, the content ratio of loxoprofen or a salt thereof to chlorpheniramine or a salt thereof in the liquid or semi-solid composition is not particularly limited. However, from the viewpoint of the discoloration suppression effect, it is preferable that chlorpheniramine or a salt thereof is contained in an amount of 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.

[0069] In the present invention, "diphenhydramine or a salt thereof" includes not only diphenhydramine itself but also pharmaceutically acceptable salts of diphenhydramine.

[0070] [ka]

[0071] 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. These are known compounds and can be produced by known methods, or commercially available products can be used.

[0072] When diphenhydramine or a salt thereof is used, the content of diphenhydramine or a salt thereof in the liquid or semi-solid composition is not particularly limited. From the viewpoint of the discoloration-inhibiting effect, however, 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, relative to the total mass of the composition.

[0073] When diphenhydramine or a salt thereof is used, the content ratio of rofecoxib or a salt thereof to diphenhydramine or a salt thereof in the liquid or semi-solid composition is not particularly limited. However, from the viewpoint of the discoloration suppression effect, it is preferable to contain 0.05 to 10 parts by mass of diphenhydramine or a salt thereof per 1 part by mass of rofecoxib or a salt thereof, calculated as anhydrous rofecoxib sodium, more preferably 0.1 to 5 parts by mass, and particularly preferably 0.3 to 3 parts by mass.

[0074] <Component (B-8)> In the present invention, the "chili pepper" is not particularly limited, and for example, chili pepper (fruit of Capsicum annuum Linne (Solanaceae)) listed in the 16th Edition of the Japanese Pharmacopoeia can be suitably used. The form of chili pepper can be adjusted as needed, and it can be cut or crushed into small pieces or chunks, or pulverized into powder. For example, "chili pepper powder" obtained by powdering chili pepper can also be used as the "chili pepper" of the present invention. Furthermore, in consideration of ease of handling during the production of compositions and pharmaceutical preparations, chili peppers that have been subjected to some kind of extraction treatment (referred to as "chili pepper extract" in this specification) may also be used. The term "chili pepper extract" also encompasses those that have been subjected to processing such as heating, drying, and pulverization in addition to extraction. Specifically, the "chili pepper extract" of the present invention includes a liquid obtained by cutting chili peppers into appropriate sizes as needed and then adding an appropriate infusion (extraction solvent), a liquid obtained by concentrating the infusion (soft extract, tincture, etc.), and further, a liquid obtained by drying these (dried extract, etc.). Furthermore, in the present invention, the "chili pepper extract" may be a known capsaicinoid, which is the main component of chili pepper. Preferred capsaicinoids include capsaicin and nonanoic acid vanillylamide (also known as nonylic acid vanillylamide).

[0075] In the present invention, the "chili pepper or extract thereof" is preferably chili pepper, chili pepper powder, chili pepper extract (soft extract, dry extract), capsaicin, or nonanoic acid vanillylamide, with chili pepper soft extract and nonanoic acid vanillylamide being particularly preferred.

[0076] The method for producing a chili pepper 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 "Extracts," "Infusions / Decoctions," "Tinctures," and "Liquid Extracts" sections of the General Provisions for Preparations in the Sixteenth Edition of the Japanese Pharmacopoeia. Specifically, for example, chili peppers can be cut, heated, dried, crushed, etc. as needed, and then extracted with an appropriate extraction solvent. The resulting extract may be further concentrated, dried, etc., as needed.

[0077] Examples of the extraction solvent include lower monohydric alcohols such as methanol, ethanol, isopropanol, and n-butanol; 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; dimethylformamide; dimethyl sulfoxide; and water (including hot water). These may be used alone or in combination. In the present invention, water, ethanol, or a water / ethanol mixture is preferred. The extraction procedure is not particularly limited, and any known method used for extraction from plants can be appropriately adopted, specifically, for example, immersion in an extraction solvent (cold immersion, hot immersion, percolation, etc.), extraction using a supercritical fluid or subcritical fluid, etc. In order 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 is preferably from about 5°C to a temperature 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 is preferably about 1 hour to 14 days.

[0078] In the present invention, commercially available products can be used as chili peppers or extracts thereof, and specific commercially available products include chili pepper extract-B, chili pepper extract-D, chili pepper extract-N, chili pepper extract-S, (local) chili pepper tincture, (local) chili pepper powder (all manufactured by Nippon Powder Pharmaceutical Co., Ltd.), nonylic acid vanillylamide (Nagaoka Jitsugyo Co., Ltd.), etc.

[0079] In the present invention, the content of chili pepper or its extract in a liquid or semi-solid composition is not particularly limited, but from the viewpoint of discoloration suppression, the chili pepper or its extract is preferably contained in an amount of 0.01 to 15% by mass, more preferably 0.05 to 10% by mass, and particularly preferably 0.1 to 8% by mass, calculated as the amount of herbal medicine relative to the total mass of the composition. Furthermore, particularly when capsaicin or a capsaicinoid such as nonanoic acid vanillylamide is used as the chili pepper or its extract, from the viewpoint of discoloration suppression, the capsaicinoid is preferably contained in an amount of 0.0001 to 2% by mass, more preferably 0.0005 to 1% by mass, even more preferably 0.001 to 0.5% by mass, and particularly preferably 0.005 to 0.1% by mass, relative to the total mass of the composition.

[0080] In the present invention, the content ratio of rofecoxib or its salt to chili pepper or its extract in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration inhibitory effect. However, from the viewpoint of the discoloration inhibitory effect, it is preferable that the content of rofecoxib or its salt in terms of anhydrous rofecoxib is 0.01 to 15 parts by mass, more preferably 0.05 to 10 parts by mass, and particularly preferably 0.1 to 8 parts by mass, of chili pepper or its extract in terms of the crude drug per part by mass of rofecoxib or its salt in terms of anhydrous rofecoxib. In particular, when capsaicin or capsaicinoids such as nonanoic acid vanillylamide are used as chili peppers or their extracts, from the viewpoint of discoloration inhibition, the capsaicinoid is preferably contained in an amount of 0.0001 to 2 parts by mass, more preferably 0.0005 to 1 part by mass, even more preferably 0.001 to 0.2 parts by mass, and particularly preferably 0.005 to 0.1 part by mass per part by mass of rofecoxib or a salt thereof, calculated as anhydrous rofecoxib sodium.

[0081] <Ingredient (B-9)> In the present invention, various types of "organic amines" are exemplified, but from the viewpoint of discoloration suppression, alkanolamines are preferred. Examples of alkanolamines include diisopropanolamine, diethanolamine, triethanolamine hydrochloride, triisopropanolamine, triethanolamine, trometamol, meglumine, monoethanolamine, etc. Among these, one type may be used alone, or two or more types may be used in combination. Among these, from the viewpoint of discoloration suppression effect, ethanolamines are preferred, triethanolamine or a salt thereof is more preferred, triethanolamine or an organic acid salt or an inorganic acid salt thereof is even more preferred, and triethanolamine hydrochloride and triethanolamine are particularly preferred.

[0082] In the present invention, the content of the organic amine in the liquid or semi-solid composition is not particularly limited. From the viewpoint of the discoloration suppression effect, the organic amine is preferably contained in an amount of 0.001 to 5 mass %, more preferably 0.01 to 1 mass %, and particularly preferably 0.05 to 0.5 mass %, relative to the total mass of the composition.

[0083] In the present invention, the content ratio of loxoprofen or a salt thereof to an organic amine in a liquid or semi-solid composition is not particularly limited. However, from the viewpoint of the discoloration suppression effect, the organic amine is preferably contained in an amount of 0.03 to 0.6 parts by mass, more preferably 0.06 to 0.4 parts by mass, and particularly preferably 0.1 to 0.2 parts by mass, per part by mass of loxoprofen or a salt thereof, calculated as anhydrous loxoprofen.

[0084] <Liquid or semi-solid composition> In the present invention, the term "liquid or semi-solid composition" means a composition that is liquid or semi-solid at room temperature (any temperature within the range of 15 to 25°C). In the present invention, the properties of the composition are not particularly limited, and may be any of a solution, a colloidal solution (sol (suspension or emulsion)), a gel, etc. Furthermore, the type and properties of the solvent or base are not particularly limited, and the solvent or base may be hydrophilic or hydrophobic, such as oily, and multiple different types of solvents and bases may be appropriately mixed and emulsified for use. Specific examples of such solvents and bases include the components exemplified below as additives.

[0085] In the present invention, from the viewpoint of safety during use of the pharmaceutical preparation, it is preferable that the liquid or semi-solid composition contains water. Here, the content of water in the composition is not particularly limited, but from the viewpoint of safety during use of the pharmaceutical preparation and discoloration suppression effect, it is preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 10% by mass or more, even more preferably 20% by mass or more, and particularly preferably 30% by mass or more, based on the total mass of the composition. Furthermore, from the same viewpoint as above, it is preferably less than 100% by mass of the total mass of the composition, more preferably 99% by mass or less, even more preferably 90% by mass or less, even more preferably 70% by mass or less, and particularly preferably 50% by mass or less. Furthermore, from the same viewpoint as above, it is more preferably 10 to 90% by mass of the total mass of the composition, even more preferably 20 to 70% by mass, and particularly preferably 30 to 50% by mass.

[0086] Furthermore, in the present invention, from the viewpoint of the usability of the pharmaceutical preparation, it is preferable that the liquid or semi-solid composition contains a lower alcohol. Here, "lower alcohol" refers to a linear or branched monohydric alcohol having 1 to 6 carbon atoms, and specific examples include ethanol, isopropanol, n-propanol, etc., with ethanol, isopropanol, and mixtures thereof being preferred. The content of the lower alcohol in the composition is not particularly limited, but from the viewpoint of the usability of the pharmaceutical preparation and the discoloration-inhibiting effect, it is preferably 5% by mass or more, more preferably 10 to 90% by mass, even more preferably 15 to 70% by mass, even more preferably 17.5 to 60% by mass, and particularly preferably 20 to 50% by mass, based on the total mass of the composition.

[0087] In the present invention, from the viewpoints of safety and usability during use of the pharmaceutical preparation, it is preferable that the liquid or semi-solid composition contains both water and a lower alcohol. Even in the case of a composition containing at least one of water and a lower alcohol (particularly a composition containing both water and a lower alcohol), discoloration is suppressed.

[0088] In the present invention, the liquid or semi-solid composition may contain, as a medicinal ingredient, one or more drugs other than those mentioned above, for example, analgesic ingredients, anti-inflammatory ingredients, antihistamine ingredients other than the compound represented by general formula (1) and salts thereof, bactericidal ingredients, astringent / protective ingredients, blood circulation promoting ingredients, local anesthetic ingredients, antitussives, noscapines, bronchodilators, expectorants, hypnotics / sedatives, vitamins, gastric mucosa protecting agents, antacids, anticholinergics, herbal medicines, Chinese herbal prescriptions, etc.

[0089] 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, seaprose, semi-alkaline proteinase, serrapeptase, proctase, pronase, and bromelain.

[0090] Examples of antihistamine ingredients other than the compound represented by the general formula (1) and salts thereof 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.

[0091] Examples of antiseptic ingredients include benzalkonium chloride. Examples of astringent and protective ingredients include zinc oxide. Examples of blood circulation promoters include benzyl nicotinate, heparinoids, and sodium polyethylene sulfonate. Examples of local anesthetic ingredients include lidocaine and belladonna extract.

[0092] 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.

[0093] Examples of noscapines include noscapine hydrochloride and noscapine. Bronchodilators include, for example, trimetoquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride, etc.

[0094] Examples of expectorants include ammonia, fennel extract, and ammonium chloride.

[0095] Examples of hypnotic sedatives include allylisopropylacetylurea and bromvalerylurea. Vitamins include, for example, 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.).

[0096] Examples of gastric mucosa protecting agents include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride, and the like. Examples of 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 hydrogen carbonate, 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 hydrogen carbonate, precipitated calcium carbonate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, squid bone, stone jelly, and sea urchin.

[0097] Examples of anticholinergic agents include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, tipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, and the like.

[0098] Examples of crude drugs include Mallotus japonicus (Mallotus japonicus), Asarum japonica (Asarum japonica), Euonymus chinensis (Euonymus chinensis), Fennel (Fennel), Turmeric (Turmeric), Corydalis chinensis (Corydalis chinensis), Scutellaria baicalensis (Scutellaria baicalensis), Phellodendron bark (Phellodendron bark), Coptis chinensis (Coptis chinensis), Onji (Atractylodes chinensis), Zedoary (Atractylodes chinensis), Valerian (Valeriana japonica), Chamomile, Calonin (Carolina rhododendron), Platycodon grandiflorum (Platycodon grandiflorum), and Apricot kernel (Prunus apricot kernel). ), Lycium chinense (Glycine max), Lycium coccineum (Lycium bark), Cinnamon bark, Cassia japonica (Cassia nut), Gentian (Gentiana chinense), Safflower (Safflower), Kobushi (Citrus chinense), Bezoar (Cattleya chinense), Schisandra chinensis (Schisandra chinensis), Asarum chinense (Asarum chinense), Gardenia chinense (Zanthoxylum chinense), Zanthoxylum chinense (Zanthoxylum chinense), Lithospermum chinense (Peony peony), Musk (Musk), Shajin (Siberian ginseng), Shazenshi (Prunus chinensis), Shazensou (Prunus chinensis), Animal gall (including bear gall), Zingiber officinale (Ginger), Jiryu (Earth Dragon), Shini (Magnolia), Horse Chestnut, Sekisan (Garlic), Senega, Cnikyu (Czech Root), Zenko (Chinese Husk), Swertia bristlecone, Atractylodes chinensis (Chinese Atractylodes), Sohakuhi (Mulberry Bark), Soybean Leaf, Garlic, Chikusetsuninjin (Bamboo Ginseng), Chinpi (Citrus Unshiu Peel), Touki (Angelica), Ipecac (Ipecac Root), Nantenjitsu ( Examples of herbal medicines include Nandina fruit, Ginseng, Fritillaria root, Ophiopogon chinensis, Pinellia japonica, Scutellaria baicalensis, Anemone chinensis, Angelica baicalensis, Atractylodes rhizome, Poria cocos, Peony bark, Prunus asiaticus bark, and Velvet antler, as well as extracts thereof (extracts, tinctures, dried extracts, etc.).

[0099] Examples of Chinese herbal prescriptions include Keishito (Keishito), Kousosan (Kousosan), Saikokeishito (Saikokeishito), Shosaikoto (Shosaikoto), Bakumondoutou (Bakumondoutou), and Hangekoubokuto (Hangekoubokuto).

[0100] In addition, in the present invention, the liquid or semi-solid composition may contain, in addition to the above-mentioned components, additives used in the pharmaceutical and cosmetic fields, etc., depending on the dosage form, administration method, etc. of the pharmaceutical preparation. Examples of such additives include gelling agents, oils and fats, emulsifiers, solubilizers, pH adjusters, antioxidants, softeners, thickeners, moisturizers, preservatives, stabilizers, transdermal absorption enhancers, flavoring agents, sweeteners, etc.

[0101] Examples of gelling agents include acrylic acid polymers such as carboxyvinyl polymers; polyvinylpyrrolidone; and the like. Examples of fats and oils include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, and petrolatum; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; higher alcohols such as behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, and oleyl alcohol; higher fatty acids such as behenic acid, lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; waxes such as carnauba wax, spermaceti, shellac, jojoba oil, beeswax, white beeswax, montan wax, lanolin, purified lanolin, and reduced lanolin; and silicone oil.

[0102] Examples of emulsifiers include polyhydric alcohol fatty acid esters or polyhydric alcohol alkyl ethers such as propylene glycol mono-fatty acid esters, ethylene glycol mono-fatty acid esters, glycerin mono-fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, methyl glucoside fatty acid esters, and alkyl polyglucosides; polyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene phytosterols, polyoxyethylene phytostanols, and polyoxyethylene polyoxypropylene alkyl ethers; and nonionic surfactants such as ether esters of polyoxyethylene mono-fatty acid esters, polyethylene glycol di-fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene methyl glucoside fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene vegetable oils, and polyoxyethylene alkyl ether fatty acid esters; and ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate. Examples of solubilizers include the nonionic surfactants and ionic surfactants exemplified above as emulsifiers, as well as liquid paraffin, crotamiton, and the like.

[0103] Examples of pH adjusters include organic acids or salts thereof such as citric acid, sodium citrate, anhydrous citric acid, malic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, acetic acid, sodium acetate, and glacial acetic acid; inorganic acids or salts thereof such as hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, and sodium hydrogen carbonate; and alkali hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide. Examples of antioxidants include sodium sulfite, ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, cysteine ​​hydrochloride, citric acid, soybean lecithin, and propyl gallate. Examples of softeners include allantoin, almond oil, olive oil, liquid paraffin, squalane, squalene, refined lanolin, medium-chain fatty acid triglycerides, rapeseed oil, castor oil, and polybutene. Examples of thickeners include polyvinylpyrrolidone, colloidal aluminum silicate, xanthan gum, locust bean gum, tragacanth gum, guar gum, gelatin, gum arabic, alginic acid, and albumin. Moisturizing agents include sodium hyaluronate, urea, sucrose, etc. Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, and aminoethylsulfonic acid. Examples of stabilizers include adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hydrogenated oil, and cysteine. Examples of the percutaneous absorption enhancer include fatty acid esters such as diisopropyl adipate. Examples of flavoring agents and sweeteners include acesulfame potassium, stevia, thaumatin, sucralose, panose, trehalose, reduced palatinose, coupling sugar, fructooligosaccharides, galactooligosaccharides, lactoferrin oligosaccharides, isomaltooligosaccharides, palatinose oligosaccharides, raffinose, aspartame, fructose, brown sugar, saccharin or its salt, lactose, white sugar, honey, glucose, maltose, and starch syrup.

[0104] In the present invention, the method for producing a liquid or semi-solid composition is not particularly limited, and the composition can be produced by a known method described in, for example, the General Provisions for Preparations in the 16th Edition of the Japanese Pharmacopoeia, etc., depending on the types and amounts of the ingredients to be blended, the properties of the composition, the shape of the container, the dosage form of the pharmaceutical preparation, the route of administration, the intended use, etc.

[0105] <Polyolefin resin container> In the present invention, the term "container" refers to a package that directly contains a liquid or semi-solid composition. The shape of the container is not particularly limited as long as it can contain a liquid or semi-solid composition, and may be determined appropriately depending on the properties of the composition, the dosage form of the pharmaceutical preparation, the route of administration, the intended use, etc. Examples of such container shapes include aerosol containers, pump spray containers, bottle containers (more specifically, bottle containers equipped with a sponge-like application member (head), roll-on containers, jar bottle containers, etc.), tube containers, eye drop containers, etc. All of these containers are known and may be produced by known methods, or commercially available products may be used.

[0106] In the present invention, the container is selected from the following (1) or (2) from the viewpoint of convenience in handling and use of the pharmaceutical preparation: (1) A container that includes a container body and an application member, such as a bottle container with a sponge-like application member, and is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port, such as a tube container; is preferred, and the container of embodiment (1) is particularly preferred.

[0107] [(1) A container comprising a container body and an application member, the application member being impregnated with a composition contained in the container body when in use] In the case of a container of this type, the composition contained in the container body can be applied by impregnating and retaining the composition in the application member and bringing the application member into contact with the area to be applied. In this case, the container body and the application member may be produced as independent members and then the application member may be attached to the container body, or they may be molded integrally. The application member may be any member that can be impregnated with and retain the liquid or semi-solid composition, and examples thereof include porous members such as sponges and brush-like members.

[0108] An example of such a container is a container that has an application member at the opening of the container body, and is used by impregnating the application member with the composition contained in the container body. A more specific example is a container comprising a container body having a mouth and a porous (sponge-like, etc.) application member attached to the mouth. In this case, the composition contained in the container body is impregnated into and retained in the porous application member, the pore size, porosity, etc. of which have been appropriately adjusted, and then the application member is brought into contact with the application target, thereby applying the composition to the application target. Another specific example is a container comprising a container body having a mouth and a brush-like applicator attached to the mouth. In this case, the composition contained in the container body is impregnated and held in a brush whose bristles have been appropriately adjusted in length, spacing, etc., and then the applicator is brought into contact with the area to be applied, thereby applying the composition to the area to be applied.

[0109] This type of container has advantages, such as the fact that the application member is impregnated with and retains the composition, making it less likely to cause dripping problems on the application site when the pharmaceutical formulation is a topical application, preventing hands from getting dirty by directly contacting the application member with the application site, and allowing for easy and flexible application of the composition by adjusting the shape and size of the application member. However, because the composition is impregnated with and retained in the application member, discoloration of the composition will occur throughout the application member. Therefore, when the application member is exposed to the outside, such as during use of the pharmaceutical formulation, the discoloration is particularly noticeable in appearance. However, the present invention has the excellent effect of suppressing discoloration of the composition, thereby solving such appearance problems and fully enjoying the above-mentioned advantages. It is particularly preferable that the container body and application member of this type of container are both made of polyolefin resin. Such a container can be particularly suitably used when the composition to be contained is, for example, a liquid composition or a low-viscosity semi-solid composition.

[0110] Containers of this type are known and are disclosed, for example, in Japanese Patent No. 5570089. In the present invention, commercially available products may be used as containers of this type, and examples of such commercially available products include containers that use MAPS (INOAC CORPORATION), an open-pore material made of low-density polyethylene, as an application member.

[0111] [(2) A container having a flexible container body and a discharge outlet] In the case of a container of this type, pressure is applied to the inside of the container, for example by pressing the flexible container body, and the composition contained inside the container is discharged from the discharge outlet, thereby allowing the composition to be applied to the area to be coated. Note that in a container of this type, the discharge outlet does not need to be provided in advance on the container, and the container may be configured so that the discharge outlet is provided by perforating the container before use, and such a container is also included in the category of "a container comprising a flexible container body and a discharge outlet."

[0112] A container of this type has advantages such as low manufacturing costs due to its simple structure, and the composition inside the container is not contaminated because the composition is discharged from the discharge port by, for example, pressing the container body. The container of this embodiment can be particularly suitably used when the composition to be contained is, for example, a semi-solid composition with high viscosity.

[0113] Containers of this type are known and are disclosed, for example, in Japanese Patent Nos. 5302550 and 5525135. In the present invention, commercially available products may also be used as containers of this type.

[0114] In the present invention, the "polyolefin resin" is not particularly limited, and may be a polymer (homopolymer) of a single type of monomer, or a copolymer (copolymer) of multiple types of monomers. In addition, in the case of a copolymer, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited. Specific examples of such polyolefin resins include polyethylene (more specifically, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, etc.), polypropylene, cyclic polyolefin, poly(4-methylpentene), polytetrafluoroethylene, ethylene-propylene copolymer, ethylene-α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, etc. In the present invention, these may be used alone or in combination of two or more. In the present invention, the polyolefin resin is preferably polyethylene, polypropylene, or a cyclic polyolefin, with polyethylene or polypropylene being particularly preferred, from the viewpoint of inhibiting discoloration. In the present invention, "made of polyolefin-based resin" means that at least a part of the material contains polyolefin-based resin, and for example, a mixture of two or more resins, i.e., polyolefin-based resin and other resins (polymer alloy), is also included in "made of polyolefin-based resin".

[0115] In the present invention, a "polyolefin resin container" refers to a "container" in which at least a portion of the portion that comes into contact with the liquid or semi-solid composition contained therein (preferably 10% or more of the portion that comes into contact with the composition during normal storage, more preferably 30% or more of the portion that comes into contact with the composition during normal storage, and particularly preferably the entire portion that comes into contact with the composition during normal storage) is "made of a polyolefin resin." Therefore, for example, a container in which a polyolefin resin layer is provided in at least a portion of the layer that comes into contact with the liquid or semi-solid composition (the innermost layer of the container), and another resin or material such as aluminum foil is laminated on the outside of the layer also falls under the category of a "polyolefin resin container." Specific examples of such containers made by laminating multiple types of materials include containers made of laminated film, in which a layer made of polyolefin resin is used as the innermost layer, aluminum foil is laminated on the outside of that, either directly or via another layer, and other layers are further laminated on the outside of that as needed.

[0116] In the present invention, the means for placing the liquid or semi-solid composition in a container is not particularly limited, and the container may be filled in a conventional manner depending on the shape of the container, the properties of the composition, etc., thereby producing the pharmaceutical preparation of the present invention.

[0117] <Pharmaceutical preparations> In the present invention, the method of administration or application of the "pharmaceutical preparation" is not particularly limited, and examples include oral and parenteral administration such as transdermal and vaginal administration. In the present invention, parenteral administration is preferred, and transdermal administration is particularly preferred, due to the properties of liquid or semi-solid compositions (which allow for flexible application of only the required amount depending on the location, shape, and area of ​​the affected area).

[0118] In the present invention, the dosage form of the pharmaceutical preparation is not particularly limited as long as the composition contained in the container is in a liquid or semi-solid form, and can be appropriately selected from dosage forms described in, for example, the General Rules for Preparations in the Japanese Pharmacopoeia, 16th Edition, etc., depending on the intended use, etc. Specific examples of such dosage forms include those described in the General Rules for Preparations in the Japanese Pharmacopoeia, 16th Edition, such as preparations to be applied to the skin, etc. (external liquids, sprays, ointments, creams, gels, etc.) and preparations to be administered orally (oral liquids, syrups, oral jellies, etc.). In the present invention, the pharmaceutical preparation is preferably in a dosage form selected from the group consisting of external liquids, sprays, ointments, creams, and gels, more preferably in a dosage form selected from the group consisting of liniments, lotions, external aerosols, pump sprays, ointments, creams, and gels, and particularly preferably in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0119] The pharmaceutical preparation of the present invention contains loxoprofen, a type of NSAID, or a salt thereof, and therefore can be used as a prescription drug or an over-the-counter drug, and is specifically useful, for example, as a topical anti-inflammatory analgesic; an antipyretic analgesic; an oral medication such as a general cold remedy (cold remedy); etc.

[0120] Next, the invention in the form of a "method" will be described below. The present invention comprises the following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Any of the following components (B-1) to (B-9); (B-1) Terpenes (B-2) A plant of the genus Lacertilia or its extract (B-3) Polyhydric alcohol (B-4) Cellulose (B-5) Tocopherols (B-6) Glycyrrhetinic acid (B-7) A compound represented by the above general formula (1) or a salt thereof (B-8) Capsicum or its extract (B-9) Organic amines The present invention also relates to a method for suppressing discoloration of a composition, which comprises a step of placing a liquid or semi-solid composition containing the above compound in a polyolefin resin container. In the invention of this aspect, the order of the step of blending component (A), the step of blending component (B), and the step of containing the composition in a polyolefin resin container is not particularly limited, as long as a liquid or semi-solid composition containing components (A) and (B) is directly or indirectly produced in a state in which it is contained in a polyolefin resin container. In this embodiment of the invention, the meanings of various terms, the amounts of each ingredient, etc. are all the same as those explained for the "pharmaceutical preparation."

[0121] This specification discloses the invention exemplified below in relation to the above embodiments, but is not limited to these in any way. [1-1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Terpenes; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container. [1-2] The pharmaceutical preparation according to [1-1], which does not include an anti-inflammatory analgesic product for external use, in which a liquid composition containing 1% by mass of loxoprofen sodium, 3% by mass of l-menthol, 52.3% by mass of ethanol, and 43.7% by mass of water is filled in a polypropylene roll-on container having one stainless steel SUS304 ball. [1-3] The pharmaceutical formulation according to [1-1] or [1-2], wherein component (A) is loxoprofen sodium hydrate. [1-4] The pharmaceutical preparation according to any one of [1-1] to [1-3], wherein component (B) is one or more selected from the group consisting of isoborneol, irone, ocimene, carveol, carbotanacetone, carvomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, silvestrene, thymol, isothujol, 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, and limonene. [1-5] The pharmaceutical preparation according to any one of [1-1] to [1-3], wherein the component (B) is a cyclic terpenoid. [1-6] The pharmaceutical preparation according to any one of [1-1] to [1-3], wherein the component (B) is a cyclic monoterpenoid. [1-7] The pharmaceutical preparation according to any one of [1-1] to [1-3], wherein the component (B) is a monocyclic or bicyclic monoterpenoid. [1-8] The pharmaceutical preparation according to any one of [1-1] to [1-3], wherein the component (B) is a monoterpenoid having a p-menthane skeleton or a monoterpenoid having a bornane skeleton. [1-9] The pharmaceutical preparation according to any one of [1-1] to [1-3], wherein the component (B) is one or more selected from the group consisting of cineole, thymol, terpineol, menthol, limonene, camphor, and borneol. [1-10] The pharmaceutical preparation according to any one of [1-1] to [1-3], wherein the component (B) is one or more selected from the group consisting of cineol, camphor, thymol, borneol and menthol. [1-11] The pharmaceutical preparation according to any one of [1-1] to [1-3], wherein the component (B) is one or more selected from the group consisting of cineole, d-camphor, dl-camphor, thymol, d-borneol, l-menthol and dl-menthol. [1-12] The pharmaceutical preparation according to any one of [1-1] to [1-3], wherein the component (B) is one or more selected from the group consisting of cineole, d-camphor, dl-camphor, thymol, l-menthol and dl-menthol.

[0122] [1-13] The pharmaceutical formulation according to any one of [1-1] to [1-12], wherein the composition contains water. [1-14] The pharmaceutical formulation according to any one of [1-1] to [1-13], wherein the composition contains a lower alcohol. [1-15] The pharmaceutical formulation according to [1-14], wherein the lower alcohol is at least one selected from the group consisting of ethanol and isopropanol. [1-16] The pharmaceutical preparation according to any one of [1-1] to [1-15], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [1-17] The pharmaceutical formulation according to any one of [1-1] to [1-16], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [1-18] The container is (1) or (2) of the following: (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The pharmaceutical preparation according to any one of [1-1] to [1-16], wherein [1-19] The pharmaceutical preparation according to any one of [1-1] to [1-16], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [1-20] The pharmaceutical preparation according to any one of [1-1] to [1-19], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, a gel, an oral liquid, a syrup, and an oral jelly. [1-21] The pharmaceutical preparation according to any one of [1-1] to [1-19], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [1-22] The pharmaceutical preparation according to any one of [1-1] to [1-19], which is in a dosage form selected from the group consisting of liniments, lotions, aerosols, pump sprays, ointments, creams, and gels. [1-23] The pharmaceutical preparation according to any one of [1-1] to [1-19], which is in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0123] [1-24] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Terpenes; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [1-25] The method described in [1-24], wherein component (A) is sodium rofecoxib hydrate. [1-26] The method according to [1-24] or [1-25], wherein component (B) is at least one selected from the group consisting of isoborneol, irone, ocimene, carveol, carbotanacetone, carvomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, silvestrene, thymol, isothujol, 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, and limonene. [1-27] The method according to [1-24] or [1-25], wherein component (B) is a cyclic terpenoid. [1-28] The method according to [1-24] or [1-25], wherein component (B) is a cyclic monoterpenoid. [1-29] The method according to [1-24] or [1-25], wherein component (B) is a monocyclic or bicyclic monoterpenoid. [1-30] The method according to [1-24] or [1-25], wherein the component (B) is a monoterpenoid having a p-menthane skeleton or a monoterpenoid having a bornane skeleton. [1-31] ​​The method according to [1-24] or [1-25], wherein the terpenes are one or more selected from the group consisting of cineole, thymol, terpineol, menthol, limonene, camphor, and borneol. [1-32] The method according to [1-24] or [1-25], wherein the component (B) is one or more selected from the group consisting of cineol, camphor, thymol, borneol, and menthol. [1-33] The method according to [1-24] or [1-25], wherein the component (B) is one or more selected from the group consisting of cineole, d-camphor, dl-camphor, thymol, d-borneol, l-menthol, and dl-menthol. [1-34] The method according to [1-24] or [1-25], wherein the component (B) is one or more selected from the group consisting of cineole, d-camphor, dl-camphor, thymol, l-menthol, and dl-menthol.

[0124] [1-35] The method according to any one of [1-24] to [1-34], wherein the composition contains water. [1-36] The method according to any one of [1-24] to [1-34], wherein the composition contains a lower alcohol. [1-37] The method according to [1-36], wherein the lower alcohol is at least one selected from the group consisting of ethanol and isopropanol. [1-38] The method according to any one of [1-24] to [1-37], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [1-39] The method according to any one of [1-24] to [1-38], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [1-40] The container is (1) or (2) of the following: (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The method according to any one of [1-24] to [1-38], wherein [1-41] The method according to any one of [1-24] to [1-38], wherein the container is a bottle container or a tube container provided with a sponge-like application member.

[0125] [2-1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) a plant of the genus Lacertilia or an extract thereof; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container. [2-2] The pharmaceutical formulation according to [2-1], wherein component (A) is sodium loxoprofen hydrate. [2-3] The pharmaceutical preparation according to [2-1] or [2-2], wherein component (B) is one or more selected from the group consisting of Arnica montana, Arnica chamissonis, Arnica fulgens, Arnica cordifolia, Arnica latifolia, Arnica longifolia, and Arnica sachalinensis, and extracts thereof. [2-4] The pharmaceutical formulation according to [2-1] or [2-2], wherein component (B) is arnica or an extract thereof. [2-5] The pharmaceutical preparation according to [2-1] or [2-2], wherein component (B) is one or more selected from the group consisting of arnica, arnica tincture, and arnica extract. [2-6] The pharmaceutical formulation according to any one of [2-1] to [2-5], wherein the composition further contains water. [2-7] The pharmaceutical formulation according to any one of [2-1] to [2-6], wherein the composition further contains a lower alcohol. [2-8] The pharmaceutical formulation according to [2-7], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [2-9] The pharmaceutical preparation according to any one of [2-1] to [2-8], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [2-10] The pharmaceutical preparation according to any one of [2-1] to [2-9], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [2-11] The container is one of the following (1) or (2): (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The pharmaceutical formulation according to any one of [2-1] to [2-9], wherein [2-12] The pharmaceutical preparation according to any one of [2-1] to [2-9], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [2-13] The pharmaceutical preparation according to any one of [2-1] to [2-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, a gel, an oral liquid, a syrup, and an oral jelly. [2-14] The pharmaceutical preparation according to any one of [2-1] to [2-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [2-15] The pharmaceutical preparation according to any one of [2-1] to [2-12], which is in a dosage form selected from the group consisting of liniments, lotions, aerosols, pump sprays, ointments, creams, and gels. [2-16] The pharmaceutical preparation according to any one of [2-1] to [2-12], which is in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0126] [2-17] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) a plant of the genus Lacertilia or an extract thereof; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [2-18] The method described in [2-17], wherein component (A) is sodium rofecoxib hydrate. [2-19] The method according to [2-17] or [2-18], wherein component (B) is one or more selected from the group consisting of Arnica montana, Arnica chamissonis, Arnica fulgens, Arnica cordifolia, Arnica latifolia, Arnica longifolia, and Arnica sachalinensis, and extracts thereof. [2-20] The method according to [2-17] or [2-18], wherein component (B) is arnica or an extract thereof. [2-21] The method according to [2-17] or [2-18], wherein component (B) is one or more selected from the group consisting of arnica, arnica tincture, and arnica extract. [2-22] The method according to any one of [2-17] to [2-21], wherein the composition further contains water. [2-23] The method according to any one of [2-17] to [2-22], wherein the composition further contains a lower alcohol. [2-24] The method according to [2-23], wherein the lower alcohol is at least one selected from the group consisting of ethanol and isopropanol. [2-25] The method according to any one of [2-17] to [2-24], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [2-26] The method according to any one of [2-17] to [2-25], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [2-27] The container is (1) or (2) of the following: (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The method according to any one of [2-17] to [2-25], wherein [2-28] The method according to any one of [2-17] to [2-25], wherein the container is a bottle container or a tube container provided with a sponge-like application member.

[0127] [3-1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) polyhydric alcohols; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container. [3-2] The pharmaceutical formulation according to [3-1], wherein component (A) is sodium loxoprofen hydrate. [3-3] The pharmaceutical formulation according to [3-1] or [3-2], wherein component (B) is one or more selected from the group consisting of lower polyhydric alcohols having 1 to 6 carbon atoms and higher polyhydric alcohols having 7 or more carbon atoms. [3-4] The pharmaceutical formulation according to any one of [3-1] to [3-3], wherein component (B) is one or more selected from the group consisting of ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, glycerin, 1,3-butylene glycol, erythritol, xylitol, sorbitol, mannitol, 1,2,6-hexanetriol, polyvinyl alcohol, polyethylene glycol, and polypropylene glycol. [3-5] The pharmaceutical formulation according to any one of [3-1] to [3-4], wherein the component (B) is 1,3-butylene glycol.

[0128] [3-6] The pharmaceutical formulation according to any one of [3-1] to [3-5], wherein the composition further contains water. [3-7] The pharmaceutical formulation according to any one of [3-1] to [3-6], wherein the composition further contains a lower alcohol. [3-8] The pharmaceutical formulation according to [3-7], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [3-9] The pharmaceutical preparation according to any one of [3-1] to [3-8], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [3-10] The pharmaceutical formulation according to any one of [3-1] to [3-9], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [3-11] The container is one of the following (1) or (2): (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The pharmaceutical formulation according to any one of [3-1] to [3-9], wherein [3-12] The pharmaceutical preparation according to any one of [3-1] to [3-9], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [3-13] The pharmaceutical preparation according to any one of [3-1] to [3-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, a gel, an oral liquid, a syrup, and an oral jelly. [3-14] The pharmaceutical preparation according to any one of [3-1] to [3-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [3-15] The pharmaceutical preparation according to any one of [3-1] to [3-12], which is in a dosage form selected from the group consisting of liniments, lotions, topical aerosols, pump sprays, ointments, creams, and gels. [3-16] The pharmaceutical preparation according to any one of [3-1] to [3-12], which is in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0129] [3-17] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) polyhydric alcohols; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [3-18] The method according to [3-17], wherein component (A) is sodium loxoprofen hydrate. [3-19] The method according to [3-17] or [3-18], wherein component (B) is one or more selected from the group consisting of lower polyhydric alcohols having 1 to 6 carbon atoms and higher polyhydric alcohols having 7 or more carbon atoms. [3-20] The method according to any one of [3-17] to [3-19], wherein component (B) is one or more selected from the group consisting of ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, glycerin, 1,3-butylene glycol, erythritol, xylitol, sorbitol, mannitol, 1,2,6-hexanetriol, polyvinyl alcohol, polyethylene glycol, and polypropylene glycol. [3-21] The method according to any one of [3-17] to [3-20], wherein the component (B) is 1,3-butylene glycol.

[0130] [3-22] The method according to any one of [3-17] to [3-21], wherein the composition further contains water. [3-23] The method according to any one of [3-17] to [3-22], wherein the composition further contains a lower alcohol. [3-24] The method according to [3-23], wherein the lower alcohol is at least one selected from the group consisting of ethanol and isopropanol. [3-25] The method according to any one of [3-17] to [3-24], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [3-26] The method according to any one of [3-17] to [3-25], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [3-27] The container is (1) or (2) of the following: (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The method according to any one of [3-17] to [3-25], wherein [3-28] The method according to any one of [3-17] to [3-25], wherein the container is a bottle container or a tube container provided with a sponge-like application member.

[0131] [4-1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Celluloses; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container. [4-2] The pharmaceutical formulation according to [4-1], wherein component (A) is sodium loxoprofen hydrate. [4-3] The pharmaceutical formulation according to [4-1] or [4-2], wherein component (B) is a cellulose ether derivative or a salt thereof. [4-4] The pharmaceutical formulation according to any one of [4-1] to [4-3], wherein component (B) is one or more selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose, and salts thereof. [4-5] The pharmaceutical formulation according to any one of [4-1] to [4-4], wherein the component (B) is hypromellose.

[0132] [4-6] The pharmaceutical formulation according to any one of [4-1] to [4-5], wherein the composition further contains water. [4-7] The pharmaceutical formulation according to any one of [4-1] to [4-6], wherein the composition further contains a lower alcohol. [4-8] The pharmaceutical formulation according to [4-7], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [4-9] The pharmaceutical preparation according to any one of [4-1] to [4-8], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [4-10] The pharmaceutical formulation according to any one of [4-1] to [4-9], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [4-11] The container is one of the following (1) or (2): (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The pharmaceutical formulation according to any one of [4-1] to [4-9], wherein [4-12] The pharmaceutical preparation according to any one of [4-1] to [4-9], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [4-13] The pharmaceutical preparation according to any one of [4-1] to [4-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, a gel, an oral liquid, a syrup, and an oral jelly. [4-14] The pharmaceutical preparation according to any one of [4-1] to [4-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [4-15] The pharmaceutical preparation according to any one of [4-1] to [4-12], which is in a dosage form selected from the group consisting of liniments, lotions, topical aerosols, pump sprays, ointments, creams, and gels. [4-16] The pharmaceutical preparation according to any one of [4-1] to [4-12], which is in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0133] [4-17] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Celluloses; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [4-18] The method according to [4-17], wherein component (A) is sodium rofecoxib hydrate. [4-19] The method according to [4-17] or [4-18], wherein component (B) is a cellulose ether derivative or a salt thereof. [4-20] The method according to any one of [4-17] to [4-19], wherein component (B) is one or more selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose, and salts thereof. [4-21] The method according to any one of [4-17] to [4-20], wherein component (B) is hypromellose.

[0134] [4-22] The method according to any one of [4-17] to [4-21], wherein the composition further contains water. [4-23] The method according to any one of [4-17] to [4-22], wherein the composition further contains a lower alcohol. [4-24] The method according to [4-23], wherein the lower alcohol is at least one selected from the group consisting of ethanol and isopropanol. [4-25] The method according to any one of [4-17] to [4-24], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [4-26] The method according to any one of [4-17] to [4-25], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [4-27] The container is (1) or (2) of the following: (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The method according to any one of [4-17] to [4-25], wherein [4-28] The method according to any one of [4-17] to [4-25], wherein the container is a bottle container or a tube container provided with a sponge-like application member.

[0135] [5-1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) tocopherols; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container. [5-2] The pharmaceutical formulation according to [5-1], wherein component (A) is sodium loxoprofen hydrate. [5-3] The pharmaceutical formulation according to [5-1] or [5-2], wherein component (B) is one or more selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof. [5-4] A pharmaceutical formulation according to any one of [5-1] to [5-3], wherein component (B) is one or more selected from the group consisting of dl-α-tocopherol, dl-α-tocopherol succinate calcium, dl-α-tocopherol acetate, and dl-α-tocopherol nicotinate. [5-5] The pharmaceutical formulation according to any one of [5-1] to [5-4], wherein the component (B) is dl-α-tocopherol acetate.

[0136] [5-6] The pharmaceutical formulation according to any one of [5-1] to [5-5], wherein the composition further contains water. [5-7] The pharmaceutical formulation according to any one of [5-1] to [5-6], wherein the composition further contains a lower alcohol. [5-8] The pharmaceutical formulation according to [5-7], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [5-9] The pharmaceutical preparation according to any one of [5-1] to [5-8], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [5-10] The pharmaceutical preparation according to any one of [5-1] to [5-9], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [5-11] The container is one of the following (1) or (2): (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The pharmaceutical formulation according to any one of [5-1] to [5-9], [5-12] The pharmaceutical preparation according to any one of [5-1] to [5-9], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [5-13] The pharmaceutical preparation according to any one of [5-1] to [5-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, a gel, an oral liquid, a syrup, and an oral jelly. [5-14] The pharmaceutical preparation according to any one of [5-1] to [5-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [5-15] The pharmaceutical preparation according to any one of [5-1] to [5-12], which is in a dosage form selected from the group consisting of liniments, lotions, topical aerosols, pump sprays, ointments, creams, and gels. [5-16] The pharmaceutical preparation according to any one of [5-1] to [5-12], which is in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0137] [5-17] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) tocopherols; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [5-18] The method according to [5-17], wherein component (A) is sodium rofecoxib hydrate. [5-19] The method according to [5-17] or [5-18], wherein component (B) is one or more selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof. [5-20] The method according to any one of [5-17] to [5-19], wherein component (B) is one or more selected from the group consisting of dl-α-tocopherol, dl-α-tocopherol succinate calcium, dl-α-tocopherol acetate, and dl-α-tocopherol nicotinate. [5-21] The method according to any one of [5-17] to [5-20], wherein component (B) is dl-α-tocopherol acetate.

[0138] [5-22] The method according to any one of [5-17] to [5-21], wherein the composition further contains water. [5-23] The method according to any one of [5-17] to [5-22], wherein the composition further contains a lower alcohol. [5-24] The method according to [5-23], wherein the lower alcohol is at least one selected from the group consisting of ethanol and isopropanol. [5-25] The method according to any one of [5-17] to [5-24], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [5-26] The method according to any one of [5-17] to [5-25], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [5-27] The container is (1) or (2) of the following: (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The method according to any one of [5-17] to [5-25], wherein [5-28] The method according to any one of [5-17] to [5-25], wherein the container is a bottle container or a tube container provided with a sponge-like application member.

[0139] [6-1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Glycyrrhetinic acids; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container. [6-2] The pharmaceutical formulation according to [6-1], wherein component (A) is sodium loxoprofen hydrate. [6-3] The pharmaceutical formulation according to [6-1] or [6-2], wherein component (B) is one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, and salts thereof. [6-4] The pharmaceutical formulation according to any one of [6-1] to [6-3], wherein component (B) is one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate, and trisodium glycyrrhizinate. [6-5] The pharmaceutical formulation according to any one of [6-1] to [6-4], wherein the component (B) is glycyrrhetinic acid.

[0140] [6-6] The pharmaceutical formulation according to any one of [6-1] to [6-5], wherein the composition further contains water. [6-7] The pharmaceutical formulation according to any one of [6-1] to [6-6], wherein the composition further contains a lower alcohol. [6-8] The pharmaceutical formulation according to [6-7], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [6-9] The pharmaceutical preparation according to any one of [6-1] to [6-8], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [6-10] The pharmaceutical formulation according to any one of [6-1] to [6-9], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [6-11] The container is one of the following (1) or (2): (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The pharmaceutical formulation according to any one of [6-1] to [6-9], [6-12] The pharmaceutical preparation according to any one of [6-1] to [6-9], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [6-13] The pharmaceutical preparation according to any one of [6-1] to [6-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, a gel, an oral liquid, a syrup, and an oral jelly. [6-14] The pharmaceutical preparation according to any one of [6-1] to [6-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [6-15] The pharmaceutical preparation according to any one of [6-1] to [6-12], which is in a dosage form selected from the group consisting of liniments, lotions, topical aerosols, pump sprays, ointments, creams, and gels. [6-16] The pharmaceutical preparation according to any one of [6-1] to [6-12], which is in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0141] [6-17] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Glycyrrhetinic acids; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [6-18] The method according to [6-17], wherein component (A) is sodium rofecoxib hydrate. [6-19] The method according to [6-17] or [6-18], wherein component (B) is one or more selected from the group consisting of glycyrrhetic acid, glycyrrhizinic acid, and salts thereof. [6-20] The method according to any one of [6-17] to [6-19], wherein component (B) is one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate, and trisodium glycyrrhizinate. [6-21] The method according to any one of [6-17] to [6-20], wherein component (B) is glycyrrhetinic acid.

[0142] [6-22] The method according to any one of [6-17] to [6-21], wherein the composition further contains water. [6-23] The method according to any one of [6-17] to [6-22], wherein the composition further contains a lower alcohol. [6-24] The method according to [6-23], wherein the lower alcohol is at least one selected from the group consisting of ethanol and isopropanol. [6-25] The method according to any one of [6-17] to [6-24], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [6-26] The method according to any one of [6-17] to [6-25], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [6-27] The container is (1) or (2) of the following: (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The method according to any one of [6-17] to [6-25], wherein [6-28] The method according to any one of [6-17] to [6-25], wherein the container is a bottle container or a tube container provided with a sponge-like application member.

[0143] [7-1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) the following general formula (1)

[0144] [ka]

[0145] [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.] A compound represented by the formula (I) or a salt thereof; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container. [7-2] The pharmaceutical formulation according to [7-1], wherein component (A) is sodium loxoprofen hydrate. [7-3] The pharmaceutical formulation according to [7-1] or [7-2], wherein component (B) is one or more selected from the group consisting of ebastine and its salts, oxatomide and its salts, carbinoxamine and its salts, clemastine and its salts, chlorpheniramine and its salts, difeterol and its salts, diphenylpyraline and its salts, diphenhydramine and its salts, cetirizine and its salts, fexofenadine and its salts, bepotastine and its salts, and homochlorcyclizine and its salts. [7-4] The pharmaceutical formulation according to [7-1] or [7-2], wherein component (B) is one or more selected from the group consisting of chlorpheniramine and its salts, and diphenhydramine and its salts. [7-5] The pharmaceutical formulation according to [7-1] or [7-2], wherein component (B) is one or more selected from the group consisting of chlorpheniramine maleate, diphenhydramine, diphenhydramine hydrochloride, and diphenhydramine salicylate.

[0146] [7-6] The pharmaceutical formulation according to any one of [7-1] to [7-5], wherein the composition further contains water. [7-7] The pharmaceutical formulation according to any one of [7-1] to [7-6], wherein the composition further contains a lower alcohol. [7-8] The pharmaceutical formulation according to [7-7], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [7-9] The pharmaceutical preparation according to any one of [7-1] to [7-8], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [7-10] The pharmaceutical preparation according to any one of [7-1] to [7-9], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [7-11] The container is one of the following (1) or (2): (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The pharmaceutical formulation according to any one of [7-1] to [7-9], wherein [7-12] The pharmaceutical preparation according to any one of [7-1] to [7-9], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [7-13] The pharmaceutical preparation according to any one of [7-1] to [7-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, a gel, an oral liquid, a syrup, and an oral jelly. [7-14] The pharmaceutical preparation according to any one of [7-1] to [7-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [7-15] The pharmaceutical preparation according to any one of [7-1] to [7-12], which is in a dosage form selected from the group consisting of liniments, lotions, aerosols, pump sprays, ointments, creams, and gels. [7-16] The pharmaceutical preparation according to any one of [7-1] to [7-12], which is in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0147] [7-17] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) a compound represented by the general formula (1) or a salt thereof; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [7-18] The method described in [7-17], wherein component (A) is sodium rofecoxib hydrate. [7-19] The method of [7-17] or [7-18], wherein component (B) is one or more selected from the group consisting of ebastine and its salts, oxatomide and its salts, carbinoxamine and its salts, clemastine and its salts, chlorpheniramine and its salts, difeterol and its salts, diphenylpyraline and its salts, diphenhydramine and its salts, cetirizine and its salts, fexofenadine and its salts, bepotastine and its salts, and homochlorcyclizine and its salts. [7-20] The method according to [7-17] or [7-18], wherein component (B) is one or more selected from the group consisting of chlorpheniramine and its salts, and diphenhydramine and its salts. [7-21] The method according to [7-17] or [7-18], wherein component (B) is one or more selected from the group consisting of chlorpheniramine maleate, diphenhydramine, diphenhydramine hydrochloride, and diphenhydramine salicylate.

[0148] [7-22] The method according to any one of [7-17] to [7-21], wherein the composition further contains water. [7-23] The method according to any one of [7-17] to [7-22], wherein the composition further contains a lower alcohol. [7-24] The method according to [7-23], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [7-25] The method according to any one of [7-17] to [7-24], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [7-26] The method according to any one of [7-17] to [7-25], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [7-27] The container is one of the following (1) or (2): (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The method according to any one of [7-17] to [7-25], wherein [7-28] The method according to any one of [7-17] to [7-25], wherein the container is a bottle container or a tube container equipped with a sponge-like application member.

[0149] [8-1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Capsicum or its extract; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container. [8-2] The pharmaceutical formulation according to [8-1], wherein component (A) is sodium loxoprofen hydrate. [8-3] The pharmaceutical preparation according to [8-1] or [8-2], wherein component (B) is one or more selected from the group consisting of chili pepper, chili pepper powder, soft chili pepper extract, dried chili pepper extract, capsaicin, and nonanoic acid vanillylamide (nonylic acid vanillylamide). [8-4] The pharmaceutical preparation according to [8-1] or [8-2], wherein component (B) is one or more selected from the group consisting of soft capsicum extract and nonanoic acid vanillylamide (nonylic acid vanillylamide).

[0150] [8-5] The pharmaceutical formulation according to any one of [8-1] to [8-4], wherein the composition further contains water. [8-6] The pharmaceutical formulation according to any one of [8-1] to [8-5], wherein the composition further contains a lower alcohol. [8-7] The pharmaceutical formulation according to [8-6], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [8-8] The pharmaceutical preparation according to any one of [8-1] to [8-7], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [8-9] The pharmaceutical preparation according to any one of [8-1] to [8-8], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [8-10] The container is one of the following (1) or (2): (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The pharmaceutical formulation according to any one of [8-1] to [8-8], wherein [8-11] The pharmaceutical preparation according to any one of [8-1] to [8-8], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [8-12] The pharmaceutical preparation according to any one of [8-1] to [8-11], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, a gel, an oral liquid, a syrup, and an oral jelly. [8-13] The pharmaceutical preparation according to any one of [8-1] to [8-11], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [8-14] The pharmaceutical preparation according to any one of [8-1] to [8-11], which is in a dosage form selected from the group consisting of liniments, lotions, aerosols, pump sprays, ointments, creams, and gels. [8-15] The pharmaceutical preparation according to any one of [8-1] to [8-11], which is in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0151] [8-16] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) Capsicum or its extract; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [8-17] The method described in [8-16], wherein component (A) is sodium rofecoxib hydrate. [8-18] The method according to [8-16] or [8-17], wherein component (B) is one or more selected from the group consisting of chili pepper, chili pepper powder, soft chili pepper extract, dried chili pepper extract, capsaicin, and nonanoic acid vanillylamide (nonylic acid vanillylamide). [8-19] The method according to [8-16] or [8-17], wherein component (B) is one or more selected from the group consisting of soft chili pepper extract and nonanoic acid vanillylamide (nonylic acid vanillylamide).

[0152] [8-20] The method according to any one of [8-16] to [8-19], wherein the composition further contains water. [8-21] The method according to any one of [8-16] to [8-20], wherein the composition further contains a lower alcohol. [8-22] The method according to [8-21], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [8-23] The method according to any one of [8-16] to [8-22], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [8-24] The method according to any one of [8-16] to [8-23], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [8-25] The container is (1) or (2) of the following: (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The method according to any one of [8-16] to [8-23], wherein [8-26] The method according to any one of [8-16] to [8-23], wherein the container is a bottle container or a tube container equipped with a sponge-like application member.

[0153] [9-1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) organic amines; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above compound and contained in a polyolefin resin container. [9-2] The pharmaceutical formulation according to [9-1], wherein component (A) is sodium loxoprofen hydrate. [9-3] The pharmaceutical formulation according to [9-1] or [9-2], wherein component (B) is an alkanolamine. [9-4] The pharmaceutical formulation according to [9-1] or [9-2], wherein component (B) is one or more selected from the group consisting of diisopropanolamine, diethanolamine, triethanolamine hydrochloride, triisopropanolamine, triethanolamine, trometamol, meglumine, and monoethanolamine. [9-5] The pharmaceutical formulation according to [9-1] or [9-2], wherein component (B) is at least one member selected from the group consisting of triethanolamine and triethanolamine hydrochloride.

[0154] [9-6] The pharmaceutical formulation according to any one of [9-1] to [9-5], wherein the composition further contains water. [9-7] The pharmaceutical formulation according to any one of [9-1] to [9-6], wherein the composition further contains a lower alcohol. [9-8] The pharmaceutical formulation according to [9-7], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [9-9] The pharmaceutical preparation according to any one of [9-1] to [9-8], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [9-10] The pharmaceutical preparation according to any one of [9-1] to [9-9], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [9-11] The container is one of the following (1) or (2): (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The pharmaceutical formulation according to any one of [9-1] to [9-9], wherein [9-12] The pharmaceutical preparation according to any one of [9-1] to [9-9], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [9-13] The pharmaceutical preparation according to any one of [9-1] to [9-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, a gel, an oral liquid, a syrup, and an oral jelly. [9-14] The pharmaceutical preparation according to any one of [9-1] to [9-12], which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [9-15] The pharmaceutical preparation according to any one of [9-1] to [9-12], which is in a dosage form selected from the group consisting of liniments, lotions, topical aerosols, pump sprays, ointments, creams, and gels. [9-16] The pharmaceutical preparation according to any one of [9-1] to [9-12], which is in a dosage form selected from the group consisting of lotions, ointments, creams, and gels.

[0155] [9-17] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) organic amines; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container. [9-18] The method according to [9-17], wherein component (A) is sodium rofecoxib hydrate. [9-19] The method according to [9-17] or [9-18], wherein component (B) is an alkanolamine. [9-20] The method according to [9-17] or [9-18], wherein component (B) is one or more selected from the group consisting of diisopropanolamine, diethanolamine, triethanolamine hydrochloride, triisopropanolamine, triethanolamine, trometamol, meglumine, and monoethanolamine. [9-21] The method according to [9-17] or [9-18], wherein the component (B) is at least one selected from the group consisting of triethanolamine and triethanolamine hydrochloride.

[0156] [9-22] The method according to any one of [9-17] to [9-21], wherein the composition further contains water. [9-23] The method according to any one of [9-17] to [9-22], wherein the composition further contains a lower alcohol. [9-24] The method according to [9-23], wherein the lower alcohol is at least one selected from the group consisting of ethanol and isopropanol. [9-25] The method according to any one of [9-17] to [9-24], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene. [9-26] The method according to any one of [9-17] to [9-25], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container. [9-27] The container is (1) or (2) of the following: (1) A container comprising a container body and an application member, which is used by impregnating the application member with the composition contained in the container body; (2) A container having a flexible container body and a discharge port; The method according to any one of [9-17] to [9-25], wherein [9-28] The method according to any one of [9-17] to [9-25], wherein the container is a bottle container or a tube container provided with a sponge-like application member. [Example]

[0157] 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.

[0158] [Test Example 1-1] Storage test (terpenes) Part 1 Liquid compositions containing the ingredients and amounts shown in Table 1 were prepared and placed in polyethylene or glass containers to prepare the pharmaceutical preparations of Example 1-1, Comparative Examples 1-1, 1-2, or Reference Example 1-1, respectively. The various pharmaceutical preparations obtained were stored in a dark place at 80°C for one week, and the presence or absence of discoloration (yellowing) after storage was evaluated visually. The results were evaluated as follows: no discoloration occurred, O; discoloration occurred, X. The results are shown in Table 1.

[0159] [Table 1]

[0160] Comparing Comparative Example 1-1 with Reference Example 1-1 (without rofecoxib), it became clear that the discoloration observed after storage at 80°C for one week was due to the incorporation of rofecoxib into the liquid composition. Furthermore, by comparing Example 1-1 with Comparative Example 1-1 (stored in a glass container) and Comparative Example 1-2 (no menthol added), it became clear that such discoloration can be suppressed by further adding 1-menthol to the liquid composition and storing it in a polyethylene container.

[0161] From the above test results, it was revealed that discoloration during high-temperature storage can be suppressed by further adding menthol to a liquid or semi-solid composition containing loxoprofen or a salt thereof and storing it in a polyethylene container.

[0162] [Test Example 1-2] Storage test (terpenes) Part 2 A liquid composition containing the ingredients and amounts shown in Table 2 was prepared and placed in a polyethylene container to prepare the pharmaceutical preparation of Example 1-2. The presence or absence of discoloration after storage in a dark place at 80°C for one week was evaluated in the same manner as in Test Example 1-1. The results are shown in Table 2.

[0163] [Table 2]

[0164] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when ethanol was used as the lower alcohol instead of isopropanol.

[0165] [Test Example 1-3] Storage test (terpenes) Part 3 Liquid compositions containing the ingredients and amounts shown in Table 3 were prepared and placed in polypropylene containers to form the pharmaceutical preparations of Examples 1-3 and 1-4. The presence or absence of discoloration after storage in a dark place at 80°C for one week was evaluated in the same manner as in Test Example 1-1. The results are shown in Table 3.

[0166] [Table 3]

[0167] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when a polypropylene container was used instead of a polyethylene container as a polyolefin-based resin container.

[0168] [Test Example 1-4] Storage test (terpenes) Part 4 Liquid compositions containing the ingredients and amounts shown in Table 4 were prepared and placed in polyethylene containers to form the pharmaceutical preparations of Examples 1-5 to 1-8. The presence or absence of discoloration after storage in a dark place at 80°C for one week was evaluated in the same manner as in Test Example 1-1. The results are shown in Table 4.

[0169] [Table 4]

[0170] From the above test results, it was confirmed that discoloration was similarly suppressed during high-temperature storage when dl-camphor or thymol was used instead of l-menthol as the terpene. Since l-menthol and thymol are monocyclic monoterpenoids and dl-camphor is a bicyclic monoterpenoid, it can be reasonably assumed that terpenes have a wide discoloration suppressing effect.

[0171] The results of the above Test Examples 1-1 to 1-4 revealed that discoloration during high-temperature storage can be suppressed by further adding terpenes, such as menthol, camphor, or thymol, to a liquid or semi-solid composition containing loxoprofen or a salt thereof and storing the composition in a container made of a polyolefin resin, such as polyethylene or polypropylene.

[0172] [Test Example 1-5] Storage test (terpenes) Part 5 A liquid composition identical to that contained in the pharmaceutical preparations of Examples 1-2, 1-5 to 1-8 was prepared, and this was impregnated into an open-cell porous material made of low-density polyethylene (MAPS: Inoac Corporation) used as an application member in the container.The composition was then stored in a dark place at 80°C for one week, but no obvious discoloration was observed in any of the compositions.

[0173] [Test Example 2-1] Preservation test (Plants of the genus Lagenaria or their extracts) Part 1 Liquid compositions containing the ingredients and amounts shown in Table 5 were prepared and placed in polyethylene or glass containers to prepare the pharmaceutical preparations of Example 2-1, Comparative Examples 2-1, 2-2, or Reference Example 2-1, respectively. The various pharmaceutical preparations obtained were stored in a dark place at 80°C for 2 weeks, and the presence or absence of discoloration (yellowing) after storage was evaluated visually. The results were evaluated as follows: no discoloration occurred, with ○; discoloration occurred, with ×. The results are shown in Table 5.

[0174] [Table 5]

[0175] Comparing Comparative Example 2-1 with Reference Example 2-1 (no rofecoxib) revealed that the discoloration observed after storage at 80°C for 2 weeks was due to the incorporation of rofecoxib into the liquid composition. Furthermore, by comparing Example 2-1 with Comparative Example 2-1 (contained in a glass container) and Comparative Example 2-2 (no arnica tincture added), it became clear that such discoloration can be suppressed by further adding arnica tincture to the liquid composition and storing it in a polyethylene container.

[0176] From the above test results, it became clear that discoloration during high-temperature storage can be suppressed by further adding a plant of the genus Aster, such as arnica tincture, or an extract thereof to a liquid or semi-solid composition containing rofecoxib or its salt, and storing it in a polyethylene container.

[0177] [Test Example 2-2] Preservation test (Plants of the genus Lagenaria or their extracts) Part 2 A liquid composition containing the ingredients and amounts shown in Table 6 was prepared and placed in a polypropylene container to give the pharmaceutical formulation of Example 2-2. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 2-1. The results are shown in Table 6.

[0178] [Table 6]

[0179] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when a polypropylene container was used instead of a polyethylene container as a polyolefin-based resin container.

[0180] The results of the above Test Examples 2-1 to 2-2 revealed that discoloration during high-temperature storage can be suppressed by further adding a plant of the genus Lagophthalmus, such as arnica tincture, or an extract thereof to a liquid or semi-solid composition containing rofecoxib or a salt thereof, and storing the composition in a container made of a polyolefin resin, such as polyethylene or polypropylene.

[0181] [Test Example 3-1] Storage test (polyhydric alcohol) Part 1 Liquid compositions containing the ingredients and amounts shown in Table 7 were prepared and placed in polypropylene or glass containers to prepare the pharmaceutical preparations of Example 3-1, Comparative Examples 3-1, 3-2, or Reference Example 3-1, respectively. The various pharmaceutical preparations obtained were stored in a dark place at 80°C for one week, and the presence or absence of discoloration (yellowing) was evaluated visually after storage for three days and one week. The results were evaluated as follows: no discoloration occurred, with ○; discoloration occurred, with ×. The results are shown in Table 7.

[0182] [Table 7]

[0183] Comparing Comparative Example 3-1 with Reference Example 3-1 (no rofecoxib) revealed that the discoloration observed after storage at 80°C for one week was due to the inclusion of rofecoxib in the liquid composition. Furthermore, by comparing Comparative Example 3-1 (containing 1,3-butylene glycol) with Comparative Example 3-2 (not containing 1,3-butylene glycol), it was confirmed that although the incorporation of 1,3-butylene glycol into the composition inhibited discoloration after storage for three days and exerted some discoloration inhibition effect, this effect was not sufficient, and discoloration occurred after storage for one week. On the other hand, by comparing Example 3-1 (contained in a polypropylene container, containing 1,3-butylene glycol) with Comparative Example 3-1 (contained in a glass container, containing 1,3-butylene glycol), it was confirmed that by incorporating 1,3-butylene glycol into the composition and then storing it in a polypropylene container, discoloration after storage for one week was also suppressed, and a sufficient discoloration suppression effect was exerted.

[0184] [Test Example 3-2] Storage test (polyhydric alcohol) Part 2 Liquid compositions containing the ingredients and amounts shown in Table 8 were prepared and placed in polypropylene containers to form the pharmaceutical preparations of Examples 3-2 and 3-3. The presence or absence of discoloration after storage in a dark place at 80°C for one week was evaluated in the same manner as in Test Example 3-1. The results are shown in Table 8.

[0185] [Table 8]

[0186] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed when ethanol was used instead of isopropanol as the lower alcohol or when no lower alcohol was added.

[0187] The results of the above Test Examples 3-1 and 3-2 revealed that discoloration during high-temperature storage can be suppressed by further adding a polyhydric alcohol, such as 1,3-butylene glycol, to a liquid or semi-solid composition containing rofecoxib or a salt thereof and storing the composition in a container made of a polyolefin resin, such as polypropylene.

[0188] [Test Example 4-1] Storage test (cellulose) Part 1 Liquid compositions containing the ingredients and amounts shown in Table 9 were prepared and placed in polypropylene or glass containers to prepare the pharmaceutical preparations of Example 4-1, Comparative Examples 4-1 and 4-2, or Reference Example 4-1, respectively. The various pharmaceutical preparations obtained were stored in a dark place at 80°C for one week, and the presence or absence of discoloration (yellowing) was evaluated visually after storage for three days and one week. The results were evaluated as follows: no discoloration occurred, with ○; discoloration occurred, with ×. The results are shown in Table 9.

[0189] [Table 9]

[0190] Comparing Comparative Example 4-1 with Reference Example 4-1 (no rofecoxib) revealed that the discoloration observed after storage at 80°C for one week was due to the incorporation of rofecoxib into the liquid composition. Furthermore, by comparing Comparative Example 4-1 (hypromellose added) with Comparative Example 4-2 (hypromellose not added), it was confirmed that although the addition of hypromellose to the composition inhibited discoloration after storage for 3 days and exerted some discoloration inhibition effect, this effect was not sufficient, and discoloration occurred after storage for 1 week. On the other hand, by comparing Example 4-1 (contained in a polypropylene container, containing hypromellose) with Comparison Example 4-1 (contained in a glass container, containing hypromellose), it was confirmed that by incorporating hypromellose into the composition and then storing it in a polypropylene container, discoloration after storage for one week was suppressed, and sufficient discoloration suppression effect was exerted.

[0191] [Test Example 4-2] Storage test (cellulose) Part 2 Liquid compositions containing the ingredients and amounts shown in Table 10 were prepared and placed in polypropylene containers to form the pharmaceutical preparations of Examples 4-2 and 4-3. The presence or absence of discoloration after storage in a dark place at 80°C for 1 week was evaluated in the same manner as in Test Example 4-1. The results are shown in Table 10.

[0192] [Table 10]

[0193] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed when ethanol was used instead of isopropanol as the lower alcohol or when no lower alcohol was added.

[0194] The results of the above Test Examples 4-1 to 4-2 revealed that discoloration during high-temperature storage can be suppressed by further adding a cellulose such as hypromellose to a liquid or semi-solid composition containing rofecoxib or a salt thereof and storing it in a container made of a polyolefin resin such as polypropylene.

[0195] [Test Example 5-1] Storage test (tocopherols) Part 1 Liquid compositions containing the ingredients and amounts shown in Table 11 were prepared and placed in polyethylene or glass containers to give pharmaceutical preparations of Example 5-1, Comparative Examples 5-1 and 5-2, respectively. The various pharmaceutical preparations obtained were stored in a dark place at 80°C for one week, and the presence or absence of discoloration (yellowing) was evaluated visually after storage for three days and one week. The results were evaluated as follows: no discoloration occurred, with ○; discoloration occurred, with ×. The results are shown in Table 11.

[0196] [Table 11]

[0197] Comparing Comparative Example 5-1 (contained in a polyethylene container) with Comparative Example 5-2 (contained in a glass container), it was confirmed that storing the composition in a polyethylene container suppressed discoloration after storage for 3 days, and exerted some discoloration suppression effect, but that this effect was not sufficient, and discoloration occurred after storage for 1 week. On the other hand, by comparing Example 5-1 (containing dl-α-tocopherol acetate, contained in a polyethylene container) with Comparison Example 5-1 (containing no dl-α-tocopherol acetate, contained in a polyethylene container), it was confirmed that by further containing dl-α-tocopherol acetate in the composition and then containing it in a polyethylene container, discoloration after storage for one week was also suppressed, and sufficient discoloration suppression effect was exerted.

[0198] From the above test results, it became clear that discoloration during high-temperature storage can be suppressed by further adding tocopherols to a liquid or semi-solid composition containing rofecoxib or a salt thereof and storing it in a container made of a polyolefin resin.

[0199] [Test Example 5-2] Storage test (tocopherols) Part 2 Liquid compositions containing the ingredients and amounts shown in Table 12 were prepared and placed in polyethylene or glass containers to form the pharmaceutical preparations of Example 5-2, Comparative Examples 5-3 and 5-4, or Reference Example 5-1, respectively. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 5-1. The results are shown in Table 12.

[0200] [Table 12]

[0201] By comparing Comparative Example 5-3 with Reference Example 5-1 (no rofecoxib), it was confirmed that the discoloration observed after storage at 80°C for 2 weeks was due to the incorporation of rofecoxib into the liquid composition. Furthermore, by comparing Example 5-2 with Comparative Example 5-3 (contained in a glass container) and Comparative Example 5-4 (no dl-α-tocopherol acetate added), it was confirmed that such discoloration can be suppressed by further adding dl-α-tocopherol acetate to the liquid composition and storing it in a polyethylene container.

[0202] [Test Example 5-3] Storage test (tocopherols) Part 3 A liquid composition containing the ingredients and amounts shown in Table 13 was prepared and placed in a polypropylene container to give the pharmaceutical formulation of Example 5-3. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 5-1. The results are shown in Table 13.

[0203] [Table 13]

[0204] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when a polypropylene container was used instead of a polyethylene container as a polyolefin-based resin container.

[0205] [Test Example 5-4] Storage test (tocopherols) Part 4 A liquid composition identical to that contained in the pharmaceutical preparation of Example 5-1 was prepared and impregnated into an open-cell porous material made of low-density polyethylene (MAPS: Inoac Corporation), which was used as an application member in the container. The composition was then stored in a dark place at 80°C for 1 week, but no obvious discoloration was observed.

[0206] [Test Example 6-1] Storage test (glycyrrhetinic acid) Part 1 Liquid compositions containing the ingredients and amounts shown in Table 14 were prepared and placed in polyethylene or glass containers to give pharmaceutical preparations of Example 6-1, Comparative Examples 6-1 and 6-2, respectively. The various pharmaceutical preparations obtained were stored in a dark place at 80°C for one week, and the presence or absence of discoloration (yellowing) was evaluated visually after storage for three days and one week. The results were evaluated as follows: no discoloration occurred, with ○; discoloration occurred, with ×. The results are shown in Table 14.

[0207] [Table 14]

[0208] Comparing Comparative Example 6-1 (contained in a polyethylene container) with Comparative Example 6-2 (contained in a glass container), it was confirmed that storing the composition in a polyethylene container suppressed discoloration after storage for 3 days, and exerted some discoloration suppression effect, but that this effect was not sufficient, and discoloration occurred after storage for 1 week. On the other hand, by comparing Example 6-1 (containing glycyrrhetinic acid, housed in a polyethylene container) with Comparative Example 6-1 (containing no glycyrrhetinic acid, housed in a polyethylene container), it was confirmed that by further adding glycyrrhetinic acid to the composition and then housing it in a polyethylene container, discoloration after storage for one week was also suppressed, and a sufficient discoloration suppression effect was exerted.

[0209] [Test Example 6-2] Storage test (glycyrrhetinic acid) Part 2 A liquid composition containing the ingredients and amounts shown in Table 15 was prepared and placed in a polyethylene container to give the pharmaceutical formulation of Example 6-2. The presence or absence of discoloration after storage in a dark place at 80°C for 1 week was evaluated in the same manner as in Test Example 6-1. The results are shown in Table 15.

[0210] [Table 15]

[0211] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when ethanol was used as the lower alcohol instead of isopropanol.

[0212] The results of Test Examples 6-1 and 6-2 above demonstrate that discoloration during high-temperature storage can be suppressed by further adding glycyrrhetinic acids to a liquid or semi-solid composition containing loxoprofen or a salt thereof and storing it in a container made of a polyolefin resin.

[0213] [Test Example 6-3] Storage test (glycyrrhetinic acid) Part 3 Liquid compositions containing the ingredients and amounts shown in Table 16 were prepared and placed in polyethylene or glass containers to form the pharmaceutical preparations of Example 6-3, Comparative Examples 6-3 and 6-4, or Reference Example 6-1, respectively. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 6-1. The results are shown in Table 16.

[0214] [Table 16]

[0215] By comparing Comparative Example 6-3 with Reference Example 6-1 (no rofecoxib), it was confirmed that the discoloration observed after storage at 80°C for 2 weeks was due to the incorporation of rofecoxib into the liquid composition. Furthermore, by comparing Example 6-3 with Comparative Example 6-3 (contained in a glass container) and Comparative Example 6-4 (no glycyrrhetinic acid added), it was confirmed that such discoloration can be suppressed by further adding glycyrrhetinic acid to the liquid composition and storing it in a polyethylene container.

[0216] [Test Example 6-4] Storage test (glycyrrhetinic acid) Part 4 Liquid compositions containing the ingredients and amounts shown in Table 17 were prepared and placed in polypropylene containers to form the pharmaceutical preparations of Examples 6-4 and 6-5. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 6-1. The results are shown in Table 17.

[0217] [Table 17]

[0218] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when a polypropylene container was used instead of a polyethylene container as a polyolefin-based resin container.

[0219] [Test Example 6-5] Storage test (glycyrrhetinic acid) Part 5 A liquid composition identical to that contained in the pharmaceutical preparations of Examples 6-1 and 6-2 was prepared, and this was impregnated into an open-cell porous material made of low-density polyethylene (MAPS: Inoac Corporation), which was used as an application member in the container.The composition was then stored in a dark place at 80°C for one week, but no obvious discoloration was observed.

[0220] [Test Example 7-1] Storage test (compound represented by general formula (1) or its salt) Part 1 Liquid compositions containing the ingredients and amounts shown in Table 18 were prepared and placed in polyethylene or glass containers to give pharmaceutical preparations of Example 7-1, Comparative Examples 7-1 and 7-2, respectively. The various pharmaceutical preparations obtained were stored in a dark place at 80°C for one week, and the presence or absence of discoloration (yellowing) was evaluated visually after storage for three days and one week. The results were evaluated as follows: no discoloration occurred, with ○; discoloration occurred, with ×. The results are shown in Table 18.

[0221] [Table 18]

[0222] Comparing Comparative Example 7-1 (stored in a polyethylene container) with Comparative Example 7-2 (stored in a glass container), it was confirmed that storing the composition in a polyethylene container suppressed discoloration after storage for three days, and exerted some discoloration suppression effect, but that this effect was not sufficient, and discoloration occurred after storage for one week. On the other hand, by comparing Example 7-1 (containing chlorpheniramine, housed in a polyethylene container) with Comparative Example 7-1 (housed in a polyethylene container), it was confirmed that by further adding chlorpheniramine to the composition and then housing it in a polyethylene container, discoloration after storage for one week was also suppressed, and a sufficient discoloration suppression effect was exerted.

[0223] From the above test results, it became clear that discoloration during high-temperature storage can be suppressed by further adding chlorpheniramine or a salt thereof to a liquid or semi-solid composition containing ibuprofen or a salt thereof and storing it in a container made of a polyolefin resin.

[0224] [Test Example 7-2] Storage test (compound represented by general formula (1) or its salt) Part 2 Liquid compositions containing the ingredients and amounts shown in Table 19 were prepared and placed in polyethylene or glass containers to give pharmaceutical preparations of Example 7-2, Comparative Examples 7-3, and 7-4, respectively. The presence or absence of discoloration after storage in a dark place at 80°C for 3 days and 1 week was evaluated in the same manner as in Test Example 7-1. The results are shown in Table 19.

[0225] [Table 19]

[0226] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed when diphenhydramine hydrochloride was added instead of chlorpheniramine maleate.

[0227] [Test Example 7-3] Storage test (compound represented by general formula (1) or its salt) Part 3 Liquid compositions containing the ingredients and amounts shown in Table 20 were prepared and placed in polyethylene containers to form the pharmaceutical preparations of Examples 7-3 and 7-4. The presence or absence of discoloration after storage in a dark place at 80°C for 1 week was evaluated in the same manner as in Test Example 7-1. The results are shown in Table 20.

[0228] [Table 20]

[0229] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when ethanol was used as the lower alcohol instead of isopropanol.

[0230] The results of the above Test Examples 7-1 to 7-3 revealed that discoloration during high-temperature storage can be suppressed by further adding a compound represented by the general formula (1) or a salt thereof, such as chlorpheniramine or a salt thereof, or diphenhydramine or a salt thereof, to a liquid or semi-solid composition containing loxoprofen or a salt thereof, and storing the composition in a container made of a polyolefin resin.

[0231] [Test Example 7-4] Storage test (compound represented by general formula (1) or its salt) Part 4 Liquid compositions containing the ingredients and amounts shown in Table 21 were prepared and placed in polyethylene or glass containers to form the pharmaceutical preparations of Example 7-5, Comparative Examples 7-5 and 7-6, or Reference Example 7-1, respectively. The presence or absence of discoloration after storage in a dark place at 80°C for 3 weeks was evaluated in the same manner as in Test Example 7-1. The results are shown in Table 21.

[0232] [Table 21]

[0233] By comparing Comparative Example 7-5 with Reference Example 7-1 (no rofecoxib), it was confirmed that the discoloration observed after storage at 80°C for 3 weeks was due to the incorporation of rofecoxib into the liquid composition. Furthermore, by comparing Example 7-5 with Comparative Example 7-5 (packaged in a glass container) and Comparative Example 7-6 (no chlorpheniramine maleate added), it was confirmed that such discoloration can be suppressed by further adding chlorpheniramine maleate to the liquid composition and packing it in a polyethylene container.

[0234] [Test Example 7-5] Storage test (compound represented by general formula (1) or its salt) Part 5 Liquid compositions containing the ingredients and amounts shown in Table 22 were prepared and placed in polypropylene containers to form the pharmaceutical preparations of Examples 7-6 to 7-9, respectively. The presence or absence of discoloration after storage in a dark place at 80°C for 1 week was evaluated in the same manner as in Test Example 7-1. The results are shown in Table 22.

[0235] [Table 22]

[0236] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when a polypropylene container was used instead of a polyethylene container as a polyolefin-based resin container.

[0237] [Test Example 7-6] Storage test (compound represented by general formula (1) or its salt) Part 6 A liquid composition identical to that contained in the pharmaceutical preparations of Examples 7-3 and 7-4 was prepared, and this was impregnated into an open-cell porous material made of low-density polyethylene (MAPS: Inoac Corporation), which was used as an application member in the container, and then stored in a dark place at 80°C for 1 week, but no obvious discoloration was observed in either composition.

[0238] [Test Example 8-1] Preservation test (chili pepper or its extract) Part 1 Liquid compositions containing the ingredients and amounts shown in Table 23 were prepared and placed in polyethylene or glass containers to give pharmaceutical preparations of Example 8-1, Comparative Examples 8-1 and 8-2, respectively. The various pharmaceutical preparations obtained were stored in a dark place at 80°C for one week, and the presence or absence of discoloration (yellowing) was evaluated visually after storage for three days and one week. The results were evaluated as follows: no discoloration occurred, with ○; discoloration occurred, with ×. The results are shown in Table 23.

[0239] [Table 23]

[0240] Comparing Comparative Example 8-1 (contained in a polyethylene container) with Comparative Example 8-2 (contained in a glass container), it was confirmed that storing the composition in a polyethylene container suppressed discoloration after storage for 3 days, and exerted some discoloration suppression effect, but that this effect was not sufficient, and discoloration occurred after storage for 1 week. On the other hand, by comparing Example 8-1 (containing soft chili pepper extract and stored in a polyethylene container) with Comparative Example 8-1 (stored in a polyethylene container), it was confirmed that by further adding soft chili pepper extract to the composition and storing it in a polyethylene container, discoloration after storage for one week was also suppressed, and sufficient discoloration suppression effect was exerted.

[0241] From the above test results, it became clear that discoloration during high-temperature storage can be suppressed by further adding chili pepper or an extract thereof to a liquid or semi-solid composition containing rofecoxib or its salt and storing it in a container made of polyolefin resin.

[0242] [Test Example 8-2] Preservation test (chili pepper or its extract) Part 2 Liquid compositions containing the ingredients and amounts shown in Table 24 were prepared and placed in polyethylene or glass containers to give pharmaceutical preparations of Example 8-2, Comparative Examples 8-3, and 8-4, respectively. The presence or absence of discoloration after storage in a dark place at 80°C for 3 days and 1 week was evaluated in the same manner as in Test Example 8-1. The results are shown in Table 24.

[0243] [Table 24]

[0244] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed when nonanoic acid vanillylamide was added instead of soft chili pepper extract.

[0245] [Test Example 8-3] Preservation test (chili pepper or its extract) Part 3 A liquid composition containing the ingredients and amounts shown in Table 25 was prepared and placed in a polyethylene container to give the pharmaceutical preparation of Example 8-3. The presence or absence of discoloration after storage in a dark place at 80°C for 1 week was evaluated in the same manner as in Test Example 8-1. The results are shown in Table 25.

[0246] [Table 25]

[0247] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when ethanol was used as the lower alcohol instead of isopropanol.

[0248] The results of the above test examples 8-1 to 8-3 revealed that discoloration during high-temperature storage can be suppressed by further adding chili pepper or its extract, such as soft chili pepper extract or nonanoic acid vanillylamide, to a liquid or semi-solid composition containing rofecoxib or its salt and storing it in a container made of polyolefin resin.

[0249] [Test Example 8-4] Preservation test (chili pepper or its extract) Part 4 Liquid compositions containing the ingredients and amounts shown in Table 26 were prepared and placed in polyethylene or glass containers to form the pharmaceutical preparations of Example 8-4, Comparative Examples 8-5 and 8-6, or Reference Example 8-1, respectively. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 8-1. The results are shown in Table 26.

[0250] [Table 26]

[0251] By comparing Comparative Example 8-5 with Reference Example 8-1 (no rofecoxib), it was confirmed that the discoloration observed after storage at 80°C for 2 weeks was due to the incorporation of rofecoxib into the liquid composition. Furthermore, by comparing Example 8-4 with Comparative Example 8-5 (contained in a glass container) and Comparative Example 8-6 (no nonanoic acid vanillylamide added), it was confirmed that such discoloration can be suppressed by further adding nonanoic acid vanillylamide to the liquid composition and storing it in a polyethylene container.

[0252] [Test Example 8-5] Preservation test (chili pepper or its extract) Part 5 Liquid compositions containing the ingredients and amounts shown in Table 27 were prepared and placed in polypropylene containers to form the pharmaceutical preparations of Examples 8-5 and 8-6. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 8-1. The results are shown in Table 27.

[0253] [Table 27]

[0254] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when a polypropylene container was used instead of a polyethylene container as a polyolefin-based resin container.

[0255] [Test Example 8-6] Preservation test (chili pepper or its extract) Part 6 Liquid compositions identical to those contained in the pharmaceutical preparations of Examples 8-1 and 8-3 were prepared and impregnated into an open-cell porous material made of low-density polyethylene (MAPS: Inoac Corporation), which was used as an application member in the container, and then stored in a dark place at 80°C for 1 week, but no obvious discoloration was observed in either composition.

[0256] [Test Example 9-1] Storage test (organic amine) Part 1 Liquid compositions containing the ingredients and amounts shown in Table 28 were prepared and placed in polypropylene or glass containers to give pharmaceutical preparations of Example 9-1, Comparative Examples 9-1 and 9-2, respectively. The various pharmaceutical preparations obtained were stored in a dark place at 80°C for one week, and the presence or absence of discoloration (yellowing) was evaluated visually after storage for three days and one week. The results were evaluated as follows: no discoloration occurred, with ○; discoloration occurred, with ×. The results are shown in Table 28.

[0257] [Table 28]

[0258] Comparing the test results of Comparative Example 9-1 (containing triethanolamine) and Comparative Example 9-2 (not containing triethanolamine), it was confirmed that although the incorporation of triethanolamine into the composition inhibited discoloration after storage for three days and exerted some discoloration inhibition effect, this effect was not sufficient, and discoloration occurred after storage for one week. On the other hand, by comparing Example 9-1 (contained in a polypropylene container, containing triethanolamine) with Comparative Example 9-1 (contained in a glass container, containing triethanolamine), it was confirmed that by adding triethanolamine to the composition and then storing it in a polypropylene container, discoloration after storage for one week was also suppressed, and a sufficient discoloration suppression effect was exerted. That is, it was found that discoloration of the composition over time or during storage at high temperatures can be suppressed by blending an organic amine into the composition and storing it in a container made of a polyolefin resin.

[0259] [Test Example 9-2] Storage test (organic amine) Part 2 Liquid compositions containing the ingredients and amounts shown in Table 29 were prepared and placed in polypropylene containers to form the pharmaceutical preparations of Examples 9-2 and 9-3. The presence or absence of discoloration after storage in a dark place at 80°C for 1 week was evaluated in the same manner as in Test Example 9-1. The results are shown in Table 29.

[0260] [Table 29]

[0261] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed when ethanol was used instead of isopropanol as the lower alcohol or when no lower alcohol was added.

[0262] The results of the above Test Examples 9-1 to 9-2 revealed that by further adding an organic amine, such as triethanolamine, to a liquid or semi-solid composition containing rofecoxib or a salt thereof and storing the composition in a container made of a polyolefin resin, such as polypropylene, discoloration of the composition over time or during storage at high temperatures can be suppressed.

[0263] An example of the production of a pharmaceutical formulation is shown below. Note that the content of the extract of a plant of the genus Lacertilia is expressed as the amount (g) of the crude drug unless otherwise specified.

[0264] Production Example 1-1 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 30 below per 100 g were prepared by conventional methods, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 1-1-1 to 1-1-8, respectively.

[0265] [Table 30]

[0266] Production Example 1-2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 30 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 1-2-1 to 1-2-8, respectively.

[0267] Production Example 1-3 (Lotion) Liquid compositions (Prescription Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 31 below per 100 g were prepared by a conventional method, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 1-3-1 to 1-3-8, respectively.

[0268] [Table 31]

[0269] Production Example 1-4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 31 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 1-4-1 to 1-4-8, respectively.

[0270] Production Example 1-5 (Gel) Semi-solid compositions (Prescription Examples 17 to 24) containing the ingredients and amounts (g) shown in Table 32 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, aluminum foil on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (gels) of Preparation Examples 1-5-1 to 1-5-8, respectively.

[0271] [Table 32]

[0272] Manufacturing Example 1-6 (Ointment) Semi-solid compositions (Prescription Examples 25 to 32) containing the ingredients and amounts (g) shown in Table 33 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a high-density polyethylene film as the innermost layer, a polyethylene terephthalate film on the outer side (middle layer), and a high-density polyethylene film on the outer side of that, to give pharmaceutical preparations (ointments) of Preparation Examples 1-6-1 to 1-6-8, respectively.

[0273] [Table 33]

[0274] Manufacturing Example 1-7 (Cream) Semi-solid compositions (Prescription Examples 33 to 40) containing the ingredients and amounts (g) shown in Table 34 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (creams) of Preparation Examples 1-7-1 to 1-7-8, respectively.

[0275] [Table 34]

[0276] Preparation Example 1-8 (Oral liquid) Liquid compositions (Prescription Examples 41 to 48) containing the ingredients and amounts (mg) shown in Table 35 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to give pharmaceutical preparations (oral liquids) of Preparation Examples 1-8-1 to 1-8-8, respectively.

[0277] [Table 35]

[0278] Manufacturing Example 2-1 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 36 below per 100 g were prepared by conventional methods, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 2-1-1 to 2-1-8, respectively.

[0279] [Table 36]

[0280] Production Example 2-2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 36 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 2-2-1 to 2-2-8, respectively.

[0281] Manufacturing Example 2-3 (Lotion) Liquid compositions (Prescription Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 37 below per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 2-3-1 to 2-3-8, respectively.

[0282] [Table 37]

[0283] Production Example 2-4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 37 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 2-4-1 to 2-4-8, respectively.

[0284] Production Example 2-5 (Gel) Semi-solid compositions (Prescription Examples 17 to 24) containing the ingredients and amounts (g) shown in Table 38 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, aluminum foil on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (gels) of Preparation Examples 2-5-1 to 2-5-8, respectively.

[0285] [Table 38]

[0286] Manufacturing Example 2-6 (Ointment) Semi-solid compositions (Prescription Examples 25 to 32) containing the ingredients and amounts (g) shown in Table 39 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a high-density polyethylene film as the innermost layer, a polyethylene terephthalate film on the outer side (middle layer), and a high-density polyethylene film on the outer side of that, to give pharmaceutical preparations (ointments) of Preparation Examples 2-6-1 to 2-6-8, respectively.

[0287] [Table 39]

[0288] Manufacturing Example 2-7 (Cream) Semi-solid compositions (Prescription Examples 33 to 40) containing the ingredients and amounts (g) shown in Table 40 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (creams) of Preparation Examples 2-7-1 to 2-7-8, respectively.

[0289] [Table 40]

[0290] Preparation Example 2-8 (Oral liquid) Liquid compositions (Prescription Examples 41 to 48) containing the ingredients and amounts (mg) shown in Table 41 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to give the pharmaceutical preparations (oral liquids) of Preparation Examples 2-8-1 to 2-8-8, respectively.

[0291] [Table 41]

[0292] Production Example 3-1 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 42 below per 100 g were prepared by a conventional method, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 3-1-1 to 3-1-8, respectively.

[0293] [Table 42]

[0294] Production Example 3-2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 42 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 3-2-1 to 3-2-8, respectively.

[0295] Production Example 3-3 (Lotion) Liquid compositions (Prescription Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 43 below per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 3-3-1 to 3-3-8, respectively.

[0296] [Table 43]

[0297] Production Example 3-4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 43 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 3-4-1 to 3-4-8, respectively.

[0298] Production Example 3-5 (Gel) Semi-solid compositions (Prescription Examples 17 to 24) containing the ingredients and amounts (g) shown in Table 44 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, aluminum foil as the outer layer (middle layer), and a low-density polyethylene film further laminated on the outer layer, to give pharmaceutical preparations (gels) of Preparation Examples 3-5-1 to 3-5-8, respectively.

[0299] [Table 44]

[0300] Manufacturing Example 3-6 (Cream) Semi-solid compositions (Prescription Examples 25 to 32) containing the ingredients and amounts (g) shown in Table 45 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (creams) of Preparation Examples 3-6-1 to 3-6-8, respectively.

[0301] [Table 45]

[0302] Manufacturing Example 3-7 (Oral liquid) Liquid compositions (Prescription Examples 33 to 40) containing the ingredients and amounts (mg) shown in Table 46 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to form the pharmaceutical preparations (oral liquids) of Preparation Examples 3-7-1 to 3-7-8, respectively.

[0303] [Table 46]

[0304] Manufacturing Example 4-1 (Lotion) Liquid compositions (Prescription Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 47 below per 100 g were prepared by a conventional method, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 4-1-1 to 4-1-8, respectively.

[0305] [Table 47]

[0306] Production Example 4-2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 47 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 4-2-1 to 4-2-8, respectively.

[0307] Manufacturing Example 4-3 (Lotion) Liquid compositions (Prescription Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 48 below per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 4-3-1 to 4-3-8, respectively.

[0308] [Table 48]

[0309] Production Example 4-4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 48 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 4-4-1 to 4-4-8, respectively.

[0310] Production Example 4-5 (Gel) Semi-solid compositions (Prescription Examples 17 to 24) containing the ingredients and amounts (g) shown in Table 49 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, aluminum foil as the outer layer (middle layer), and a low-density polyethylene film further laminated on the outer layer, to give pharmaceutical preparations (gels) of Preparation Examples 4-5-1 to 4-5-8, respectively.

[0311] [Table 49]

[0312] Manufacturing Example 4-6 (Ointment) Semi-solid compositions (Prescription Examples 25 to 32) containing the ingredients and amounts (g) shown in Table 50 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a high-density polyethylene film as the innermost layer, a polyethylene terephthalate film on the outer side (middle layer), and a high-density polyethylene film on the outer side of that, to give pharmaceutical preparations (ointments) of Preparation Examples 4-6-1 to 4-6-8, respectively.

[0313] [Table 50]

[0314] Manufacturing Example 4-7 (Cream) Semi-solid compositions (Prescription Examples 33 to 40) containing the ingredients and amounts (g) shown in Table 51 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (creams) of Preparation Examples 4-7-1 to 4-7-8, respectively.

[0315] [Table 51]

[0316] Preparation Example 4-8 (Oral liquid) Liquid compositions (Prescription Examples 41 to 48) containing the ingredients and amounts (mg) shown in Table 52 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to give pharmaceutical preparations (oral liquids) of Preparation Examples 4-8-1 to 4-8-8, respectively.

[0317] [Table 52]

[0318] Production Example 5-1 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 53 below per 100 g were prepared by conventional methods, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 5-1-1 to 5-1-8, respectively.

[0319] [Table 53]

[0320] Production Example 5-2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 53 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 5-2-1 to 5-2-8, respectively.

[0321] Production Example 5-3 (Lotion) Liquid compositions (Prescription Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 54 below per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 5-3-1 to 5-3-8, respectively.

[0322] [Table 54]

[0323] Production Example 5-4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 54 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 5-4-1 to 5-4-8, respectively.

[0324] Production Example 5-5 (Gel) Semi-solid compositions (Prescription Examples 17 to 24) containing the ingredients and amounts (g) shown in Table 55 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, aluminum foil on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (gels) of Preparation Examples 5-5-1 to 5-5-8, respectively.

[0325] [Table 55]

[0326] Manufacturing Example 5-6 (Ointment) Semi-solid compositions (Prescription Examples 25 to 32) containing the ingredients and amounts (g) shown in Table 56 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a high-density polyethylene film as the innermost layer, a polyethylene terephthalate film on the outer side (middle layer), and a high-density polyethylene film on the outer side of that, to give pharmaceutical preparations (ointments) of Preparation Examples 5-6-1 to 5-6-8, respectively.

[0327] [Table 56]

[0328] Manufacturing Example 5-7 (Cream) Semi-solid compositions (Prescription Examples 33 to 40) containing the ingredients and amounts (g) shown in Table 57 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (creams) of Preparation Examples 5-7-1 to 5-7-8, respectively.

[0329] [Table 57]

[0330] Preparation Example 5-8 (Oral liquid) Liquid compositions (Prescription Examples 41 to 48) containing the ingredients and amounts (mg) shown in Table 58 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to give pharmaceutical preparations (oral liquids) of Preparation Examples 5-8-1 to 5-8-8, respectively.

[0331] [Table 58]

[0332] Production Example 6-1 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) listed in Table 59 below per 100 g were prepared in a conventional manner, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 6-1-1 to 6-1-8, respectively.

[0333] [Table 59]

[0334] Production Example 6-2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 59 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 6-2-1 to 6-2-8, respectively.

[0335] Production Example 6-3 (Lotion) Liquid compositions (Prescription Examples 9 to 16) containing the ingredients and amounts (g) listed in Table 60 below per 100 g were prepared in a conventional manner, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 6-3-1 to 6-3-8, respectively.

[0336] [Table 60]

[0337] Production Example 6-4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) listed in Table 60 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 6-4-1 to 6-4-8, respectively.

[0338] Production Example 6-5 (Gel) Semi-solid compositions (Prescription Examples 17 to 24) containing the ingredients and amounts (g) shown in Table 61 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, aluminum foil on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (gels) of Preparation Examples 6-5-1 to 6-5-8, respectively.

[0339] [Table 61]

[0340] Manufacturing Example 6-6 (Ointment) Semi-solid compositions (Prescription Examples 25 to 32) containing the ingredients and amounts (g) listed in Table 62 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a high-density polyethylene film as the innermost layer, a polyethylene terephthalate film on the outer side (middle layer), and a high-density polyethylene film on the outer side of that, to produce pharmaceutical preparations (ointments) of Preparation Examples 6-6-1 to 6-6-8, respectively.

[0341] [Table 62]

[0342] Manufacturing Example 6-7 (Cream) Semi-solid compositions (Prescription Examples 33 to 40) containing the ingredients and amounts (g) shown in Table 63 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (creams) of Preparation Examples 6-7-1 to 6-7-8, respectively.

[0343] [Table 63]

[0344] Preparation Example 6-8 (Oral liquid) Liquid compositions (Prescription Examples 41 to 48) containing the ingredients and amounts (mg) shown in Table 64 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to give pharmaceutical preparations (oral liquids) of Preparation Examples 6-8-1 to 6-8-8, respectively.

[0345] [Table 64]

[0346] Production Example 7-1 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) listed in Table 65 below per 100 g were prepared in a conventional manner, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 7-1-1 to 7-1-8, respectively.

[0347] [Table 65]

[0348] Production Example 7-2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) listed in Table 65 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 7-2-1 to 7-2-8, respectively.

[0349] Production Example 7-3 (Lotion) Liquid compositions (Prescription Examples 9 to 16) containing the ingredients and amounts (g) listed in Table 66 below per 100 g were prepared in a conventional manner, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 7-3-1 to 7-3-8, respectively.

[0350] [Table 66]

[0351] Manufacturing Example 7-4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) listed in Table 66 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 7-4-1 to 7-4-8, respectively.

[0352] Production Example 7-5 (Gel) Semi-solid compositions (Prescription Examples 17 to 24) containing the ingredients and amounts (g) shown in Table 67 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a low-density polyethylene film as the innermost layer, aluminum foil on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (gels) of Preparation Examples 7-5-1 to 7-5-8, respectively.

[0353] [Table 67]

[0354] Manufacturing Example 7-6 (Ointment) Semi-solid compositions (Prescription Examples 25 to 32) containing the ingredients and amounts (g) listed in Table 68 below per 100 g were prepared in a conventional manner, and placed in laminated film tube containers (laminated tubes) with a high-density polyethylene film as the innermost layer, a polyethylene terephthalate film on the outer side (middle layer), and a high-density polyethylene film on the outer side of that, to produce pharmaceutical preparations (ointments) of Preparation Examples 7-6-1 to 7-6-8, respectively.

[0355] [Table 68]

[0356] Manufacturing Example 7-7 (Cream) Semi-solid compositions (Prescription Examples 33 to 40) containing the ingredients and amounts (g) shown in Table 69 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side, to give pharmaceutical preparations (creams) of Preparation Examples 7-7-1 to 7-7-8, respectively.

[0357] [Table 69]

[0358] Preparation Example 7-8 (Oral liquid) Liquid compositions (Prescription Examples 41 to 48) containing the ingredients and amounts (mg) shown in Table 70 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to give pharmaceutical preparations (oral liquids) of Preparation Examples 7-8-1 to 7-8-8, respectively.

[0359] [Table 70]

[0360] Manufacturing Example 8-1 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 71 below per 100 g were prepared by conventional methods, and placed in bottle containers with a sponge-like polyurethane applicator attached to the mouth of a polypropylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 8-1-1 to 8-1-8, respectively.

[0361] [Table 71]

[0362] Production Example 8-2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 71 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 8-2-1 to 8-2-8, respectively.

[0363] Manufacturing Example 8-3 (Lotion) Liquid compositions (Prescription Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 72 below per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like polyurethane applicator attached to the mouth of a polypropylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 8-3-1 to 8-3-8, respectively.

[0364] [Table 72]

[0365] Manufacturing Example 8-4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 72 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 8-4-1 to 8-4-8, respectively.

[0366] Production Example 8-5 (Gel) Semi-solid compositions (Prescription Examples 17 to 24) containing the ingredients and amounts (g) shown in Table 73 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a low-density polyethylene film as the innermost layer, aluminum foil on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (gels) of Preparation Examples 8-5-1 to 8-5-8, respectively.

[0367] [Table 73]

[0368] Manufacturing Example 8-6 (Ointment) Semi-solid compositions (Prescription Examples 25 to 32) containing the ingredients and amounts (g) shown in Table 74 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a high-density polyethylene film as the innermost layer, a polyethylene terephthalate film on the outer side (middle layer), and a high-density polyethylene film on the outer side of that, to give pharmaceutical preparations (ointments) of Preparation Examples 8-6-1 to 8-6-8, respectively.

[0369] [Table 74]

[0370] Manufacturing Example 8-7 (Cream) Semi-solid compositions (Prescription Examples 33 to 40) containing the ingredients and amounts (g) shown in Table 75 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (creams) of Preparation Examples 8-7-1 to 8-7-8, respectively.

[0371] [Table 75]

[0372] Manufacturing Example 8-8 (Oral liquid) Liquid compositions (Prescription Examples 41 to 48) containing the ingredients and amounts (mg) shown in Table 76 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to give pharmaceutical preparations (oral liquids) of Preparation Examples 8-8-1 to 8-8-8, respectively.

[0373] [Table 76]

[0374] Manufacturing Example 9-1 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 77 below per 100 g were prepared in a conventional manner, and placed in bottle containers with a sponge-like polyurethane applicator attached to the mouth of a polypropylene container body, to produce pharmaceutical preparations (lotions) of Preparation Examples 9-1-1 to 9-1-8, respectively.

[0375] [Table 77]

[0376] Production Example 9-2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 77 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 9-2-1 to 9-2-8, respectively.

[0377] Manufacturing Example 9-3 (Lotion) Liquid compositions (Prescription Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 78 below per 100 g were prepared in a conventional manner, and placed in bottle containers with a spongy polyurethane applicator attached to the mouth of a polypropylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 9-3-1 to 9-3-8, respectively.

[0378] [Table 78]

[0379] Manufacturing Example 9-4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 78 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 9-4-1 to 9-4-8, respectively.

[0380] Production Example 9-5 (Gel) Semi-solid compositions (Prescription Examples 17 to 24) containing the ingredients and amounts (g) shown in Table 79 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a low-density polyethylene film as the innermost layer, aluminum foil as the outer layer (middle layer), and a low-density polyethylene film further laminated on the outer layer, to give pharmaceutical preparations (gels) of Preparation Examples 9-5-1 to 9-5-8, respectively.

[0381] [Table 79]

[0382] Manufacturing Example 9-6 (Cream) Semi-solid compositions (Prescription Examples 25 to 32) containing the ingredients and amounts (g) shown in Table 80 below per 100 g were prepared by a conventional method, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give pharmaceutical preparations (creams) of Preparation Examples 9-6-1 to 9-6-8, respectively.

[0383] [Table 80]

[0384] Preparation Example 9-7 (Oral liquid) Liquid compositions (Prescription Examples 33 to 40) containing the ingredients and amounts (mg) shown in Table 81 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to form the pharmaceutical preparations (oral liquids) of Preparation Examples 9-7-1 to 9-7-8, respectively.

[0385] [Table 81] [Industrial Applicability]

[0386] According to the present invention, discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during high-temperature storage can be suppressed, and therefore a drug containing loxoprofen or a salt thereof with excellent storage stability can be provided, which can be suitably used in the pharmaceutical industry, etc.

Claims

[Claim 1] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) the following component (B-1); (B-1) A menthol content of 1 to 8% by mass based on the total mass of the composition and a liquid composition containing 2 to 5 parts by mass of menthol per 1 part by mass of loxoprofen or a salt thereof calculated as anhydrous loxoprofen sodium, the liquid composition being contained in a polyolefin resin container.

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