JP2022069434A - Composition - Google Patents

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

The present invention relates to compositions and the like.

Conventionally, compounds having a steroid skeleton have been widely used as active ingredients of pharmaceutical products. For example, for the treatment of inflammatory skin diseases such as inflammation and dermatitis associated with insect bites, a drug containing a corticosteroid having an anti-inflammatory effect is used. Examples of the corticosteroid used in such a drug include dexamethasone and prednisolone. Further, as a drug containing a steroid, for example, a skin external preparation containing a combination of prednisolone valerate acetate and an antihistamine (Patent Document 1) is known. However, the steroid-containing drugs conventionally provided have not always been sufficiently stable.

Therefore, as a technique for improving the stability in the preparation of steroids, for example, a skin external preparation containing steroid, glycerin and polar oil (Patent Document 2), 0.005 to 0.05% by weight of steroid as an active ingredient, It is a poultice containing 15% by weight or less of crotamiton and a surfactant as a stabilizer in the base, and the amount of crotamiton is 200 to 3000 times by weight of the amount of steroid, and the surface active agent. Contains a steroid-containing poultice (Patent Document 3), a steroid-based anti-inflammatory agent, and an amount of acrylic acid polymer effective for stabilizing the steroid-containing poultice, which is 1/20 to 1/5 times by weight of the amount of crotamitone. An anhydrous composition for external use (Patent Document 4), an external preparation containing a benzoate ester-based local anesthetic and an oxycarboxylic acid together with a steroid (Patent Document 5) have been proposed.

JP-A-2002-356430. Japanese Unexamined Patent Publication No. 2001-247436 Japanese Unexamined Patent Publication No. 2000-26299 Japanese Unexamined Patent Publication No. 2001-233772 International Publication No. 2007/7923 Pamphlet

An object of the present invention is to provide a new means for improving the stability of steroids.

Therefore, as a result of diligent studies to solve the above problems, the present inventor has found that the stability of steroids can be improved by further incorporating salicylic acids typified by glycol salicylate into the composition containing steroids. The present invention has been completed.

That is, in the present invention, the following components (A) and (B):
(A) Steroids;
(B) Salicylic acids;
To provide a liquid or semi-solid composition containing.
Further, in the present invention, the following components (A) and (B):
(A) Steroids;
(B) Salicylic acids;
It is intended to provide a composition in a container in which a liquid or semi-solid composition containing the above is contained in a container.

According to the present invention, the stability of steroids in liquid or semi-solid compositions can be improved.

<Ingredient (A)>
In the present invention, the "steroid" is not limited to the adrenocortical hormone and includes all compounds having a steroid skeleton, but the adrenocortical hormone is preferable. Examples of such steroids include cortisone, hydrocortisone, amcinonide, prednisolone, methylprednisolone, diflucortron, dexamethasone, betamethasone, diflorazone, diflupredone, triamcinolone, triamcinolone acetonide, halcinonide, flumethasone, butesonide, mometasone. Examples include, but are not limited to, metron, fludoxycortisone, alcromethasone, clobetasol, deprodone, betamethasone, clobetazone and their esters, ketals, acetals and hemiacetal derivatives, and salts thereof.
In the present invention, the steroid is selected from the group consisting of cortisone, dexamethasone, hydrocortisone and prednisolone and esters thereof (for example, esters with saturated fatty acids having 1 to 6 carbon atoms such as acetic acid ester, butyric acid ester and valeric acid ester). More than one selected from the group consisting of cortisone acetate, dexamethasone, dexamethasone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate and prednisolone valerate acetate. Preferably, one or more selected from the group consisting of dexamethasone, dexamethasone acetate, prednisolone, prednisolone acetate and prednisolone valerate acetate are more preferably, and more preferably one or more selected from the group consisting of dexamethasone and dexamethasone acetate. Preferred, dexamethasone acetate is particularly preferred.
All of these are known compounds and can be produced by known methods, or commercially available compounds can be used.

In the present invention, the content of the steroid in the liquid or semi-solid composition is not particularly limited, and may be appropriately examined and determined according to the desired pharmacological action and the like. 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 0.01 to 0. It is particularly preferable to contain 1% by mass.

<Ingredient (B)>
In the present invention, "salicylic acid" refers to salicylic acid and its derivatives (for example, esters of salicylic acid (specifically, for example, methyl salicylic acid, ethyl salicylate, glycol salicylate, etc.)) and salts thereof (for example, potassium salt, sodium). It means one or more kinds selected from alkali metal salts such as salts; ammonium salts and the like).
In the present invention, the salicylic acids are preferably one or more selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate and methyl salicylate, and are selected from the group consisting of glycol salicylate and methyl salicylate, from the viewpoint of improving the stability of steroids. One or more of them are more preferable, and glycol salicylate is particularly preferable.
All of these are known compounds and can be produced by known methods, or commercially available compounds can be used.

In the present invention, the content of salicylic acid in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of improving the stability of the steroid, salicylic acid is 0.0001 to 50 based on the total mass of the composition. It is preferably contained in an amount of 0.001 to 10% by mass, more preferably 0.01 to 5% by mass, and particularly preferably 0.1 to 2% by mass.

In the present invention, the content ratio of the steroid to the salicylic acid in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of improving the stability of the steroid, the steroid is 1 part by mass and the salicylic acid is 0. It is preferably contained in an amount of 1 to 1000 parts by mass, more preferably 1 to 500 parts by mass, further preferably 10 to 100 parts by mass, and particularly preferably 35 to 85 parts by mass.

<Liquid or semi-solid composition>
In the present invention, the "liquid or semi-solid composition" means a liquid or semi-solid composition 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 and the like. Further, the type and properties of the solvent or the base are not particularly limited, and the solvent or the base may be hydrophilic or hydrophobic such as oily, and a plurality of different kinds of solvents and bases may be appropriately mixed and emulsified. May be used. Specific examples of such a solvent / base include components exemplified as additives described later.

In the present invention, it is preferable that the liquid or semi-solid composition contains water from the viewpoint of safety during use and usability. Steroids, particularly steroids having an ester bond in the molecule, are susceptible to decomposition reactions in liquid or semi-solid compositions containing water and are unstable. If good stability is obtained.
Here, the content of water in the composition is not particularly limited, but is preferably 1% by mass or more with respect to the total mass of the composition from the viewpoint of improving safety during use and stability of steroids. It is more preferably 5% by mass or more, further preferably 10 to 90% by mass, further preferably 20 to 80% by mass, further preferably 30 to 70% by mass, and 40. It is particularly preferable that it is ~ 65% by mass.

Further, in the present invention, from the viewpoint of usability, it is preferable that the liquid or semi-solid composition contains a lower alcohol. Here, the "lower alcohol" means a linear or branched monohydric alcohol having 1 to 6 carbon atoms, and specific examples thereof include ethanol, isopropanol, n-propanol and the like. One of them may be used alone or in combination of two or more. Among these, ethanol, isopropanol and a mixture thereof are preferable.
The content of the lower alcohol in the composition is not particularly limited, but from the viewpoint of usability, it is preferably 5% by mass or more, more preferably 10 to 80% by mass, and 15 by mass with respect to the total mass of the composition. It is more preferably to 75% by mass, further preferably 20 to 70% by mass, further preferably 25 to 60% by mass, and particularly preferably 30 to 50% by mass.

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

In the present invention, the liquid or semi-solid composition may contain a drug other than the above as a pharmaceutical ingredient. Examples of such drugs include antihistamines, crotamits, glycyrrhizic acids, allantoin, bactericides, astringent / protective agents, local anesthetics, terpenes, essential oils containing terpenes, aqueous ammonia, vitamin Es, and vitamin As. One kind or two or more kinds selected from the group consisting of the above can be mentioned.

Examples of the antihistamine include azelastin hydrochloride, alimemazine tartrate, isotipendyl hydrochloride, iproheptin hydrochloride, evastin, epinastine hydrochloride, emedastin fumarate, oxatomid, carbinoxamine diphenyldisulfonate, and carbinoxamine maleic acid. Salt, Cremastine Fumarate, d-Chlorpheniramine Maleate, dl-Chlorpheniramine Maleate, Ketotiphenfumarate, Diphenhydramine Hydrochloride, Diphenhydramine Phosphate, Diphenylpyraline Hydrochloride, Diphenylpyraline Theocle Acid, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetilysin hydrochloride, triprolysine hydrochloride, tryperenamine hydrochloride, tondylamine hydrochloride, fexophenazine, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate , Bepotastine besilate, homochlorcyclidine hydrochloride, mequitazine, metodilazine hydrochloride, mebuhydrolinnapadisylate and the like.
Examples of glycyrrhizic acids include glycyrrhizic acid and its derivatives, salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), glycyrrhetinic acid and the like.
Examples of the bactericidal agent include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, isobutyl paraoxybenzoate, benzyl paraoxybenzoate, sodium benzoate, benzoic acid, and benzoic acid. Examples thereof include benzyl acid acid, isopropylmethylphenol, benzalconium chloride, cetylpyridinium chloride, benzethonium chloride and the like.
Examples of the astringent / protective agent include calamine and zinc oxide.
Examples of the local anesthetic include ethyl aminobenzoate, oxypolyethoxydodecane, dibucaine, dibucaine hydrochloride, lidocaine, lidocaine hydrochloride and the like.
Examples of terpenes include isobornole, iron, ossimen, carbeol, carbotanaceton, carbomenthol, carboxylic, kalen, caron, camphene, camphor, geraniol, sabinen, safranal, cyclocitral, citral, citronellal, citronellic acid, citronell and cineol. , Simen, Sylvestren, Timor, Isotujor, Tujon, Terpineol, Terpinen, Terpineol, Tricyclen, Nerrol, Pinene, Pinocanfeol, Pinol, Piperitenon, Ferrandral, Ferrandren, Fenchen, Fentyl Alcohol, Perylyl Alcohol, Examples thereof include perylaldehyde, borneol, milsen, menthol, menthol, yonor, yonon, linalool, limonene and the like.
Essential oils containing terpenes include, for example, anis oil, ylang ylang oil, iris oil, uikyo oil, orange oil, cananga oil, chamomile oil, kayapto oil, caraway oil, kubeb oil, grapefruit oil, kehi oil, coriander oil, etc. Saffron oil, sansho oil, perilla oil, citriodora oil, citronella oil, ginger oil, ginger oil, ginger oil, spearmint oil, peppermint oil, geranium oil, daiwikyo oil, chow oil, television oil, tohi Oil, neroli oil, basil oil, peppermint oil, palmarosa oil, piment oil, petitgrain oil, bay oil, peniroyal oil, henoposi oil, bergamot oil, boadrose oil, peppermint oil, majoran oil, mandarin oil, melissa oil, eucalyptus oil, Examples thereof include lime oil, lavender oil, linaroe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil.
Examples of vitamin Es include tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinic acid ester and the like.
Examples of vitamin A include vitamin A oil, retinol palmitate, and the like.

Further, in the present invention, the liquid or semi-solid composition may contain additives used in the pharmaceutical field and the like depending on the dosage form, administration method and the like of the composition. Such additives include, for example, gelling agents, polyhydric alcohols, fats and oils, emulsifiers, solubilizers, pH regulators, antioxidants, softeners, thickeners, moisturizers, preservatives, stabilizers, etc. Examples include a transdermal absorption promoter, a flavoring agent, and a sweetening agent. It should be noted that one of these may be used alone or two or more thereof may be used in combination.

Examples of the gelling agent include acrylic acid-based polymers such as carboxyvinyl polymers; water-soluble or water-swellable cellulose-based polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, and ethyl cellulose; polyvinylpyrrolidone and the like. Can be mentioned.
Examples of the polyhydric alcohol include glycerin, ethylene glycol, propylene glycol, butylene glycol, macrogol, polypropylene glycol and the like.
Examples of fats and oils include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, and vaseline; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; behenyl alcohol, lauryl alcohol, and myristyl alcohol. Higher alcohols such as 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; Rows such as Mitsurou, Sarashi Mitsurou, Montan wax, lanolin, purified lanolin, reduced lanolin, etc .; silicone oil and the like can be mentioned.

Examples of the emulsifier include polyhydric alcohols such as propylene glycol mono fatty acid ester, ethylene glycol mono fatty acid ester, glycerin mono fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, methyl glucoside fatty acid ester, and alkyl polyglucoside. Fatty acid ester or polyhydric alcohol alkyl ether; polyoxyethylene ether such as polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene polyoxypropylene alkyl ether; polyoxy Ethylene mono fatty 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 In addition to nonionic surfactants such as castor oil, polyoxyethylene vegetable oil, and ether esters such as polyoxyethylene alkyl ether fatty acid esters, ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate can be mentioned.
Examples of the solubilizer include nonionic surfactants or ionic surfactants exemplified as the above emulsifiers, as well as liquid paraffin, crotamiton and the like.

Examples of the pH adjuster include citric acid, sodium citrate, anhydrous citric acid, malic acid, maleic acid, succinic acid, fumaric acid, tartrate acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, acetic acid, sodium acetate, and ice. Organic acids such as acetic acid or salts thereof; inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium hydrogen carbonate or the like; sodium hydroxide , Alkali hydroxides such as potassium hydroxide, calcium hydroxide, magnesium hydroxide; amines such as triethanolamine, diethanolamine, diisopropanolamine and the like.
Examples of the antioxidant include sodium sulfite, ascorbic acid, sodium hydrogen sulfite, sodium edetate, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol, tocopherol acetate, soybean lecithin, propyl gallate and the like.
Examples of the softening agent include allantin, almond oil, olive oil, glycerin, liquid paraffin, squalane, squalene, refined lanolin, medium chain fatty acid triglyceride, rapeseed oil, castor oil, propylene glycol, polybutene and the like.
Examples of the thickener include polyvinylpyrrolidone, carboxymethyl cellulose, colloidal aluminum silicate, xanthan gum, locust bean gum, tragant gum, guar gum, gelatin, arabic rubber, alginic acid, albumin and the like.
Examples of the moisturizer include sodium hyaluronate, glycerin, 1,3-butylene glycol, propylene glycol, urea, sucrose, erythritol, sorbitol and the like.
Examples of the stabilizer include adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hydrogenated oil, cysteine and the like.
Examples of the transdermal absorption promoter include fatty acid esters such as diisopropyl adipate.
Examples of the flavoring agent / sweetening agent include acesulfam potassium, stevia, somatin, sucralose, panose, trehalose, erythritol, lactitol, reduced palatinose, coupling sugar, fructose oligosaccharide, galactooligosaccharide, milk fruit oligosaccharide, isomaltooligosaccharide, and palatinose. Examples thereof include oligosaccharides, raffinose, aspartame, fructose, xylitol, brown sugar, saccharin or salts thereof, sorbitol, lactose, sucrose, honey, glucose, martitol, maltose, mannitol, water candy and the like.

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 the components to be blended, the properties of the composition, the dosage form, the administration route, the intended use, etc., for example, the seventeenth. It can be manufactured by the known method described in the revised Japanese Pharmacopoeia General Regulations for Formulation.

In the present invention, the method of administration / application of the liquid or semi-solid composition is not particularly limited, and examples thereof include oral; transdermal, transvaginal and the like parenteral. In the present invention, it is not due to the pharmacological action of steroids and the characteristics of liquid or semi-solid compositions (the point that it is possible to flexibly apply only a required amount according to the position, shape and range of the affected area). Oral is preferred, and transdermal administration is particularly preferred.

In the present invention, the dosage form of the liquid or semi-solid composition is not particularly limited as long as the composition is liquid or semi-solid, and depending on the purpose of use thereof, for example, the seventeenth. It can be appropriately selected from the dosage forms described in the revised Japanese Pharmacopoeia General Regulations for Formulations. Specific examples of such dosage forms include preparations applied to the skin and the like (external liquids, sprays, ointments, creams, gels, etc.) and orally administered preparations (oral liquids, syrups, oral jelly). Etc.) and so on.
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, and liniments, lotions and external applications. A dosage form selected from the group consisting of an aerosol agent, a pump spray agent, an ointment agent, a cream agent and a gel agent is more preferable, and a dosage form selected from the group consisting of a lotion agent, an ointment agent, a cream agent and a gel agent is further preferable. Lotions are particularly preferred.

Next, the composition in a container of the present invention will be described.
The composition in a container of the present invention comprises the liquid or semi-solid composition of the present invention contained in a container.
Examples of the material of the container include glass and plastic, but from the viewpoint of improving the stability of the steroid, plastic is preferable, and a polyolefin-based resin container is more preferable.

<Polyolefin resin container>
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 accommodate a liquid or semi-solid composition, and may be determined by appropriately considering the properties, dosage form, administration route, use, etc. of the composition. good.
Examples of the shape of such a container include a container for an aerosol agent, a container for a pump spray agent, and a bottle container (more specifically, for example, a bottle container provided with a sponge-like coating member (head), a roll-on container, and a jar bottle container. Etc.), tube containers, instillation containers, etc. All of these containers are known and may be manufactured by a known method, or commercially available products may be used.

In the present invention, the container is described in the following (1) or (2): from the viewpoint of handling of the pharmaceutical product and convenience at the time of use.
(1) A container having a container body and a coating member, such as a bottle container having a sponge-like coating member, and impregnating the coating 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 preferable, and the container of the aspect (1) is particularly preferable.

[(1) A container provided with a container body and a coating member, and used by impregnating the coating member with the composition contained in the container body]
In the case of a container of such an embodiment, the composition can be applied by impregnating and holding the composition contained in the container body in the coating member and bringing the coating member into contact with the portion to be coated. In this case, the container body and the coating member may be manufactured as independent members and then the coating member may be attached to the container body or integrally molded.
The coating member may have a structure capable of impregnating and holding a liquid or semi-solid composition, and examples thereof include a porous member such as a sponge and a brush-like member.

Examples of such a container include a container having a coating member at the mouth of the container body and impregnating the coating member with the composition contained in the container body.
More detailed specific examples include, for example, a container body having a mouth portion and a container provided with a porous (sponge-like or the like) coating member attached to the mouth portion. In this case, the composition contained in the container body is impregnated and held in a porous coating member whose pore size, porosity, etc. are appropriately adjusted, and then the coating member is brought into contact with the coated portion to form a composition. An object can be applied to the portion to be coated.
Further, as another specific example, for example, a container body having a mouth portion and a container provided with a brush-like coating member attached to the mouth portion and the like can be mentioned. In this case, the composition contained in the container body is impregnated and held in a brush whose hair length, spacing, etc. are appropriately adjusted, and then the coated member is brought into contact with the coated portion to obtain the composition. It can be applied to the part to be coated.

Since the container of such an embodiment is used by impregnating and holding the composition in the coating member, for example, when the composition is an external coating agent, the problem of liquid dripping does not easily occur in the coated portion, and the coating member is directly applied. There are merits such as that the fingers do not get dirty by using it in contact with the part to be coated, or that the area to which the composition is applied can be easily adjusted by adjusting the shape and size of the coating member. Have. In the case of the container of such an embodiment, it is particularly preferable that both the container body and the coating member are made of a polyolefin resin.
In addition, such a container can be particularly preferably adopted when the composition to be accommodated is, for example, a liquid composition or a low-viscosity semi-solid composition.

Containers of such an embodiment are known and are disclosed in, for example, Japanese Patent No. 5570809. Further, in the present invention, a commercially available product may be used as the container of such an embodiment, and such a commercially available product is, for example, MAPS Co., Ltd., which is a communication porous body made of low-density polyethylene as a coating member. Examples include containers using (corporation).

[(2) A container provided with a flexible container body and a discharge port]
In the case of a container of such an embodiment, pressure is applied to the inside of the container by pressing the flexible container body or the like, and the composition contained in the container is discharged from the discharge port, whereby the composition is applied to the portion to be coated. Can be applied to. In the container of such an embodiment, the discharge port may not be provided in advance in the container, and the container may be provided with a discharge port by drilling or the like before the start of use, and the container of such an embodiment also has "flexibility". It is included in "a container provided with a container body having a container and a discharge port".

Since the container of such an embodiment has a simple structure, the manufacturing cost is low, and the composition in the container is not contaminated because the composition is discharged from the discharge port by pressing the container body or the like. Has.
The container of such an embodiment can be particularly preferably adopted when the composition to be accommodated is, for example, a highly viscous semi-solid composition.

Containers of such an embodiment are known, and are disclosed in, for example, Japanese Patent No. 5302550, Japanese Patent No. 5525135, and the like. Further, in the present invention, a commercially available product may be used as the container of such an embodiment.

In the present invention, the "polyolefin-based resin" is not particularly limited, and may be a polymer of a single type of monomer (homopolymer) or a copolymer of a plurality of types of monomers (copolymer). Further, in the case of a copolymer, the polymerization mode is not particularly limited, and random polymerization or block polymerization may be used. Furthermore, its stereoregularity (tacticity) is not particularly limited.
Specific examples of such a polymer-based resin include polyethylene (more specifically, for example, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, etc.), polypropylene, and cyclic resin. Polyethylene, poly (4-methylpentene), polytetrafluoroethylene, ethylene / propylene copolymer, ethylene / α-olefin copolymer, ethylene / acrylic acid copolymer, ethylene / methacrylic acid copolymer, ethylene / acetic acid Examples thereof include vinyl copolymers, polyethylene / ethyl acrylate copolymers, and the like, and in the present invention, one or a combination of two or more of these can be used.
In the present invention, as the polyolefin-based resin, polyethylene, polypropylene, and cyclic polyolefin are preferable, and polyethylene and polypropylene are particularly preferable, from the viewpoint of improving the stability of steroids.
In the present invention, "made of a polyolefin-based resin" means that at least a part of the material contains a polyolefin-based resin, and for example, two or more kinds of resins of a polyolefin-based resin and another resin. The mixture (polymer alloy) of the above is also included in "made of polyolefin resin".

In the present invention, the "polyolefin-based resin container" refers to at least a part of the container in contact with the liquid or semi-solid composition contained therein (preferably, the composition during normal storage). 10% or more of the portion in contact with the composition, more preferably 30% or more of the portion in contact with the composition during normal storage, particularly preferably the entire portion in contact with the composition during normal storage) is "polyolefin-based". It means "container" which is "made of resin". Therefore, for example, a layer of a polyolefin-based resin is provided on at least a part of a layer (innermost layer of a container) in contact with a liquid or semi-solid composition, and a resin of another material, a material such as aluminum foil, or the like is laminated on the outside thereof. The container to be made is also a “polyolefin resin container”.
As a container in which a plurality of types of materials are laminated or the like, specifically, for example, a layer made of a polyolefin resin is used as the innermost layer, and an aluminum foil is directly outside the layer or via another layer. Examples thereof include a container made of a laminated film, which is formed by laminating the above-mentioned material and optionally laminating another layer on the outside thereof.

In the present invention, the means for accommodating the liquid or semi-solid composition in the container is not particularly limited, and the composition may be filled by a conventional method according to the shape of the container, the properties of the composition, and the like. Can produce the composition in a container of the present invention.

Since the liquid or semi-solid composition and the composition in a container of the present invention contain steroids, they can be used as pharmaceuticals or quasi-drugs, for example, as antipruritic and anti-inflammatory agents, more specifically, for example. , Eczema, dermatitis, soreness, rash, rash, itching, rash, insect bites and urticaria.

In the present invention, the following component (A):
(A) Steroids;
In the liquid or semi-solid composition containing the following component (B):
(B) Salicylic acids;
It also relates to a method for stabilizing a steroid, including a step of incorporating the steroid. In this case, a method for stabilizing a steroid, which further comprises a step of accommodating a liquid or semi-solid composition in a container (preferably a polyolefin-based resin container), is particularly preferable.
In the invention of such an embodiment, the order of the step of blending the component (A), the step of blending the component (B), and the step of accommodating the composition in the container is not particularly limited, and the components (A) and (B). A liquid or semi-solid composition containing the above, or a state in which the composition is contained in a container may be directly or indirectly produced.
In the invention of such an embodiment, the meanings of various words, the blending amount of each component, and the like are all the same as those described for "liquid or semi-solid composition" and "composition in a container".

The present specification discloses, for example, the inventions exemplified below in relation to the above embodiments, but is not limited thereto.
[1] The following components (A) and (B):
(A) Steroids;
(B) Salicylic acids;
A liquid or semi-solid composition containing.
[2] The composition according to [1], wherein the component (A) is one or more selected from the group consisting of cortisone, dexamethasone, hydrocortisone and prednisolone, and esters of these with saturated fatty acids having 1 to 6 carbon atoms.
[3] One or more of the components (A) selected from the group consisting of cortisone acetate, dexamethasone, dexamethasone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate and prednisolone valerate acetate. The composition according to [1].
[4] The composition according to any one of [1] to [3], wherein the component (B) is at least one 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 containing water.
[6] The composition according to any one of [1] to [5], wherein the dosage form is a dosage form selected from the group consisting of an external solution, 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.

[8] A composition in a container, wherein the composition according to any one of [1] to [7] is contained in a container.
[9] The composition in a container according to [8], wherein the container is a polyolefin-based resin container.
[10] The composition in a container according to [9], wherein the polyolefin-based resin is at least one selected from the group consisting of polyethylene and polypropylene.
[11] The container is the following (1) or (2):
(1) A container having a container body and a coating member, such as a bottle container having a sponge-like coating member, and impregnating the coating 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 composition in a container according to any one of [8] to [10].

[12] Next component (A):
(A) Steroids;
In the liquid or semi-solid composition containing the following component (B):
(B) Salicylic acids;
A method for stabilizing a steroid, which comprises a step of incorporating the steroid.
[13] The method according to [12], wherein the component (A) is one or more selected from the group consisting of cortisone, dexamethasone, hydrocortisone and prednisolone, and esters of these with saturated fatty acids having 1 to 6 carbon atoms.
[14] One or more of the components (A) selected from the group consisting of cortisone acetate, dexamethasone, dexamethasone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate and prednisolone valerate acetate. The method according to [12].
[15] The method according to any one of [12] to [14], wherein the component (B) is at least one 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 dosage form of the composition is 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 agent.

[19] The method according to any one of [12] to [18], further comprising a step of containing a liquid or semi-solid composition in a container, a method for stabilizing a steroid.
[20] The method according to [19], wherein the container is a polyolefin-based resin container.
[21] The method according to [20], wherein the polyolefin-based resin is at least one selected from the group consisting of polyethylene and polypropylene.
[22] The container is the following (1) or (2):
(1) A container having a container body and a coating member, such as a bottle container having a sponge-like coating member, and impregnating the coating 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].

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

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

[Number 1]
Residual rate of dexamethasone acetate (%) = Content of dexamethasone acetate after storage / Content of dexamethasone acetate before storage x 100

From the results shown in Table 1, 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 was compared with that of Sample 1 which did not contain it. Was found to be significantly improved.
Based on the above test results, the stability of steroids can be improved by further incorporating salicylic acids typified by glycol salicylate into a liquid or semi-solid composition containing steroids typified by dexamethasone acetate. It became clear that

[Test Example 2] Preservation test 2
The same liquid composition as Sample 2 of 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 this was prepared in a glass bottle (2K standard). Bottle), polyethylene container (use the same container as Lidomex Cowa Lotion 0.3% (manufactured by Kowa Co., Ltd.)) or polypropylene container (use the same container as Unakowa Cool α (manufactured by Kowa Co., Ltd.)) Contained in.
The obtained various samples were stored at 60 ° C. in a dark place for 1 week, and the residual ratio of dexamethasone acetate after storage at 60 ° C. for 1 week was calculated by the same method as in Test Example 1.
The results are shown in Table 2.

As shown in the results shown in Table 2, when the liquid composition containing the dexamethasone acetate and the glycol salicylate was housed in a polyethylene container or a polypropylene container, the temperature was 60 ° C. as compared with the case where the liquid composition was housed in a glass bottle. An improvement in the residual rate of dexamethasone acetate after storage for 1 week was observed.
As described above, a liquid or semi-solid composition containing steroids typified by dexamethasone acetate and salicylic acids typified by glycol salicylate is placed in a container made of a polyolefin resin typified by polyethylene or polypropylene. The stability of the steroid could be further improved by accommodating it in.

Production Example 1 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production Example 1-1 or 1-2, respectively.
Diphenhydramine Hydrochloride 2.0g
Glycol salicylate 2.0g
Glycyrrhetinic acid 0.2g
dl-camphor 6.0g
l-Menthol 2.0g
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 2 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production Example 2-1 or 2-2, respectively.
Dexamethasone acetate 0.025g
Glycol salicylate 2.0g
Glycyrrhetinic acid 0.2g
dl-camphor 6.0g
l-Menthol 2.0g
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 3 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production Example 3-1 or 3-2, respectively.
Diphenhydramine Hydrochloride 2.0g
Glycol salicylate 1.0g
Lidocaine 0.5g
dl-camphor 2.0g
l-Menthol 3.0g
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 4 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production 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
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 5 (lotion agent)
A liquid composition containing the following components and amounts in 100 mL is produced by a conventional method, and a container (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or a container (cap: polypropylene, inner plug: polyethylene and polypropylene) is produced. , Bottle: Polypropylene) to obtain the lotion agent of Production Example 5-1 or 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
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 6 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production 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
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 7 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production 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
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 8 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production 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
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 9 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production Example 9-1 or 9-2, respectively.
Prednisolone Valeric Acid Ester Acetate 0.15g
Diphenhydramine Hydrochloride 2.0g
Glycol salicylate 0.5g
Crotamiton 2.0g
Lidocaine 0.5g
l-Menthol 5.0g
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 10 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production Example 10-1 or 10-2, respectively.
Hydrocortisone 0.5g
Glycol salicylate 0.5g
Crotamiton 2.0g
Lidocaine 0.5g
l-Menthol 5.0g
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 11 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production Example 11-1 or 11-2, respectively.
Prednisolone Valeric Acid Ester Acetate 0.15g
Methyl salicylate 5.0g
Lidocaine 1.0g
dl-camphor 7.0g
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 12 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production Example 12-1 or 12-2, respectively.
Hydrocortisone 0.5g
Diphenhydramine Hydrochloride 2.0g
Methyl salicylate 5.0g
Lidocaine 1.0g
dl-camphor 7.0g
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 13 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production Example 13-1 or 13-2, respectively.
Prednisolone Valeric Acid Ester Acetate 0.15g
Diphenhydramine Hydrochloride 2.0g
Glycol salicylate 1.5g
Lidocaine 1.5g
dl-camphor 2.0g
Appropriate amount of citric acid hydrate, ethanol and purified water

Production Example 14 (lotion agent)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL is produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene) is produced. And polypropylene, bottle: polypropylene) to obtain the lotion agent of Production Example 14-1 or 14-2, respectively.
Hydrocortisone 0.5g
Methyl salicylate 1.0g
dl-camphor 1.0g
l-Menthol 5.0g
Appropriate amount of citric acid hydrate, ethanol and purified water

According to the present invention, the stability of steroids in liquid or semi-solid compositions can be improved. Therefore, it is possible to provide a drug containing a steroid having excellent storage stability, and it can be suitably used in the pharmaceutical industry and the like.

Claims (8)

The following components (A) and (B):
(A) Steroids;
(B) Salicylic acids;
A liquid or semi-solid composition containing. The composition according to claim 1, wherein the component (A) is at least one selected from the group consisting of cortisone, dexamethasone, hydrocortisone and prednisolone, and esters thereof. The composition according to claim 1 or 2, wherein the component (A) is at least one selected from the group consisting of dexamethasone and an ester thereof. The composition according to any one of claims 1 to 3, wherein the component (B) is at least one selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate and methyl salicylate. The composition according to any one of claims 1 to 4, wherein the component (B) is glycol salicylate. The composition according to any one of claims 1 to 5, which is a dosage form selected from the group consisting of an external liquid agent, a spray agent, an ointment agent, a cream agent and a gel agent. A composition in a container, wherein the composition according to any one of claims 1 to 6 is contained in a polyolefin-based resin container. Next component (A):
(A) Steroids;
In the liquid or semi-solid composition containing the following component (B):
(B) Salicylic acids;
A method for stabilizing a steroid, which comprises a step of incorporating the steroid.