Pharmaceutical preparation containing loxoprofen

Abstract

To provide means that inhibits discoloration of a liquid or semisolid composition containing loxoprofen or a salt thereof, during high temperature storage.SOLUTION: The present invention provides a pharmaceutical preparation wherein a liquid or semisolid composition containing following components (A) and (B): (A) loxoprofen or a salt thereof and (B) nicotinic acid, is stored in a polyolefin resin-made container.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] Loxoprofen is a kind of phenylpropionic acid-based non-steroidal anti-inflammatory drug (NSAID) (Non-Patent Document 1) and exhibits an excellent anti-inflammatory and analgesic effect. Therefore, it is widely used as an active ingredient of topical anti-inflammatory and analgesic agents, and topical patches (poultices, tapes, etc.) and topical application agents (gel agents, etc.) that have anti-inflammatory and analgesic effects on diseases and symptoms such as osteoarthritis, muscle pain, swelling and pain after trauma, etc. have been developed and marketed (Non-Patent Document 2).

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] When loxoprofen is used as an active ingredient of a topical agent, it is preferably used by applying it to the affected area as a liquid or semi-solid composition, such as a topical application agent like a lotion, a gel agent, or a cream agent, from the viewpoint of flexibly administering the necessary amount according to the position, shape, and range of the affected area. Also, if a technique 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 agents but also to oral medications (oral liquid agents, etc.). Therefore, in order to establish a technique for stably formulating loxoprofen in a liquid or semi-solid composition, the present inventors prepared a liquid or semi-solid composition containing loxoprofen or a salt thereof and evaluated its storage stability. Unexpectedly, it was found that discoloration could occur over time during storage under high-temperature conditions.

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

Means for Solving the Problems

[0006] Therefore, the present inventors further studied to solve this problem and found that by adding nicotinic acids typified by benzyl nicotinate to a liquid or semi-solid composition containing loxoprofen or a salt thereof and storing it in a container made of a polyolefin resin typified by polyethylene, discoloration during high-temperature storage can be suppressed, and thus the present invention was completed.

[0007] That is, the present invention provides a pharmaceutical preparation comprising the following components (A) and (B): (A) Loxoprofen or a salt thereof; (B) Nicotinic acids; wherein the liquid or semi-solid composition containing the same is contained in a container made of a polyolefin resin. Further, the present invention provides a method for suppressing discoloration of a composition, which comprises a step of containing a liquid or semi-solid composition containing the following components (A) and (B): (A) Loxoprofen or a salt thereof; (B) Nicotinic acids; in a container made of a polyolefin resin.

Effects of the Invention

[0008] According to the present invention, discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during storage at high temperatures can be suppressed. Therefore, it is possible to provide a pharmaceutical containing loxoprofen or a salt thereof, which has excellent storage stability.

Embodiments for Carrying Out the Invention

[0009] First, the invention in the aspect of "pharmaceutical preparation" will be described below. <Component (A)> In the present invention, the "loxoprofen or a salt thereof" includes loxoprofen itself, pharmaceutically acceptable salts of loxoprofen, and further solvates of loxoprofen or its pharmaceutically acceptable salts with water, alcohol, etc. These are known compounds, which can be produced by known methods, and commercially available products can also be used. In the present invention, as the loxoprofen or a salt thereof, loxoprofen sodium hydrate (chemical name: Monosodium 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate dihydrate) is preferable.

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

[0011] <Component (B)> In the present invention, the term "nicotinic acids" means one or more selected from nicotinic acid and its derivatives (for example, nicotinic acid esters (specifically, for example, methyl nicotinate, β-butoxyethyl nicotinate, benzyl nicotinate, inositol hexanicotinate, heptronicate, etc.), nicotinamide, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, etc.) and salts thereof. As the nicotinic acid ester, a monoester of nicotinic acid is preferred. In the present invention, from the viewpoint of the discoloration suppressing effect, one or more selected from the group consisting of benzyl nicotinate and nicotinamide are more preferred as the nicotinic acids, and benzyl nicotinate is particularly preferred. These are all known compounds and can be produced by known methods, and commercially available products can also be used.

[0012] In the present invention, the content of nicotinic acids in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration suppressing effect, it is preferably 0.001 to 2% by mass, more preferably 0.005 to 1% by mass, still more preferably 0.01 to 0.5% by mass, and particularly preferably 0.01 to 0.25% by mass based on the total mass of the composition.

[0013] In the present invention, the content ratio of loxoprofen or its salt and nicotinic acids in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration suppressing effect, it is preferably 0.002 to 2 parts by mass of nicotinic acids with respect to 1 part by mass of loxoprofen or its salt in terms of anhydrous loxoprofen, more preferably 0.006 to 1 part by mass, and particularly preferably 0.02 to 0.4 parts by mass.

[0014] <Liquid or semi-solid composition> In the present invention, the "liquid or semi-solid composition" means a composition that is liquid or semi-solid at normal 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 it may be any of a solution, a colloidal solution (sol (suspension or emulsion)), a gel, etc. Further, the type, properties, etc. of the solvent or base are not particularly limited, and it may be hydrophilic or hydrophobic such as oily, and furthermore, a plurality of different types of solvents and bases may be appropriately mixed, emulsified, etc. and used. Specific examples of such solvents and bases include the components exemplified as the additives described below.

[0015] In the present invention, from the viewpoint of the safety during the use of the pharmaceutical preparation, it is preferable that the liquid or semi-solid composition contains water. Here, the water content in the composition is not particularly limited, but from the viewpoints of the safety during the use of the pharmaceutical preparation and the discoloration suppressing effect, it is preferably 1% by mass or more, more preferably 5% by mass or more, still more preferably 10 to 90% by mass, even more preferably 20 to 70% by mass, and particularly preferably 30 to 50% by mass based on the total mass of the composition.

[0016] Further, in the present invention, from the viewpoint of the usability of the pharmaceutical preparation, it is preferable that the liquid or semi-solid composition contains a lower alcohol. Here, "lower alcohol" means a linear or branched monohydric alcohol having 1 to 6 carbon atoms, and specific examples include ethanol, isopropanol, n-propanol, etc., and one of these may be used alone or in combination of two or more. 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 viewpoints of the usability of the pharmaceutical preparation and the discoloration suppressing effect, it is preferably 5% by mass or more, more preferably 10 to 90% by mass, still 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.

[0017] In the present invention, from the viewpoints of safety and usability during the use of pharmaceutical preparations, it is preferable that the liquid or semi-solid composition contains both water and a lower alcohol. Even when the composition contains at least one of water or a lower alcohol (particularly a composition containing both water and a lower alcohol), discoloration is suppressed.

[0018] In the present invention, the liquid or semi-solid composition may contain, as a pharmaceutical component, one or more selected from the group consisting of drugs other than those described above, for example, analgesic components, anti-inflammatory components, antihistamine components, bactericidal components, astringent / protective components, blood circulation promoting components, warming components, local anesthetic components, antitussives, noscapines, bronchodilators, expectorants, hypnotic sedatives, vitamins, gastric mucosal protectants, antacids, anticholinergics, crude drugs, Chinese herbal prescriptions, etc.

[0019] Examples of the analgesic component include aspirin, aluminum aspirin, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, salsalate, salicylamide, salicylic acid, ethylene glycol salicylate, glycol salicylate, sodium salicylate, methyl salicylate, tiaramide hydrochloride, lactylphenetidine, and the like. Examples of the anti-inflammatory component include sodium guaiazulenesulfonate, glycyrrhizic acid and its derivatives and their salts (for example, dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.), glycyrrhetinic acid, seraprozyme, semi-alkali proteinase, serrapeptase, procaterase, pronase, bromelain, and the like.

[0020] 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, dipheteol hydrochloride, dipheteol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetirizine hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, tonzylamine hydrochloride, fexofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besilate, homochlorcyclizine hydrochloride, mequitazine, methdilazine hydrochloride, mebhydroline napadisylate, and the like.

[0021] Examples of bactericidal components include benzalkonium chloride and the like. Examples of astringent / protecting components include zinc oxide and the like. Examples of blood circulation promoting components include tocopherol acetate, heparin-like substances, sodium polyethylene sulfonate, and the like. Examples of warming sensation components include vanillyl amide of nonanoic acid, capsaicin, red pepper, and the like. Examples of local anesthetic components include lidocaine, clove oil, belladonna extract, and the like.

[0022] Examples of antitussives include allokramide hydrochloride, eprazinone hydrochloride, carbetapentane citrate, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dime morpholine phosphate, tipepidine citrate, tipepidine hibenzate, and the like.

[0023] Examples of noscapines include noscapine hydrochloride, noscapine, and the like. Examples of bronchodilators include trimethoquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride, and the like.

[0024] Examples of expectorants include, for example, ammonia and houttuynia cordata extract, ammonium chloride, etc.

[0025] Examples of hypnotics and sedatives include, for example, allylisopropylacetylurea, bromovalerylurea, etc. Examples of vitamins include, for example, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B 12 , vitamin C, hesperidin and its derivatives, and salts thereof, etc. (for example, thiamine, thiamine hydrochloride, thiamine nitrate, dithiothiamine hydrochloride, cetotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, ciclotiamine, thiamine disulfide, bisibuthiamine, bisbentiamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate ester, riboflavin butyrate ester, sodium riboflavin phosphate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate ester, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.)

[0026] Examples of gastric mucosal protectants include, for example, gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride, etc. Examples of antacids include aminoacetic acid, magnesium aluminosilicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, magnesium aluminum hydroxide, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitated product of aluminum hydroxide and sodium bicarbonate, coprecipitated product of aluminum hydroxide, calcium carbonate and magnesium carbonate, magnesium hydroxide, coprecipitated product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, sodium bicarbonate, precipitated calcium carbonate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, cuttlefish bone, nacre, borax, etc.

[0027] Examples of anticholinergic drugs include oxyfencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, tipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyl dioxolane iodide, etc.

[0028] Examples of crude drugs include, for example, Akamegashiwa (Red Bud Cypress), Asenyaku (Arsenic Drug), Arnica, Inyoukaku (Epimedium), Uikyou (Fennel), Ukon (Turmeric), Engosaku (Rhizoma Corydalis), Ougon (Scutellaria baicalensis), Ousei (Polygonatum sibiricum), Oubaku (Phellodendron amurense), Ouhi (Cherry Bark), Ouren (Coptis chinensis), Onji (Polygala tenuifolia), Gajuts (Atractylodes lancea), Kanokosou (Pyrola incarnata), Chamomile, Karonin (Gourd Seed), Kikyou (Platycodon grandiflorum), Kyou'nin (Apricot Kernel), Kukoshi (Wolfberry Fruit), Kukoyo (Wolfberry Leaf), Keigai (Schizonepeta tenuifolia), Keihi (Cinnamon), Ketsumeishi (Cassia Seed), Gentiana, Gen'noshouko (Evidence), Koukka (Safflower), Koukubushi (Cyperus rotundus), Gouou (Calculus Bovis), Gomishi (Schisandra chinensis), Saishin (Asarum sieboldii), Sanshishi (Gardenia jasminoides), Sanshou (Prickly Ash), Shion (Aster tataricus), Jikoppi (Lycium chinense Mill.), Shikon (Purple Root), Shakuyaku (Paeonia lactiflora), Jakou (Moschus), Shajin (Adenophora stricta), Shazen-shi (Plantago asiatica L.), Shazen-sou (Plantago major L.), Animal Bile (including Yuutan (Bear Bile)), Shoukyou (Ginger), Jiryuu (Pheretima aspergillum), Shin'i (Magnolia liliflora Desr.), European Beech, Sekisan (Lycoris radiata), Senega, Senkyuu (Rhizoma Chuanxiong), Zenko (Peucedanum praeruptorum Dunn), Senburi (unknown), Soushutsu (Atractylodes lancea), Souhakuhi (Mulberry Bark), Soyou (Perilla frutescens), Taisan (Garlic), Chikusetsu-ninjin (Panax japonicus Torr.), Chinpi (Dried Tangerine Peel), Touki (Angelica sinensis), Tokon (Ipecacuanha), Nantenjitsu (Nandina Fruit), Ninjin (Ginseng), Baimo (Fritillaria thunbergii Miq.), Bakumondou (Ophiopogon japonicus), Hange (Pinellia ternata), Bankouka (Crocus sativus), Hanpi (Agkistrodon acutus), Byakushi (unknown), Byakujutsu (Atractylodes macrocephala Koidz.), Bukuryou (Poria cocos Wolf), Botanpi (Moutan bark), Youbaihi (Myrica rubra Sieb. et Zucc.), Rokujou (Cornu Cervi Pantotrichum), etc. of crude drugs and their extracts (extracts, tinctures, dry extracts, etc.).

[0029] Examples of Kampo prescriptions include, for example, Keishitou (Cinnamon Twig Decoction), Kousosan (Aromatic Perilla Powder), Saikokeishitou (Bupleurum and Cinnamon Twig Decoction), Shousaikotou (Minor Bupleurum Decoction), Bakumondoutou (Ophiopogon Decoction), Hangekoubokutou (Pinellia and Magnolia Bark Decoction), etc.

[0030] In the present invention, additives used in the pharmaceutical field, cosmetic field, etc. may be blended in the liquid or semi-solid composition according to the dosage form of the pharmaceutical preparation, administration method, etc. Examples of such additives include gelling agents, polyhydric alcohols, fats and oils, emulsifiers, solubilizers, pH adjusters, antioxidants, softeners, thickeners, humectants, preservatives, stabilizers, transdermal absorption promoters, flavoring agents / sweeteners, terpenes, and the like.

[0031] Examples of the gelling agent include acrylic acid-based polymers such as carboxyvinyl polymer; water-soluble or water-swellable cellulose-based polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, and ethyl cellulose; and polyvinyl pyrrolidone. Examples of the polyhydric alcohol include glycerin, ethylene glycol, propylene glycol, butylene glycol, macrogol, and polypropylene glycol. Examples of the 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 wax, shellac, jojoba oil, beeswax, white beeswax, montan wax, lanolin, purified lanolin, and reduced lanolin; and silicone oil.

[0032] Examples of the emulsifier include polyhydric alcohol fatty acid esters or polyhydric alcohol alkyl ethers such as propylene glycol monofatty acid ester, ethylene glycol monofatty acid ester, glycerin monofatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, methyl glucoside fatty acid ester, and alkyl polyglucoside; polyoxyethylene ethers such as polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, and polyoxyethylene polyoxypropylene alkyl ether; ether esters such as nonionic surfactants like polyoxyethylene monofatty acid ester, polyethylene glycol di-fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene vegetable oil, and polyoxyethylene alkyl ether fatty acid ester, or 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 as the above emulsifiers, liquid paraffin, chlorotrimeton, and the like.

[0033] Examples of the pH adjuster include organic acids or their salts 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, glacial acetic acid; inorganic acids or their salts such as hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium bicarbonate; alkalis such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide; and amines such as triethanolamine, diethanolamine, and diisopropanolamine. Examples of antioxidants include sodium sulfite, ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol, tocopherol acetate, soy lecithin, propyl gallate, and the like. Examples of softeners include allantoin, almond oil, olive oil, glycerin, liquid paraffin, squalane, squalene, purified lanolin, medium-chain fatty acid triglycerides, 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, albumin, and the like. Examples of humectants include sodium hyaluronate, glycerin, 1,3-butylene glycol, propylene glycol, urea, sucrose, erythritol, sorbitol, and the like. Examples of preservatives include methyl paraben, ethyl paraben, propyl paraben, isopropyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, aminoethylsulfonic acid, and the like. Examples of stabilizers include adipic acid, ascorbic acid, sodium sulfite, sodium bisulfite, sodium chloride, hydrogenated oil, cysteine, and the like. Examples of transdermal absorption enhancers 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, fructooligosaccharide, galactooligosaccharide, lactulose, isomaltooligosaccharide, palatinose oligosaccharide, raffinose, aspartame, fructose, xylitol, brown sugar, saccharin or its salts, sorbitol, lactose, granulated sugar, honey, glucose, maltitol, maltose, mannitol, and molasses, among others.

[0034] Examples of terpenes include isoborneol, iron, ocimene, carveol, carvotanacetone, carvomenthol, carvone, caryophyllene, carone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, sylvestrene, thymol, isotsugiol, tsugene, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocamphoneol, pinol, pipertitenone, ferrarel, ferrarelene, fenchene, fenchyl alcohol, perillyl alcohol, perillyl aldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, limonene, and the like. Among these, camphor and menthol are preferred.

[0035] Examples of essential oils containing terpenoids include, for example, anise oil, ylang-ylang oil, iris oil, star anise oil, orange oil, cananga oil, chamomile oil, kayapto oil, clove oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, sansho oil, perilla oil, citriodora oil, citronella oil, ginger oil, shoga oil, camphor oil, gingergrass oil, spearmint oil, peppermint oil, geranium oil, star anise oil, clove oil, turpentine oil, cypress oil, neroli oil, basil oil, mint oil, palmarosa oil, pimento oil, ptychoglena oil, bay oil, pennyroyal oil, henopodium oil, bergamot oil, boadroas oil, fennel oil, marjoram oil, mandarin oil, melissa oil, eucalyptus oil, lime oil, lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, roman chamomile oil, etc.

[0036] In the present invention, the method for producing a liquid or semi-solid composition is not particularly limited, and depending on the type and amount of components to be blended, the properties of the composition, the shape of the container, the dosage form of the pharmaceutical preparation, the administration route and use, etc., it can be produced by a known method described in, for example, the General Rules for Preparations of the Sixteenth Revision of the Japanese Pharmacopoeia.

[0037] <Container made of polyolefin resin> In the present invention, the "container" means a package that directly contains a liquid or semi-solid composition. The shape of the container is not particularly limited as long as it can contain a liquid or semi-solid composition, and it may be appropriately considered and determined according to the properties of the composition, the dosage form of the pharmaceutical preparation, the administration route and use, etc. Examples of such container shapes include, for example, containers for aerosol preparations, containers for pump sprays, bottle containers (more specifically, for example, bottle containers equipped with a sponge-like application member (head), roll-on containers, jar bottle containers, etc.), tube containers, eye drop containers, etc. Note that all of these containers are known and can be manufactured by known methods, or commercially available products may be used.

[0038] In the present invention, from the viewpoints of convenience in handling pharmaceutical preparations and use, etc., as the container, the following (1) or (2): (1) A container including a container body and an application member, such as a bottle container provided with a sponge-like application member, and impregnating the composition accommodated in the container body into the application member for use; (2) A container including a flexible container body and a discharge port, such as a tube container; is preferable, and the container of the aspect (1) is particularly preferable.

[0039] [(1) A container including a container body and an application member, and impregnating the composition accommodated in the container body into the application member for use] In the case of the container of such an aspect, the composition accommodated in the container body can be impregnated and held in the application member, and the composition can be applied by bringing the application member into contact with the portion to be coated. 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 may be integrally molded. In addition, as the application member, any configuration may be used as long as it can impregnate and hold a liquid or semi-solid composition, and examples thereof include porous members such as sponge-like members and brush-like members.

[0040] Examples of such a container include a container provided with an application member at the mouth of the container body, and impregnating the composition accommodated in the container body into the application member for use. As a more detailed specific example, for example, a container including a container body having a mouth and a porous (such as sponge-like) application member attached to the mouth can be mentioned. In this case, after impregnating and holding the composition accommodated in the container body in the porous application member whose pore diameter, porosity, etc. are appropriately adjusted, the composition can be applied to the portion to be coated by bringing the application member into contact with the portion to be coated. As another specific example, for instance, a container including a container body having a mouth portion and a brush-shaped coating member attached to the mouth portion can be mentioned. In this case, after impregnating and holding the composition stored in the container body in the brush with appropriately adjusted hair length, interval, etc., the composition can be applied to the portion to be coated by bringing the coating member into contact with the portion to be coated.

[0041] For a container of such a mode, since the composition is impregnated and held in the coating member for use, for example, when a pharmaceutical preparation is an external preparation, it is less likely to cause dripping problems at the portion to be coated, the fingers will not get dirty by directly bringing the coating member into contact with the portion to be coated, or by adjusting the shape, size, etc. of the coating member, the area for easily applying the composition can be flexibly adjusted, and it has merits such as this. However, since the composition is impregnated and held in the coating member, if discoloration occurs in the composition, discoloration will occur over the entire coating member. Therefore, when the coating member is exposed to the outside, for example, when using a pharmaceutical preparation, the discoloration will be particularly conspicuous in terms of appearance. However, according to the present invention, since discoloration of the composition is suppressed, it has an excellent effect of solving such appearance problems and fully enjoying the above merits. In the case of a container of such a mode, it is particularly preferable that both the container body and the coating member are made of a polyolefin-based resin. In addition, such a container can be particularly preferably adopted when the composition to be stored is, for example, a liquid composition or a semi-solid composition with low viscosity.

[0042] A container of such a mode is known and is disclosed, for example, in Japanese Patent No. 5570089 Gazette. Also, in the present invention, a commercially available product may be used as a container of such a mode, and examples of such a commercially available product include a container using MAPS (Inoac Corporation) which is a low-density polyethylene-made communicating porous body as a coating member.

[0043] [(2) A container including a flexible container body and a discharge port] In the case of a container of such an aspect, by applying pressure to the flexible container body, etc., pressure is applied inside the container, and by discharging the composition accommodated inside the container from the discharge port, the composition can be applied to the application part. Note that in a container of such an aspect, the discharge port does not necessarily have to be provided in the container in advance, and it may be configured to provide the discharge port by perforating the container or the like before the start of use. A container of such an aspect is also included in the "container comprising a flexible container body and a discharge port".

[0044] A container of such an aspect has advantages such as a low manufacturing cost because of its simple structure, and the composition inside the container is not contaminated because the composition is discharged from the discharge port by pressing the container body or the like. Note that a container of such an aspect can be particularly preferably adopted when the composition to be accommodated is, for example, a highly viscous semi-solid composition.

[0045] A container of such an aspect is known and is disclosed in, for example, Japanese Patent No. 5302550, Japanese Patent No. 5525135, etc. Also, in the present invention, a commercially available product may be used as a container of such an aspect.

[0046] In the present invention, the "polyolefin resin" is not particularly limited and may be a polymer (homopolymer) of a single type of monomer or a copolymer (copolymer) of a plurality of types of monomers. Also, in the case of a copolymer, the polymerization mode is not particularly limited and may be random polymerization or block polymerization. Further, its stereoregularity (tacticity) is not particularly limited. Examples of such polyolefin resins include, specifically, 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, one or more of these can be used in combination. In the present invention, as the polyolefin resin, from the viewpoint of the discoloration suppressing effect, polyethylene, polypropylene, and cyclic polyolefin are preferable, and polyethylene and polypropylene are particularly preferable. In the present invention, "made of polyolefin resin" means that at least a part of the material contains a polyolefin resin. For example, a mixture (polymer alloy) of two or more resins such as a polyolefin resin and another resin is also included in "made of polyolefin resin".

[0047] In the present invention, the "container made of polyolefin resin" means a "container" in which at least a part (preferably, 10% or more of the part in contact with the liquid or semi-solid composition stored therein during normal storage, more preferably, 30% or more of the part in contact with the composition during normal storage, particularly preferably, the whole of the part in contact with the composition during normal storage) of the part in contact with the liquid or semi-solid composition stored therein is "made of polyolefin resin". Therefore, for example, a container in which a layer of a polyolefin resin is provided at least in part of the layer (the innermost layer of the container) in contact with the liquid or semi-solid composition, and other resin materials such as aluminum foil are laminated on the outside also corresponds to the "container made of polyolefin resin". Examples of such containers formed by laminating multiple types of materials include, specifically, for example, containers made of laminated films in which a layer made of a polyolefin resin is used as the innermost layer, an aluminum foil is laminated directly on the outside or via another layer, and optionally another layer is laminated on the outside as needed.

[0048] In the present invention, the means for accommodating a liquid or semi-solid composition in a container is not particularly limited, and it may be filled by a conventional method according to the shape of the container, the properties of the composition, etc., whereby the pharmaceutical preparation of the present invention can be manufactured.

[0049] <Pharmaceutical preparation> In the present invention, the method of administration and application of the "pharmaceutical preparation" is not particularly limited, and examples include oral, percutaneous, transvaginal, and other parenteral routes. In the present invention, parenteral administration is preferred, and percutaneous administration is particularly preferred, due to the characteristics of the liquid or semi-solid composition (the fact that it can be applied in a flexible amount as necessary according to the location, shape, and range of the affected area).

[0050] 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 liquid or semi-solid, and it can be appropriately selected from dosage forms described in, for example, the General Rules of Preparations of the 16th Revised Japanese Pharmacopoeia according to the purpose of use, etc. Specific examples of such dosage forms include dosage forms described in the General Rules of Preparations of the 16th Revised Japanese Pharmacopoeia, such as preparations for application to the skin (external liquid preparations, spray preparations, ointment preparations, cream preparations, gel preparations, etc.), preparations for oral administration (oral liquid preparations, syrup preparations, oral jelly preparations, etc.). In the present invention, the pharmaceutical preparation is preferably a dosage form selected from the group consisting of external liquid preparations, spray preparations, ointment preparations, cream preparations, and gel preparations, more preferably a dosage form selected from the group consisting of liniment preparations, lotion preparations, external aerosol preparations, pump spray preparations, ointment preparations, cream preparations, and gel preparations, and particularly preferably a dosage form selected from the group consisting of lotion preparations, ointment preparations, cream preparations, and gel preparations.

[0051] Since the pharmaceutical preparation of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, it can be used as a medical pharmaceutical or an OTC pharmaceutical. Specifically, for example, it is useful as an external anti-inflammatory and analgesic agent; an oral medicine such as an antipyretic analgesic or a general cold medicine.

[0052] Next, the invention of the "method" aspect will be described below. The present invention relates to the following components (A) and (B): (A) Loxoprofen or a salt thereof; (B) Nicotinic acids; The present invention also relates to a method for suppressing discoloration of a composition, which includes a step of accommodating a liquid or semi-solid composition containing the above components in a container made of a polyolefin resin. In the invention of such an aspect, the order of the steps of blending component (A), blending component (B), and accommodating the composition in a container made of a polyolefin resin is not particularly limited, as long as a state in which the liquid or semi-solid composition containing components (A) and (B) is accommodated in a container made of a polyolefin resin is directly or indirectly created. In addition, in the invention of such an aspect, the meanings of various phrases, the blending amounts of each component, etc. are all the same as those described for the "pharmaceutical preparation".

[0053] This specification discloses inventions exemplified below, for example, in relation to the above embodiments, but is not limited thereto. [1] A pharmaceutical preparation, wherein a liquid or semi-solid composition containing the following components (A) and (B): (A) Loxoprofen or a salt thereof; (B) Nicotinic acids; is accommodated in a container made of a polyolefin resin. [2] The pharmaceutical preparation according to [1], wherein component (A) is loxoprofen sodium hydrate. [3] The pharmaceutical preparation according to [1] or [2], wherein component (B) is at least one selected from the group consisting of nicotinic acid, methyl nicotinate, β-butoxyethyl nicotinate, benzyl nicotinate, nicotinamide, inositol hexanicotinate, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, heptonicate, and salts thereof. [4] The pharmaceutical preparation according to any one of [1] to [3], wherein component (B) is at least one selected from the group consisting of benzyl nicotinate and nicotinamide. [5] The pharmaceutical preparation according to any one of [1] to [4], wherein component (B) is benzyl nicotinate.

[0054] [6] The pharmaceutical preparation according to any one of [1] to [5], wherein the composition further contains water. [7] The pharmaceutical preparation according to any one of [1] to [6], wherein the composition further contains a lower alcohol. [8] The pharmaceutical preparation according to [7], wherein the lower alcohol is at least one 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 preparation 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 the following (1) or (2): (1) A container comprising a container body and an application member, and impregnating the composition accommodated in the container body into the application member for use; (2) A container comprising a flexible container body and a discharge port. The pharmaceutical preparation 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 provided with a sponge-like application member. 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, spray preparations, ointment preparations, cream preparations, gel preparations, oral liquid preparations, syrup preparations, and oral jelly preparations. 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, spray preparations, ointment preparations, cream preparations, and gel preparations. The pharmaceutical preparation according to any one of [1] to

[12] , which is in a dosage form selected from the group consisting of liniment preparations, lotion preparations, external aerosol preparations, pump spray preparations, ointment preparations, cream preparations, and gel preparations. The pharmaceutical preparation according to any one of [1] to

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

[0055]

[17] The following components (A) and (B): (A) Loxoprofen or a salt thereof; (B) Nicotinic acids; A method for suppressing discoloration of a composition, which includes a step of accommodating a liquid or semi-solid composition containing the above in a container made of a polyolefin resin. The method according to

[17] , wherein component (A) is loxoprofen sodium hydrate. The method according to

[17] or

[18] , wherein component (B) is at least one selected from the group consisting of nicotinic acid, methyl nicotinate, β-butoxyethyl nicotinate, benzyl nicotinate, nicotinamide, inositol hexanicotinate, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, hepronicate, and salts thereof. The method according to any one of

[17] to

[19] , wherein component (B) is at least one selected from the group consisting of benzyl nicotinate and nicotinamide. The method according to any one of

[17] to

[20] , wherein component (B) is benzyl nicotinate.

[0056]

[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 at least one 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 the following (1) or (2): (1) A container comprising a container body and an application member, and impregnating the composition accommodated in the container body into the application member for use; (2) A container comprising 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 provided with a sponge-like application member.

Examples

[0057] The present invention will be described in detail with reference to the following examples, but the present invention is not limited to these examples at all.

[0058] [Test Example 1] Storage Test Part 1 A liquid composition containing the components and amounts shown in Table 1 was prepared and stored in a polyethylene or glass container to obtain pharmaceutical preparations of Example 1, Comparative Examples 1 and 2, and Reference Example 1, respectively. Each of the obtained pharmaceutical preparations was stored in the dark at 80°C for 2 weeks, and the presence or absence of discoloration (yellowing) after 2 weeks of storage was visually evaluated. The results were evaluated as ○ for those without discoloration and × for those with discoloration. The results are shown in Table 1.

[0059]

Table 1

[0060] From the comparison between Comparative Example 1 and Reference Example 1 (without loxoprofen), it was confirmed that the discoloration observed after storage at 80°C for 2 weeks was due to the incorporation of loxoprofen into the liquid composition. And from the comparison between Example 1 and Comparative Example 1 (contained in a glass container), Comparative Example 2 (without benzyl nicotinate), it became clear that such discoloration can be suppressed by further incorporating benzyl nicotinate into the liquid composition and containing it in a polyethylene container.

[0061] [Test Example 2] Storage Test Part 2 A liquid composition containing the components and amounts shown in Table 2 was prepared, contained in a polypropylene or polyethylene container to obtain the pharmaceutical preparations of Examples 2 to 4, and the presence or absence of discoloration after storage in the dark at 80°C for 2 weeks was evaluated by the same method as in Test Example 1. The results are shown in Table 2.

[0062]

Table 2

[0063] From the above test results, even when a polypropylene container was used instead of a polyethylene container as the polyolefin resin container (Examples 2 and 4), or when ethanol was used instead of isopropanol as the lower alcohol (Examples 3 and 4), suppression of discoloration during high-temperature storage was similarly confirmed.

[0064] From the results of the above Test Examples 1 and 2, it became clear that by further incorporating nicotinic acids into a liquid or semi-solid composition containing loxoprofen or a salt thereof and containing this in a polyolefin resin container, discoloration during high-temperature storage can be suppressed.

[0065] [Test Example 3] Storage Test 3 A liquid composition identical to that contained in the pharmaceutical preparation of Example 3 was prepared. After impregnating a low-density polyethylene communication porous body (MAPS: Inoac Corporation) used as an application member in a container with this composition, it was stored in the dark at 80°C for 2 weeks, but no obvious discoloration was observed.

[0066] Production Example 1 (Lotion) By a conventional method, liquid compositions (Formulation Examples 1 to 8) containing the components and amounts (g) shown in Table 3 below in 100 g were produced, and they were stored in bottle containers equipped with sponge-like polyurethane application members at the mouths of the container bodies made of polypropylene, and used as pharmaceutical preparations (lotions) of Production Examples 1-1 to 1-8, respectively.

[0067]

Table 3

[0068] Production Example 2 (Lotion) By a conventional method, liquid compositions (Formulation Examples 1 to 8) containing the components and amounts (g) shown in Table 3 above in 100 g were produced, and they were stored in bottle containers equipped with sponge-like low-density polyethylene application members (MAPS: Inoac Corporation) at the mouths of the container bodies made of polyethylene, and used as pharmaceutical preparations (lotions) of Production Examples 2-1 to 2-8, respectively.

[0069] Production Example 3 (Lotion) By a conventional method, liquid compositions (Formulation Examples 9 to 16) containing the components and amounts (g) shown in Table 4 below in 100 g were produced, and they were stored in bottle containers equipped with sponge-like polyurethane application members at the mouths of the container bodies made of polypropylene, and used as pharmaceutical preparations (lotions) of Production Examples 3-1 to 3-8, respectively.

[0070]

Table 4

[0071] Production Example 4 (Lotion) By a conventional method, liquid compositions (Formulation Examples 9 to 16) containing the components and amounts (g) shown in Table 4 above in 100 g were produced, and they were stored in bottle containers equipped with sponge-like low-density polyethylene coating members (MAPS: Inoac Corporation) at the mouths of the container bodies made of polyethylene, and were made into pharmaceutical preparations (lotions) of Production Examples 4-1 to 4-8, respectively.

[0072] Production Example 5 (Gel) By a conventional method, semi-solid compositions (Formulation Examples 17 to 24) containing the components and amounts (g) shown in Table 5 below in 100 g were produced, and they were stored in laminated film tubes (laminate tubes) with a laminated film having a low-density polyethylene film as the innermost layer, an aluminum foil on the outside (intermediate layer) thereof, and a low-density polyethylene film on the outside thereof, and were made into pharmaceutical preparations (gels) of Production Examples 5-1 to 5-8, respectively.

[0073]

Table 5

[0074] Production Example 6 (Ointment) By a conventional method, semi-solid compositions (Formulation Examples 25 to 32) containing the components and amounts (g) shown in Table 6 below in 100 g were produced, and they were stored in laminated film tubes (laminate tubes) with a laminated film having a high-density polyethylene film as the innermost layer, a polyethylene terephthalate film on the outside (intermediate layer) thereof, and a high-density polyethylene film on the outside thereof, and were made into pharmaceutical preparations (ointments) of Production Examples 6-1 to 6-8, respectively.

[0075]

Table 6

[0076] Production Example 7 (Cream) By a conventional method, semi-solid compositions (Formulation Examples 33 to 40) containing the components and amounts (g) shown in Table 7 below in 100 g were produced, and a film made of low-density polyethylene was used as the innermost layer, and a nylon film was laminated on the outside (intermediate layer), and further a film made of low-density polyethylene was laminated on the outside thereof. The resulting laminated film tube containers (laminated tubes) were filled with the pharmaceutical preparations (cream preparations) of Production Examples 7-1 to 7-8, respectively.

[0077]

Table 7

[0078] Production Example 8 (Oral Liquid) By a conventional method, liquid compositions (Formulation Examples 41 to 48) containing the components and amounts (mg) shown in Table 8 below in 30 mL were produced, and the resulting compositions were filled into polypropylene bottle containers. The resulting products were used as the pharmaceutical preparations (oral liquids) of Production Examples 8-1 to 8-8, respectively.

[0079]

Table 8

Industrial Applicability

[0080] According to the present invention, discoloration of a liquid or semi-solid composition containing loxoprofen or a salt thereof during storage at high temperature can be suppressed. Therefore, a pharmaceutical containing loxoprofen or a salt thereof, which has excellent storage stability, can be provided and can be suitably used in the pharmaceutical industry and the like.

Claims

1. The following components (A) and (B): (A) loxoprofen or a salt thereof; (B) nicotinic acids; A pharmaceutical preparation comprising a liquid or semi-solid composition containing the above in a polyolefin resin container.

2. 2. The pharmaceutical formulation according to claim 1, wherein the component (B) is at least one member selected from the group consisting of nicotinic acid benzyl ester and nicotinic acid amide.

3. 3. The pharmaceutical formulation according to claim 1 or 2, wherein component (B) is nicotinic acid benzyl ester.

4. The pharmaceutical preparation according to any one of claims 1 to 3, 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.

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