Composition

Abstract

To provide novel means for improving the stability of a steroid.SOLUTION: A liquid or semisolid composition contains the following components (A) and (B): (A) steroid; and (B) salicylic acids.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition and the like. [Background technology]

[0002] Compounds having a steroid skeleton have been widely used as active ingredients in pharmaceuticals. For example, pharmaceuticals containing adrenocortical hormones with anti-inflammatory activity are used to treat inflammatory skin diseases such as inflammation and dermatitis associated with insect bites. Examples of adrenocortical hormones used in such pharmaceuticals include dexamethasone and prednisolone. Furthermore, pharmaceuticals containing steroids include, for example, topical skin preparations containing a combination of prednisolone valerate acetate and an antihistamine (Patent Document 1). However, the stability of the steroids in pharmaceuticals containing steroids that have been available up to now has not always been sufficient.

[0003] Therefore, as techniques for improving the stability of steroids in formulations, the following have been proposed: a topical skin preparation containing a steroid, glycerin, and a polar oil (Patent Document 2); a steroid-containing cataplasm containing 0.005 to 0.05% by weight of a steroid as an active ingredient, 15% by weight or less of crotamiton as a stabilizer, and a surfactant in a base, where the amount of crotamiton is 200 to 3,000 times the amount of steroid by weight and the amount of surfactant is 1 / 20 to 1 / 5 times the amount of crotamiton by weight (Patent Document 3); an anhydrous topical composition containing a steroidal anti-inflammatory drug and an acrylic acid polymer in an amount effective for stabilizing it (Patent Document 4); and a topical preparation containing a steroid, a benzoate ester-based local anesthetic, and an oxycarboxylic acid together with a steroid (Patent Document 5). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2002-356430 [Patent Document 2] Japanese Patent Application Laid-Open No. 2001-247463 [Patent Document 3] Japanese Patent Application Laid-Open No. 2000-26299 [Patent Document 4] Japanese Patent Application Laid-Open No. 2001-233772 [Patent Document 5] International Publication No. 2007 / 72923 Brochure Summary of the Invention [Problem to be solved by the invention]

[0005] The object of the present invention is to provide a new means for improving the stability of steroids. [Means for solving the problem]

[0006] Therefore, the present inventors have conducted extensive research to solve the above problems and have found that the stability of steroids can be improved by further adding a salicylic acid, typified by glycol salicylate, to a composition containing a steroid, thereby completing the present invention.

[0007] That is, the present invention provides a composition comprising the following components (A) and (B): (A) steroids; (B) Salicylic acids; The present invention provides a liquid or semi-solid composition comprising: The present invention also provides a composition comprising the following components (A) and (B): (A) steroids; (B) Salicylic acids; The present invention provides a container-packed composition in which a liquid or semi-solid composition containing the above is packed in a container. [Effects of the Invention]

[0008] According to the present invention, the stability of steroids in liquid or semi-solid compositions can be improved. DETAILED DESCRIPTION OF THE INVENTION

[0009] <Component (A)> In the present invention, "steroid" is not limited to adrenocortical hormones, but includes all compounds having a steroid skeleton, with adrenocortical hormones being preferred. Examples of such steroids include, but are not limited to, cortisone, hydrocortisone, amcinonide, prednisolone, methylprednisolone, diflucortolone, dexamethasone, betamethasone, diflorasone, difluprednate, triamcinolone, triamcinolone acetonide, halcinonide, flumethasone, budesonide, mometasone, fluocinolone, fluometholone, fludoxycortide, alclometasone, clobetasol, deprodone, beclomethasone, clobetasone, and their esters, ketals, acetals, and hemiacetal derivatives, as well as their salts. In the present invention, the steroid is preferably one or more selected from the group consisting of cortisone, dexamethasone, hydrocortisone, prednisolone, and esters thereof (e.g., esters with saturated fatty acids having 1 to 6 carbon atoms, such as acetate, butyrate, and valerate), more preferably one or more selected from the group consisting of cortisone acetate, dexamethasone, dexamethasone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate, and prednisolone valerate acetate, even more preferably one or more selected from the group consisting of dexamethasone, dexamethasone acetate, prednisolone, prednisolone acetate, and prednisolone valerate acetate, even more preferably one or more selected from the group consisting of dexamethasone and dexamethasone acetate, with dexamethasone acetate being particularly preferred. These are all known compounds and can be produced by known methods, or commercially available compounds can be used.

[0010] In the present invention, the content of steroid in the liquid or semi-solid composition is not particularly limited and may be determined appropriately depending on the desired pharmacological effect, etc. In the present invention, the steroid is preferably contained in an amount of 0.0001 to 1% by mass, more preferably 0.001 to 0.5% by mass, and particularly preferably 0.01 to 0.1% by mass, based on the total mass of the composition.

[0011] <Ingredient (B)> In the present invention, the term "salicylic acids" refers to one or more compounds selected from salicylic acid and its derivatives (e.g., esters of salicylic acid (specifically, for example, methyl salicylate, ethyl salicylate, glycol salicylate, etc.)) and salts thereof (e.g., alkali metal salts such as potassium salts and sodium salts; ammonium salts, etc.). In the present invention, from the viewpoint of improving the stability of the steroid, the salicylic acids are preferably one or more selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate, and methyl salicylate, more preferably one or more selected from the group consisting of glycol salicylate and methyl salicylate, and particularly preferably glycol salicylate. These are all known compounds and can be produced by known methods, or commercially available compounds can be used.

[0012] In the present invention, the content of salicylic acids in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of improving the stability of the steroid, the content of salicylic acids is preferably 0.0001 to 50% by mass, more preferably 0.001 to 10% by mass, even more preferably 0.01 to 5% by mass, and particularly preferably 0.1 to 2% by mass, relative to the total mass of the composition.

[0013] In the present invention, the content ratio of the steroid to the salicylic acids in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of improving the stability of the steroid, the content of the salicylic acids is preferably 0.1 to 1000 parts by mass, more preferably 1 to 500 parts by mass, even more preferably 10 to 100 parts by mass, and particularly preferably 35 to 85 parts by mass, per part by mass of the steroid.

[0014] <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 the solvent or base may be hydrophilic or hydrophobic, such as oily, and 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 below as additives.

[0015] In the present invention, from the viewpoints of safety during use and the feeling when used, it is preferable that the liquid or semi-solid composition contains water. Steroids, particularly steroids having an ester bond in the molecule, are prone to decomposition reactions and are unstable in liquid or semi-solid compositions containing water, but even in such cases, good stability can be obtained according to the present invention. Here, the content of water in the composition is not particularly limited, but from the viewpoint of safety during use and improving the stability of the steroid, it is preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 10 to 90% by mass, even more preferably 20 to 80% by mass, even more preferably 30 to 70% by mass, and particularly preferably 40 to 65% by mass, relative to the total mass of the composition.

[0016] In addition, in the present invention, from the viewpoint of usability, it is preferable that the liquid or semi-solid composition contains a lower alcohol. Here, "lower alcohol" means a linear or branched monohydric alcohol having 1 to 6 carbon atoms, and specific examples thereof include ethanol, isopropanol, n-propanol, etc., and one of these may be used alone or two or more may be used in combination. Among these, ethanol, isopropanol, and mixtures thereof are preferred. The content of the lower alcohol in the composition is not particularly limited, but from the viewpoint of the feel when used, it is preferably 5% by mass or more, more preferably 10 to 80% by mass, even more preferably 15 to 75% by mass, even more preferably 20 to 70% by mass, even more preferably 25 to 60% by mass, and particularly preferably 30 to 50% by mass, relative to the total mass of the composition.

[0017] In the present invention, from the viewpoints of safety during use and feeling during use, it is preferable that the liquid or semi-solid composition contains both water and a lower alcohol.

[0018] 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 antihistamines, crotamiton, glycyrrhizic acids, allantoin, disinfectants, astringents / protectants, local anesthetics, terpenes, essential oils containing terpenes, aqueous ammonia, vitamin E, and vitamin A.

[0019] Examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, carbinoxamine diphenyldisulfonate, carbinoxamine maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, difeterol hydrochloride, difeterol phosphate, diphenylpyridine Examples of such an active ingredient include benzodiazepine hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetirizine hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine methylenedisalicylate, bepotastine besilate, homochlorcyclizine hydrochloride, mequitazine, methdilazine hydrochloride, and mebhydroline napadisilate. Examples of glycyrrhizinic acids include glycyrrhizinic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), glycyrrhetinic acid, etc. Examples of disinfectants include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, isopropylmethylphenol, benzalkonium chloride, cetylpyridinium chloride, and benzethonium chloride. Astringent and protective agents include, for example, calamine and zinc oxide. Examples of local anesthetics include ethyl aminobenzoate, oxypolyethoxydodecane, dibucaine, dibucaine hydrochloride, lidocaine, and lidocaine hydrochloride. 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, silvestrene, thymol, isothujole, 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, Japanese pepper oil, perilla oil, citriodora oil, citronella oil, ginger oil, cardamom oil, camphor oil, ginger grass oil, spearmint oil, peppermint oil, geranium oil, Examples of oils that can be used include star anise oil, clove oil, turpentine oil, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, chenopodium oil, bergamot oil, bois de rose oil, basil 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. Examples of vitamin E include tocopherol, tocopherol succinate, tocopherol acetate, and tocopherol nicotinate. Examples of vitamin A include vitamin A oil and retinol palmitate.

[0020] Furthermore, in the present invention, the liquid or semi-solid composition may be blended with additives used in the pharmaceutical field, etc., depending on the dosage form, administration method, etc. of the composition. Examples of such additives include gelling agents, polyhydric alcohols, oils and fats, emulsifiers, solubilizers, pH adjusters, antioxidants, softeners, thickeners, moisturizers, preservatives, stabilizers, transdermal absorption enhancers, flavoring agents, sweeteners, etc. These may be used alone or in combination of two or more.

[0021] Examples of gelling agents include acrylic acid polymers such as carboxyvinyl polymers; water-soluble or water-swellable cellulose polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, and ethyl cellulose; and polyvinylpyrrolidone. Examples of polyhydric alcohols include glycerin, ethylene glycol, propylene glycol, 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, purified lanolin, and reduced lanolin; and silicone oil.

[0022] Examples of emulsifiers 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 alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene phytosterols, polyoxyethylene phytostanols, and polyoxyethylene polyoxypropylene alkyl ethers; and nonionic surfactants such as ether esters of polyoxyethylene mono-fatty acid esters, polyethylene glycol di-fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene methyl glucoside fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene vegetable oils, and polyoxyethylene alkyl ether fatty acid esters. In addition, ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate can be mentioned. Examples of solubilizers include the nonionic surfactants and ionic surfactants exemplified above as emulsifiers, as well as liquid paraffin, crotamiton, and the like.

[0023] 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 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, purified lanolin, medium-chain fatty acid triglycerides, rapeseed oil, castor oil, propylene glycol, and polybutene. Examples of thickeners include polyvinylpyrrolidone, carboxymethylcellulose, colloidal aluminum silicate, xanthan gum, locust bean gum, tragacanth gum, guar gum, gelatin, gum arabic, alginic acid, and albumin. Moisturizing agents include sodium hyaluronate, glycerin, 1,3-butylene glycol, propylene glycol, urea, sucrose, erythritol, and sorbitol. Examples of stabilizers include adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hydrogenated oil, and cysteine. Examples of the percutaneous absorption enhancer include fatty acid esters such as diisopropyl adipate. Examples of flavoring agents and sweeteners include acesulfame potassium, stevia, thaumatin, sucralose, panose, trehalose, erythritol, lactitol, reduced palatinose, coupling sugar, fructooligosaccharides, galactooligosaccharides, lactoferrin oligosaccharides, isomaltooligosaccharides, palatinose oligosaccharides, raffinose, aspartame, fructose, xylitol, brown sugar, saccharin or its salt, sorbitol, lactose, white sugar, honey, glucose, maltitol, maltose, mannitol, and starch syrup.

[0024] In the present invention, the method for producing a liquid or semi-solid composition is not particularly limited, and the composition can be produced by a known method, for example, as described in the General Provisions for Preparations in the Seventeenth Edition of the Japanese Pharmacopoeia, etc., depending on the types and amounts of ingredients to be blended, the properties of the composition, the dosage form, the route of administration, the intended use, etc.

[0025] 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 administration and parenteral administration such as transdermal and vaginal administration. In the present invention, parenteral administration is preferred, and transdermal administration is particularly preferred, in view of the pharmacological action of the steroid and the properties of the liquid or semi-solid composition (which allow for flexible application of only the required amount depending on the location, shape, and area of ​​the affected area).

[0026] In the present invention, the dosage form of the liquid or semi-solid composition is not particularly limited as long as the composition is in a liquid or semi-solid form, and can be appropriately selected, for example, from dosage forms described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia, etc., depending on the intended use, etc. Specific examples of such dosage forms include preparations to be applied to the skin, etc. (external liquid preparations, sprays, ointments, creams, gels, etc.) and preparations to be administered orally (oral liquid preparations, syrups, oral jellies, etc.). In the present invention, the dosage form of the liquid or semi-solid composition is preferably a dosage form selected from the group consisting of external liquids, sprays, ointments, creams, and gels, more preferably a dosage form selected from the group consisting of liniments, lotions, external aerosols, pump sprays, ointments, creams, and gels, even more preferably a dosage form selected from the group consisting of lotions, ointments, creams, and gels, and particularly preferably a lotion.

[0027] Next, the containerized composition of the present invention will be described. The containerized composition of the present invention is a liquid or semi-solid composition of the present invention contained in a container. The container may be made of glass or plastic, but from the viewpoint of improving the stability of the steroid, plastic is preferred, and a container made of polyolefin resin is more preferred.

[0028] <Polyolefin resin container> In the present invention, the term "container" refers to a package that directly contains a liquid or semi-solid composition. The shape of the container is not particularly limited as long as it can contain a liquid or semi-solid composition, and may be determined appropriately depending on the properties, dosage form, administration route, and intended use 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.

[0029] In the present invention, the container is selected from the following (1) or (2) from the viewpoint of convenience in handling and use of the pharmaceutical preparation: (1) A container that includes a container body and an application member, such as a bottle container with 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.

[0030] [(1) A container comprising a container body and an application member, the application member being impregnated with a composition contained in the container body when in use] In the case of a container of this type, the composition contained in the container body can be applied by impregnating and retaining the composition in the application member and bringing the application member into contact with the area to be applied. 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 that can be impregnated with and retain the liquid or semi-solid composition, and examples thereof include porous members such as sponges and brush-like members.

[0031] An example of such a container is a container that has an application member at the opening 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.) application member attached to the mouth. In this case, the composition contained in the container body is impregnated into and retained in the porous application member, the pore size, porosity, etc. of which have been appropriately adjusted, and then the application member is brought into contact with the application target, thereby applying the composition to the application target. Another specific example is a container comprising a container body having a mouth and a brush-like applicator attached to the mouth. In this case, the composition contained in the container body is impregnated and held in a brush whose bristles have been appropriately adjusted in length, spacing, etc., and then the applicator is brought into contact with the area to be applied, thereby applying the composition to the area to be applied.

[0032] The container of this embodiment is used by impregnating and retaining the composition in the application member, and therefore has the following advantages: for example, when the composition is an external application agent, the problem of dripping at the application site is unlikely to occur; the application member is used by directly contacting the application site, so the fingers do not get dirty; and the area to which the composition is applied can be easily and flexibly adjusted by adjusting the shape, size, etc. of the application member. In the case of a container of this embodiment, it is particularly preferable that both the container body and the application member are made of a polyolefin-based resin. Such a container can be particularly suitably used when the composition to be contained is, for example, a liquid composition or a low-viscosity semi-solid composition.

[0033] Containers of this type are known and are disclosed, for example, in Japanese Patent No. 5570089. In the present invention, commercially available products may be used as containers of this type, and examples of such commercially available products include containers that use MAPS (INOAC CORPORATION), an open-pore material made of low-density polyethylene, as an application member.

[0034] [(2) A container having a flexible container body and a discharge outlet] In the case of a container of this type, pressure is applied to the inside of the container, for example by pressing the flexible container body, and the composition contained inside the container is discharged from the discharge outlet, thereby allowing the composition to be applied to the area to be coated. Note that in a container of this type, the discharge outlet does not need to be provided in advance on the container, and the container may be configured so that the discharge outlet is provided by perforating the container before use, and such a container is also included in the category of "a container comprising a flexible container body and a discharge outlet."

[0035] A container of this type 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 to be contained is, for example, a semi-solid composition with high viscosity.

[0036] Containers of this type are known and are disclosed, for example, in Japanese Patent Nos. 5302550 and 5525135. In the present invention, commercially available products may also be used as containers of this type.

[0037] In the present invention, the "polyolefin resin" is not particularly limited, and may be a polymer (homopolymer) of a single type of monomer, or a copolymer (copolymer) of multiple types of monomers. In addition, in the case of a copolymer, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited. Specific examples of such polyolefin resins include polyethylene (more specifically, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, etc.), polypropylene, cyclic polyolefin, poly(4-methylpentene), polytetrafluoroethylene, ethylene-propylene copolymer, ethylene-α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, etc. In the present invention, these may be used alone or in combination of two or more. In the present invention, the polyolefin resin is preferably polyethylene, polypropylene or a cyclic polyolefin, with polyethylene and polypropylene being particularly preferred, from the viewpoint of improving the stability of the steroid. In the present invention, "made of polyolefin-based resin" means that at least a part of the material contains polyolefin-based resin, and for example, a mixture of two or more resins, i.e., polyolefin-based resin and other resins (polymer alloy), is also included in "made of polyolefin-based resin".

[0038] In the present invention, a "polyolefin resin container" refers to a "container" in which at least a portion of the portion that comes into contact with the liquid or semi-solid composition contained therein (preferably 10% or more of the portion that comes into contact with the composition during normal storage, more preferably 30% or more of the portion that comes into contact with the composition during normal storage, and particularly preferably the entire portion that comes into contact with the composition during normal storage) is "made of a polyolefin resin." Therefore, for example, a container in which a polyolefin resin layer is provided in at least a portion of the layer that comes into contact with the liquid or semi-solid composition (the innermost layer of the container), and another resin or material such as aluminum foil is laminated on the outside of the layer also falls under the category of a "polyolefin resin container." Specific examples of such containers made by laminating multiple types of materials include containers made of laminated film, in which a layer made of polyolefin resin is used as the innermost layer, aluminum foil is laminated on the outside of that, either directly or via another layer, and other layers are further laminated on the outside of that as needed.

[0039] In the present invention, the means for storing the liquid or semi-solid composition in a container is not particularly limited, and the container may be filled or otherwise processed in a conventional manner depending on the shape of the container, the properties of the composition, etc., thereby producing the container-packed composition of the present invention.

[0040] The liquid or semi-solid composition and containerized composition of the present invention contain a steroid, and therefore can be used as a pharmaceutical or quasi-drug, and can be suitably used, for example, as an antipruritic and anti-inflammatory drug, more specifically, as an antipruritic and anti-inflammatory drug having efficacy or effects of one or more selected from eczema, dermatitis, sores, heat rash, rash, itching, chilblains, insect bites, and hives.

[0041] The present invention relates to a method for producing a composition comprising the following component (A): (A) steroids; A liquid or semi-solid composition containing the following component (B): (B) Salicylic acids; In this case, the method for stabilizing a steroid further preferably includes the step of placing the liquid or semi-solid composition in a container (preferably a container made of a polyolefin resin). In the invention of this aspect, the order of the step of blending component (A), the step of blending component (B), and the step of placing the composition in a container is not particularly limited, as long as a liquid or semi-solid composition containing components (A) and (B) or a state in which such a composition is placed in a container 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" and the "container-packaged composition."

[0042] This specification discloses the invention exemplified below in relation to the above embodiments, but is not limited to these in any way. [1] The following components (A) and (B): (A) steroids; (B) Salicylic acids; A liquid or semi-solid composition comprising: [2] The composition according to [1], wherein component (A) is one or more members selected from the group consisting of cortisone, dexamethasone, hydrocortisone, prednisolone, and esters of these with saturated fatty acids having 1 to 6 carbon atoms. [3] The composition according to [1], wherein component (A) is one or more selected from the group consisting of cortisone acetate, dexamethasone, dexamethasone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate, and prednisolone valerate acetate. [4] The composition according to any one of [1] to [3], wherein component (B) is one or more members selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate, and methyl salicylate. [5] The composition according to any one of [1] to [4], further comprising water. [6] The composition according to any one of [1] to [5], wherein the dosage form is selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel. [7] The composition according to any one of [1] to [6], which is an antipruritic and anti-inflammatory drug.

[0043] [8] A container-packaged composition, comprising the composition according to any one of [1] to [7] contained in a container. [9] The container-packaged composition according to [8], wherein the container is made of a polyolefin resin.

[10] The container-packed composition according to [9], wherein the polyolefin resin is at least one selected from the group consisting of polyethylene and polypropylene.

[11] The container is one of the following: (1) A container that includes a container body and an application member, such as a bottle container with 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; The container-packed composition according to any one of [8] to

[10] , wherein

[0044]

[12] The following component (A): (A) steroids; A liquid or semi-solid composition containing the following component (B): (B) Salicylic acids; A method for stabilizing a steroid, comprising the step of incorporating

[13] The method according to

[12] , wherein component (A) is one or more members selected from the group consisting of cortisone, dexamethasone, hydrocortisone, prednisolone, and esters of these with saturated fatty acids having 1 to 6 carbon atoms.

[14] The method according to

[12] , wherein component (A) is one or more selected from the group consisting of cortisone acetate, dexamethasone, dexamethasone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate, and prednisolone valerate acetate.

[15] The method according to any one of

[12] to

[14] , wherein the component (B) is one or more selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate, and methyl salicylate.

[16] The method according to any one of

[12] to

[15] , wherein the composition further contains water.

[17] The method according to any one of

[12] to

[16] , wherein the composition is in a dosage form selected from the group consisting of an external solution, a spray, an ointment, a cream, and a gel.

[18] The method according to any one of

[12] to

[17] , wherein the composition is an antipruritic and anti-inflammatory drug.

[0045]

[19] A method for stabilizing a steroid according to any one of

[12] to

[18] , further comprising the step of placing the liquid or semi-solid composition in a container.

[20] The method according to

[19] , wherein the container is made of a polyolefin resin.

[21] The method according to

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

[22] The container is (1) or (2) of the following: (1) A container that includes a container body and an application member, such as a bottle container with 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; The method according to any one of

[19] to

[21] , wherein [Example]

[0046] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0047] [Test Example 1] Preservation test Part 1 A liquid composition containing the components and amounts (g) shown in Table 1 below per 100 mL was prepared by a conventional method and placed in a glass bottle (2K standard bottle). The obtained samples were stored in the dark at 60°C for 1 week. The dexamethasone acetate content in the samples before and after storage was quantified by the internal standard method using liquid chromatography (HPLC). The residual dexamethasone acetate content after 1 week of storage at 60°C was calculated from the dexamethasone acetate content in each sample before and after storage according to the following formula: The results are shown in Table 1.

[0048] [Number 1] Residual rate of dexamethasone acetate (%) = content of dexamethasone acetate after storage / content of dexamethasone acetate before storage × 100

[0049] [Table 1]

[0050] The results shown in Table 1 reveal that by adding glycol salicylate to the liquid composition (Samples 2 and 3), the residual rate of dexamethasone acetate after storage at 60°C for 1 week is significantly improved compared to Sample 1, which does not contain glycol salicylate. From the above test results, it was revealed that the stability of steroids can be improved by further adding salicylic acids, such as glycol salicylate, to liquid or semi-solid compositions containing steroids, such as dexamethasone acetate.

[0051] [Test Example 2] Preservation test Part 2 A liquid composition identical to Sample 2 in Test Example 1 (a liquid composition containing 0.025 g of dexamethasone acetate and 1.0 g of glycol salicylate per 100 mL) was prepared by a conventional method and placed in a glass bottle (a 2K standard bottle), a polyethylene container (the same container as Lidomex Kowa Lotion 0.3% (manufactured by Kowa Co., Ltd.) was used), or a polypropylene container (the same container as Unakowa Cool α (manufactured by Kowa Co., Ltd.) was used). The obtained samples were stored in a dark place at 60°C for 1 week, and the remaining percentage of dexamethasone acetate after storage at 60°C for 1 week was calculated in the same manner as in Test Example 1. The results are shown in Table 2.

[0052] [Table 2]

[0053] As shown in the results in Table 2, when the liquid composition containing dexamethasone acetate and glycol salicylate was placed in a polyethylene container or a polypropylene container, the residual rate of dexamethasone acetate after storage at 60°C for 1 week was improved compared to when the composition was placed in a glass bottle. In this way, by storing a liquid or semi-solid composition containing a steroid, such as dexamethasone acetate, and a salicylic acid, such as glycol salicylate, in a container made of a polyolefin resin, such as polyethylene or polypropylene, the stability of the steroid can be further improved.

[0054] Production Example 1 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 1-1 and 1-2, respectively. Diphenhydramine hydrochloride 2.0g Glycol salicylate 2.0g Glycyrrhetinic acid 0.2g dl-Camphor 6.0g l-menthol 2.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0055] Production Example 2 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 2-1 and 2-2, respectively. Dexamethasone acetate 0.025g Glycol salicylate 2.0g Glycyrrhetinic acid 0.2g dl-Camphor 6.0g l-menthol 2.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0056] Production Example 3 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 3-1 and 3-2, respectively. Diphenhydramine hydrochloride 2.0g Glycol salicylate 1.0g Lidocaine 0.5g dl-Camphor 2.0g l-menthol 3.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0057] Production Example 4 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Example 4-1 or 4-2, respectively. Diphenhydramine hydrochloride 2.0g Methyl salicylate 2.5g Lidocaine 1.0g dl-Camphor 7.0g l-menthol 1.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0058] Production Example 5 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or a container (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 5-1 and 5-2, respectively. Dexamethasone acetate 0.025g Diphenhydramine hydrochloride 2.0g Methyl salicylate 2.5g Lidocaine 1.0g dl-Camphor 7.0g l-menthol 1.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0059] Production Example 6 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Example 6-1 or 6-2, respectively. Dexamethasone acetate 0.025g Diphenhydramine hydrochloride 2.0g Glycol salicylate 1.0g Lidocaine 0.5g dl-Camphor 2.0g l-menthol 3.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0060] Production Example 7 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Example 7-1 or 7-2, respectively. Diphenhydramine hydrochloride 2.0g Isopropylmethylphenol 0.1g Lidocaine 2.0g dl-Camphor 4.0g l-menthol 4.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0061] Production Example 8 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Example 8-1 or 8-2, respectively. Dexamethasone acetate 0.025g Diphenhydramine hydrochloride 2.0g Isopropylmethylphenol 0.1g Lidocaine 2.0g dl-Camphor 4.0g l-menthol 4.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0062] Production Example 9 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 9-1 and 9-2, respectively. Prednisolone valerate acetate 0.15g Diphenhydramine hydrochloride 2.0g Glycol salicylate 0.5g Crotamiton 2.0g Lidocaine 0.5g l-menthol 5.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0063] Production Example 10 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 10-1 and 10-2, respectively. Hydrocortisone 0.5g Glycol salicylate 0.5g Crotamiton 2.0g Lidocaine 0.5g l-menthol 5.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0064] Production Example 11 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 11-1 and 11-2, respectively. Prednisolone valerate acetate 0.15g Methyl salicylate 5.0g Lidocaine 1.0g dl-Camphor 7.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0065] Production Example 12 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 12-1 and 12-2, respectively. Hydrocortisone 0.5g Diphenhydramine hydrochloride 2.0g Methyl salicylate 5.0g Lidocaine 1.0g dl-Camphor 7.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0066] Production Example 13 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 13-1 and 13-2, respectively. Prednisolone valerate acetate 0.15g Diphenhydramine hydrochloride 2.0g Glycol salicylate 1.5g Lidocaine 1.5g dl-Camphor 2.0g Citric acid hydrate, ethanol and purified water (appropriate amount)

[0067] Production Example 14 (Lotion) A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in container 1 (cap: polypropylene, inner stopper: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner stopper: polyethylene and polypropylene, bottle: polypropylene) to obtain lotions of Preparation Examples 14-1 and 14-2, respectively. Hydrocortisone 0.5g Methyl salicylate 1.0g dl-Camphor 1.0g l-menthol 5.0g Citric acid hydrate, ethanol and purified water (appropriate amount) [Industrial Applicability]

[0068] According to the present invention, the stability of a steroid in a liquid or semi-solid composition can be improved, and therefore, a steroid-containing drug or the like having excellent storage stability can be provided, which can be suitably used in the pharmaceutical industry or the like.

Claims

1. The following components (A) and (B): (A) dexamethasone acetate; (B) glycol salicylate; and a liquid or semi-solid composition containing 10 to 85 parts by mass of glycol salicylate per 1 part by mass of dexamethasone acetate, the liquid or semi-solid composition being contained in a polyolefin resin container (excluding the case where the container is a non-aerosol foamer container).

2. A containerized composition as described in claim 1, wherein the content ratio of glycol salicylate to 1 part by mass of dexamethasone acetate is 35 to 85 parts by mass.

3. 3. The containerized composition according to claim 1, which is in a dosage form selected from the group consisting of external liquids, sprays, ointments, creams and gels.

4. The following component (A): (A) dexamethasone acetate; A liquid or semi-solid composition containing the following component (B): (B) glycol salicylate; so that the content ratio of glycol salicylate per 1 part by mass of dexamethasone acetate is 10 to 85 parts by mass; and placing the liquid or semi-solid composition in a polyolefin resin container (excluding cases where the container is a non-aerosol foam container).

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