JP2021113221A - Pharmaceutical preparation containing loxoprofen - Google Patents

Abstract

To provide means of suppressing discoloration of a liquid or a semi-solid composition comprising loxoprofen or a salt thereof when stored at high temperature.SOLUTION: A method of suppressing discoloration of a composition includes the step of storing, in a polyolefin resin container, a liquid or semi-solid composition comprising the following components (A) and (B): (A) loxoprofen or a salt thereof; and (B) capsicum or its extract.SELECTED DRAWING: None

Description

The present invention relates to a pharmaceutical preparation containing loxoprofen, which is also known as an active ingredient of loxonin (registered trademark).

Loxoprofen is a type of phenylpropionic acid-based non-steroidal anti-inflammatory drug (NSAID) (Non-Patent Document 1), and exhibits an excellent anti-inflammatory analgesic effect.
Therefore, it is widely used as an active ingredient of topical anti-inflammatory analgesics, and has been applied externally for the purpose of anti-inflammatory / analgesic of diseases such as osteoarthritis, muscle pain, post-traumatic swelling / pain, and symptoms. Agents (popping agents, tape agents, etc.) and external coating agents (gel agents, etc.) have been developed and put on the market (Non-Patent Document 2).

By the way, peppers such as capsicum and vanillylamide nonanoic acid (vanillylamide nonylate) or their extracts are blended in external anti-inflammatory analgesics and the like, and external preparations blended with loxoprofen are already known (for example, Patent Document 1). 2, 2).

International Publication No. 2014/002599 Pamphlet Japanese Unexamined Patent Publication No. 2015-98469

16th Amendment Japanese Pharmacy Guidebook Hirokawa Shoten Co., Ltd. C-5359-5364 Loxonin® Gel 1% Pharmaceutical Interview Form Daiichi Sankyo Co., Ltd. October 2010 Revised (3rd Edition)

When loxoprofen is used as an active ingredient of an external preparation, it is used by applying it to the affected area as a liquid or semi-solid composition like an external coating such as a lotion, a gel or a cream. It is preferable from the viewpoint of flexibly administering the required amount according to the position, shape and range of the affected area. Further, if a technique for stably blending loxoprofen into a liquid or semi-solid composition can be established, it can be applied not only to external preparations but also to internal medicines (oral liquid preparations, etc.).
Therefore, in order to establish a technique for stably blending loxoprofen into a liquid or semi-solid composition, the present inventor prepares a liquid or semi-solid composition containing loxoprofen or a salt thereof to improve storage stability. As a result of evaluation, it was surprisingly found that discoloration may occur over time when stored under high temperature conditions.

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 at high temperature storage.

Therefore, the present inventor further investigated to solve this problem, and found that a liquid or semi-solid composition containing loxoprofene or a salt thereof was further combined with a soft and chili pepper extract, a capsicum represented by nonanoic acid vanillylamide, or an extraction thereof. The present invention has been completed by finding that discoloration during high-temperature storage can be suppressed by containing a substance and storing it in a container made of a polyolefin resin typified by polyethylene.

That is, the present invention describes the following components (A) and (B):
(A) Loxoprofen or a salt thereof;
(B) Capsicum or its extract;
The liquid or semi-solid composition containing the above is contained in a polyolefin-based resin container to provide a pharmaceutical preparation.
Further, in the present invention, the following components (A) and (B):
(A) Loxoprofen or a salt thereof;
(B) Capsicum or its extract;
The present invention provides a method for suppressing discoloration of a composition, which comprises a step of accommodating a liquid or semi-solid composition containing the above in a polyolefin-based resin container.

According to the present invention, discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof at high temperature storage can be suppressed. Therefore, it is possible to provide a drug containing loxoprofen or a salt thereof, which has excellent storage stability.

First, the invention of the aspect of the "pharmaceutical preparation" will be described below.
<Ingredient (A)>
In the present invention, "loxoprofen or a salt thereof" includes not only loxoprofen itself, but also a pharmaceutically acceptable salt of loxoprofen, and a solvate of loxoprofen or a pharmaceutically acceptable salt thereof and water, alcohol, or the like. Is done. These are known compounds and can be produced by known methods, or commercially available compounds can be used. In the present invention, as loxoprofen or a salt thereof, loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate) is preferable.

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 appropriately examined and determined according to the desired anti-inflammatory and analgesic effect. In the present invention, loxoprofen or a salt thereof is preferably contained in an amount of 0.01 to 10% by mass, more preferably 0.1 to 5% by mass, in terms of loxoprofen sodium anhydride, based on the total mass of the composition. , 0.5 to 3% by mass is particularly preferable.

<Ingredient (B)>
In the present invention, "capsicum" is not particularly limited, and for example, capsicum (fruit of Capsicum annuum Linne (Solanaceae)) listed in the 16th revised Japanese Pharmacopoeia can be preferably used. The morphology of capsicum can be adjusted as needed, and it can be cut or crushed into small pieces or lumps, or crushed into powder. Can be used as. In addition, in consideration of convenience of handling at the time of manufacturing the composition / pharmaceutical preparation, a red pepper that has undergone some extraction treatment (referred to as “red pepper extract” in the present specification) may be used.
The "capsicum extract" also includes those subjected to processing treatments such as heating, drying, and crushing in addition to the extraction treatment. Specifically, after making the capsicum into an appropriate size as needed, a solution leached by adding an appropriate leachate (extraction solvent), a solution obtained by concentrating the leachate (soft extract, tincture, etc.), and further, these are added. Dried products (dried extracts, etc.) are also included in the "capsicum extract" of the present invention.
Further, in the present invention, as the "extract of capsicum", a known capsaicinoid which is the main component of capsicum may be used. As the capsaicinoid, capsaicin and nonanoic acid vanillylamide (also known as nonylic acid vanillylamide) are preferable.

In the present invention, as the "capsicum or its extract", capsicum, capsicum powder, capsicum extract (soft extract, dried extract), capsaicin, nonanoic acid vanillylamide are preferable, and capsicum soft extract and nonanoic acid vanillylamide are particularly preferable.

The method for producing the extract of Togarashi is not particularly limited, and for example, the description in the sections of "extract", "immersion / decoction", "tincture", "flow extract", etc. , Can be produced with reference to a known method for producing a plant extract. Specifically, for example, it can be produced by cutting, heating, drying, crushing or the like, if necessary, and then adding an appropriate extraction solvent for extraction. The obtained extract may be further concentrated, dried or the like, if necessary.

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; benzene, toluene and the like Aromatic hydrocarbons; dimethylformamide; dimethylsulfoxide; water (including hot water) and the like. Each of these may be used alone, or two or more thereof may be used in combination. In the present invention, water, ethanol, or a water / ethanol mixed solution is preferable.
The extraction operation is not particularly limited, and a known method used for the extraction operation from a plant can be appropriately adopted. Specifically, for example, immersion in an extraction solvent (cold immersion, warm immersion, percolation, etc.), Extraction using supercritical fluid or subcritical fluid can be mentioned. In addition, in order to improve the extraction efficiency, it may be homogenized with stirring or in an extraction solvent.
The extraction temperature is not particularly limited and varies depending on the extraction solvent used, the extraction operation and the like, but it is preferably a temperature of about 5 ° C. to a temperature equal to or lower than the boiling point of the extraction solvent.
The extraction time is not particularly limited and varies depending on the extraction solvent used, the extraction operation and the like, but is preferably about 1 hour to 14 days.

In the present invention, a commercially available product can be used as the capsicum or an extract thereof, and specific commercial products include, for example, capsicum extract-B, capsicum extract-D, capsicum extract-N, capsicum extract-S, ( (Bureau) capsicum tincture, (bureau) capsicum powder (above, Nippon Powder Chemicals Co., Ltd.), nonylate vanillylamide (Nagaoka Kogyo Co., Ltd.) and the like.

In the present invention, the content of capsicum or its extract in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration suppressing action, the capsicum or its extract is used as a crude drug equivalent amount in the total mass of the composition. It 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. Further, particularly when a capsaicinoid such as capsaicin or nonanoic acid vanillylamide is used as the capsaicin or an extract thereof, it is recommended that the capsaicinoid be contained in an amount of 0.0001 to 2% by mass based on the total mass of the composition from the viewpoint of suppressing discoloration. It is preferably contained in an amount of 0.0005 to 1% by mass, more preferably 0.001 to 0.5% by mass, and particularly preferably 0.005 to 0.1% by mass.

In the present invention, the content ratio of loxoprofen or a salt thereof and an extract of loxoprofen or an extract thereof in a liquid or semi-solid composition is not particularly limited and may be appropriately examined and determined from the viewpoint of discoloration suppressing action. From the viewpoint of inhibitory action, loxoprofen or a salt thereof is preferably contained in an amount of 0.01 to 15 parts by mass, preferably 0.05 to 15 parts by mass in terms of a protozoan, with respect to 1 part by mass in terms of loxoprofen anhydride. It is more preferably contained in an amount of 10 parts by mass, and particularly preferably 0.1 to 8 parts by mass. In particular, when capsaicinoids such as capsaicin and nonanoic acid vanillylamide are used as capsaicin or its extract, from the viewpoint of discoloration inhibitory action, loxoprofen or a salt thereof is converted to 1 part by mass in terms of loxoprofen sodium anhydride, and capsaicinoid is 0. It is preferably contained in an amount of .0001 to 2 parts by mass, more preferably 0.0005 to 1 part by mass, further preferably 0.001 to 0.2 part by mass, and 0.005 to 0.1 part by mass. It is particularly preferable to contain a portion.

<Liquid or semi-solid composition>
In the present invention, the "liquid or semi-solid composition" means a liquid or semi-solid composition 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 and the like. The type and properties of the solvent or base are not particularly limited, and may be hydrophilic or hydrophobic such as oily, and a plurality of different solvents and bases may be appropriately mixed and emulsified. May be used. Specific examples of such a solvent / base include components exemplified as additives described later.

In the present invention, from the viewpoint of safety when using a pharmaceutical preparation, the liquid or semi-solid composition preferably contains water. Here, the content of water in the composition is not particularly limited, but is preferably 1% by mass or more with respect to the total mass of the composition from the viewpoint of safety during use of the pharmaceutical preparation and discoloration suppressing action. It is more preferably 5% by mass or more, further preferably 10 to 90% by mass, further preferably 20 to 70% by mass, and particularly preferably 30 to 50% by mass.

Further, 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, the "lower alcohol" means a linear or branched monohydric alcohol having 1 to 6 carbon atoms, and specific examples thereof include ethanol, isopropanol, n-propanol and the like. Isopropanol and mixtures thereof are preferred. Here, the content of the lower alcohol in the composition is not particularly limited, but is preferably 5% by mass or more, preferably 5% by mass or more, based on the total mass of the composition, from the viewpoint of the usability of the pharmaceutical preparation and the effect of suppressing discoloration. It is more preferably 90% by mass, further preferably 15 to 70% by mass, and particularly preferably 20 to 50% by mass.

In the present invention, from the viewpoint of safety and usability when using a pharmaceutical preparation, it is preferable that the liquid or semi-solid composition contains both water and a lower alcohol. Even when the composition is 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.

In the present invention, the liquid or semi-solid composition may contain other drugs as pharmaceutical components, such as analgesic components, anti-inflammatory components, antihistamine components, bactericidal components, astringent / protective components, blood circulation promoting components, and warming components. Select from the group consisting of sensory ingredients, local anesthetic ingredients, antitussives, noscapines, bronchial dilators, sputum, hypnotic sedatives, vitamins, gastric mucosa protectants, antacids, anticholinergic agents, crude drugs, Chinese herbal prescriptions, etc. It may contain one kind or two or more kinds.

Examples of analgesic ingredients include aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, etenzamid, sazapyrin, salicylamide, salicylic acid, ethylene glycol salicylate, glycol salicylate, sodium salicylate, methyl salicylate, thialamide hydrochloride, and lactylphenetidine. And so on.
Examples of anti-inflammatory components include sodium gualenate sulfonate, glycyrrhizic acid and its derivatives, and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), glycyrrhetinic acid, seapronase, semi-alkali proteinase, therapeptase, proctase, etc. Pronase, bromeline and the like can be mentioned.

Examples of the antihistamine component include azerastin hydrochloride, alimemazine tartrate, isotipendyl hydrochloride, iproheptin hydrochloride, evastin, epinastine hydrochloride, emedastin fumarate, oxatomide, carbinoxamine diphenyldisulfonate, and carbinoxamine. Maleate, Cremastine Fumarate, d-Chlorpheniramine Maleate, dl-Chlorpheniramine Maleate, Ketotiphenfumarate, Diffeterol Hydrochloride, Diffeterol Phosphate, Diphenylpyraline Hydrochloride, Diphenylpyraline Theocrulate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetilidine hydrochloride, triprolidine hydrochloride, tryperenamine hydrochloride, tonzilamine hydrochloride, hexofenazine, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylenedi Examples thereof include salicylate, bepotastine besilate, homochlorcyclidine hydrochloride, mequitazine, metodilazine hydrochloride, mebuhydrolinnapadisylate and the like.

Examples of the bactericidal component include benzalkonium chloride and the like. Examples of the astringent / protective component include zinc oxide and the like. Examples of the blood circulation promoting component include tocopherol acetate, benzyl nicotinate, heparinoid, sodium polyethylene sulfonate and the like. Examples of the local anesthetic component include lidocaine, clove oil, belladonna extract and the like.

Antitussives include, for example, allocramid hydrochloride, epradinone hydrochloride, carbetapentanetanate, cloperastine hydrochloride, cloperastin fendizoate, dibunato sodium, dimemorphan phosphate, tipepidin citrate, etc. Examples thereof include tipepidin hibenzate.

Examples of noscapines include noscapine hydrochloride, noscapine and the like.
Examples of the bronchodilator include trimetokinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and the like.

Examples of the sputum-removing agent include ammonia / fennel spirit, ammonium chloride and the like.

Examples of the hypnotic sedative include allylisopropylacetylurea and bromvalerylurea.
Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, etc.). Thiamine nitrate, disetiamine hydrochloride, setothiamine hydrochloride, flusultiamine, flusultiamine hydrochloride, octothiamine, sicothamine, thiamine disulfide, bisibuchiamine, bisbenchamine, prosultiamine, benfothamine, riboflavin, riboflavin phosphorus Acid ester, riboflavin butyrate, sodium riboflavin phosphate, pantenol, pantetin, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate ester, cyanocobalamine, mecobalamine, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.) Be done.

Examples of the gastric mucosa protective agent include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride and the like.
Examples of the acid suppressant include aminoacetic acid, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, magnesium hydroxide, magnesium hydroxide, aluminum hydroxide gel, and dried. Aluminum hydroxide gel, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium hydrogen carbonate co-precipitated product, aluminum hydroxide / calcium carbonate / magnesium carbonate co-precipitated product, magnesium hydroxide, magnesium hydroxide・ Co-precipitated products of potassium aluminum sulfate, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, pirate bones, stone determination, volley, etc. ..

Examples of anticholinergic agents include oxyphencyclimine hydrochloride, dicyclamine hydrochloride, methixene hydrochloride, tipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide and the like. Can be mentioned.

Examples of crude drugs include red bud wrinkles (red buds), asenyaku (Asenyaku), Arnica, tincture (innocent sheep), uikyo (scented scent), corn (depressed gold), engosaku (extended ginger), ogong (yellow ginger), and ausei (yellow sardine). Yellow spirit), Oubaku (Huang Kashiwa), Ouhi (Cherry bark), Ouren (Huangren), Onji (Distant), Gajutsu (Ginger), Kanokosou (Kagokusa), Kamitsure, Karonin (Karoujin), Kikyo (Kikyou) , Kyonin (Apricot), Kukoshi (Tincture), Kukoyo (Tincture leaf), Keigai (Tincture), Keihi (Chenpi), Ketsumeishi (Chenpi), Gentiana, Gennoshoko (Present evidence), Kouka (Red flower), Kobushi (Koubushi) ), Goou (Beef Yellow), Gomishi (Gomiko), Saishin (Spicy), Sanshishi (Sanjoko), Sansho (Sansho), Zion (Shien), Jikoppi (Chenpi), Shikon (Purple Root), Shakuyaku (Crude Drug) , Jakou (Musuka), Shajin (Sasan), Shazenshi (Car front child), Shazensou (Car front grass), Beast ginger (including Yutan (Kuma gall)), Ginger (Ginger), Jiryu (Chenpi), Shini ( Spicy), Tincture, Sexan (Ishibuki), Senega, Senkyu (Kawakyu), Zenko (Maekhu), Senburi (Senburi), Soujutsu (Aoi), Souhakuhi (Kuwashirohide), Soyo (Suha), Taisan (Ginger), Chikusetsu carrot (Takebushi ginger), Chinpi (Chenpi), Touki (Toki), Tokon (Vomiting root), Nantenjitsu (Nantenmi), Carrot (Ginger), Baimo (Ginger), Bakumondou (Wheat gate) Winter), Hange (half-summer), Bankouka (bankohana), Hanpi (anti-nose), Byakushi (white), Byakujutsu (white extract), Bukuryo (茯 蓓), Buttonpi (peony skin), Youbaihi (yang plum skin), Rokujo Examples thereof include crude drugs such as (ginger mushroom) and extracts thereof (extracts, tinctures, dried extracts, etc.).

Chinese cinnamon prescriptions include, for example, cinnamon (Keishito), Kososan (Kososan), Psychokeisito (Saiko Keishito), Shosaikoto (Shosaikoto), Bakumondoto (Mai Men Dong Tang), and Hange. Examples include Sho-saiko-to (Hangekobokuto).

Further, in the present invention, the liquid or semi-solid composition may contain additives used in the pharmaceutical field, cosmetics field, etc., depending on the dosage form, administration method, etc. of the pharmaceutical preparation. Such additives include, for example, gelling agents, polyhydric alcohols, fats and oils, emulsifiers, solubilizers, pH regulators, antioxidants, softeners, thickeners, moisturizers, preservatives, stabilizers, etc. Examples thereof include transdermal absorption promoters, flavoring agents / sweeteners, and terpenes.

Examples of the gelling agent include acrylic acid-based polymers such as carboxyvinyl polymers; water-soluble or water-swellable cellulosic polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, and ethyl cellulose; polyvinyl alcohol; Polyvinylpyrrolidone and the like can be mentioned.
Examples of the polyhydric alcohol include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, macrogol, polypropylene glycol and the like.
Examples of fats and oils include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, and vaseline; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; behenyl alcohol, lauryl alcohol, and myristyl alcohol. Higher alcohols such as cetyl alcohol, stearyl alcohol, isostearyl alcohol, and oleyl alcohol; higher fatty acids such as behenic acid, lanolinic acid, myristic acid, stearic acid, isostearic acid, and oleic acid; Rows such as honeydew, sardine honeydew, monttan wax, lanolin, refined lanolin, reduced lanolin; silicone oil and the like can be mentioned.

Examples of the emulsifier include polyhydric alcohols such as propylene glycol mono fatty acid ester, ethylene glycol mono fatty acid ester, glycerin mono fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, methyl glucoside fatty acid ester, and alkyl polyglucoside. Fatty acid ester or polyhydric alcohol alkyl ether; polyoxyethylene ether such as polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene polyoxypropylene alkyl ether; polyoxyethylene ether; Ethylene mono fatty acid ester, polyethylene glycol di fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene Nonionic surfactants such as castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid esters, ether esters such as polyoxyethylene polyoxypropylene glycol, or ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate. And so on.
Examples of the solubilizer include glycerin, liquid paraffin, crotamitone, macrogol, and the like, in addition to the nonionic surfactant or ionic surfactant exemplified as the emulsifier described above.

Examples of the pH adjuster include citric acid, sodium citrate, anhydrous citric acid, malic acid, maleic acid, succinic acid, fumaric acid, tartrate acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, acetic acid, sodium acetate, and ice. Organic acids such as acetic acid or salts thereof; inorganic acids such as citric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium hydrogen carbonate or the like; sodium hydroxide , Alkyl hydroxide such as potassium hydroxide, calcium hydroxide, magnesium hydroxide; amines such as triethanolamine, diethanolamine, diisopropanolamine and the like can be mentioned.
Examples of the antioxidant include sodium sulfite, ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol, tocopherol acetate, soybean lecithin, propyl gallate and the like.
Examples of the softening agent include allantoin, almond oil, olive oil, glycerin, liquid paraffin, squalane, squalene, refined lanolin, medium chain fatty acid triglyceride, rapeseed oil, castor oil, propylene glycol, polybutene and the like.
Examples of the thickener include polyvinylpyrrolidone, carboxymethyl cellulose, colloidal aluminum silicate, xanthan gum, locust bean gum, tragant gum, guar gum, gelatin, arabic gum, alginic acid, albumin and the like.
Examples of the moisturizer include sodium hyaluronate, glycerin, 1,3-butylene glycol, propylene glycol, urea, sucrose, erythritol, sorbitol and the like.
Examples of preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, isobutyl paraoxybenzoate, benzyl paraoxybenzoate, sodium benzoate, benzoic acid, and benzoic acid. Examples thereof include benzyl acid acid, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, aminoethylsulfonic acid and the like.
Examples of the stabilizer include adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hydrogenated oil, cysteine and the like.
Examples of the transdermal absorption promoter include fatty acid esters such as diisopropyl adipate.
Examples of flavoring agents and sweeteners include assesulfam potassium, stevia, somatin, sucralose, panose, trehalose, erythritol, lactitol, reduced palatinose, coupling sugar, fructo-oligosaccharide, galactooligosaccharide, milk fruit oligosaccharide, isomalto-oligosaccharide, and palatinose. Examples thereof include oligosaccharides, raffinose, aspartame, fructose, xylitol, brown sugar, saccharin or a salt thereof, sorbitol, lactose, sucrose, honey, glucose, martitol, maltose, mannitol, water candy and the like.

Examples of terpenes include isobornole, iron, osimene, carbeol, carbotanaceton, carbomenton, carboxylic, kalen, karon, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellal and cineol. , Simen, sylvestren, timole, isotsjor, tsujeong, terpineol, terpinene, terpinene, tricyclene, nerol, pinene, pinocampeol, pinol, piperitenon, ferlandral, ferlandren, fenchen, fentyl alcohol, perylyl alcohol, Examples thereof include perylaldehyde, borneol, milsen, menthol, menthon, yonor, yonon, linalool and limonene.

Essential oils containing terpenes include, for example, anis oil, ylang ylang oil, iris oil, uikyo oil, orange oil, cananga oil, chamomile oil, kayapto oil, caraway oil, kubeb oil, grapefruit oil, kehi oil, coriander oil, etc. Saffron oil, sansho oil, perilla oil, citriodora oil, citronella oil, ginger oil, ginger oil, ginger oil, spearmint oil, peppermint oil, geranium oil, daiuikyo oil, chow oil, television oil, tohi Oil, neroli oil, basil oil, peppermint oil, palmarosa oil, piment oil, petitgrain oil, bay oil, peniroyal oil, henoposi oil, bergamot oil, boadrose oil, peppermint oil, majoran oil, mandarin oil, melissa oil, eucalyptus oil, Examples thereof include lime oil, lavender oil, linaroe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil.

In the present invention, the method for producing a liquid or semi-solid composition is not particularly limited, and the type and amount of the components to be blended, the properties of the composition, the shape of the container, the dosage form of the pharmaceutical preparation, the administration route, the application, etc. Accordingly, for example, it can be produced by a known method described in the 16th revised Japanese Pharmacopoeia General Regulations for Formulation.

<Polyolefin-based resin container>
In the present invention, the "container" means 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 accommodate a liquid or semi-solid composition, and is appropriately examined according to the properties of the composition, the dosage form of the pharmaceutical preparation, the administration route, the application, and the like. You just have to decide.
Examples of the shape of such a container include a container for an aerosol agent, a container for a pump spray agent, and a bottle container (more specifically, for example, a bottle container provided with a sponge-like coating member (head), a roll-on container, and a jar bottle container. Etc.), tube containers, eye drop containers, etc. All of these containers are known and may be manufactured by a known method, or commercially available products may be used.

In the present invention, as the container, the following (1) or (2):
(1) A container provided with a container body and a coating member, such as a bottle container having a sponge-like coating member, and used by impregnating the coating 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 preferable, and the container of the aspect (1) is particularly preferable.

[(1) A container provided with a container body and a coating member, and used by impregnating the coating member with the composition contained in the container body]
In the case of a container of such an embodiment, the composition can be applied by impregnating and holding the composition contained in the container body in the coating member and bringing the coating member into contact with the portion to be coated. In this case, the container body and the coating member may be manufactured as independent members, and then the coating member may be attached to the container body or integrally molded.
The coating member may have a structure capable of impregnating and holding a liquid or semi-solid composition, and examples thereof include a porous member such as a sponge and a brush-like member.

Examples of such a container include a container in which a coating member is provided at the mouth of the container body and the coating member is impregnated with the composition contained in the container body.
More detailed specific examples include, for example, a container body having a mouth portion and a container provided with a porous (sponge-like or the like) coating member attached to the mouth portion. In this case, the composition contained in the container body is impregnated and held in a porous coating member whose pore size, porosity, etc. are appropriately adjusted, and then the coating member is brought into contact with the coated portion to form a composition. An object can be applied to the portion to be coated.
Further, as another specific example, for example, a container body having a mouth portion and a container provided with a brush-like coating member attached to the mouth portion and the like can be mentioned. In this case, the composition contained in the container body is impregnated and held in a brush whose hair length, spacing, etc. are appropriately adjusted, and then the coated member is brought into contact with the portion to be coated to obtain the composition. It can be applied to the part to be coated.

Since the container of such an embodiment is used by impregnating and holding the composition in the coating member, for example, when the pharmaceutical preparation is an external coating agent, the problem of liquid dripping does not easily occur in the coated portion, and the coating member is directly applied. There are merits such as that the fingers do not get dirty by using it in contact with the part to be coated, or that the area to which the composition is applied can be easily adjusted by adjusting the shape and size of the coating member. Have. However, since the composition is impregnated and retained in the coated member, if the composition is discolored, the discoloration occurs over the entire coated member. Therefore, when the coated member is exposed to the outside, for example, when a pharmaceutical preparation is used, discoloration is particularly noticeable in appearance. However, according to the present invention, since discoloration of the composition is suppressed, there is an excellent effect that such an appearance problem can be solved and the above-mentioned merits can be fully enjoyed. In the case of the container of such an embodiment, it is particularly preferable that both the container body and the coating member are made of a polyolefin resin.
In addition, such a container can be particularly preferably adopted when the composition to be accommodated is, for example, a liquid composition or a low-viscosity semi-solid composition.

Containers of such an embodiment are known and are disclosed, for example, in Japanese Patent No. 5570809. Further, in the present invention, a commercially available product may be used as the container of such an embodiment, and such a commercially available product is, for example, MAPS Co., Ltd., which is a communicating porous body made of low-density polyethylene as a coating member. Examples include containers using (corporation).

[(2) A container provided with a flexible container body and a discharge port]
In the case of a container of such an embodiment, pressure is applied to the inside of the container by pressing the flexible container body or the like, and the composition contained in the container is discharged from the discharge port, whereby the composition is applied to the portion to be coated. Can be applied to. In addition, in the container of such an embodiment, the discharge port does not have to be provided in advance in the container, and the container may be provided with a discharge port by perforating the container before the start of use. It is included in "a container having a container body and a discharge port".

Since the container of such an embodiment has a simple structure, the manufacturing cost is low, and the composition in the container is not contaminated because the composition is discharged from the discharge port by pressing the container body or the like. Has.
The container of such an embodiment can be particularly preferably adopted when the composition to be contained is, for example, a highly viscous semi-solid composition.

Containers of such an embodiment are known, and are disclosed in, for example, Japanese Patent No. 5302550, Japanese Patent No. 5525135, and the like. Further, in the present invention, a commercially available product may be used as the container of such an embodiment.

In the present invention, the "polyolefin-based resin" is not particularly limited, and may be a polymer of a single type of monomer (homopolymer) or a copolymer of a plurality of types of monomers (copolymer). Further, in the case of a copolymer, the polymerization mode is not particularly limited, and random polymerization or block polymerization may be used. Furthermore, its stereoregularity (tacticity) is not particularly limited.
Specific examples of such polyolefin-based resins include polyethylene (more specifically, for example, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, etc.), polypropylene, and cyclic resin. Polyolefin, poly (4-methylpentene), polytetrafluoroethylene, ethylene / propylene copolymer, ethylene / α-olefin copolymer, ethylene / acrylic acid copolymer, ethylene / methacrylic acid copolymer, ethylene / acetic acid Examples thereof include vinyl copolymers, ethylene / ethyl acrylate copolymers, and the like, and in the present invention, one or a combination of two or more of these can be used.
In the present invention, the polyolefin-based resin is preferably polyethylene, polypropylene or cyclic polyolefin, and particularly preferably polyethylene or polypropylene, from the viewpoint of suppressing discoloration.
In the present invention, "made of a polyolefin-based resin" means that at least a part of the material contains a polyolefin-based resin. For example, two or more kinds of resins, a polyolefin-based resin and another resin, are used. (Polymer alloy) is also included in "made of polyolefin resin".

In the present invention, the "polyolefin-based resin container" refers to at least a part (preferably, the composition during normal storage) of the container in contact with the liquid or semi-solid composition contained therein. 10% or more of the portion in contact with the composition, more preferably 30% or more of the portion in contact with the composition during normal storage, particularly preferably the entire portion in contact with the composition during normal storage) is "polyolefin-based". It means "container" which is "made of resin". Therefore, for example, a polyolefin-based resin layer is provided on at least a part of the layer (innermost layer of the container) in contact with the liquid or semi-solid composition, and other materials such as resin and aluminum foil are laminated on the outside thereof. The container to be used also falls under the category of "polyolefin resin container".
As a container formed by laminating a plurality of types of materials as described above, specifically, for example, a layer made of a polyolefin resin is used as the innermost layer, and an aluminum foil is provided on the outer side of the container directly or via another layer. Examples thereof include a container made of a laminated film, which is formed by laminating the above-mentioned materials and further laminating other layers on the outside thereof, if necessary.

In the present invention, the means for accommodating the liquid or semi-solid composition in the container is not particularly limited, and the composition may be filled by a conventional method according to the shape of the container, the properties of the composition, and the like. Therefore, the pharmaceutical preparation of the present invention can be produced.

<Pharmaceutical product>
In the present invention, the administration method and application method of the "pharmaceutical preparation" are not particularly limited, and examples thereof include oral, transdermal, and parenteral such as transvaginal. In the present invention, parenteral is preferable because of the characteristics of the liquid or semi-solid composition (the point that it can be flexibly applied in a required amount according to the position, shape and range of the affected area). Skin administration is particularly preferred.

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 state, and for example, the sixteenth amendment is made according to the purpose of use thereof. It can be appropriately selected from the dosage forms described in the Japanese Pharmacopoeia General Regulations for Formulation. Specific examples of such dosage forms include preparations applied to the skin and the like (external liquids, sprays, ointments, creams, gels, etc.) and orally administered preparations (oral liquids, syrups, oral jelly). Etc.), etc., and the dosage forms described in the 16th Amendment of the General Regulations for Pharmaceutical Formulations of the Japanese Pharmacy.
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, and liniments, lotions, external aerosols, pump sprays, etc. The dosage form selected from the group consisting of ointments, creams and gels is more preferable, and the dosage form selected from the group consisting of lotions, ointments, creams and gels is particularly preferable.

Since the pharmaceutical preparation of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, it can be used as a medical drug or an OTC drug. It is useful as an internal medicine such as a medicine (cold medicine); etc.

Next, the invention of the aspect of the "method" will be described below.
In the present invention, the following components (A) and (B):
(A) Loxoprofen or a salt thereof;
(B) Capsicum or its extract;
It also relates to a method for suppressing discoloration of the composition, which comprises a step of accommodating the liquid or semi-solid composition containing the above in a polyolefin-based resin container.
In the invention of such an embodiment, the order of the step of blending the component (A), the step of blending the component (B), and the step of accommodating the composition in the polyolefin resin container is not particularly limited, and the step of blending the component (A) is not particularly limited. The state in which the liquid or semi-solid composition containing (B) and (B) is contained in a polyolefin-based resin container may be directly or indirectly created.
In the invention of such an aspect, the meanings of various words, the blending amount of each component, and the like are all the same as those described for the "pharmaceutical preparation".

The present specification discloses, for example, the inventions exemplified below in relation to the above embodiments, but is not limited thereto.
[1] The following components (A) and (B):
(A) Loxoprofen or a salt thereof;
(B) Capsicum or its extract;
A pharmaceutical preparation in which a liquid or semi-solid composition containing the above is contained in a polyolefin-based resin container.
[2] The pharmaceutical preparation according to [1], wherein the component (A) is loxoprofen sodium hydrate.
[3] The component (B) is at least one selected from the group consisting of capsicum, capsicum powder, capsicum soft extract, capsicum dried extract, capsaicin and nonanoic acid vanillylamide (nonyl acid vanillylamide), [1] or [2]. ] Described pharmaceutical preparation.
[4] The pharmaceutical preparation according to [1] or [2], wherein the component (B) is at least one selected from the group consisting of soft pepper extract and vanillylamide nonanoic acid (vanillylamide nonamic acid).

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

[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, which comprises a step of accommodating a liquid or semi-solid composition containing the above in a polyolefin-based resin container.
[17] The method according to [16], wherein the component (A) is loxoprofen sodium hydrate.
[18] The component (B) is at least one selected from the group consisting of capsicum, capsicum powder, capsicum soft extract, capsicum dried extract, capsaicin and nonanoic acid vanillylamide (nonyl acid vanillylamide), [16] or [17]. ] The method described.
[19] The method according to [16] or [17], wherein the component (B) is at least one selected from the group consisting of a soft pepper extract and vanillylamide nonanoic acid (vanillylamide nonamic acid).

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

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

[Test Example 1] Preservation test 1
A liquid composition containing the components and amounts shown in Table 1 was prepared and contained in a polyethylene or glass container to prepare the pharmaceutical preparations of Example 1 and Comparative Examples 1 and 2, respectively.
The obtained various pharmaceutical preparations were stored in a dark place at 80 ° C. for 1 week, and the presence or absence of discoloration (yellowing) after storage for 3 days and 1 week was visually evaluated. The results were evaluated as ◯ for those without discoloration and x for those with discoloration.
The results are shown in Table 1.

From the comparison between Comparative Example 1 (containing in a polyethylene container) and Comparative Example 2 (accommodating in a glass container), by accommodating the composition in a polyethylene container, discoloration after storage for 3 days was suppressed and a slight discoloration suppressing action was performed. However, its action was not sufficient, and it was confirmed that discoloration occurred after storage for 1 week.
On the other hand, in comparison with Example 1 (combined with capsicum soft extract, contained in a polyethylene container) and Comparative Example 1 (contained in a polyethylene container), the composition is further blended with the capsicum soft extract and then contained in a polyethylene container. As a result, it was confirmed that discoloration after storage for one week was also suppressed and a sufficient discoloration suppressing effect was exhibited.

Based on the above test results, a liquid or semi-solid composition containing loxoprofen or a salt thereof is further impregnated with capsicum or an extract thereof, and the temperature is increased by storing the pepper in a container made of a polyolefin resin. It was clarified that discoloration during storage can be suppressed.

[Test Example 2] Preservation test 2
A liquid composition containing the components and amounts shown in Table 2 was prepared and contained in a polyethylene or glass container to prepare pharmaceutical formulations of Examples 2, Comparative Examples 3 and 4, respectively, as in Test Example 1. The presence or absence of discoloration after storage in a dark place at 80 ° C. for 3 days and 1 week was evaluated by the above method.
The results are shown in Table 2.

From the above test results, it was confirmed that discoloration was similarly suppressed during high-temperature storage even when pelargonic acid vanillylamide was contained instead of the soft pepper extract.

[Test Example 3] Preservation test No. 3
A liquid composition containing the components and amounts shown in Table 3 was prepared, contained in a polyethylene container to form the pharmaceutical preparation of Example 3, and placed in a dark place at 80 ° C. for 1 week by the same method as in Test Example 1. The presence or absence of discoloration after storage was evaluated.
The results are shown in Table 3.

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

Based on the results of Test Examples 1 to 3 above, the liquid or semi-solid composition containing loxoprofen or a salt thereof is further impregnated with a soft and chili pepper extract, a capsicum typified by nonanoic acid vanillylamide, or an extract thereof. , It was clarified that discoloration during high temperature storage can be suppressed by storing in a container made of polyolefin resin.

[Test Example 4] Preservation test No. 4
A liquid composition containing the components and amounts shown in Table 4 was prepared and contained in a polyethylene or glass container to prepare the pharmaceutical preparations of Example 4, Comparative Examples 5, 6 or Reference Example 1, respectively, for testing. The presence or absence of discoloration after storage in a dark place at 80 ° C. for 2 weeks was evaluated by the same method as in Example 1.
The results are shown in Table 4.

From the comparison between Comparative Example 5 and Reference Example 1 (without loxoprofen), the discoloration confirmed after storage at 80 ° C. for 2 weeks may be due to the addition of loxoprofen to the liquid composition. confirmed.
Then, by comparing Example 4 with Comparative Example 5 (contained in a glass container) and Comparative Example 6 (without pelargonic acid vanillylamide), the liquid composition was further blended with pelargonic acid vanillylamide and made of polyethylene. It was confirmed that such discoloration can be suppressed by containing the mixture in a container.

[Test Example 5] Preservation test No. 5
A liquid composition containing the components and amounts shown in Table 5 was prepared, contained in a polypropylene container to prepare the pharmaceutical preparations of Examples 5 and 6, and placed in a dark place at 80 ° C. by the same method as in Test Example 1. The presence or absence of discoloration after storage for 2 weeks was evaluated.
The results are shown in Table 5.

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

[Test Example 6] Preservation test No. 6
A communication porous body (MAPS: Co., Ltd .) made of low-density polyethylene, which is used as a coating member in a container by preparing the same liquid composition as contained in the pharmaceutical preparations of Examples 1 and 3. ) Inoac Corporation) and then stored in a dark place at 80 ° C. for 1 week, but no obvious discoloration was observed in any of the compositions.

Production Example 1 (lotion agent)
A liquid composition (formulation examples 1 to 8) containing the components and amounts (g) shown in Table 6 below in 100 g is produced by a conventional method, and sponge-like polyurethane is formed on the mouth of a polypropylene container body. The product was housed in a bottle container equipped with a coating member, and used as a pharmaceutical preparation (lotion agent) of Production Examples 1-1 to 1-8, respectively.

Production Example 2 (lotion agent)
A liquid composition (formulation examples 1 to 8) containing the components and the amount (g) shown in Table 6 above in 100 g is produced by a conventional method, and a sponge-like low density polyethylene container body is provided at the mouth. It was housed in a bottle container equipped with a coating member made of density polyethylene (MAPS: Inoac Corporation), and used as a pharmaceutical preparation (lotion agent) of Production Examples 2-1 to 2-8, respectively.

Production Example 3 (lotion agent)
A liquid composition (formulation examples 9 to 16) containing the components and amounts (g) shown in Table 7 below in 100 g is produced by a conventional method, and sponge-like polyurethane is formed on the mouth of a polypropylene container body. The product was housed in a bottle container equipped with a coating member, and used as a pharmaceutical preparation (lotion agent) of Production Examples 3-1 to 3-8, respectively.

Production Example 4 (lotion agent)
A liquid composition (formulation examples 9 to 16) containing the components and the amount (g) shown in Table 7 above in 100 g is produced by a conventional method, and a sponge-like low density polyethylene container body is formed at the mouth. It was housed in a bottle container equipped with a coating member made of density polyethylene (MAPS: Inoac Corporation), and used as a pharmaceutical preparation (lotion agent) of Production Examples 4-1 to 4-8, respectively.

Production Example 5 (Gel agent)
A semi-solid composition (Formulation Examples 17 to 24) containing the components and amounts (g) shown in Table 8 below in 100 g is produced by a conventional method, and the film made of low-density polyethylene is used as the innermost layer. The pharmaceutical preparations of Production Examples 5-1 to 5-8 are housed in a tube container (laminated tube) made of a laminated film in which an aluminum foil is laminated on the outer side (intermediate layer) and a low-density polyethylene film is laminated on the outer side thereof. Gel agent).

Production Example 6 (ointment)
A semi-solid composition (Formulation Examples 25 to 32) containing the components and amounts (g) shown in Table 9 below in 100 g is produced by a conventional method, and the film made of high-density polyethylene is used as the innermost layer. It is housed in a tube container (laminated tube) made of a laminated film in which a polyethylene terephthalate film is laminated on the outer side (intermediate layer) and a high-density polyethylene film is laminated on the outer side thereof. It was used as a pharmaceutical preparation (ointment).

Production Example 7 (Cream)
A semi-solid composition (Formulation Examples 33 to 40) containing the components and amounts (g) shown in Table 10 below in 100 g is produced by a conventional method, and a film made of low-density polyethylene is used as the innermost layer. It is housed in a tube container (laminated tube) made of a laminated film in which a nylon film is laminated on the outer side (intermediate layer) and a low-density polyethylene film is laminated on the outer side thereof. It was prepared as a preparation (cream).

Production Example 8 (oral solution)
A liquid composition (Formulation Examples 41 to 48) containing the components and amounts (mg) shown in Table 11 below in 30 mL is produced by a conventional method, and is contained in a polypropylene bottle container, and each of them is produced in Production Example 8. It was prepared as a pharmaceutical preparation (oral solution) of -1 to 8-8.

According to the present invention, discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof at high temperature storage can be suppressed. Therefore, it is possible to provide a drug containing loxoprofen or a salt thereof, which has excellent storage stability, and can be suitably used in the pharmaceutical industry and the like.

Claims (1)

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, which comprises a step of accommodating a liquid or semi-solid composition containing the above in a polyolefin-based resin container.