JP2023080151A - Loxoprofen-containing pharmaceutical formulation - Google Patents

Abstract

To provide means for preventing discoloration of, during high-temperature storage, a liquid or semisolid composition containing loxoprofen or a salt thereof.SOLUTION: The present invention provides a method for preventing discoloration of compositions, including a step of storing a liquid or semisolid composition in a polyolefin resin container, the composition containing following components: (A) loxoprofen or a salt thereof and (B) capsicum or extract thereof.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to pharmaceutical preparations 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 analgesic (NSAID) (Non-Patent Document 1), and exhibits excellent anti-inflammatory and analgesic effects.
Therefore, it is widely used as an active ingredient in topical anti-inflammatory analgesics. Agents (plasts, tapes, etc.) and external application agents (gels, etc.) have been developed and put on the market (Non-Patent Document 2).

By the way, hot peppers, hot peppers such as nonanoic acid vanillylamide (nonylic acid vanillylamide) 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).

International Publication No. 2014/002599 pamphlet JP 2015-98469 A

Japanese Pharmacopoeia 16th Edition Commentary Hirokawa Shoten Co., Ltd. C-5359-5364 pages Loxonin (registered trademark) Gel 1% Pharmaceutical Interview Form Daiichi Sankyo Co., Ltd. Revised October 2010 (3rd edition)

When loxoprofen is used as an active ingredient of an external preparation, it is best to apply it to the affected area as a liquid or semi-solid composition, such as lotions, gels, creams, and other external application agents. It is preferable from the viewpoint of flexibly administering only the necessary amount according to the position, shape and range of the affected area. Moreover, if a technique for stably blending loxoprofen into a liquid or semi-solid composition can be established, it will be possible to apply not only external preparations but also 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 prepared a liquid or semi-solid composition containing loxoprofen or a salt thereof to improve storage stability. Upon evaluation, it was unexpectedly found that storage under high temperature conditions can cause discoloration over time.

Accordingly, an object of the present invention is to provide means for suppressing discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during storage at high temperature.

Therefore, the present inventors have made further studies to solve this problem, and have found that a liquid or semi-solid composition containing loxoprofen or a salt thereof, a hot pepper soft extract, a hot pepper typified by nonanoic acid vanillylamide, or an extract thereof The present inventors have found that discoloration during high-temperature storage can be suppressed by containing a substance and storing it in a container made of polyolefin resin represented by polyethylene, and completed the present invention.

Thus, the present invention provides the following components (A) and (B):
(A) loxoprofen or a salt thereof;
(B) capsicum or an extract thereof;
A liquid or semi-solid composition containing
The present invention also provides the following components (A) and (B):
(A) loxoprofen or a salt thereof;
(B) capsicum or an extract thereof;
A method for suppressing discoloration of a composition, which comprises the step of housing a liquid or semi-solid composition containing in a container made of polyolefin resin.

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. Therefore, it is possible to provide a loxoprofen or a salt thereof-containing medicament with excellent storage stability.

First, the invention of the aspect of "pharmaceutical formulation" will be described below.
<Component (A)>
In the present invention, "loxoprofen or a salt thereof" includes loxoprofen itself, a pharmaceutically acceptable salt of loxoprofen, and a solvate of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol, or the like. be These are known compounds and can be produced by known methods, or commercially available ones 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).

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 according to 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 in terms of loxoprofen sodium anhydride, relative to the total mass of the composition. , 0.5 to 3% by weight is particularly preferred.

<Component (B)>
In the present invention, "capsicum" is not particularly limited, and for example, chili pepper (fruit of Capsicum annuum Linne (Solanaceae)) listed in the Japanese Pharmacopoeia 16th Edition can be suitably used. The form of the pepper can be adjusted as necessary, and it can be cut or crushed into small pieces, small pieces, or pulverized into powder. can be used as In addition, in consideration of the convenience of handling at the time of manufacturing the composition/pharmaceutical preparation, etc., it is also possible to use a chili pepper that has been subjected to some kind of extraction treatment (referred to herein as a “capsicum extract”).
The term “capsicum extract” also includes those subjected to processing such as heating, drying, and pulverization in addition to extraction. Specifically, after sizing the pepper to an appropriate size as necessary, a liquid obtained by adding an appropriate leachate (extraction solvent) to the leachate, a liquid obtained by concentrating the leachate (soft extract, tincture, etc.), and further these Dried ones (dry extract etc.) are also included in the "extract of hot pepper" of the present invention.
Furthermore, in the present invention, known capsaicinoids, which are the main components of red pepper, may be used as the “red pepper extract”. Capsaicin and nonanoic acid vanillylamide (another name: nonylic acid vanillylamide) are preferable as the capsaicinoid.

In the present invention, the "pepper or its extract" is preferably hot pepper, hot pepper powder, hot pepper extract (soft extract, dry extract), capsaicin, nonanoic acid vanillylamide, and particularly preferred hot pepper soft extract or nonanoic acid vanillylamide.

The production method of the capsicum extract is not particularly limited. , 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, pulverizing, etc., as required, and then adding an appropriate extraction solvent for extraction. The obtained extract may be further concentrated, dried, etc., 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; dimethylformamide; dimethylsulfoxide; water (including hot water); Each of these may be used alone, or two or more thereof may be used in combination. Water, ethanol, or a water/ethanol mixture is preferred in the present invention.
The extraction operation is not particularly limited, and known methods used for extraction operations from plants can be appropriately employed. Specific examples include immersion in an extraction solvent (cold immersion, digestion, percolation, etc.), Examples include extraction using a supercritical fluid or subcritical fluid. In addition, in order to increase the extraction efficiency, it may be stirred or homogenized in an extraction solvent.
The extraction temperature is not particularly limited, and varies depending on the extraction solvent to be used, the extraction procedure, etc., but is preferably from about 5° C. to the boiling point of the extraction solvent or less.
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.

In the present invention, as the capsicum or its extract, commercially available products can be used, and specific commercial products include, for example, capsicum extract-B, capsicum extract-D, capsicum extract-N, capsicum extract-S, ( Dept.) Pepper tincture, (Dept.) Pepper powder (above, Nippon Kobayaku Co., Ltd.), nonylic acid vanillylamide (Nagaoka Jitsugyo 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 suppressing discoloration, capsicum or its extract is added in terms of crude drug, and the total mass of the composition is The content is preferably 0.01 to 15% by mass, more preferably 0.05 to 10% by mass, and particularly preferably 0.1 to 8% by mass. In addition, particularly when capsacinoids such as capsaicin and nonanoic acid vanillylamide are used as capsicum or its extract, it is preferable to contain capsaicinoids in an amount of 0.0001 to 2% by mass with respect to the total mass of the composition from the viewpoint of discoloration suppressing action. The content is preferably 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 capsicum or an extract thereof in the liquid or semi-solid composition is not particularly limited, and may be appropriately determined from the viewpoint of discoloration suppressing action. From the viewpoint of inhibitory action, it is preferable to contain 0.01 to 15 parts by mass of capsicum or its extract in terms of crude drug equivalent to 1 part by mass of loxoprofen or its salt in terms of loxoprofen anhydride, and 0.05 to It is more preferable to contain 10 parts by mass, and it is particularly preferable to contain 0.1 to 8 parts by mass. In particular, when capsaicinoids such as capsaicin and nonanoic acid vanillylamide are used as hot peppers or their extracts, from the viewpoint of suppressing discoloration, 0 capsaicinoid is added to 1 part by mass of loxoprofen or a salt thereof in terms of loxoprofen sodium anhydride. It preferably contains 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 0.005 to 0.1 parts by mass Part containing is particularly preferred.

<Liquid or semi-solid composition>
In the present invention, a "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 a solution, colloidal solution (sol (suspension or emulsion)), gel, or the like. In addition, the type and properties of the solvent or base are not particularly limited, and may be hydrophilic or hydrophobic such as oily. may be used as Specific examples of such solvents/bases include components exemplified as additives described later.

In the present invention, the liquid or semi-solid composition preferably contains water from the viewpoint of safety during use of the pharmaceutical preparation. 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 suppressing action, it is preferably 1% by mass or more relative to the total mass of the composition. It is more preferably 5% by mass or more, still more preferably 10 to 90% by mass, even more preferably 20 to 70% by mass, and particularly preferably 30 to 50% by mass.

Moreover, in the present invention, the liquid or semi-solid composition preferably contains a lower alcohol from the viewpoint of the usability of the pharmaceutical preparation. Here, the term "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 from the viewpoint of the feeling of use of the pharmaceutical preparation and the effect of suppressing discoloration, it is preferably 5% by mass or more relative to the total mass of the composition, and 10 to 10% by mass. It is more preferably 90% by mass, even more preferably 15 to 70% by mass, and particularly preferably 20 to 50% by mass.

In the present invention, the liquid or semi-solid composition preferably contains both water and a lower alcohol, from the viewpoint of safety and feel during use of the pharmaceutical preparation. Discoloration is suppressed even when the composition contains at least one of water and a lower alcohol (in particular, a composition containing both water and a lower alcohol).

In the present invention, the liquid or semi-solid composition contains drugs other than the above as pharmaceutical ingredients, such as analgesic ingredients, anti-inflammatory ingredients, antihistamine ingredients, bactericidal ingredients, astringent/protective ingredients, blood circulation promoting ingredients, and warming ingredients. Selected from the group consisting of sensitive ingredients, local anesthetic ingredients, antitussives, noscapines, bronchodilators, expectorants, hypnotic sedatives, vitamins, gastric mucosa protective agents, antacids, anticholinergics, crude drugs, Chinese herbal prescriptions, etc. may contain one or two or more.

Examples of analgesic ingredients include aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, sazapyrin, salicylamide, salicylic acid, ethylene glycol salicylate, glycol salicylate, sodium salicylate, methyl salicylate, thiaramide hydrochloride, and lactylphenetidine. etc.
Anti-inflammatory components include, for example, sodium guaiazulene sulfonate, glycyrrhizic acid and its derivatives, and salts thereof (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), glycyrrhetinic acid, seaprose, semi-alkaline proteinase, serrapeptase, proctase, pronase, bromelain and the like.

Examples of antihistamine components include azelastine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, carbinoxamine diphenyldisulfonate, and carbinoxamine. Maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, difererol hydrochloride, difererol phosphate, diphenylpyraline hydrochloride, diphenylpyraline Theocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetirizine hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, tondylamine hydrochloride, fexofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene dihydrochloride salicylates, bepotastine besilate, homochlorcyclidine hydrochloride, mequitazine, methdilazine hydrochloride, mebhydrolin napadisilate and the like.

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

Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane citrate, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dimemomorphan phosphate, tipepidine citrate, tipepidine hibenzate and the like.

Examples of noscapines include noscapine hydrochloride and noscapine.
Bronchodilators include, for example, trimetoquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and the like.

Examples of expectorants include ammonia, fennel essence, ammonium chloride, and the like.

Hypnotic sedatives include, for example, allylisopropylacetylurea, bromvalerylurea, and the like.
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 (e.g., thiamine, thiamine chloride hydrochloride, Thiamine nitrate, dicetiamine hydrochloride, cetotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, cicotiamine, thiamine disulfide, bisivtiamine, bisbentiamine, prosultiamine, benfotiamine, riboflavin, riboflavinlin acid ester, riboflavin butyrate, riboflavin sodium phosphate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.). be done.

Gastric mucosa protective agents include, for example, gefarnate, cetraxate hydrochloride, sofalcon, 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, aluminum hydroxide/magnesium carbonate mixed dry gel, aluminum hydroxide/sodium hydrogen carbonate coprecipitate product, aluminum hydroxide/calcium carbonate/magnesium carbonate coprecipitate product, magnesium hydroxide, magnesium hydroxide - Coprecipitation products of aluminum potassium sulfate, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, squid bone, stone septum, boley, etc. .

Examples of anticholinergics include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, tipepidinium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, and the like. mentioned.

Herbal medicines include, for example, Akamegashiwa (red bud oak), Asenyaku (Asenyaku), Arnica, Inyoukaku (Lady), Fennel, Turmeric, Corydalis, Scutellaria root (Ogon), Ousei ( Yellow spirit), Phellodendron bark, Ouhi (cherry bark), Coptis (huangren), Onji (Zenzi), Zebra (Gajutsu), Valerian (bad grass), Chamomile, Caronin (Karonin), Bellflower (bellflower) , Kyounin (apricot kernel), wolfberry (Kukoshi), kukoyou (枸杞葉), keigai (荊芥), cinnamon (cinnamon bark), Ketsumeishi (decision), gentian, gennoshoko (actual evidence), kouka (safflower), kobushi (kobushi) ), goou (beef yellow), gomishi (winter), saishin (spicy), sanshishi (yamashishi), sansho (sansho), shion (purple), jikoppi (ground bone skin), shikon (purple root), peony (peony) , Musk (Musk), Shajin (Shajin), Shazenshi (Kurumaeko), Shazensou (Kurumaeko), Beast Bile (including Yutan (Kumabori)), Ginger (Ginger), Jiryu (Earth Dragon), Shinyi ( Shini), horse chestnut, sekisan (pebble garlic), senega, cnidium officinale, zenko, senburi, sojutsu, souhakuhi, soyou, taisan (garlic), chikusetsu carrot (bamboo ginseng), chimpi (chimpi), touki (touki), tokon (salmon root), nantenjitsu (nantenjitsu), carrot (carrot), fritillaria (shellfish mother), bakumondou (barley gate) Winter), hange (half summer), bankouca (safflower), hampi (anti-nosed), byakushi (white), byakujutsu (white), bukuryo (bukuryo), botanpi (peony skin), yobaihi (yang plum skin), rokujo (antler) and other crude drugs and their extracts (extracts, tinctures, dried extracts, etc.).

Kampo prescriptions include, for example, Keishito (Keishito), Kososan (Kousosan), Saiko Keishito (Saikokeishito), Shosaikoto (Shosaikoto), Bakumondoto (Bakumondoto), Hange Koubokutou (Hangekobokuto) and the like can be mentioned.

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

Examples of gelling agents include acrylic acid-based polymers such as carboxyvinyl polymer; water-soluble or water-swellable cellulose-based polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose and ethyl cellulose; polyvinyl alcohol; Examples include polyvinylpyrrolidone.
Examples of polyhydric alcohols 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, petrolatum; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; behenyl alcohol, lauryl alcohol, myristyl alcohol; Higher alcohols such as 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 beeswax, bleached beeswax, montan wax, lanolin, refined lanolin and reduced lanolin; and silicone oils.

Examples of emulsifiers include polyhydric alcohols 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, methylglucoside fatty acid esters, and alkyl polyglucosides. fatty acid ester or polyhydric alcohol alkyl ether; polyoxyethylene ether such as polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene polyoxypropylene alkyl 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 oils, 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 etc.
Examples of solubilizers include glycerin, liquid paraffin, crotamiton, macrogol, etc., in addition to the nonionic surfactants and ionic surfactants exemplified as emulsifiers above.

pH adjusters include, for example, 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, ice Organic acids such as acetic acid or salts thereof; Inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium hydrogen carbonate or salts thereof; sodium hydroxide , alkali hydroxides such as potassium hydroxide, calcium hydroxide and magnesium hydroxide; and amines such as triethanolamine, diethanolamine and diisopropanolamine.
Examples of antioxidants 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.
Softening agents include, for example, allantoin, almond oil, olive oil, glycerin, liquid paraffin, squalane, squalene, refined lanolin, medium chain fatty acid triglycerides, rapeseed oil, castor oil, propylene glycol, polybutene and the like.
Thickeners include, for example, polyvinylpyrrolidone, carboxymethylcellulose, colloidal aluminum silicate, xanthan gum, locust bean gum, tragacanth gum, guar gum, gelatin, gum arabic, alginic acid, albumin and the like.
Moisturizers include sodium hyaluronate, glycerin, 1,3-butylene glycol, propylene glycol, urea, sucrose, erythritol, sorbitol and the like.
Examples of antiseptics include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, and benzoin. benzyl acid, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, aminoethylsulfonic acid and the like.
Stabilizers include, for example, adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hydrogenated oil, cysteine and the like.
Percutaneous absorption enhancers include, for example, fatty acid esters such as diisopropyl adipate.
Examples of corrigents/sweeteners include acesulfame potassium, stevia, thaumatin, sucralose, panose, trehalose, erythritol, lactitol, reduced palatinose, coupling sugar, fructo-oligosaccharide, galacto-oligosaccharide, milk oligosaccharide, isomalto-oligosaccharide, and palatinose. Oligosaccharide, raffinose, aspartame, fructose, xylitol, brown sugar, saccharin or its salt, sorbitol, lactose, sucrose, honey, glucose, maltitol, maltose, mannitol, starch syrup and the like.

Examples of terpenes include isoborneol, iron, ocimene, carveol, carbotanacetone, carbomentone, carvone, carene, caron, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, and cineol. , cymene, sylvestrene, thymol, isotjol, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocane, pinol, piperitenone, ferrandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, yonol, yonone, linalool, limonene and the like.

Examples of essential oils containing terpenes include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayaput oil, caraway oil, kubeb oil, grapefruit oil, cinnamon oil, coriander oil, Saffron oil, Japanese pepper oil, perilla oil, citriodora oil, citronella oil, ginger oil, shozuku oil, camphor oil, gingergrass oil, spearmint oil, mint oil, geranium oil, radish oil, clove oil, turpentine oil, spruce oil oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, peniroyal oil, henoposi oil, bergamot oil, boad rose oil, pepper oil, marjoran oil, mandarin oil, melissa oil, eucalyptus oil, Lime oil, lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, Roman chamomile oil and the like.

In the present invention, the method for producing a liquid or semi-solid composition is not particularly limited, and may vary depending on the type and amount of 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 application, and the like. Accordingly, it can be produced by a known method described in, for example, the Japanese Pharmacopoeia 16th Edition, General Rules for Pharmaceutical Preparations.

<Container made of polyolefin resin>
In the present invention, the "container" means a package that directly accommodates 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 it should be considered appropriately according to the properties of the composition, the dosage form of the pharmaceutical preparation, the route of administration, the application, etc. You just have to decide.
The shape of such a container includes, for example, an aerosol agent container, a pump spray agent container, a bottle container (more specifically, for example, a bottle container having a spongy application member (head), a roll-on container, a jar bottle container, etc.). etc.), tube containers, eye drop containers, and the like. All of these containers are publicly known and may be manufactured by known methods, or commercially available products may be used.

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 comprising a container body and an application member, such as a bottle container having a spongy application member, and used by impregnating the application member with a composition contained in the container body;
(2) A container comprising a flexible container body and a discharge port, such as a tube container;
is preferred, and the container of embodiment (1) is particularly preferred.

[(1) A container comprising a container body and an application member, and used by impregnating the composition contained in the container body into the application member]
In the case of the container of such an aspect, the composition can be applied by impregnating and holding the composition contained in the container main body in the application member and bringing the application member into contact with the part to be applied. In this case, the container body and the application member may be manufactured as independent members, and then the application member may be attached to the container body, or may be integrally molded.
The application member may be any structure as long as it can be impregnated and held with a liquid or semi-solid composition, and examples thereof include a sponge-like porous member and a brush-like member.

Examples of such a container include a container that is provided with an application member at the mouth of the container body, and that is used by impregnating the application member with the composition contained in the container body.
A more detailed specific example includes a container comprising a container body having a mouth portion and a porous (sponge-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 part to be coated to obtain the composition. An object can be applied to the applied part.
Another specific example is a container comprising a container body having a mouth portion and a brush-like application member attached to the mouth portion. In this case, after impregnating and holding the composition contained in the container main body in a brush whose bristles are appropriately adjusted in length, spacing, etc., the composition is applied by bringing the application member into contact with the part to be coated. It can be applied to the part to be coated.

Since the container of such an aspect is used by impregnating and holding the composition in the application member, for example, when the pharmaceutical preparation is an external application agent, the problem of liquid dripping on the applied part is unlikely to occur, and the application member is directly attached. It has advantages such as keeping fingers clean by using it in contact with the part to be coated, and being able to flexibly adjust the area to be coated with the composition easily by adjusting the shape and size of the coating member. have. However, since the composition is impregnated and held in the coating member, when the composition is discolored, the entire coating member is discolored. Therefore, when the applicator member is exposed to the outside, such as when using a pharmaceutical preparation, discoloration is particularly conspicuous in terms of appearance. On the other hand, according to the present invention, the discoloration of the composition is suppressed, so that it has the excellent effect of solving the problem of appearance and fully enjoying the above merits. In the case of such a container, it is particularly preferable that both the container body and the application member are made of polyolefin resin.
Such a container can be particularly suitably employed when the composition to be accommodated is, for example, a liquid composition or a low-viscosity semi-solid composition.

Such a container is well known and disclosed in, for example, Japanese Patent No. 5570089. In addition, in the present invention, a commercially available product may be used as the container of such an aspect. As such a commercially available product, for example, MAPS (INOAC Co., Ltd.), which is a communicating porous body made of low-density polyethylene as an application member, may be used. Corporation).

[(2) A container comprising a flexible container body and a discharge port]
In the case of the container of such an aspect, pressure is applied to the inside of the container by pressing the flexible container body, etc., and the composition accommodated inside the container is discharged from the discharge port, so that the composition is applied to the part to be coated. can be applied to In addition, in the container of such an aspect, the discharge port may not 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. and a discharge port”.

Such a container has advantages such as low manufacturing cost due to its simple structure and no contamination of the composition in the container because the composition is discharged from the discharge port by pressing the container body or the like. have
In addition, the container of such an aspect can be particularly suitably employed when the composition to be accommodated is, for example, a highly viscous semi-solid composition.

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

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 a plurality of types of monomers. Moreover, in the case of a copolymer, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, its stereoregularity (tacticity) is not particularly limited.
Specific examples of such polyolefin-based 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/acetic acid Examples include vinyl copolymers and ethylene/ethyl acrylate copolymers, and in the present invention, these can be used alone or in combination of two or more.
In the present invention, the polyolefin 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 polyolefin resin" means that at least part of the material contains polyolefin resin. A mixture of (polymer alloy) is also included in "made of polyolefin resin".

In the present invention, the term "polyolefin resin container" refers to at least a portion of the portion of the container that is in contact with the liquid or semi-solid composition contained therein (preferably, the composition is 10% or more of the portion in contact with, 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 a "container" that is "made of resin". Therefore, for example, a layer of polyolefin resin is provided at least in part of the layer (the innermost layer of the container) that comes into contact with the liquid or semi-solid composition, and a resin of another material or a material such as aluminum foil is laminated on the outside thereof. A container formed by lamination also corresponds to a "polyolefin-based resin container."
As such a container made by laminating a plurality of kinds of materials, specifically, for example, a layer composed of polyolefin resin is the innermost layer, and aluminum foil is placed on the outer side directly or via another layer. is laminated, and other layers are optionally laminated on the outer side thereof, such as a laminated film container.

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

<Pharmaceutical formulation>
In the present invention, the administration method and application method of the "pharmaceutical formulation" are not particularly limited, and include oral and parenteral administration such as percutaneous and vaginal administration. In the present invention, parenteral administration is preferred because of the characteristics of the liquid or semi-solid composition (it is possible to flexibly apply the 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 housed in the container is liquid or semisolid. It can be appropriately selected from the dosage forms described in the Japanese Pharmacopoeia General Rules for Preparations. Specific examples of such dosage forms include formulations applied to the skin (external liquids, sprays, ointments, creams, gels, etc.), formulations administered orally (oral liquids, syrups, oral jellys, etc.). etc.), and other dosage forms described in the Japanese Pharmacopoeia 16th Edition, General Rules for Formulations.
In the present invention, the pharmaceutical preparation is preferably a dosage form selected from the group consisting of liquids for external use, sprays, ointments, creams and gels, liniments, lotions, external aerosols, pump sprays, More preferred are dosage forms selected from the group consisting of ointments, creams and gels, and particularly preferred are dosage forms selected from the group consisting of lotions, ointments, creams and gels.

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

Next, the invention of the "method" aspect will be described below.
The present invention provides the following components (A) and (B):
(A) loxoprofen or a salt thereof;
(B) capsicum or an extract thereof;
It also relates to a method for suppressing discoloration of a composition, which comprises the step of housing a liquid or semi-solid composition containing 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 housing the composition in a polyolefin resin container is not particularly limited. and a liquid or semi-solid composition containing (B) is directly or indirectly stored in a container made of polyolefin resin.
In addition, in the invention of this aspect, the meaning of various words, the compounding amount of each component, etc. are all the same as those explained for the "pharmaceutical preparation".

This specification discloses the inventions exemplified below, for example, 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 an extract thereof;
A pharmaceutical preparation comprising a liquid or semi-solid composition containing
[2] The pharmaceutical preparation according to [1], wherein component (A) is loxoprofen sodium hydrate.
[3] Component (B) is one or more selected from the group consisting of red pepper, red pepper powder, hot red pepper soft extract, hot red pepper dry extract, capsaicin and nonanoic acid vanillylamide (nonylic acid vanillylamide) [1] or [2 ] pharmaceutical formulations described.
[4] The pharmaceutical preparation according to [1] or [2], wherein component (B) is one or more selected from the group consisting of hot pepper soft extract and nonanoic acid vanillylamide (nonylic acid vanillylamide).

[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 formulation of [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 resin is one or more 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 an aerosol container, a pump spray container, a bottle container, a tube container or an eye drop container.
[10] The container has the following (1) or (2):
(1) A container comprising a container body and an application member, and used by impregnating the composition contained in the container body into the application member;
(2) A container comprising 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 tube container provided with a sponge-like application member.
[12] The dosage form according to any one of [1] to [11], which is selected from the group consisting of external liquids, sprays, ointments, creams, gels, oral liquids, syrups and oral jellys. Pharmaceutical formulation.
[13] The pharmaceutical preparation according to any one of [1] to [11], which is in a dosage form selected from the group consisting of external solutions, sprays, ointments, creams and gels.
[14] The pharmaceutical preparation according to any one of [1] to [11], which is in a dosage form selected from the group consisting of liniments, lotions, aerosols, pump sprays, ointments, creams and gels.
[15] The pharmaceutical preparation according to any one of [1] to [11], which is in 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 an extract thereof;
A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing in a polyolefin resin container.
[17] The method of [16], wherein component (A) is loxoprofen sodium hydrate.
[18] Component (B) is one or more selected from the group consisting of red pepper, red pepper powder, red pepper soft extract, hot red pepper dry extract, capsaicin and nonanoic acid vanillylamide (nonylic acid vanillylamide), [16] or [17] ] method described.
[19] The method according to [16] or [17], wherein the component (B) is one or more selected from the group consisting of soft red pepper extract and nonanoic acid vanillylamide (nonylic acid vanillylamide).

[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 of [21], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol.
[23] The method according to any one of [16] to [22], wherein the polyolefin resin is one or more selected from the group consisting of polyethylene and polypropylene.
[24] The method according to any one of [16] to [23], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container or an eye drop container.
[25] The container has (1) or (2):
(1) A container comprising a container body and an application member, and used by impregnating the composition contained in the container body into the application member;
(2) A container comprising 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 tube container having a spongy application member.

EXAMPLES The present invention will be described in detail with reference to Examples below, but the present invention is not limited to these Examples.

[Test Example 1] Storage Test Part 1
Liquid compositions containing the components and amounts shown in Table 1 were prepared and placed in polyethylene or glass containers to obtain pharmaceutical preparations of Example 1 and Comparative Examples 1 and 2, respectively.
The obtained various pharmaceutical formulations 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 after storage for 1 week was visually evaluated. The results were evaluated as ◯ when no discoloration occurred, and x when discoloration occurred.
Table 1 shows the results.

From the comparison between Comparative Example 1 (contained in a polyethylene container) and Comparative Example 2 (contained in a glass container), discoloration after storage for 3 days was suppressed by housing the composition in a polyethylene container, and some discoloration suppression effect was obtained. However, the effect was not sufficient, and it was confirmed that discoloration occurred after storage for one week.
On the other hand, from the comparison between Example 1 (contained in a polyethylene container containing a soft pepper extract) and Comparative Example 1 (contained in a polyethylene container), the composition was further mixed with a soft capsicum extract and then contained in a polyethylene container. As a result, discoloration after storage for one week was also suppressed, and it was confirmed that a sufficient discoloration-suppressing effect was exhibited.

From the above test results, by adding capsicum or its extract to the liquid or semi-solid composition containing loxoprofen or a salt thereof and placing it in a container made of polyolefin resin, high temperature It was found that discoloration during storage can be suppressed.

[Test Example 2] Storage test 2
A liquid composition containing the components and amounts shown in Table 2 was prepared and placed in a polyethylene or glass container to obtain the pharmaceutical preparations of Example 2, Comparative Examples 3 and 4, respectively, in the same manner as in Test Example 1. Presence or absence of discoloration after storage in a dark place at 80° C. for 3 days and 1 week was evaluated by the method of No.
Table 2 shows the results.

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

[Test Example 3] Storage Test Part 3
A liquid composition containing the components and amounts shown in Table 3 was prepared, placed in a polyethylene container to obtain the pharmaceutical preparation of Example 3, and subjected to the same method as in Test Example 1 in a dark place at 80°C for 1 week. The presence or absence of discoloration after storage was evaluated.
Table 3 shows the results.

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

From the results of Test Examples 1 to 3 above, the liquid or semi-solid composition containing loxoprofen or a salt thereof further contains capsicum or an extract thereof typified by capsicum soft extract and nonanoic acid vanillylamide, and , discoloration during high-temperature storage can be suppressed by housing in a container made of polyolefin resin.

[Test Example 4] Storage test 4
A liquid composition containing the components and amounts shown in Table 4 was prepared, placed in a polyethylene or glass container, and used as the pharmaceutical preparation of Example 4, Comparative Examples 5 and 6, or Reference Example 1, respectively, and tested. The same method as in Example 1 was used to evaluate the presence or absence of discoloration after storage in a dark place at 80° C. for 2 weeks.
Table 4 shows the results.

From the comparison between Comparative Example 5 and Reference Example 1 (loxoprofen not blended), the discoloration confirmed after storage at 80° C. for 2 weeks was attributed to the blending of loxoprofen in the liquid composition. confirmed.
Then, in comparison with Example 4, Comparative Example 5 (accommodated in a glass container), and Comparative Example 6 (no nonanoic acid vanillylamide blended), the liquid composition was further blended with nonanoic acid vanillylamide, and polyethylene-made It was confirmed that such discoloration can be suppressed by housing in a container.

[Test Example 5] Storage Test Part 5
A liquid composition containing the components and amounts shown in Table 5 was prepared, placed in a polypropylene container to obtain the pharmaceutical preparations of Examples 5 and 6, and placed in a dark place at 80°C in the same manner as in Test Example 1. The presence or absence of discoloration after storage for 2 weeks was evaluated.
Table 5 shows the results.

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

[Test Example 6] Storage test 6
The same liquid composition as contained in the pharmaceutical formulations of Examples 1 and 3 was prepared, and this was applied to a low-density polyethylene communicating porous body (MAPS: ) INOAC CORPORATION) and then stored in a dark place at 80° C. for 1 week, but no clear discoloration was observed in any of the compositions.

Production Example 1 (lotion)
A liquid composition (formulation examples 1 to 8) containing 100 g of the components and amounts (g) shown in Table 6 below was produced by a conventional method, and sponge-like polyurethane was added to the mouth of a polypropylene container body. These were stored in a bottle container equipped with an application member to prepare pharmaceutical preparations (lotions) of Production Examples 1-1 to 1-8, respectively.

Production Example 2 (lotion)
Liquid compositions (formulation examples 1 to 8) containing 100 g of the components and amounts (g) shown in Table 6 above were produced by a conventional method, and a spongy low-pressure liquid was applied to the mouth of a polyethylene container body. They were placed in bottle containers fitted with density polyethylene application members (MAPS: INOAC CORPORATION) to prepare pharmaceutical formulations (lotions) of Production Examples 2-1 to 2-8.

Production Example 3 (lotion)
A liquid composition (formulation examples 9 to 16) containing 100 g of the components and amounts (g) shown in Table 7 below was produced by a conventional method, and a spongy polyurethane was added to the mouth of a polypropylene container body. These were stored in a bottle container equipped with an application member to prepare pharmaceutical preparations (lotions) of Production Examples 3-1 to 3-8, respectively.

Production Example 4 (lotion)
Liquid compositions (formulation examples 9 to 16) containing 100 g of the components and amounts (g) shown in Table 7 above were produced by a conventional method, and a spongy low-pressure liquid was applied to the mouth of a polyethylene container body. They were placed in bottle containers fitted with high-density polyethylene application members (MAPS: INOAC CORPORATION) to prepare pharmaceutical preparations (lotions) of Production Examples 4-1 to 4-8, respectively.

Production Example 5 (Gel)
By a conventional method, a semi-solid composition (formulation examples 17 to 24) containing the components and amounts (g) shown in Table 8 below in 100 g was produced, and a low-density polyethylene film was used as the innermost layer. Housed in a laminated film tube container (laminated tube) in which an aluminum foil is laminated on the outside (intermediate layer) and a low-density polyethylene film is laminated on the outside (laminated tube), and the pharmaceutical preparations of Production Examples 5-1 to 5-8 ( gel).

Production Example 6 (Ointment)
By a conventional method, a semi-solid composition (formulation examples 25 to 32) containing 100 g of the components and amounts (g) shown in Table 9 below was produced, and a high-density polyethylene film was used as the innermost layer. Housed in a laminated film tube container (laminated tube) in which a polyethylene terephthalate film is laminated on the outside (intermediate layer) and a high-density polyethylene film is laminated on the outside, respectively, in Production Examples 6-1 to 6-8. A pharmaceutical preparation (ointment) was prepared.

Production Example 7 (Cream)
By a conventional method, a semi-solid composition (formulation examples 33 to 40) containing the components and amounts (g) shown in Table 10 below in 100 g was produced, and a low-density polyethylene film was used as the innermost layer. Housed in a laminated film tube container (laminated tube) in which a nylon film is laminated on the outside (intermediate layer) and a low-density polyethylene film is laminated on the outside (laminated tube), and the pharmaceuticals of Production Examples 7-1 to 7-8, respectively A formulation (cream) was prepared.

Production Example 8 (oral liquid)
By a conventional method, a liquid composition (formulation examples 41 to 48) containing the components and amounts (mg) shown in Table 11 below in 30 mL was produced and placed in a polypropylene bottle container, respectively Production Example 8 -1 to 8-8 pharmaceutical preparations (oral liquid preparations).

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. Therefore, a drug containing loxoprofen or a salt thereof with excellent storage stability can be provided, 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 an extract thereof;
A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing in a polyolefin resin container.