Pharmaceutical preparation containing loxoprofen

Abstract

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

Description

[Technical field]

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

[0002] Loxoprofen is a type of phenylpropionic acid-based nonsteroidal anti-inflammatory drug (NSAID) (Non-Patent Document 1), and exhibits excellent anti-inflammatory and analgesic effects. For this reason, it is widely used as an active ingredient in topical anti-inflammatory and analgesic agents, and topical patches (cataplasms, tapes, etc.) and topical 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). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Commentary on the 16th revised Japanese Pharmacopoeia, Hirokawa Publishing Co., Ltd., pages C-5359-5364 [Non-Patent Document 2] Loxonin (registered trademark) Gel 1% Pharmaceutical Interview Form Daiichi Sankyo Co., Ltd. October 2010 revised version (3rd edition) Summary of the Invention [Problem to be solved by the invention]

[0004] When loxoprofen is used as an active ingredient in a topical preparation, it is preferable to use it by applying it to the affected area as a liquid or semi-solid composition, such as a topical application such as a lotion, gel, or cream, from the viewpoint of flexibly administering only the required amount depending on the location, shape, and area of ​​the affected area. Furthermore, if a technology for stably blending loxoprofen into a liquid or semi-solid composition can be established, it will be possible to apply it not only to topical preparations but also to oral medications (oral liquids, etc.). Therefore, in order to establish a technology for stably incorporating rofecoxib into liquid or semi-solid compositions, the present inventors prepared liquid or semi-solid compositions containing rofecoxib or a salt thereof and evaluated their storage stability. Surprisingly, they found that discoloration may occur over time when stored under high temperature conditions.

[0005] Therefore, an object of the present invention is to provide a means for suppressing discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during high-temperature storage. [Means for solving the problem]

[0006] The inventors therefore conducted further studies to solve this problem and discovered that discoloration during high-temperature storage can be suppressed by adding a tocopherol, such as dl-α-tocopherol acetate, to a liquid or semi-solid composition containing rofecoxib or a salt thereof and by storing the composition in a container made of a polyolefin resin, such as polyethylene, and thus completed the present invention.

[0007] That is, the present invention relates to a composition comprising the following components (A) and (B): (A) loxoprofen or a salt thereof; (B) tocopherols; 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) tocopherols; 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. Effect of the Invention

[0008] According to the present invention, discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during high-temperature storage can be suppressed, and therefore a medicine containing loxoprofen or a salt thereof having excellent storage stability can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] 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).

[0010] In the present invention, the content of loxoprofen or a salt thereof in the liquid or semi-solid composition is not particularly limited and may be appropriately determined 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 mass %, more preferably 0.1 to 5 mass %, and particularly preferably 0.5 to 3 mass %, calculated as loxoprofen sodium anhydrous, based on the total mass of the composition.

[0011] <Ingredient (B)> In the present invention, the term "tocopherols" refers to one or more selected from tocopherol, tocotrienol, and their derivatives (e.g., esterified derivatives such as acetate, succinate, and nicotinate), and their salts (e.g., alkaline earth metal salts such as calcium salt and magnesium salt). Here, the tocopherol may be any of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, with α-tocopherol being preferred. In addition, the tocotrienol may be any of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, with α-tocotrienol being preferred. In the present invention, from the viewpoint of discoloration suppression, one or more selected from the group consisting of α-tocopherol, its acetate, its succinate, and its nicotinate, and their salts are preferred. In addition, although optical isomers may exist in tocopherols and tocotrienols, in the present invention, all isomers are included unless otherwise specified. In other words, in the present invention, unless a specific optical isomer is specified as the component name of tocopherols, such component notation includes all of the various optical isomers alone and their mixtures in any ratio, and may be a single optical isomer or a mixture of various optical isomers in any ratio (for example, the description of "acetate ester of α-tocopherol" includes both acetate ester of dl-α-tocopherol and acetate ester of d-α-tocopherol). In addition, as the tocopherols of the present invention, "tocopherol", "tocopherol succinate calcium", "tocopherol acetate", "tocopherol nicotinate", etc. listed in the 16th revised Japanese Pharmacopoeia can be suitably used.

[0012] In the present invention, from the viewpoint of inhibiting discoloration, the tocopherols are preferably one or more selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof, more preferably one or more selected from the group consisting of tocopherol, tocopherol succinate calcium, tocopherol acetate, and tocopherol nicotinate, even more preferably one or more selected from the group consisting of dl-α-tocopherol, dl-α-tocopherol succinate calcium, dl-α-tocopherol acetate, and dl-α-tocopherol nicotinate, and particularly preferably dl-α-tocopherol acetate.

[0013] In the present invention, the content of tocopherols in the liquid or semi-solid composition is not particularly limited. From the viewpoint of the discoloration suppression effect, the tocopherols are preferably contained in an amount of 0.01 to 8 mass % relative to the total mass of the composition, more preferably 0.05 to 4 mass %, and particularly preferably 0.1 to 2 mass %.

[0014] In the present invention, the content ratio of rofecoxib or a salt thereof to tocopherols in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration inhibition effect. However, from the viewpoint of the discoloration inhibition effect, it is preferable that the composition contains 0.01 to 5 parts by mass of tocopherols per 1 part by mass of rofecoxib or a salt thereof, calculated as rofecoxib anhydride, more preferably 0.05 to 3 parts by mass, and particularly preferably 0.1 to 1 part by mass.

[0015] <Liquid or semi-solid composition> In the present invention, the term "liquid or semi-solid composition" refers to 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 oil-based, and further, a plurality of different 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.

[0016] In the present invention, from the viewpoint of safety during use of the pharmaceutical preparation, the liquid or semi-solid composition preferably contains water. Here, the content of water in the composition is not particularly limited, but from the viewpoint of safety during use of the pharmaceutical preparation and discoloration suppression effect, it is preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 10 to 90% by mass, even more preferably 20 to 70% by mass, and particularly preferably 30 to 50% by mass, based on the total mass of the composition.

[0017] In addition, in the present invention, from the viewpoint of the feeling of use of the pharmaceutical preparation, it is preferable that the liquid or semi-solid composition contains a lower alcohol. Here, the "lower alcohol" means a linear or branched monohydric alcohol having 1 to 6 carbon atoms, specifically, for example, ethanol, isopropanol, n-propanol, etc., and one of these may be used alone or two or more may be used in combination. Among these, 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 feeling of use 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, even more preferably 17.5 to 60% by mass, and particularly preferably 20 to 50% by mass, based on the total mass of the composition.

[0018] 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 if the composition contains at least one of water and a lower alcohol (particularly, a composition containing both water and a lower alcohol), discoloration is suppressed.

[0019] 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, anticholinergic agents, herbal medicines, Chinese herbal prescriptions, and the like.

[0020] 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. Anti-inflammatory ingredients include, for example, 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.

[0021] Examples of antihistamine components 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, diphenylpi Examples of such compounds include larine 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.

[0022] Examples of the bactericidal component include benzalkonium chloride. Examples of the astringent / protective component include zinc oxide. Examples of the blood circulation promoter component include benzyl nicotinate, heparinoids, sodium polyethylene sulfonate, etc. Examples of the warming component include vanillylamide nonanoate, capsaicin, and red pepper. Examples of the local anesthetic component include lidocaine, clove oil, and belladonna extract.

[0023] Examples of antitussives include alloclamide hydrochloride, eprazinone hydrochloride, carbetapentane citrate, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate and the like.

[0024] Examples of noscapines include noscapine hydrochloride and noscapine. Bronchodilators include, for example, trimetoquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride, and the like.

[0025] Examples of expectorants include ammonia, fennel extract, and ammonium chloride.

[0026] Examples of hypnotic sedatives include allylisopropylacetylurea and bromvalerylurea. Vitamins include, for example, vitamin B 1 , Vitamin B 2 , Vitamin B 5 , Vitamin B 6 , Vitamin B 12 , vitamin C, hesperidin and its derivatives and salts thereof (e.g., thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, setotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, shikotiamine, thiamine disulfide, bis-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.).

[0027] 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, coprecipitation product of aluminum hydroxide-sodium hydrogen carbonate, coprecipitation product of aluminum hydroxide-calcium carbonate-magnesium carbonate, magnesium hydroxide, coprecipitation 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 borey.

[0028] Examples of anticholinergic drugs include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, tipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, and the like.

[0029] Examples of herbal medicines include Mallotus japonicus (red bud oak), Asanonia arvensis (asian medicine), Arnica, Coix seed stalk (infern), Fennel (fennel), Turmeric (turmeric), Corydalis chinensis (corbicula var. rhamnoides), Scutellaria baicalensis (scutellaria), Phellodendron bark (cherry bark), Coptis japonica (coptis), Onji (apricot), Zedoary (gajus), Valerian (valerian), Chamomile, Calonin (carotenoid), Platycodon grandiflorum (bellflower), Apricot kernel (apricot kernel), Lycium chinense (wolfberry fruit), Lycium chinense (wolfberry leaf), and Kei (keiko). Gai (thorn), Cinnamon bark, Cassia japonica seed, Gentiana chinensis, Gentian (gentiana), 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), Horse Chestnut, Sekisan (Garlic), Senega, Cnikyu (Chinese Cabbage), Zenko (Chinese Husk), Swertia britannica, Soujutsu (Blue Atractylodes), Sohakuhi (Mulberry Bark), Soyou (Persea Grass), Taisan (Garlic), Chikusetsuninjin (Bamboo Ginseng), Chinpi (Citrine Peel), Touki (Angelica), Ipecac (Ipe Root), Nantengjitsu ( Examples of herbal medicines include Nandina fruit, Carrot, Fritillaria, Bakumondou, Pinellia gracilis, Banko ka, Hanpi, Byakshi, Byakkushou, Poria Root, Peony Bark, Youbaihi, and Velvet Antler, as well as extracts thereof (extracts, tinctures, dried extracts, etc.).

[0030] Examples of Chinese herbal prescriptions include Keishito (Keishito), Kousosan (Kososan), Saikokeishito (Saikokeishito), Shosaikoto (Shosaikoto), Bakumondouto (Bakumondouto), and Hangekoubokuto (Hangekoubokuto).

[0031] 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. 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, terpenes, etc.

[0032] 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; 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.

[0033] 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 ether esters 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, and polyoxyethylene alkyl ether fatty acid esters; and ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate. Examples of the solubilizer include the nonionic surfactants or ionic surfactants exemplified above as the emulsifier, as well as liquid paraffin, crotamiton, and the like.

[0034] 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, 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, and sorbitol. 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 its salt, sorbitol, lactose, white sugar, honey, glucose, maltitol, maltose, mannitol, and starch syrup.

[0035] 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.

[0036] 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, Examples of oils that may be used include anise oil, clove oil, turpentine oil, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, henopodium oil, bergamot oil, bois de rose oil, linalool 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.

[0037] In the present invention, the method for producing a liquid or semi-solid composition is not particularly limited, and the composition can be produced by a known method described in, for example, General Provisions for Preparations in the Japanese Pharmacopoeia, 16th Edition, depending on the types and amounts of the components to be blended, the properties of the composition, the shape of the container, the dosage form of the pharmaceutical preparation, the administration route, the application, and the like.

[0038] <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, 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 well known and may be produced by well-known methods, or commercially available products may be used.

[0039] 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.

[0040] [(1) A container comprising a container body and an application member, the application member being impregnated with a composition contained in the container body when in use] In the case of a container of this embodiment, the composition contained in the container body can be impregnated and held in an application member, and the application member can be brought into contact with a 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.

[0041] 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 comprising a container body having an opening and a porous (sponge-like, etc.) application member attached to the opening. In this case, the composition contained in the container body is impregnated and held in a porous application member whose pore size, porosity, etc. are appropriately adjusted, and then the application member is brought into contact with the application target, whereby the composition can be applied to the application target. Another specific example is a container comprising a container body having a mouth and a brush-like applicator attached to the mouth. In this case, the composition contained in the container body is impregnated and held in a brush 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.

[0042] 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, which is an excellent effect. 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.

[0043] Containers of this type are known and are disclosed, for example, in Japanese Patent No. 5570089. In the present invention, a commercially available product may be used as the container of this type, and examples of such commercially available products include containers using MAPS (INOAC CORPORATION), which is an open porous body made of low-density polyethylene, as the coating member.

[0044] [(2) A container having a flexible container body and a discharge port] 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."

[0045] 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.

[0046] Containers of this embodiment are known and are disclosed, for example, in Japanese Patent No. 5302550 and Japanese Patent No. 5525135. In the present invention, a commercially available product may be used as the container of this embodiment.

[0047] 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 polyolefin, poly(4-methylpentene), polytetrafluoroethylene, ethylene-propylene copolymer, ethylene-α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, etc. In the present invention, these can be used alone or in combination of two or more kinds. In the present invention, as the polyolefin resin, polyethylene, polypropylene and cyclic polyolefins are preferred from the viewpoint of inhibiting discoloration, and polyethylene and polypropylene are particularly preferred. In the present invention, "made of polyolefin-based resin" means that at least a part of the material contains polyolefin-based resin; 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".

[0048] 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.

[0049] In the present invention, the means for containing the liquid or semi-solid composition in a container is not particularly limited, and the composition may be filled or otherwise processed in a conventional manner depending on the shape of the container, the properties of the composition, and the like, thereby producing the pharmaceutical preparation of the present invention.

[0050] <Pharmaceutical preparations> In the present invention, the method of administration or application of the "pharmaceutical preparation" is not particularly limited, and includes 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 area of ​​the affected area).

[0051] 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 liquid preparations, sprays, ointments, creams, gels, etc.) and preparations to be administered orally (oral liquid preparations, 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.

[0052] Since the pharmaceutical preparation of the present invention contains loxoprofen, which is a type of NSAID, or a salt thereof, it can be used as a medical drug or an OTC drug, and specifically, it is useful, for example, as an external anti-inflammatory analgesic; an antipyretic analgesic, an oral medication such as a general cold remedy (cold medicine); etc.

[0053] 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) tocopherols; 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".

[0054] 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) tocopherols; 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 tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof. [4] The pharmaceutical formulation according to any one of [1] to [3], wherein component (B) is one or more members selected from the group consisting of dl-α-tocopherol, dl-α-tocopherol calcium succinate, dl-α-tocopherol acetate and dl-α-tocopherol nicotinate. [5] The pharmaceutical formulation according to any one of [1] to [4], wherein component (B) is dl-α-tocopherol acetate.

[0055] [6] The pharmaceutical formulation according to any one of [1] to [5], wherein the composition further contains water. [7] The pharmaceutical formulation according to any one of [1] to [6], wherein the composition further contains a lower alcohol. [8] The pharmaceutical formulation described in [7], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol. [9] The pharmaceutical preparation according to any one of [1] to [8], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene.

[10] The pharmaceutical formulation according to any one of [1] to [9], wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container, or an eye drop container.

[11] The container is any of the following: (1) A container having 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 [9],

[12] The pharmaceutical preparation according to any one of [1] to [9], wherein the container is a bottle container or a tube container equipped with a sponge-like application member.

[13] The pharmaceutical preparation according to any one of [1] to

[12] , which is in a dosage form selected from the group consisting of an external liquid preparation, a spray, an ointment, a cream, a gel, an oral liquid preparation, a syrup, and an oral jelly preparation.

[14] The pharmaceutical preparation according to any one of [1] to

[12] , which is in a dosage form selected from the group consisting of external liquid preparations, sprays, ointments, creams and gels.

[15] The pharmaceutical preparation according to any one of [1] to

[12] , which is 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.

[16] The pharmaceutical formulation according to any one of [1] to

[12] , which is in a dosage form selected from the group consisting of a lotion, an ointment, a cream, and a gel.

[0056]

[17] The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) tocopherols; A method for suppressing discoloration of a composition, comprising the step of placing a liquid or semi-solid composition containing the above in a polyolefin resin container.

[18] The method according to

[17] , wherein component (A) is sodium rofecoxib hydrate.

[19] The method according to

[17] or

[18] , wherein component (B) is one or more members selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof.

[20] The method according to any of

[17] to

[19] , wherein component (B) is one or more selected from the group consisting of dl-α-tocopherol, dl-α-tocopherol calcium succinate, dl-α-tocopherol acetate and dl-α-tocopherol nicotinate.

[21] The method according to any one of

[17] to

[20] , wherein component (B) is dl-α-tocopherol acetate.

[0057]

[22] The method according to any one of

[17] to

[21] , wherein the composition further contains water.

[23] The method according to any one of

[17] to

[22] , wherein the composition further contains a lower alcohol.

[24] The method according to

[23] , wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol.

[25] The method according to any one of

[17] to

[24] , wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene.

[26] The method according to any one of

[17] to

[25] , wherein the container is an aerosol container, a pump spray container, a bottle container, a tube container or an eye drop container.

[27] The container is any of the following: (1) A container having 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

[17] to

[25] ,

[28] The method according to any one of

[17] to

[25] , wherein the container is a bottle container or a tube container equipped with a sponge-like application member. EXAMPLES

[0058] The present invention will be described in detail below by way of examples, but the present invention is not limited to these examples in any way.

[0059] [Test Example 1] Preservation 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, and x was observed. The results are shown in Table 1.

[0060] [Table 1]

[0061] Comparing Comparative Example 1 (contained in a polyethylene container) with Comparative Example 2 (contained in a glass container), it was confirmed that, although storing 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 dl-α-tocopherol acetate, contained in a polyethylene container) with Comparative Example 1 (not containing dl-α-tocopherol acetate, contained in a polyethylene container), it was confirmed that by further containing dl-α-tocopherol acetate in the composition and then containing it in a polyethylene container, discoloration after storage for one week was also suppressed, and a sufficient discoloration suppression effect was exerted.

[0062] From the above test results, it became clear that by further adding tocopherols to a liquid or semi-solid composition containing rofecoxib or a salt thereof and storing it in a container made of a polyolefin-based resin, discoloration during high-temperature storage can be suppressed.

[0063] [Test Example 2] Preservation test Part 2 Liquid compositions containing the ingredients and amounts shown in Table 2 were prepared and placed in polyethylene or glass containers to give the pharmaceutical preparations of Example 2, Comparative Examples 3 and 4, 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 2.

[0064] [Table 2]

[0065] Comparing Comparative Example 3 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 2 with Comparative Example 3 (contained in a glass container) and Comparative Example 4 (no dl-α-tocopherol acetate), it was confirmed that such discoloration can be suppressed by further incorporating dl-α-tocopherol acetate into the liquid composition and containing it in a polyethylene container.

[0066] [Test Example 3] Preservation test Part 3 A liquid composition containing the ingredients and amounts shown in Table 3 was prepared and placed in a polypropylene container to give the pharmaceutical formulation of Example 3. The presence or absence of discoloration after storage in a dark place at 80°C for 2 weeks was evaluated in the same manner as in Test Example 1. The results are shown in Table 3.

[0067] [Table 3]

[0068] From the above test results, it was confirmed that discoloration during high-temperature storage was similarly suppressed even when a polypropylene container was used instead of a polyethylene container as a polyolefin-based resin container.

[0069] [Test Example 4] Preservation test No. 4 A liquid composition identical to that contained in the pharmaceutical preparation of Example 1 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, but no obvious discoloration was observed.

[0070] Production Example 1 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the components and amounts (g) shown in Table 4 below per 100 g were prepared by a conventional method, and placed in bottle containers with 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.

[0071] [Table 4]

[0072] Production Example 2 (Lotion) Liquid compositions (Formulation Examples 1 to 8) containing the ingredients and amounts (g) shown in Table 4 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 2-1 to 2-8, respectively.

[0073] Production Example 3 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the ingredients and amounts (g) shown in Table 5 below per 100 g were prepared by a conventional method, and placed in bottle containers with 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.

[0074] [Table 5]

[0075] Production Example 4 (Lotion) Liquid compositions (Formulation Examples 9 to 16) containing the components and amounts (g) shown in Table 5 above per 100 g were prepared by a conventional method, and placed in bottle containers with a sponge-like low-density polyethylene applicator (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body, to give pharmaceutical preparations (lotions) of Preparation Examples 4-1 to 4-8, respectively.

[0076] Production Example 5 (Gel) Semi-solid compositions (Formulation Examples 17 to 24) containing the components and amounts (g) shown in Table 6 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) having a low-density polyethylene film as the innermost layer, aluminum foil as the outer layer (middle layer), and a low-density polyethylene film laminated on the outer layer of that, to give pharmaceutical preparations (gels) of Preparation Examples 5-1 to 5-8, respectively.

[0077] [Table 6]

[0078] Manufacturing Example 6 (Ointment) Semi-solid compositions (Formulation Examples 25 to 32) containing the ingredients and amounts (g) shown in Table 7 below per 100 g were prepared in a conventional manner, 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 of that, to give pharmaceutical preparations (ointments) of Preparation Examples 6-1 to 6-8, respectively.

[0079] [Table 7]

[0080] Production Example 7 (cream) Semi-solid compositions (Formulation Examples 33 to 40) containing the ingredients and amounts (g) shown in Table 8 below per 100 g were prepared by a conventional method, and placed in laminated film tube containers (laminated tubes) with a low-density polyethylene film as the innermost layer, a nylon film as the outermost layer (middle layer), and a low-density polyethylene film laminated on the outermost layer, to give pharmaceutical preparations (creams) of Preparation Examples 7-1 to 7-8, respectively.

[0081] [Table 8]

[0082] Production Example 8 (Oral Liquid) Liquid compositions (Formulation Examples 41 to 48) containing the ingredients and amounts (mg) shown in Table 9 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers to give the pharmaceutical preparations (oral liquids) of Preparation Examples 8-1 to 8-8, respectively.

[0083] [Table 9] [Industrial Applicability]

[0084] According to the present invention, it is possible to suppress discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during high-temperature storage, and therefore it is possible to provide a medicine containing loxoprofen or a salt thereof having excellent storage stability, which can be suitably used in the pharmaceutical industry, etc.

Claims

[Claim 1] The following components (A) and (B): (A) Loxoprofen or a salt thereof; (B) One or more tocopherols selected from the group consisting of tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof; A pharmaceutical preparation comprising a liquid or gel composition containing water, wherein the ratio of component (B) to component (A) in terms of anhydrous loxoprofen is 0.1 to 3 parts by mass, and the composition is housed in one or more polyolefin resin containers selected from the group consisting of polyethylene and polypropylene, wherein the liquid composition is a solution and the dosage form is a lotion or gel.