JP7600294B2 - Pharmaceutical preparations containing loxoprofen (3) - Google Patents

Description

The present invention relates to pharmaceutical preparations containing loxoprofen, which is also known as the active ingredient of Loxonin (registered trademark).

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

Incidentally, chili peppers, nonanoic acid vanillylamide (nonylic acid vanillylamide), and other chili peppers or their extracts are incorporated into topical anti-inflammatory and analgesic agents, and topical preparations incorporating loxoprofen are also already known (e.g., Patent Documents 1 and 2).

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

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

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

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

The inventors have further investigated the problem and found that discoloration during high-temperature storage can be suppressed by adding capsicum soft extract or capsicum vanillylamide nonanoate to a liquid or semi-solid composition containing loxoprofen or a salt thereof and storing the composition in a container made of a polyolefin resin such as polyethylene, thereby completing the present invention.

That is, the present invention relates to a composition comprising the following components (A) and (B):
(A) loxoprofen or a salt thereof;
(B) Capsicum or an extract thereof;
The present invention provides a pharmaceutical preparation comprising a liquid or semi-solid composition containing the above in a polyolefin resin container.
The present invention also relates to a composition comprising the following components (A) and (B):
(A) loxoprofen or a salt thereof;
(B) Capsicum or an extract thereof;
The present invention provides a method for suppressing discoloration of a composition, the method comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container.

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 medicine containing loxoprofen or a salt thereof with excellent storage stability can be provided.

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

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

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

In the present invention, the "chili pepper or an extract thereof" is preferably chili pepper, chili pepper powder, chili pepper extract (soft extract, dry extract), capsaicin, or nonanoic acid vanillylamide, and more preferably chili pepper soft extract or nonanoic acid vanillylamide.

The method for producing the chili pepper extract is not particularly limited, and it can be produced by referring to the known methods for producing plant extracts, such as those described in the General Provisions for Preparations of the 16th Revised Japanese Pharmacopoeia, under the headings "Extracts," "Infusions/Decoctions," "Tinctures," and "Liquid Extracts." Specifically, for example, chili peppers can be cut, heated, dried, crushed, etc. as necessary, and then extracted by adding an appropriate extraction solvent. The obtained extract may be further concentrated, dried, etc., as 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; aromatic hydrocarbons such as benzene and toluene; dimethylformamide; dimethyl sulfoxide; and water (including hot water). These may be used alone or in combination of two or more. In the present invention, water, ethanol, or a water/ethanol mixture is preferred.
The extraction procedure is not particularly limited, and any known method used for extraction from plants can be appropriately adopted, specifically, for example, immersion in an extraction solvent (cold immersion, hot immersion, percolation, etc.), extraction using a supercritical fluid or subcritical fluid, etc. In order to increase the extraction efficiency, stirring or homogenization in the extraction solvent may be performed.
The extraction temperature is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but is preferably from about 5° C. to a temperature below the boiling point of the extraction solvent.
The extraction time is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but is preferably about 1 hour to 14 days.

In the present invention, commercially available products can be used as chili pepper or its extract. Specific commercially available products include, for example, chili pepper extract-B, chili pepper extract-D, chili pepper extract-N, chili pepper extract-S, (local) chili pepper tincture, (local) chili pepper powder (all from Nippon Powder Pharmaceutical Co., Ltd.), nonylic acid vanillylamide (Nagaoka Jitsugyo Co., Ltd.), etc.

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

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

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

In the present invention, from the viewpoint of safety during use of the pharmaceutical preparation, it is preferable that the liquid or semi-solid composition contains water. Here, the content of water in the composition is not particularly limited, but from the viewpoint of safety during use of the pharmaceutical preparation and discoloration suppression effect, it is preferable that the content of water in the composition is 1% by mass or more, more preferably 5% by mass or more, even more preferably 10 to 90% by mass, even more preferably 20 to 70% by mass, and particularly preferably 30 to 50% by mass.

In addition, in the present invention, from the viewpoint of the usability of the pharmaceutical preparation, it is preferable that the liquid or semi-solid composition contains a lower alcohol. Here, "lower alcohol" means a linear or branched monohydric alcohol having 1 to 6 carbon atoms, and specific examples thereof include ethanol, isopropanol, n-propanol, etc., and ethanol, isopropanol, and mixtures thereof are preferable. Here, the content of the lower alcohol in the composition is not particularly limited, but from the viewpoint of the usability of the pharmaceutical preparation and the discoloration suppression effect, it is preferably 5% by mass or more, more preferably 10 to 90% by mass, even more preferably 15 to 70% by mass, and particularly preferably 20 to 50% by mass relative to the total mass of the composition.

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

In the present invention, the liquid or semi-solid composition may contain, as a medicinal ingredient, one or more drugs other than those mentioned above, such as analgesic ingredients, anti-inflammatory ingredients, antihistamine ingredients, bactericidal ingredients, astringent/protective ingredients, blood circulation promoting ingredients, warming ingredients, local anesthetic ingredients, cough suppressants, noscapines, bronchodilators, expectorants, hypnotics and sedatives, vitamins, gastric mucosa protecting agents, antacids, anticholinergics, herbal medicines, Chinese herbal prescriptions, etc.

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

Examples of antihistamine ingredients include azelastine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, difeterol hydrochloride, difeterol phosphate, diphenylpyrazol, and tetrahydrofuran. Examples of such drugs include phosphate hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetirizine hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine methylenedisalicylate, bepotastine besilate, homochlorcyclizine hydrochloride, mequitazine, methdilazine hydrochloride, and mebhydroline napadisilate.

Examples of antibacterial ingredients include benzalkonium chloride. Examples of astringent/protective ingredients include zinc oxide. Examples of blood circulation promoting ingredients include tocopherol acetate, benzyl nicotinate, heparinoids, sodium polyethylene sulfonate, etc. Examples of local anesthetic ingredients include lidocaine, clove oil, belladonna extract, etc.

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

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 extract, and ammonium chloride.

Examples of hypnotic sedatives include allylisopropylacetylurea and bromvalerylurea.
Examples of vitamins include vitamin _B1 , vitamin _B2 , vitamin _B5 , vitamin _B6 , vitamin _B12 , vitamin C, hesperidin and its derivatives and salts thereof (e.g., thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, setotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, shikotiamine, thiamine disulfide, bis-ibuthiamine, bis-bentiamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin sodium phosphate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

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

Examples of anticholinergic drugs include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, tipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, etc.

Examples of herbal medicines include Mallotus japonicus (red bud oak), Asanonia arvensis (asenia), Arnica, Coix seed stalk (inyang huang), Fennel (fennel), Turmeric (turmeric), Corydalis chinensis (corbicula var. esculenta), Scutellaria baicalensis (scutellaria), Phellodendron bark (cypress), Coptis japonica (coptis), Onji (apricot), Valerian (valerian), Chamomile, Calonin (carotenoid), Platycodon grandiflorum (bellflower), Apricot kernel (almond kernel), Lycium chinense (wolfberry), Lycium chinense leaf (wolfberry leaf), and Kei. Gai (thorn), Cinnamon bark, Cassia japonica (cassia seed), Gentiana chinensis, Gennoshoko (genus evidence), Kouka (safflower), Kobushi (corn berry), Goou (bezoar), Gomishi (schisandra berry), Saishin (spicy spiciness), Sanshishi (gardenia berry), Sansho (Japanese pepper), Shion (asperm), Jikoppi (earth bone bark), Shikon (purple root), Paeonia lactiflora (peony), Musk, Shajin (shrimp), Shazenshi (plant gall), Shazensou (plant gall), Animal gall (including bear gall), Zingiber officinale (ginger), Jiryu (earth dragon), Shini (magnolia), European horse chestnut, Sekisan (garlic), Senega, Cnidium rhizome, Zenko (forsythia), Senburi (thousand-flying ash), Soujutsu (blue atractylodes), Sohakuhi (mulberry bark), Soyou (persimmon leaf), Taisan (garlic), Chikusetsuninjin (bamboo joint ginseng), Chinpi (citrus peel), Touki (angelica), Ipecac (ipecac), Nantenjitsu (southern Herbal medicines such as Tenjiku (Citrus serrata), Ninjin (Carrot), Fritillaria rosa (Fritillaria), Bakumondou (Oryza sativa), Pinellia gracilis (Prunus persica), Bankouka (Safflower), Hanpi (Hanpi), Byakshi (White Atractylodes), Byakkushou (White Atractylodes), Poria cocos (Poria cocos), Botanpi (Moutan Peel), Youbaihi (Plum Skin), and Rokujo (Deer Antler), as well as their extracts (extracts, tinctures, dried extracts, etc.), etc.

Examples of herbal prescriptions include Keishito (Keishito), Kousosan (Kousosan), Saikokeishito (Saikokeishito), Shosaikoto (Shosaikoto), Bakumondoutou (Bakumondoutou), and Hangekobokuto (Hangekobokuto).

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

Examples of gelling agents include acrylic acid polymers such as carboxyvinyl polymers; water-soluble or water-swellable cellulose polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, and ethyl cellulose; polyvinyl alcohol; and polyvinylpyrrolidone.
Examples of polyhydric alcohols include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, macrogol, and polypropylene glycol.
Examples of fats and oils include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, and petrolatum; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; higher alcohols such as behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, and oleyl alcohol; higher fatty acids such as behenic acid, lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; waxes such as carnauba wax, spermaceti, shellac, jojoba oil, beeswax, white beeswax, montan wax, lanolin, refined lanolin, and reduced lanolin; and silicone oils.

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

Examples of pH adjusters include organic acids or salts thereof, such as citric acid, sodium citrate, anhydrous citric acid, malic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, acetic acid, sodium acetate, and glacial acetic acid; inorganic acids or salts thereof, such as hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, and sodium hydrogen carbonate; alkali hydroxides, such as sodium hydroxide, 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, and propyl gallate.
Examples of softeners 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 thickeners include polyvinylpyrrolidone, carboxymethylcellulose, colloidal aluminum silicate, xanthan gum, locust bean gum, tragacanth gum, guar gum, gelatin, gum arabic, alginic acid, and albumin.
Moisturizing agents include sodium hyaluronate, glycerin, 1,3-butylene glycol, propylene glycol, urea, sucrose, erythritol, sorbitol, and the like.
Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, and aminoethylsulfonic acid.
Examples of stabilizers include adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hardened oil, and cysteine.
Examples of the percutaneous absorption enhancer include fatty acid esters such as diisopropyl adipate.
Examples of flavoring agents and sweeteners include acesulfame potassium, stevia, thaumatin, sucralose, panose, trehalose, erythritol, lactitol, reduced palatinose, coupling sugar, fructooligosaccharides, galactooligosaccharides, lactoferrin oligosaccharides, isomaltooligosaccharides, palatinose oligosaccharides, raffinose, aspartame, fructose, xylitol, brown sugar, saccharin or a salt thereof, sorbitol, lactose, white sugar, honey, glucose, maltitol, maltose, mannitol, and starch syrup.

Examples of terpenes include isoborneol, irone, ocimene, carveol, carbotanacetone, carbomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, sylvestrene, thymol, isothujol, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampheol, pinol, piperitenone, phellandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, and limonene.

Examples of essential oils containing terpenes include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayaputo oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, pepper oil, perilla oil, citriodora oil, citronella oil, ginger oil, cardamom oil, camphor oil, ginger grass oil, spearmint oil, peppermint oil, geranium oil, daphne oil, and daphne oil. Examples include anise oil, clove oil, turpentine, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, henopodium oil, bergamot oil, borealis oil, hossam oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime oil, lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil.

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

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

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

[(1) A container comprising a container body and an application member, the application member being impregnated with a composition contained in the container body when in use]
In the case of the container of this embodiment, the composition contained in the container body is impregnated and held in the application member, and the application member is brought into contact with the part to be applied, thereby applying the composition. In this case, the container body and the application member may be produced as independent members, and then the application member may be attached to the container body, or they may be molded integrally.
The application member may be any member capable of being impregnated with and holding the liquid or semi-solid composition, and examples of such members include porous members such as sponges and brush-like members.

An example of such a container is a container that has an application member at the mouth of the container body and is used by impregnating the application member with the composition contained in the container body.
A more specific example is a container including a container body having a mouth and a porous (sponge-like, etc.) coating member attached to the mouth. In this case, the composition contained in the container body is impregnated and held in a porous coating member having an appropriately adjusted pore size, porosity, etc., and then the coating member is brought into contact with the coating portion, whereby the composition can be applied to the coating portion.
Another specific example is a container comprising a container body having a mouth and a brush-like applicator attached to the mouth. In this case, the composition contained in the container body is impregnated and held in a brush having appropriately adjusted bristles length, spacing, etc., and then the applicator is brought into contact with the part to be coated, thereby applying the composition to the part to be coated.

The container of this embodiment has the advantages that, for example, when the pharmaceutical preparation is an external application, the problem of liquid dripping is unlikely to occur at the application site, the application member is directly in contact with the application site, and the area to which the composition is applied can be easily and flexibly adjusted by adjusting the shape and size of the application member. However, since the composition is impregnated and held in the application member, if the composition discolors, the discoloration will occur over the entire application member. Therefore, when the application member is exposed to the outside, for example, when the pharmaceutical preparation is used, the discoloration will be particularly noticeable in appearance. However, according to the present invention, the discoloration of the composition is suppressed, and the above-mentioned problems in appearance can be solved and the above-mentioned advantages can be fully enjoyed. In addition, in the case of the container of this embodiment, 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 used when the composition contained therein is, for example, a liquid composition or a low-viscosity semi-solid composition.

Containers of this type are known and are disclosed, for example, in Japanese Patent No. 5570089. In addition, in the present invention, commercially available products may be used as containers of this type. Examples of such commercially available products include containers that use MAPS (INOAC Corporation), a porous material made of low-density polyethylene, as the coating member.

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

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

Containers of this type are known and are disclosed, for example, in Japanese Patent No. 5302550 and Japanese Patent No. 5525135. In addition, in the present invention, commercially available products may be used as containers of this type.

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

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

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

<Pharmaceutical Preparations>
In the present invention, the method of administration/application of the "pharmaceutical preparation" is not particularly limited, and examples thereof include oral and parenteral administration such as transdermal and vaginal administration. In the present invention, parenteral administration is preferred, and transdermal administration is particularly preferred, due to the characteristics of the liquid or semi-solid composition (the ability to flexibly apply only the required amount depending on the location, shape, and range of the affected area).

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

The pharmaceutical preparation of the present invention contains loxoprofen, a type of NSAID, or a salt thereof, and can be used as a medical drug or an OTC drug, and is useful, for example, as an external anti-inflammatory analgesic; an antipyretic analgesic, an oral drug such as a general cold remedy; etc.

Next, the invention in the form of a "method" will be described below.
The present invention comprises the following components (A) and (B):
(A) loxoprofen or a salt thereof;
(B) Capsicum or an extract thereof;
The present invention also relates to a method for suppressing discoloration of a composition, the method comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container.
In the invention of such an embodiment, the order of the step of blending component (A), the step of blending component (B), and the step of containing the composition in a polyolefin-based resin container is not particularly limited, as long as a liquid or semi-solid composition containing components (A) and (B) is directly or indirectly produced in a state in which it is contained in a polyolefin-based resin container.
In this embodiment of the invention, the meanings of various terms, the amounts of each ingredient, etc. are all the same as those explained for the "pharmaceutical preparation".

This specification discloses the invention exemplified below in relation to the above-mentioned embodiments, but is not limited to these in any way.
[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 the above in a polyolefin resin container.
[2] The pharmaceutical formulation described in [1], wherein component (A) is sodium rofecoxib hydrate.
[3] The pharmaceutical formulation according to [1] or [2], wherein component (B) is one or more members selected from the group consisting of chili pepper, chili pepper powder, chili pepper soft extract, chili pepper dry extract, capsaicin, and nonanoic acid vanillylamide (nonylic acid vanillylamide).
[4] The pharmaceutical formulation according to [1] or [2], wherein component (B) is one or more members selected from the group consisting of capsicum soft extract and nonanoic acid vanillylamide (nonylic acid vanillylamide).

[5] The pharmaceutical formulation according to any one of [1] to [4], wherein the composition further contains water.
[6] The pharmaceutical formulation according to any one of [1] to [5], wherein the composition further contains a lower alcohol.
[7] The pharmaceutical formulation according to [6], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol.
[8] The pharmaceutical formulation 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 formulation 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 is any of the following (1) or (2):
(1) A container comprising a container body and an application member, the application member being impregnated with a composition contained in the container body when in use;
(2) A container having a flexible container body and a discharge port;
The pharmaceutical formulation 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 equipped with a sponge-like application member.
[12] The pharmaceutical preparation according to any one of [1] to [11], which is in a dosage form selected from the group consisting of external liquid preparations, sprays, ointments, creams, gels, oral liquid preparations, syrups, and oral jellies.
[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 liquid preparations, 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 a lotion, an ointment, a cream, and a gel.

[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 the above in a polyolefin resin container.
[17] The method described in [16], wherein component (A) is sodium rofecoxib hydrate.
[18] The method according to [16] or [17], wherein component (B) is one or more members selected from the group consisting of chili pepper, chili pepper powder, chili pepper soft extract, chili pepper dry extract, capsaicin, and nonanoic acid vanillylamide (nonylic acid vanillylamide).
[19] The method according to [16] or [17], wherein component (B) is one or more members selected from the group consisting of capsicum soft extract and nonanoic 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 according to [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 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 an aerosol container, a pump spray container, a bottle container, a tube container or an eye drop container.
[25] The container is any of the following (1) or (2):
(1) A container comprising a container body and an application member, the application member being impregnated with a composition contained in the container body when in use;
(2) A container having 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 equipped with a sponge-like application member.

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

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

Comparing Comparative Example 1 (contained in a polyethylene container) with Comparative Example 2 (contained in a glass container), it was confirmed that, although containing the composition in a polyethylene container suppressed discoloration after storage for three days and exerted some discoloration suppression effect, the effect was not sufficient and discoloration occurred after storage for one week.
On the other hand, by comparing Example 1 (containing soft chili pepper extract, contained in a polyethylene container) with Comparative Example 1 (contained in a polyethylene container), it was confirmed that by further containing soft chili pepper extract in the composition and then containing it in a polyethylene container, discoloration after storage for one week was also suppressed, and a sufficient discoloration suppression effect was exerted.

The above test results demonstrate that discoloration during high-temperature storage can be suppressed by further adding chili pepper or an extract thereof to a liquid or semi-solid composition containing loxoprofen or a salt thereof and storing it in a container made of a polyolefin resin.

[Test Example 2] Storage test No. 2
Liquid compositions containing the ingredients and amounts shown in Table 2 were prepared and placed in polyethylene or glass containers to give pharmaceutical preparations of Example 2, Comparative Examples 3 and 4, respectively. The presence or absence of discoloration after storage in a dark place at 80°C for 3 days and 1 week was evaluated in the same manner as in Test Example 1.
The results are shown in Table 2.

The above test results confirmed that discoloration during high-temperature storage was similarly suppressed when nonanoic acid vanillylamide was used instead of soft chili pepper extract.

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

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

The results of Test Examples 1 to 3 above demonstrate that discoloration during high-temperature storage can be suppressed by adding capsicum soft extract or capsicum or its extract, such as nonanoic acid vanillylamide, to a liquid or semi-solid composition containing loxoprofen or a salt thereof and storing the composition in a polyolefin resin container.

[Test Example 4] Storage test No. 4
Liquid compositions containing the components and amounts shown in Table 4 were prepared and placed in polyethylene or glass containers to give the pharmaceutical preparations of Example 4, Comparative Examples 5 and 6, or Reference Example 1, respectively. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 1.
The results are shown in Table 4.

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

[Test Example 5] Storage test No. 5
Liquid compositions containing the components and amounts shown in Table 5 were prepared and placed in polypropylene containers to give the pharmaceutical preparations of Examples 5 and 6. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 1.
The results are shown in Table 5.

The above test results confirmed that discoloration during high-temperature storage was similarly suppressed even when polypropylene containers were used instead of polyethylene containers as polyolefin resin containers.

[Test Example 6] Storage test No. 6
A liquid composition identical to that contained in the pharmaceutical preparations of Examples 1 and 3 was prepared and impregnated into an open-cell porous material made of low-density polyethylene (MAPS: Inoac Corporation), which was used as a coating member in the container, and then stored in a dark place at 80° C. for 1 week. No obvious discoloration was observed in any of the compositions.

Production Example 1 (Lotion)
Liquid compositions (Formulation Examples 1 to 8) containing the components and amounts (g) shown in Table 6 below per 100 g were prepared by a conventional method, and placed in a bottle container having a sponge-like polyurethane coating member attached to the mouth of a polypropylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 1-1 to 1-8, respectively.

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

Production Example 3 (Lotion)
Liquid compositions (Formulation Examples 9 to 16) containing the components and amounts (g) shown in Table 7 below per 100 g were prepared by a conventional method, and placed in bottle containers having a sponge-like polyurethane coating member attached to the mouth of a polypropylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 3-1 to 3-8, respectively.

Production Example 4 (Lotion)
Liquid compositions (Formulation Examples 9 to 16) containing the components and amounts (g) shown in Table 7 above per 100 g were produced by a conventional method, and were placed in bottle containers having a polyethylene container body with a sponge-like low-density polyethylene coating member (MAPS: Inoac Corporation) attached to the mouth thereof, to give pharmaceutical preparations (lotions) of Production Examples 4-1 to 4-8, respectively.

Production Example 5 (Gel)
Semi-solid compositions (Formulation Examples 17 to 24) containing the components and amounts (g) shown in Table 8 below per 100 g were produced by a conventional method, and placed in tube containers (laminated tubes) made of laminated film having a low-density polyethylene film as the innermost layer, aluminum foil as the outermost layer (middle layer), and a low-density polyethylene film further laminated on the outermost layer, to give pharmaceutical preparations (gels) of Production Examples 5-1 to 5-8, respectively.

Production Example 6 (Ointment)
Semi-solid compositions (Formulation Examples 25 to 32) containing the components and amounts (g) shown in Table 9 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) having a high-density polyethylene film as the innermost layer, a polyethylene terephthalate film as the outermost layer (middle layer), and a high-density polyethylene film laminated on the outermost layer, to give pharmaceutical preparations (ointments) of Preparation Examples 6-1 to 6-8, respectively.

Production Example 7 (Cream)
Semi-solid compositions (Formulation Examples 33 to 40) containing the components and amounts (g) shown in Table 10 below per 100 g were produced by a conventional method, and placed in laminated film tube containers (laminated tubes) having a low-density polyethylene film as the innermost layer, a nylon film as the outermost layer (middle layer), and a low-density polyethylene film laminated on the outermost layer, to give pharmaceutical preparations (creams) of Production Examples 7-1 to 7-8, respectively.

Production Example 8 (Oral Liquid)
Liquid compositions (Formulation Examples 41 to 48) containing the components and amounts (mg) shown in Table 11 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to give pharmaceutical preparations (oral liquids) of Preparation Examples 8-1 to 8-8, respectively.

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 medicine containing loxoprofen or a salt thereof with excellent storage stability can be provided, which can be suitably used in the pharmaceutical industry, etc.

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 after storage at 80° C. for one week , comprising the step of placing a liquid or semi-solid composition containing the above formula (I) in a polyolefin resin container.