JP7488643B2 - Compositions containing loxoprofen - Google Patents

Description

The present invention relates to a composition 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).

When using loxoprofen as an active ingredient in topical preparations, 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 can be established to stably incorporate loxoprofen into a liquid or semi-solid composition, it will be possible to apply it not only to topical preparations but also to oral medications (oral liquids, etc.).

However, in recent years, it has been found that liquid or semi-solid compositions containing loxoprofen or a salt thereof may discolor over time when stored under high temperature conditions. Therefore, the applicant has found that discoloration during high temperature storage can be suppressed by (1) adding a plant of the genus Lagophthalmus, such as arnica tincture, or an extract thereof to a liquid or semi-solid composition containing loxoprofen or a salt thereof and storing the composition in a polyolefin resin container, such as polyethylene or polypropylene, or (2) adding a cellulose, such as hypromellose, to a liquid or semi-solid composition containing loxoprofen or a salt thereof and storing the composition in a polyolefin resin container, such as polypropylene, and has previously filed patent applications for each of these methods (Patent Documents 1 and 2).

JP 2018-21027 A JP 2017-155042 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)

The object of the present invention is to provide a new 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 conducted extensive research to solve the above problems and have found that when a liquid or semi-solid composition containing loxoprofen or a salt thereof further contains a plant of the genus Lagenaria, such as arnica tincture, or an extract thereof, in combination with a cellulose, such as hypromellose, discoloration during high-temperature storage can be significantly suppressed compared to when each of the components is contained alone, and that such a combination provides sufficient discoloration suppression without the use of a polyolefin resin container, thereby completing the present invention.

That is, the present invention relates to a composition comprising the following components (A), (B) and (C):
(A) loxoprofen or a salt thereof;
(B) a plant of the genus Lacertilia or an extract thereof;
(C) celluloses;
The present invention provides a liquid or semi-solid composition comprising:

The present invention also relates to the following component (A):
(A) loxoprofen or a salt thereof;
A liquid or semi-solid composition comprising the following components (B) and (C):
(B) a plant of the genus Lacertilia or an extract thereof;
(C) celluloses;
The present invention provides a method for inhibiting discoloration of a composition, the method comprising the step of incorporating:

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 "liquid or semi-solid composition" 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 term "plants of the genus Arnica" refers to a plant body belonging to the genus Arnica (Arnica genus) of the Asteraceae family, and the specific species is not particularly limited as long as it belongs to the genus, and examples thereof include plants with the following scientific names: Arnica montana, Arnica chamissonis, Arnica fulgens, Arnica cordifolia, Arnica latifolia, Arnica longifolia, Arnica sachalinensis, etc. In the present invention, a single species of plant may be used as Arnica, or a combination of multiple different species of plants may be used. In the present invention, it is preferable to use Arnica montana from the viewpoint of discoloration suppression. In addition, in the present invention, the part of the plant of the genus Arnica that is used is not particularly limited, and the whole plant or a part thereof (flowers, inflorescences, spikes, buds, leaves, branches, roots, etc.), or a combination of two or more of them, may be used.

The form of the plant of the genus Lacertilia can be adjusted as necessary, and it can be cut or crushed into small pieces or small chunks, or crushed into powder. In addition, in consideration of the convenience of handling during the production of the composition, a plant of the genus Lacertilia that has been subjected to some kind of extraction treatment (referred to as "an extract of a plant of the genus Lacertilia" in this specification) may be used.
The term "extract of a plant of the genus Lacertilia" also includes those that have been subjected to processing such as heating, drying, pulverization, etc. in addition to extraction. Specifically, the "extract of a plant of the genus Lacertilia" of the present invention includes a liquid obtained by cutting a plant of the genus Lacertilia into an appropriate size as necessary and then adding an appropriate leachate (extraction solvent) to the plant, a liquid obtained by concentrating the leachate (soft extract, tincture, etc.), and further a liquid obtained by drying the above (dried extract, etc.).

The method for producing an extract of a plant of the genus Lagophthalmus is not particularly limited, and it can be produced by referring to 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, the plant of the genus Lagophthalmus 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, propylene glycol, 1,3-butylene glycol, or a mixture of two or more of these is preferred.
The extraction procedure is not particularly limited, and any known method used for extraction from plants can be appropriately adopted, specifically, for example, immersion in an extraction solvent (cold immersion, hot immersion, percolation, etc.), extraction using a supercritical fluid or subcritical fluid, etc. In order to increase the extraction efficiency, stirring or homogenization in the extraction solvent may be performed.
The extraction temperature is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but is preferably from about 5° C. to a temperature below the boiling point of the extraction solvent.
The extraction time is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but is preferably about 1 hour to 14 days.

In the present invention, the "plant of the genus Amplexica or an extract thereof" is preferably Arnica montana or an extract thereof. Examples of Arnica extracts include Arnica tincture and Arnica extract. As the plant of the genus Amplexica or an extract thereof, one or more types of Arnica extract selected from Arnica tincture and Arnica extract (soft extract, dry extract) are more preferred, Arnica tincture and Arnica extract listed in the Quasi-drug Raw Materials Standards 2006 are even more preferred, and Arnica tincture is particularly preferred.

In the present invention, commercially available products can be used as the plant of the genus Lacertilia or an extract thereof. Specific commercially available products include, for example, Arnica tincture (Alps Pharmaceutical Co., Ltd.), Arnica extract (Maruzen Pharmaceutical Co., Ltd.), Falcorex arnica (Ichimaru Falcos Co., Ltd.), Arnica extract, Arnica tincture (all Nippon Funa Yakuhin Co., Ltd.), etc.

In the present invention, the content of the plant of the genus Lagophthalmus or an extract thereof in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration suppression effect, the plant of the genus Lagophthalmus or an extract thereof is preferably contained in an amount of 0.00001 to 5% by mass, more preferably 0.00005 to 2% by mass, and particularly preferably 0.0007 to 0.7% by mass, in terms of the amount of the raw herbal medicine, relative to the total mass of the composition. In particular, when arnica is used as the plant of the genus Lagophthalmus, from the viewpoint of the discoloration suppression effect, the plant of the genus Lagophthalmus or an extract thereof is preferably contained in an amount of 0.0001 to 3% by mass, more preferably 0.0005 to 1% by mass, and particularly preferably 0.001 to 0.5% by mass, in terms of the amount of the raw herbal medicine, relative to the total mass of the composition.
In the present invention, the content ratio of loxoprofen or its salt and the plant of the genus Lagophthalmus or its extract in the liquid or semi-solid composition is not particularly limited and may be appropriately determined from the viewpoint of discoloration suppression, but from the viewpoint of discoloration suppression, the composition preferably contains 0.00001 to 5 parts by mass, more preferably 0.00005 to 2 parts by mass, and particularly preferably 0.0007 to 0.7 parts by mass of the plant of the genus Lagophthalmus, per part by mass of loxoprofen or its salt in terms of loxoprofen anhydrous, and particularly preferably contains 0.0001 to 3 parts by mass, more preferably 0.0005 to 1 part by mass, and particularly preferably 0.001 to 0.5 ...5 to 1 part by mass, and particularly preferably contains 0.001 to 0.5 parts by mass of the plant of the genus Lagophthalmus.

<Component (C)>
In the present invention, the term "celluloses" refers not only to cellulose or a salt thereof itself, but also to a derivative or a salt thereof in which all or a part of the hydroxyl groups of cellulose form an ether bond (hereinafter referred to as a "cellulose ether derivative or a salt thereof." Note that the cellulose ether derivative or a salt thereof may be further modified, such as esterified or crosslinked, as necessary, in addition to the ether bond.) The salt is not particularly limited, and specific examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and the like.

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

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

In the present invention, the content of cellulose in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration suppression effect, it is preferable that the content be 0.001 to 5 mass % relative to the total mass of the composition, more preferably 0.005 to 3 mass %, and particularly preferably 0.01 to 2 mass %.

In the present invention, the content ratio of loxoprofen or its salt and cellulose in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of discoloration inhibition effect. From the viewpoint of discoloration inhibition effect, however, it is preferable that the cellulose is contained in an amount of 0.002 to 4 parts by mass, more preferably 0.02 to 1.5 parts by mass, and particularly preferably 0.02 to 1 part by mass, of loxoprofen or its salt, calculated as loxoprofen anhydride.

In the present invention, the content ratio of the plant of the genus Lagerstroemia or an extract thereof and the celluloses in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration suppression effect. From the viewpoint of the discoloration suppression effect, however, it is preferable that the composition contains 1 to 5,000 parts by mass of the celluloses per 1 part by mass of the plant of the genus Lagerstroemia or an extract thereof in terms of the crude drug equivalent, more preferably 10 to 1,000 parts by mass, and particularly preferably 50 to 500 parts by mass.

<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 liquid or semi-solid composition, 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 liquid or semi-solid composition and discoloration suppression effect, it is preferable that the content of water 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 60% by mass, based on the total mass of the composition.

In addition, in the present invention, from the viewpoint of the feeling of use of the liquid or semi-solid composition, 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., with ethanol, isopropanol, and mixtures thereof being preferred. The content of the lower alcohol in the composition is not particularly limited, but from the viewpoint of the feeling of use of the liquid or semi-solid composition 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 liquid or semi-solid composition, 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, local stimulating 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, indomethacin, ethenzamide, etodolac, ketoprofen, sazapyrine, salicylamide, salicylic acid, ethylene glycol salicylate, glycol salicylate, sodium salicylate, methyl salicylate, diclofenac sodium, tiaramide hydrochloride, naproxen, piroxicam, felbinac, meloxicam, 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, and diphenylpyraline hydrochloride. , diphenylpyraline teoclate, diphenhydramine, 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, mebhydroline napadisilate, etc.

Examples of the bactericidal component include benzalkonium chloride. Examples of the astringent/protective component include zinc oxide. Examples of the blood circulation promoting component include tocopherol, tocopherol acetate, benzyl nicotinate, heparinoids, sodium polyethylene sulfonate, etc. Examples of the local stimulating component include vanillylamide nonanoate, capsaicin, and red pepper. Examples of the local anesthetic component include lidocaine and belladonna extract.
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.
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, ammonium chloride, and the like.

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 arborescens (asian medicine), Euonymus chinensis (fennigrum), Fennel (fennel), Turmeric (turmeric), Corydalis chinensis (corbiculatus), Scutellaria baicalensis (scutellaria), Phellodendron amplexicaule (yellow bark), Coptis chinensis (crysanthemum), Onji (apricot), Valerian (valerian), Chamomile (chamomile), Platycodon grandiflorum (bellflower), Apricot kernel, Lycium chinense (wolfberry), Lycium chinense leaf (wolfberry), Cinnamon bark (cinnamon), Cassia japonica (cassia seed), Gentiana chinensis (gentiana), Gennoshoko (genshouko), Kouka (safflower), Kobushi (kobushi), Go Ou (Bezoar), Gomishi (Schismischerii), Saishin (Asian Spicy Rice), Sanshishi (Gardenia Root), Sansho (Japanese Pepper), Shion (Asian Purple Root), Jikoppi (Earth Bark), Shikon (Purple Root), Shakuyaku (Peony Root), Musk, Shajin (Siberian Ginseng), Shazenshi (Prunus Root), Shazensou (Prunus Formosum), Animal Gall (including Yutan (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), Byakushi (White Atractylodes), Byakshotsu (White Atractylodes), Poria rosa (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, administration method, etc. 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, flavorings/sweeteners, terpenes, etc.

Examples of the gelling agent include acrylic acid polymers such as carboxyvinyl polymers; 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, 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 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 blended, the properties of the composition, the dosage form, the route of administration, the intended use, etc.

In the present invention, a liquid or semi-solid composition may be contained in a container depending on its properties, dosage form, etc. Here, 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, dosage form, administration route, use, etc. of the composition.
Examples of such container shapes include aerosol containers, pump spray containers, bottle containers (more specifically, bottle containers equipped with a sponge-like application member (head), roll-on containers, jar bottle containers, etc.), tube containers, eye drop containers, etc. All of these containers are known and may be produced by known methods, or commercially available products may be used.

In the present invention, the container is, from the viewpoint of convenience in handling and using the liquid or semi-solid composition, the following (1) or (2):
(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 comprising 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 whose pore size, porosity, etc. are appropriately adjusted, 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 in length and spacing, 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 composition is an external application agent, the problem of liquid dripping is unlikely to occur at the applied part, the application member is directly in contact with the applied part, 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 composition 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 application area. 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 material of the container is not particularly limited, and may be appropriately selected depending on the shape of the container. Specific examples include glass, plastic, cellulose, pulp, rubber, metal, etc. From the viewpoints of processability, squeezability, and durability, plastic is preferable. The resin of the plastic container is preferably a thermoplastic resin, and examples thereof include polyolefin-based resins such as low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, polypropylene, and cyclic polyolefin; polyester-based resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, and poly(1,4-cyclohexylene dimethylene terenaphthalate); polyphenylene ether-based resins; polycarbonate-based resins; polysulfone-based resins; polyamide-based resins; polyvinyl chloride resins; and styrene-based resins, and may be mixtures of these (polymer alloys).

Among the above thermoplastic resins, polyolefin resins are preferred from the viewpoint of discoloration suppression. In the present invention, by adopting a container made of polyolefin resin as the container, the discoloration suppression effect is further enhanced. Here, 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, among the polyolefin resins, polyethylene, polypropylene and cyclic polyolefins are preferred from the viewpoint of discoloration suppression effect, and polyethylene and polypropylene are particularly preferred.

In this specification, "made of polyolefin resin" means that at least a portion of the material contains polyolefin resin. For example, a mixture of two or more resins, such as polyolefin resin and other resins (polymer alloy), is also included in "made of polyolefin resin".

The above-mentioned "polyolefin resin container" means a "container" in which at least a part of the part in contact with the liquid or semi-solid composition contained therein (preferably 10% or more of the part in contact with the composition during normal storage, more preferably 30% or more of the part in contact with the composition during normal storage, and particularly preferably the entire part in contact with the composition during normal storage) is "made of polyolefin resin". Therefore, for example, a container in which a layer of polyolefin resin is provided in at least a part of the layer in 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 that directly or through another layer, and other layers are further laminated on the outside of that as necessary.

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

In the present invention, the method of administration or application of the liquid or semi-solid composition is not particularly limited, and examples include oral and parenteral administration such as transdermal and vaginal administration. In the present invention, parenteral administration is preferred, and transdermal administration is particularly preferred, due to the 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).

In the present invention, the dosage form of the liquid or semi-solid composition is not particularly limited, and can be appropriately selected from, for example, dosage forms described in the General Rules for Preparations of the Japanese Pharmacopoeia, 17th Edition, etc., depending on the intended use, etc. Specific examples of such dosage forms include those described in the General Rules for Preparations of the Japanese Pharmacopoeia, 16th Edition, such as preparations for application to the skin, etc. (external liquids, sprays, ointments, creams, gels, patches, etc.) and preparations for oral administration (oral liquids, syrups, oral jellies, etc.).
In the present invention, the dosage form is preferably selected from the group consisting of external liquids, sprays, ointments, creams, gels, and patches, more preferably selected from the group consisting of liniments, lotions, external aerosols, pump sprays, ointments, creams, gels, tapes, and poultices, and particularly preferably selected from the group consisting of lotions, ointments, creams, and gels.

The liquid or semi-solid composition of the present invention contains loxoprofen, which is a type of NSAID, or a salt thereof, and therefore can be used as a pharmaceutical composition, more specifically as a medical drug or an OTC drug, and is useful, for example, as an external anti-inflammatory analgesic; an antipyretic analgesic, a general cold remedy, and other internal medications.

Next, the invention in the form of a "method" will be described below.
The present invention relates to a composition comprising the following component (A):
(A) loxoprofen or a salt thereof;
A liquid or semi-solid composition comprising the following components (B) and (C):
(B) a plant of the genus Lacertilia or an extract thereof;
(C) celluloses;
The present invention also relates to a method for inhibiting discoloration of a composition, comprising the step of incorporating:
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 blending component (C) is not particularly limited, as long as a liquid or semi-solid composition containing component (A), component (B), and component (C) is produced directly or indirectly.
In this embodiment of the invention, the meanings of various terms, the amounts of each component, etc. are all the same as those explained for the "liquid or semi-solid composition."

This specification discloses the invention exemplified below in relation to the above-mentioned embodiments, but is not limited to these in any way.
[1A] The following components (A), (B) and (C):
(A) loxoprofen or a salt thereof;
(B) a plant of the genus Lacertilia or an extract thereof;
(C) celluloses;
A liquid or semi-solid composition comprising:
[2A] The composition described in [1A], wherein component (A) is sodium rofecoxib hydrate.
[3A] The composition according to [1A] or [2A], wherein component (B) is one or more selected from the group consisting of Arnica montana, Arnica chamissonis, Arnica fulgens, Arnica cordifolia, Arnica latifolia, Arnica longifolia, and Arnica sachalinensis, and extracts thereof.
[4A] The composition according to [1A] or [2A], wherein component (B) is arnica or an extract thereof.
[5A] The composition according to [1A] or [2A], wherein component (B) is one or more selected from the group consisting of arnica, arnica tincture, and arnica extract.
[6A] The composition according to any one of [1A] to [5A], wherein the component (C) is a cellulose ether derivative or a salt thereof.
[7A] The composition according to any one of [1A] to [6A], wherein component (C) is one or more members selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, and carboxyalkyl cellulose, and salts thereof.
[8A] The composition according to any one of [1A] to [7A], wherein component (C) is hypromellose.

[9A] The composition according to any one of [1A] to [8A], further comprising water.
[10A] The composition according to any one of [1A] to [9A], further comprising a lower alcohol.
[11A] The composition according to [10A], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol.
[12A] The composition according to any one of [1A] to [11A], which is in a dosage form selected from the group consisting of external liquid preparations, sprays, ointments, creams, gels, patches, oral liquid preparations, syrups, and oral jellies.
[13A] The composition according to any one of [1A] to [11A], which is in a dosage form selected from the group consisting of external liquid preparations, sprays, ointments, creams, gels and patches.
[14A] The composition according to any one of [1A] to [11A], which is in a dosage form selected from the group consisting of liniments, lotions, aerosols, pump sprays, ointments, creams, gels, tapes, and poultices.
[15A] The composition according to any one of [1A] to [11A], which is in a dosage form selected from the group consisting of a lotion, an ointment, a cream, and a gel.

[1B] The following component (A):
(A) loxoprofen or a salt thereof;
A liquid or semi-solid composition comprising the following components (B) and (C):
(B) a plant of the genus Lacertilia or an extract thereof;
(C) celluloses;
A method for inhibiting discoloration of a composition, comprising the step of incorporating:
[2B] The method described in [1B], wherein component (A) is sodium rofecoxib hydrate.
[3B] The method according to [1B] or [2B], wherein the component (B) is one or more selected from the group consisting of Arnica montana, Arnica chamissonis, Arnica fulgens, Arnica cordifolia, Arnica latifolia, Arnica longifolia, and Arnica sachalinensis, and extracts thereof.
[4B] The method described in [1B] or [2B], wherein component (B) is arnica or an extract thereof.
[5B] The method according to [1B] or [2B], wherein component (B) is one or more selected from the group consisting of arnica, arnica tincture and arnica extract.

[6B] The method according to any one of [1B] to [5B], wherein the component (C) is a cellulose ether derivative or a salt thereof.
[7B] The method according to any one of [1B] to [6B], wherein component (C) is one or more selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, and carboxyalkyl cellulose, and salts thereof.
[8B] The method according to any one of [1B] to [7B], wherein component (C) is hypromellose.
[9B] The method according to any one of [1B] to [8B], wherein the composition further contains water.
[10B] The method according to any one of [1B] to [9B], wherein the composition further contains a lower alcohol.
[11B] The method according to [10B], wherein the lower alcohol is one or more selected from the group consisting of ethanol and isopropanol.

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 Liquid compositions of Example 1 or Comparative Examples 1 to 3 were prepared containing the components and amounts shown in Table 1. Each of the resulting compositions was placed in a glass container and stored in a dark place at 80° C. for 4 weeks, and the presence or absence of discoloration (yellowing) was visually evaluated 2 weeks and 4 weeks after the start of storage.
The results were evaluated as follows: no discoloration occurred, as ◯; discoloration occurred, as ×.
The results are shown in Table 1.

A liquid composition containing arnica tincture together with rofecoxib (Comparative Example 1), a liquid composition containing hypromellose together with rofecoxib (Comparative Example 2), and a liquid composition containing rofecoxib without arnica tincture or hypromellose (Comparative Example 3) discolored after being stored at high temperatures for two weeks.
In contrast, comparing Example 1 with Comparative Examples 1 and 2, in the liquid composition (Example 1) containing a combination of arnica tincture and hypromellose in addition to rofecoxib, discoloration during high-temperature storage was significantly suppressed, and no discoloration was observed even after storage for 4 weeks.

The above test results demonstrate that when a liquid or semi-solid composition containing loxoprofen or a salt thereof is further supplemented with a plant of the genus Lagenaria, such as arnica tincture, or an extract thereof, and a cellulose, such as hypromellose, discoloration during high-temperature storage can be significantly suppressed compared to when each of these is contained alone.

Although glass containers were used in this test, it was found that when a liquid or semi-solid composition containing loxoprofen or a salt thereof is further combined with a plant of the genus Lagenaria, such as arnica tincture, or an extract thereof, and a cellulose, such as hypromellose, a sufficient discoloration inhibition effect can be obtained without using a container made of polyolefin resin, and the composition can be stably stored in containers made of a wide variety of materials.

The following shows an example of the production of the liquid or semi-solid composition of the present invention. The content of the extract of the plant of the genus Lacertilia is expressed as the amount (g) of the original herbal medicine, unless otherwise specified.

Production Example 1 (Lotion)
Liquid compositions (lotions: Formulation Examples 1 to 8) containing the components and amounts (g) shown in Table 2 below per 100 g were produced 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. These were designated as Production Examples 1-1 to 1-8, respectively.

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

Production Example 3 (Lotion)
Liquid compositions (lotions: Formulation Examples 1 to 8) containing the components and amounts (g) shown in Table 2 above per 100 g were produced by a conventional method, and placed in bottle containers having a sponge-like low-density polyethylene application member (MAPS: Inoac Corporation) attached to the mouth of a glass container body. These were designated as Production Examples 3-1 to 3-8, respectively.

Production Example 4 (Lotion)
Liquid compositions (lotions: Formulation Examples 9 to 16) containing the components and amounts (g) shown in Table 3 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. These were designated as Preparation Examples 4-1 to 4-8, respectively.

Production Example 5 (Lotion)
Liquid compositions (lotions: Formulation Examples 9 to 16) containing the components and amounts (g) shown in Table 3 above per 100 g were produced by a conventional method, and placed in bottle containers having a sponge-like low-density polyethylene application member (MAPS: Inoac Corporation) attached to the mouth of a polyethylene container body. These were designated as Production Examples 5-1 to 5-8, respectively.

Production Example 6 (Lotion)
Liquid compositions (lotions: Formulation Examples 9 to 16) containing the components and amounts (g) shown in Table 3 above per 100 g were produced by a conventional method, and placed in bottle containers having a sponge-like low-density polyethylene application member (MAPS: Inoac Corporation) attached to the mouth of a glass container body. These were designated as Production Examples 6-1 to 6-8, respectively.

Production Example 7 (Gel)
Semi-solid compositions (gels: Formulation Examples 17 to 24) containing the components and amounts (g) shown in Table 4 below per 100 g were produced by a conventional method, and placed in tube containers (laminated tubes) made of a laminate film 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 thereof. These were designated as Production Examples 7-1 to 7-8, respectively.

Production Example 8 (Ointment)
Semi-solid compositions (ointments: Formulation Examples 25 to 32) containing the ingredients and amounts (g) shown in Table 5 below per 100 g were prepared in a conventional manner, and placed in tube containers made of laminated films (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. These were designated as Preparation Examples 8-1 to 8-8, respectively.

Production Example 9 (Cream)
Semi-solid compositions (creams: Formulation Examples 33 to 40) containing the ingredients and amounts (g) shown in Table 6 below per 100 g were produced in a conventional manner, and placed in tube containers made of laminated film (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. These were designated Production Examples 9-1 to 9-8, respectively.

Production Example 10 (Oral Liquid)
Liquid compositions (oral liquid: Formulation Examples 41 to 48) containing the components and amounts (mg) shown in Table 7 below in 30 mL were prepared by a conventional method, and placed in polypropylene bottle containers. These were designated as Preparation Examples 10-1 to 10-8, respectively.

Production Example 11 (Lotion)
A liquid composition (lotion) containing the following components and amounts per 100 g was produced in a conventional manner and placed in a polypropylene bottle.
Loxoprofen sodium hydrate 1.13g
l-Menthol 3g
Arnica tincture 0.5g (equivalent to 110mg of raw herbal medicine)
Hypromellose, lactic acid, ethanol and purified water (appropriate amount)

Production Example 12 (Cream)
A semi-solid composition (cream) containing the following ingredients and amounts per 100 g was prepared in a conventional manner and placed in a polyethylene tube container.
Loxoprofen sodium hydrate 1.13g
l-Menthol 3g
Arnica tincture 0.5g (equivalent to 110mg of raw herbal medicine)
Hypromellose, carboxyvinyl polymer, sodium edetate hydrate, diisopropanolamine, polyoxyethylene behenyl ether, liquid paraffin, ethanol and purified water (appropriate amount)

Production Example 13 (Cream)
A semi-solid composition (cream) containing the following ingredients and amounts per 100 g was prepared in a conventional manner and placed in a polyethylene tube container.
Loxoprofen sodium hydrate 1.13g
l-Menthol 3g
Arnica tincture 0.5g (equivalent to 110mg of raw herbal medicine)
Carboxyvinyl polymer, octyldodecyl myristate, diisopropyl adipate, lipophilic glyceryl monostearate, sorbitan monostearate, polysorbate 60, polyoxyethylene cetyl ether, sodium hydroxide, sodium edetate hydrate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, ethanol and purified water
Appropriate amount

Production Example 14 (Pot)
A semi-solid composition (plaster) containing the following ingredients and amounts per 100 g was prepared by a conventional method, and the resulting plaster was applied to a nonwoven fabric (shrinkage rate 58.0%, denier number 32.1 g, course number 64.8/inch, wale number 50.4/inch) in an amount of 5 g per sheet (10 cm x 7 cm), which was then covered with a release liner (made of polyester) and cut into individual sheets. The resulting poultice was placed in a medicine bag (PE/Al/PE/paper).
Loxoprofen sodium hydrate 1.13g
l-Menthol 1.2g
Arnica tincture 1mL (equivalent to 200mg of raw herbal medicine)
Carmellose sodium, partially neutralized polyacrylic acid, methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion, polyvinyl alcohol (partially saponified), sorbitan monooleate, glycerin, sorbitol, sodium edetate hydrate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, dihydroxyaluminum aminoacetate, tartaric acid, diisopropanolamine, macrogol, diisopropyl adipate and purified water (appropriate amount)

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 (7)

The following components (A), (B) and (C):
(A) loxoprofen or a salt thereof;
(B) a plant of the genus Lacertilia or an extract thereof;
(C) celluloses;
A liquid or semi-solid composition (excluding the case where it is contained in a polyolefin resin container) comprising: The composition according to claim 1, wherein component (B) is arnica or an extract thereof. The composition according to claim 1 or 2, wherein component (B) is arnica, arnica tincture or arnica extract. The composition according to any one of claims 1 to 3, wherein component (C) is a cellulose ether derivative or a salt thereof. The composition according to any one of claims 1 to 4, wherein component (C) is one or more selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, carmellose, and salts thereof. The composition according to any one of claims 1 to 5, wherein component (C) is hypromellose. The composition according to any one of claims 1 to 6, which is in a dosage form selected from the group consisting of external liquids, sprays, ointments, creams, gels, patches, oral liquids, syrups, and oral jellies.