JP2023111894A - Packaged composition - Google Patents

Abstract

To provide a pharmaceutical composition that comprises a betamethasone ester and suppresses a change of smell during high-temperature storage.SOLUTION: A packaged composition comprises a pharmaceutical composition comprising following components (A) and (B): (A) a betamethasone ester; and (B) a terpene, the pharmaceutical composition being included in an airtight package.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a package stuffing composition and the like.

Since steroids exhibit a wide range of physiological activities even in very small amounts, they have been widely used as therapeutic agents for various diseases. For example, corticosteroids, which are a type of steroid, have excellent anti-inflammatory effects and are therefore used as active ingredients in therapeutic drugs for inflammatory diseases. Various compounds have been provided as adrenocortical steroids. Betamethasone (9-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione), one of them, has a long blood half-life and a Since it also binds strongly, it is widely used as an active ingredient in therapeutic agents for inflammatory diseases (Non-Patent Document 1).

Also, corticosteroids have been chemically modified in various ways for the purpose of improving their physiological activity. Among them, corticosteroids (esterified steroids) modified by esterification such as fatty acid esters are effective as topical preparations for the treatment of inflammatory skin diseases such as atopic dermatitis because of their high affinity for the skin. suitable for use as a component. As for betamethasone, various esterified modifications (betamethasone esters) such as betamethasone valerate, betamethasone butyrate propionate, and betamethasone dipropionate have been developed and marketed.

It has been pointed out that esterified steroids are generally easily decomposed in formulations (Patent Documents 1 and 2). However, betamethasone valerate, which is a betamethasone ester, is stable with no color change even when stored for 4 weeks at 40°C and 75% RH, and suppresses the coloring of other ingredients such as isopropylmethylphenol. It has been reported that it has an effect to

JP-A-2005-343890 JP-A-2005-343891 International publication 2021/187592 pamphlet

Today's therapeutic drug 2004 edition, Nankodo Co., Ltd., pp. 197-198

Therefore, it is believed that the use of betamethasone esters will enable the development of a pharmaceutical composition that is useful as an external preparation for treating inflammatory skin diseases, etc., and that has excellent storage stability.
Therefore, in view of the above situation, the present inventors investigated the storage stability of betamethasone ester itself in order to develop a pharmaceutical composition containing betamethasone ester. It was found that the odor changed and a sweat-like irritating odor was produced. Especially after the pharmaceutical composition has been delivered to the patient, it may be stored under particularly high temperature conditions. Developing a technology that suppresses changes in the
An object of the present invention is to provide a pharmaceutical composition containing a betamethasone ester, in which the change in odor during high-temperature storage is suppressed.

Therefore, as a result of intensive studies to solve the above problems, the present inventors combined betamethasone ester with terpenes typified by camphor and menthol to form a pharmaceutical composition, which is packaged in an airtight package typified by a bottle. Surprisingly, the inventors found that the change in odor during high-temperature storage is suppressed compared to the case where the terpenes are not contained or the case where the terpene is not contained in the airtight package, and the present invention was completed.

Thus, the present invention provides the following components (A) and (B):
(A) betamethasone ester;
(B) terpenes;
A pharmaceutical composition containing is contained in an airtight package to provide a package-filled composition.

ADVANTAGE OF THE INVENTION According to this invention, the composition containing betamethasone ester which the change of the smell at the time of high temperature storage was suppressed can be provided.

<Component (A)>
As used herein, "betamethasone ester" (hereinafter sometimes referred to as "component (A)" in this specification) refers to an ester derivative of betamethasone (e.g., acetate, pivalate, propionate, butyric acid Carboxylic acid esters such as esters and valerates; It means one or more selected from the group. Examples of betamethasone ester include, for example, betamethasone valerate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone sodium phosphate, and the like listed in the 18th revision of the Japanese Pharmacopoeia. be done.
Among the above betamethasone esters, one or more selected from the group consisting of betamethasone valerate, betamethasone dipropionate, and betamethasone butyrate propionate is preferable from the viewpoint of suppressing odor change, and betamethasone valerate is particularly preferred. preferable.

The content of component (A) in the pharmaceutical composition is not particularly limited, and may be determined by appropriate consideration, but the total content is preferably 0.01 to 60% by mass with respect to the total mass of the pharmaceutical composition. , more preferably 0.05 to 55% by mass, and particularly preferably 0.1 to 50% by mass.

<Component (B)>
As used herein, "terpenes" (hereinafter sometimes referred to as "component (B)" in this specification) include terpene hydrocarbons, terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpenes It means a generic term (terpenoid) including lactones and the like. The structure of terpenes is not particularly limited, and examples thereof include monoterpene, sesquiterpene, derivatives thereof, and the like.
Moreover, the terpenes may be cyclic or chain, and may be saturated or unsaturated terpenes.

Specific examples of such terpenes include isopropylmethylphenol, isoborneol, iron, ocimene, carveol, carbotanacetone, carbomentone, carvone, carene, caron, camphene, camphor, geraniol, sabinene, safranal, and cyclocitral. , citral, citronellal, citronellic acid, citronellol, cineol, cymene, sylvestrene, thymol, isotjol, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocanepheol, pinol, piperitenone, ferrandral, phellandrene, Fenchen, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, yonol, yonone, linalool, limonene and the like can be mentioned, and these can be used alone or in combination of two or more. In addition, when optical isomers exist in these terpenes, all isomers are included unless otherwise specified. That is, in the present specification, unless a specific optical isomer is specified as a component name of terpenes, such component description includes all of various optical isomers alone and mixtures thereof in any ratio, and a single It may be an optical isomer or a mixture of various optical isomers at any ratio (for example, the term “menthol” includes both dl-menthol and l-menthol. ).

Among the above terpenes, from the viewpoint of suppressing odor change, cyclic terpenoids are preferable, cyclic monoterpenoids are more preferable, monocyclic or bicyclic monoterpenoids are more preferable, and a p-menthane skeleton is used. monoterpenoids (e.g., unsaturated derivatives of p-menthane such as cymene, thymol, terpinene, terpinolene, phellandrene, and limonene; carveol, terpineol, monoterpene alcohols having a p-menthane skeleton such as menthol; carvone, menthone, etc.) , monoterpene ketones having a p-menthane skeleton; monoterpene aldehydes having a p-menthane skeleton such as perillaldehyde; monoterpene ethers having a p-menthane skeleton such as cineole), isomers of p-menthane Monoterpenoids having a skeleton (e.g., unsaturated derivatives of isomers of p-menthane such as 3-methyl-4-isopropylphenol (isopropylmethylphenol)) or monoterpenoids having a bornane skeleton (e.g., bornane such as borneol monoterpene alcohols having a skeleton; monoterpene ketones having a bornane skeleton such as camphor, etc.) are even more preferred, and one or more selected from the group consisting of thymol, menthol, isopropylmethylphenol, camphor and borneol are even more preferred, One or more selected from the group consisting of thymol, l-menthol, dl-menthol, isopropylmethylphenol, d-camphor, dl-camphor and d-borneol is even more preferred, l-menthol, dl-menthol, d-camphor and dl-camphor are particularly preferred.
When the terpenes are contained in the pharmaceutical composition, the terpenes may be used as they are, or an essential oil containing the terpenes (for example, peppermint oil, etc.) may be used.

The content of component (B) in the pharmaceutical composition is not particularly limited, and may be determined after appropriate consideration. The content is preferably 60% by mass, more preferably 0.1 to 55% by mass, and particularly preferably 1 to 50% by mass.

In addition, the content ratio of the component (A) and the component (B) contained in the pharmaceutical composition is not particularly limited, and may be determined after appropriate consideration. Component (B) is preferably contained in an amount of 1 to 5000 parts by mass, more preferably 1 to 1000 parts by mass, even more preferably 1 to 600 parts by mass, based on 1 part by mass in terms of solids. It is particularly preferable to contain up to 10 parts by mass.

The "pharmaceutical composition" can be produced, for example, by a known method described in the Japanese Pharmacopoeia 18th Edition, General Rules for Pharmaceutical Preparations, and the like.
Moreover, the dosage form is not particularly limited, and may be solid, semi-solid, or liquid, and can be in a form that is usually used according to the purpose of use. Dosage forms include, for example, oral preparations (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets), capsules, granules (including effervescent granules), powders , oral liquid preparations (including elixirs, suspensions, emulsions, and limonade preparations), syrups (including preparations for syrups), oral jelly preparations, oral film preparations (including orally disintegrating film preparations), etc.) , injections (including infusions, implanted injections, long-acting injections, and liposome injections), inhalants (including inhalation powders, inhalation solutions, and inhalation aerosols), preparations administered to the eye (eye drops) , ophthalmic ointment, etc.), ear drops, nasal drops (including nasal powders and nasal liquids), preparations applied to the rectum (suppositories, rectal semi-solids, enemas, etc.), vaginal Preparations to be applied (vaginal tablets, vaginal suppositories, etc.), preparations to be applied to the skin (external solid preparations (including external powders), external liquid preparations (including liniments and lotions), sprays (external aerosol preparations) , including pump sprays), ointments, creams, gels, patches (including tapes and poultices)), and the like.
Among these, semi-solid or liquid preparations are preferred, and dosage forms selected from external liquids, ointments, creams and gels, patches (including tapes and poultices) are preferred. More preferred are dosage forms selected from lotions, ointments, creams and gels.

The pharmaceutical composition of the present invention preferably further contains water from the viewpoint of safety during use of the drug. Here, the amount of water in the pharmaceutical composition is not particularly limited, but it is preferably 1% by mass or more relative to the total mass of the pharmaceutical composition from the viewpoint of safety during use of the drug and odor change suppressing action. , more preferably 5% by mass or more, more preferably 20 to 80% by mass, and particularly preferably 30 to 60% by mass.

In addition, the pharmaceutical composition of the present invention preferably contains a lower alcohol from the viewpoint of the feeling of use of the pharmaceutical composition. 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, etc. These It may be used alone or in combination of two or more. Among these, ethanol, isopropanol and mixtures thereof are preferred. Here, the content of the lower alcohol in the pharmaceutical composition is not particularly limited, but from the viewpoint of the feeling of use of the pharmaceutical composition and the effect of suppressing odor change, it is preferably 5% by mass or more based on the total mass of the pharmaceutical composition. It is preferably from 20 to 65% by mass, still more preferably from 30 to 60% by mass, and particularly preferably from 40 to 55% by mass.
The pharmaceutical composition of the present invention is preferably a liquid or semi-solid composition containing both water and a lower alcohol, from the viewpoints of safety and feel during use of the pharmaceutical composition.

The pharmaceutical composition may contain ingredients other than those described above as active ingredients. Such medicinal ingredients are not particularly limited, but for example, antihistamines, crotamiton, glycyrrhetinic acids, salicylic acids, allantoin, bactericides, antiseptics, astringents/protective agents, local anesthetics, aqueous ammonia, vitamin E, panthenol, Vitamin A, Rohto extract, vasoconstrictor, sulfa drug, antiphlogistic agent, crude drug, anti-tinea agent, keratolytic agent and the like.

Antihistamines include isothipendyl hydrochloride, chlorpheniramine, chlorpheniramine maleate, diphenylpyraline hydrochloride, diphenhydramine, diphenhydramine hydrochloride, diphenhydramine salicylate and the like.
Glycyrrhetinic acids include glycyrrhetinic acid and derivatives thereof (e.g., glycyrrhizic acid, sugar-added derivatives of glycyrrhetinic acid, etc.) and salts thereof (e.g., alkali metal salts such as potassium salts and sodium salts; ammonium salts, etc.). One or more selected from the group may be mentioned, and specific examples include glycyrrhizic acid, glycyrrhizic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate and the like.
Examples of salicylic acids include glycol salicylate and methyl salicylate.
Bactericides include benzalkonium chloride, benzethonium chloride, acrinol, alkylpolyaminoethylglycine, cetylpyridinium chloride, dequalinium chloride, dequalinium acetate, berberine chloride, berberine benzoate, chlorhexidine hydrochloride, chlorine Xidine gluconate solution, cetrimide, resorcinol, and the like.
Preservatives include benzoic acid, chlorobutanol, acetic acid, phenol, tincture of iodine, and the like.
Examples of astringent/protective agents include calamine, zinc oxide, chlorohydroxyaluminum, and the like.
Local anesthetics include ethyl aminobenzoate, oxypolyethoxide decane, dibucaine, dibucaine hydrochloride, procaine, procaine hydrochloride, mepivacaine, meprilcaine hydrochloride, lidocaine, lidocaine hydrochloride and the like.
Examples of vitamin E include tocopherol and tocopherol acetate.
Examples of vitamin A include vitamin A oil, retinol palmitate, liver oil, and strong liver oil.

Vasoconstrictors include epinephrine solution, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride and the like.
Sulfa drugs include sulfadiazine, sulfisomidine, sulfisomidine sodium, homosulfamine and the like.
Antiphlogistic agents include allantoin, aluminum chlorohydroxyallantoinate, aldioxa, ictamol, lysozyme chloride, dry aluminum potassium sulfate, dimethylisopropylazulene, egg yolk oil, aluminum potassium sulfate and the like.
Herbal medicines include lichen, horse chestnut seeds, hamamelis, processed daisan, and the like.
Anti-ringworm agents include undecylenic acid, zinc undecylenate, phenyl-11-iodo-10-undecinoate, exalamide, clotrimazole, econazole nitrate, miconazole nitrate, tioconazole, zinc diethyldithiocarbamate, ciclopirox olamine, siccanin, tricomycin, pyrrolnitrin, thianthol, 2,4,6-tribromophenylcaproic acid ester, trimethylcetylammonium pentachlorophenate, tolucyclate, tolnaftate, haloprozin, sulfur, bark of tree bark and the like.
Keratolytic agents include urea and diethyl phthalate.

Further, in the present invention, the pharmaceutical composition may contain, in addition to the above components, additives used in the fields of pharmaceuticals, cosmetics, etc. depending on the dosage form, administration method, etc. of the composition. Such additives include, for example, gelling agents, polyhydric alcohols, oils and fats, emulsifiers, solubilizers, pH adjusters, antioxidants, softeners, thickeners, moisturizers, preservatives, stabilizers, Percutaneous absorption enhancers, corrigents, sweeteners and the like can be mentioned.

Examples of gelling agents include acrylic acid-based polymers such as carboxyvinyl polymer; water-soluble or water-swellable cellulose-based polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose and ethyl cellulose; polyvinyl alcohol; Examples include polyvinylpyrrolidone.
Examples of polyhydric alcohols include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, macrogol, polypropylene glycol and the like.
Examples of fats and oils include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petrolatum; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; behenyl alcohol, lauryl alcohol, 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; Waxes such as beeswax, bleached beeswax, montan wax, lanolin, refined lanolin and reduced lanolin; and silicone oils.

Examples of emulsifiers include polyhydric alcohols 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, methylglucoside fatty acid esters, and alkyl polyglucosides. fatty acid ester or polyhydric alcohol alkyl ether; polyoxyethylene ether such as polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene polyoxypropylene alkyl ether; 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 Nonionic surfactants such as castor oil, polyoxyethylene vegetable oils, polyoxyethylene alkyl ether fatty acid esters, ether esters such as polyoxyethylene polyoxypropylene glycol, or ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate etc.
Examples of solubilizers include glycerin, liquid paraffin, crotamiton, macrogol, etc., in addition to the nonionic surfactants and ionic surfactants exemplified as emulsifiers above.

pH adjusters include, for example, 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, 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 salts thereof; sodium hydroxide , alkali hydroxides such as potassium hydroxide, calcium hydroxide and magnesium hydroxide; and amines such as triethanolamine, diethanolamine and diisopropanolamine.
Examples of antioxidants include sodium sulfite, ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol, tocopherol acetate, soybean lecithin, propyl gallate and the like.
Softening agents include, for example, allantoin, almond oil, olive oil, glycerin, liquid paraffin, squalane, squalene, refined lanolin, medium chain fatty acid triglycerides, rapeseed oil, castor oil, propylene glycol, polybutene and the like.
Thickeners include, for example, polyvinylpyrrolidone, carboxymethylcellulose, colloidal aluminum silicate, xanthan gum, locust bean gum, tragacanth gum, guar gum, gelatin, gum arabic, alginic acid, albumin and the like.
Moisturizers include sodium hyaluronate, glycerin, 1,3-butylene glycol, propylene glycol, urea, sucrose, erythritol, sorbitol and the like.
Examples of antiseptics include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, and benzoin. benzyl acid, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, aminoethylsulfonic acid and the like.
Stabilizers include, for example, adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hydrogenated oil, cysteine and the like.
Percutaneous absorption enhancers include, for example, fatty acid esters such as diisopropyl adipate.
Examples of corrigents/sweeteners include acesulfame potassium, stevia, thaumatin, sucralose, panose, trehalose, erythritol, lactitol, reduced palatinose, coupling sugar, fructo-oligosaccharide, galacto-oligosaccharide, milk oligosaccharide, isomalto-oligosaccharide, and palatinose. Oligosaccharide, raffinose, aspartame, fructose, xylitol, brown sugar, saccharin or its salt, sorbitol, lactose, sucrose, honey, glucose, maltitol, maltose, mannitol, starch syrup and the like.

The manufacturing method of the pharmaceutical composition is not particularly limited. It can be produced by the known method described.

The route of administration of the pharmaceutical composition is not particularly limited, and can be appropriately determined according to the disease to be applied, the type of formulation, the sex, age, symptoms, etc. of the recipient. is preferred. In addition, the pharmaceutical composition can be administered in about 1 to 4 divided doses per day before meals, between meals, after meals, before bedtime, and the like.

As used herein, “suppression” of change in odor (change in odor) means that after storing the packaging composition of the present invention under high-temperature conditions (for example, 80° C.) for a certain period of time, the change in odor from before storage is reduced. The degree is that the packaging composition excluding the component (B) from the packaging composition or the composition containing the components (A) and (B) but not housed in an airtight package is subjected to high temperature conditions ( For example, it means that the degree of odor change after storage at 80° C. for a certain period of time is smaller than that before storage. The degree of odor change can be evaluated, for example, by a panelist.

In the present invention, the pharmaceutical composition is housed in an airtight package (in the present specification, a pharmaceutical composition housed in an airtight package is referred to as a "packaged composition").
As specifically disclosed in Test Example 1 below, when a pharmaceutical composition containing betamethasone ester is stored at 80°C for 1 day, the odor changes. By housing in an airtight package, such a change in odor can be suppressed. In this case, in addition to the airtight package, the packaged composition may further include a package that does not correspond to the following "airtight package" (hereinafter also referred to as "other package"), The pharmaceutical composition may be contained directly or indirectly in an airtight package. Examples of modes in which the pharmaceutical composition is indirectly housed in an airtight package include a mode in which the pharmaceutical composition is housed in the above-mentioned "other package" and housed in the airtight package.

As used herein, the term "airtight packaging" refers to packaging that can prevent solid or liquid foreign matter from entering during normal handling, transportation, storage, etc. It is a concept that includes an “airtight container” and a “sealed container”. As the airtight package, both fixed and irregular shapes can be used, and specific examples include bottles, containers for aerosol agents, containers for pump spray agents, and bottle containers (more specifically, for example, sponge-like containers). bottles, roll-on containers, jar bottles, etc.), tube containers and the like. All of these containers are publicly known and may be manufactured by known methods, or commercially available products may be used.

The packaging material (material) of the airtight package is not particularly limited, and examples thereof include glass, plastic (polyester such as polyethylene terephthalate and polyethylene naphthalate; Polyolefins such as polypropylene; polycarbonate; polystyrene, etc.), metals (aluminum, etc.), materials used in the fields of pharmaceuticals and foods, etc., can be used singly or in combination of two or more. can.

The method of housing the pharmaceutical composition in an airtight package is not particularly limited, and can be achieved by arranging the composition in the package by an appropriate means such as putting the composition into the package.

The packaged composition of the present invention contains betamethasone ester, which is an adrenocortical steroid, in the pharmaceutical composition, and therefore is effective for inflammatory diseases and the like. Therefore, the packaged composition of the present invention can be used as, for example, an antipruritic antiphlogistic drug, an external hemorrhoid drug, and the like. Antipruritic and antiphlogistic drug for symptoms such as urticaria; External hemorrhoidal drug for relief and disinfection of pain, itching, swelling, bleeding and sores of hemorrhoids and hemorrhoids warts.

The present invention also provides the following component (A):
(A) betamethasone ester;
and the following component (B):
(B) terpenes;
It also relates to a method for suppressing change in odor of a composition, comprising the step of containing both in the same composition, and the step of housing the composition in an airtight package.
In the invention of this aspect, the order of the step of containing the component (A), the step of containing the component (B), and the step of housing the composition in an airtight package is not particularly limited. ) is contained in an airtight package directly or indirectly.
In this aspect of the invention, the meaning of various terms, the amount of each component, etc. are all the same as those described above for the "packaging composition".

Although the present specification is not limited to these, for example, the following aspects of the invention are disclosed.
[1A] The following components (A) and (B):
(A) betamethasone ester;
(B) terpenes;
A packaging-filled composition comprising a pharmaceutical composition containing
[2A] Component (A) is preferably one or more selected from the group consisting of betamethasone valerate, betamethasone dipropionate, betamethasone butyrate propionate, and betamethasone sodium phosphate, more preferably The packaging composition according to [1A], which is at least one selected from the group consisting of betamethasone valerate, betamethasone dipropionate and betamethasone butyrate propionate, more preferably betamethasone valerate.
[3A] Component (B) is preferably a cyclic terpenoid, more preferably a cyclic monoterpenoid, even more preferably a monocyclic or bicyclic monoterpenoid, still more preferably p - monoterpenoids having a menthane skeleton, monoterpenoids having an isomer of p-menthane as a skeleton, more preferably one or more selected from the group consisting of menthol, camphor and borneol, still more preferably l- The packaging composition according to [1A] or [2A], which is one or more selected from the group consisting of menthol, dl-menthol, d-camphor, dl-camphor and d-borneol.
[4A] Component (B) is preferably added in an amount of 1 to 5,000 parts by mass, more preferably 1 to 1,000 parts by mass, still more preferably 1 to 600 parts by mass, and still more preferably 1 part by mass of component (A) in terms of free form. The packaging composition according to any one of [1A] to [3A], containing 1 to 10 parts by mass.
[5A] Semi-solid or liquid formulations, preferably formulations selected from topical liquids, ointments, creams and gels, patches (including tapes and poultices), particularly preferably lotions and ointments The packaging composition according to any one of [1A] to [4A], which is in a dosage form selected from pharmaceutical agents, creams and gels.
[6A] The packaging composition according to any one of [1A] to [5A], which does not contain glycyrrhetinic acids, allantoin and isopropylmethylphenol.

[1B] The following component (A):
(A) betamethasone ester;
and the following component (B):
(B) terpenes;
A method for suppressing change in odor of a composition, comprising a step of containing in the same composition, and a step of housing the composition in an airtight package.
[2B] Component (A) is preferably one or more selected from the group consisting of betamethasone valerate, betamethasone dipropionate, betamethasone butyrate propionate, and betamethasone sodium phosphate, more preferably The method of [1B], which is at least one selected from the group consisting of betamethasone valerate, betamethasone dipropionate and betamethasone butyrate propionate, more preferably betamethasone valerate.
[3B] Component (B) is preferably a cyclic terpenoid, more preferably a cyclic monoterpenoid, even more preferably a monocyclic or bicyclic monoterpenoid, still more preferably p - monoterpenoids having a menthane skeleton, monoterpenoids having an isomer of p-menthane as a skeleton, more preferably one or more selected from the group consisting of menthol, camphor and borneol, still more preferably l- The method of [1B] or [2B], which is one or more selected from the group consisting of menthol, dl-menthol, d-camphor, dl-camphor and d-borneol.
[4B] Component (B) is preferably added in an amount of 1 to 5,000 parts by mass, more preferably 1 to 1,000 parts by mass, still more preferably 1 to 600 parts by mass, and still more preferably 1 part by mass of component (A) in terms of free form. is contained in 1 to 10 parts by mass, the method according to any one of [1B] to [3B].
[5B] The dosage form of the composition is selected from semi-solid or liquid preparations, preferably liquids for external use, ointments, creams and gels, patches (including tapes and poultices), The method according to any one of [1B] to [4B], which is particularly preferably a dosage form selected from lotions, ointments, creams and gels.
[6B] The method according to any one of [1B] to [5B], wherein the composition does not contain glycyrrhetinic acids, allantoin and isopropylmethylphenol.

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.

[Test Example 1] Stability test Each sample shown below was placed in a glass bottle (2K standard bottle). It was airtightly packed and stored at 80°C for 3 days.
One panelist confirmed the odor of samples 1 to 6 before the start of storage, after storage for 1 day, and after storage for 3 days. ), and the presence or absence of change in odor from before the start of storage was evaluated. In addition, when there was a change in odor from before the start of storage, the kind of change in odor was also evaluated.
Before the start of storage, no irritating odor or peculiar odor was detected in any of Samples 1 to 6.
Table 1 shows the results.

[Samples 1 and 2]
0.5 g of betamethasone valerate (BETAMETHASONE VALERATE: manufactured by HENAN LIHUA PHARMACEUTICAL CO., LTD.) was directly used as samples 1 and 2 (sample 1: no lid, sample 2: airtight packaging).

[Samples 3 and 4]
0.5 g of betamethasone valerate (BETAMETHASONE VALERATE: manufactured by HENAN LIHUA PHARMACEUTICAL CO., LTD.) and 0.5 g of dl-camphor (DL-camphor: manufactured by FUJIAN GREEN PINE CO., LTD.) were mixed to obtain The mixtures were designated as samples 3 and 4 (sample 3: no lid, sample 4: airtight packaging).

[Samples 5 and 6]
0.5 g of betamethasone valerate (BETAMETHASONE VALERATE: manufactured by HENAN LIHUA PHARMACEUTICAL CO., LTD.) and 0.5 g of l-menthol (L-menthol: manufactured by Takasago International Corporation) were mixed, and the resulting mixture was used as a sample. 5 and 6 (sample 5: no lid, sample 6: airtight packaging).

As shown in Table 1, betamethasone valerate itself was stored in a glass bottle with the lid open, and the odor changed after storage at 80°C for 1 day, and an irritating odor (sweaty odor) was observed. Also, in Sample 2, in which betamethasone valerate was placed in a glass bottle and capped, no irritating odor was observed after storage at 80°C for 1 day, but a peculiar odor (smoky odor) different from this was observed.
Sample 3, in which the mixture of betamethasone valerate and dl-camphor was stored in a glass bottle with the lid open, and Sample 5, in which the mixture of betamethasone valerate and l-menthol was stored in a glass bottle with the lid open, In both cases, after storage at 80°C for 3 days, the odor changed and a strong irritating odor (sweat-like odor) was observed. On the other hand, Sample 4, in which a mixture of betamethasone valerate and dl-camphor was placed in a glass bottle and capped, and Sample 6, in which a mixture of betamethasone valerate and l-menthol was placed in a glass bottle and capped, were used. , no change in odor was observed even after storage at 80°C for 3 days.
Although the present invention is not bound by the following conjecture, if an odor (irritating odor or peculiar odor) occurs in Samples 4 and 6 stored after the lid is closed and airtightly packaged, when the lid is opened A strong odor should be recognized. In spite of this, no change in odor was actually observed from Samples 4 and 6. From this, it was reasonably assumed that in Samples 4 and 6, the generation of irritating odor or peculiar odor itself was suppressed.

From the above test results, a pharmaceutical composition containing a betamethasone ester typified by betamethasone valerate and a terpene typified by dl-camphor and l-menthol was packaged in an airtight package typified by a bottle. It was clarified that the change in odor during high-temperature storage can be relatively suppressed by housing.

Production Example 1 (lotion)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL was produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene and polypropylene, bottle: polypropylene) to obtain the lotion of Production Example 1, respectively.
Betamethasone Valerate 0.12g
Diphenhydramine 1g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
Allantoin 0.2g
1g panthenol
Citric acid hydrate, ethanol and purified water Appropriate amount

Production Example 2 (lotion)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL was produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene and polypropylene, bottle: polypropylene) to obtain the lotion of Production Example 2, respectively.
Betamethasone Valerate 0.12g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Isopropylmethylphenol 0.1g
Glycol salicylate 1g
2g eucalyptus oil
Citric acid hydrate, ethanol and purified water Appropriate amount

Production Example 3 (lotion)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL was produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene and polypropylene, bottle: polypropylene) to obtain the lotion of Production Example 3.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
Citric acid hydrate, ethanol and purified water Appropriate amount

Production Example 4 (lotion)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL was produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene and polypropylene, bottle: polypropylene) to obtain the lotion of Production Example 4, respectively.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Glycol salicylate 1g
l-menthol 3.5g
dl-camphor 1g
Citric acid hydrate, ethanol and purified water Appropriate amount

Production Example 5 (lotion)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL was produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene and polypropylene, bottle: polypropylene) to obtain the lotion of Production Example 5, respectively.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Glycyrrhetinic acid 0.2g
Citric acid hydrate, ethanol and purified water Appropriate amount

Production Example 6 (lotion)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL was produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene and polypropylene, bottle: polypropylene) to obtain the lotion of Production Example 6.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
dl-camphor 1 g
Glycyrrhetinic acid 0.2g
Allantoin 0.2g
Tannic acid 0.06g
Citric acid hydrate, ethanol and purified water Appropriate amount

Production Example 7 (lotion)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL was produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene and polypropylene, bottle: polypropylene) to obtain the lotion of Production Example 7, respectively.
Betamethasone Valerate 0.12g
Diphenhydramine 1g
l-menthol 3.5g
dl-camphor 1 g
5g crotamiton
Glycyrrhetinic acid 0.2g
Isopropylmethylphenol 0.1g
Allantoin 0.2g
Citric acid hydrate, ethanol and purified water Appropriate amount

Production Example 8 (lotion)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL was produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene and polypropylene, bottle: polypropylene) to obtain the lotion of Production Example 8.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
l-menthol 3.5g
5g crotamiton
Isopropylmethylphenol 0.1g
1g panthenol
Citric acid hydrate, ethanol and purified water Appropriate amount

Production Example 9 (lotion)
By a conventional method, a liquid composition containing the following components and amounts in 100 mL was produced, and container 1 (cap: polypropylene, inner plug: polyethylene, bottle: polypropylene) or container 2 (cap: polypropylene, inner plug: polyethylene and polypropylene, bottle: polypropylene) to obtain the lotion of Production Example 9.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
5g crotamiton
Citric acid hydrate, ethanol and purified water Appropriate amount

Production Example 10 (Gel)
By a conventional method, a semisolid composition containing the following components and amounts in 100 g was produced, and a container (cap: polypropylene, inner plug: polyethylene, tube: polyethylene, polyethylene terephthalate and aluminum laminated material, shoulder: polyethylene ) to obtain a gel preparation of Production Example 10.
Betamethasone Valerate 0.12g
Diphenhydramine 1g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Allantoin 0.2g
1g panthenol
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and purified water appropriate amount

Production Example 11 (Gel)
By a conventional method, a semisolid composition containing the following components and amounts in 100 g was produced, and a container (cap: polypropylene, inner plug: polyethylene, tube: polyethylene, polyethylene terephthalate and aluminum laminated material, shoulder: polyethylene ) to obtain a gel preparation of Production Example 11.
Betamethasone Valerate 0.12g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Isopropylmethylphenol 0.1g
Glycol salicylate 1g
2g eucalyptus oil
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and purified water appropriate amount

Production Example 12 (Gel)
By a conventional method, a semisolid composition containing the following components and amounts in 100 g was produced, and a container (cap: polypropylene, inner plug: polyethylene, tube: polyethylene, polyethylene terephthalate and aluminum laminated material, shoulder: polyethylene ) to obtain a gel preparation of Production Example 12.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and purified water appropriate amount

Production Example 13 (Gel)
By a conventional method, a semisolid composition containing the following components and amounts in 100 g was produced, and a container (cap: polypropylene, inner plug: polyethylene, tube: polyethylene, polyethylene terephthalate and aluminum laminated material, shoulder: polyethylene ) to obtain a gel preparation of Production Example 13.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Glycol salicylate 1g
l-menthol 3.5g
dl-camphor 1 g
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and purified water appropriate amount

Production Example 14 (Gel)
By a conventional method, a semisolid composition containing the following components and amounts in 100 g was produced, and a container (cap: polypropylene, inner plug: polyethylene, tube: polyethylene, polyethylene terephthalate and aluminum laminated material, shoulder: polyethylene ) to obtain a gel preparation of Production Example 14.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Glycyrrhetinic acid 0.2g
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and purified water appropriate amount

Production Example 15 (Gel)
By a conventional method, a semisolid composition containing the following components and amounts in 100 g was produced, and a container (cap: polypropylene, inner plug: polyethylene, tube: polyethylene, polyethylene terephthalate and aluminum laminated material, shoulder: polyethylene ) to obtain a gel preparation of Production Example 15.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
dl-camphor 1 g
Glycyrrhetinic acid 0.2g
Allantoin 0.2g
Tannic acid 0.06g
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and purified water appropriate amount

Production Example 16 (Gel)
By a conventional method, a semisolid composition containing the following components and amounts in 100 g was produced, and a container (cap: polypropylene, inner plug: polyethylene, tube: polyethylene, polyethylene terephthalate and aluminum laminated material, shoulder: polyethylene ) to obtain a gel preparation of Production Example 16.
Betamethasone Valerate 0.12g
Diphenhydramine 1g
l-menthol 3.5g
dl-camphor 1g
5g crotamiton
Glycyrrhetinic acid 0.2g
Isopropylmethylphenol 0.1g
Allantoin 0.2g
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and purified water appropriate amount

Production Example 17 (Gel)
By a conventional method, a semisolid composition containing the following components and amounts in 100 g was produced, and a container (cap: polypropylene, inner plug: polyethylene, tube: polyethylene, polyethylene terephthalate and aluminum laminated material, shoulder: polyethylene ) to obtain a gel preparation of Production Example 17.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
l-menthol 3.5g
5g crotamiton
Isopropylmethylphenol 0.1g
1g panthenol
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and purified water appropriate amount

Production Example 18 (Gel)
By a conventional method, a semisolid composition containing the following components and amounts in 100 g was produced, and a container (cap: polypropylene, inner plug: polyethylene, tube: polyethylene, polyethylene terephthalate and aluminum laminated material, shoulder: polyethylene ) to obtain a gel preparation of Production Example 18.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
5g crotamiton
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and purified water appropriate amount

Production Example 19 (Cream)
By a conventional method, a semi-solid composition containing the following components and amounts per 100 g was produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and cream of Production Example 19. got
Betamethasone Valerate 0.12g
Diphenhydramine 1g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Allantoin 0.2g
1g panthenol
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, Sorbitan monostearate and purified water appropriate amount

Production Example 20 (Cream)
By a conventional method, a semi-solid composition containing the following components and amounts per 100 g was produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and cream of Production Example 20. got
Betamethasone Valerate 0.12g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
Isopropylmethylphenol 0.1g
Glycol salicylate 1g
2g eucalyptus oil
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, Sorbitan monostearate and purified water appropriate amount

Production Example 21 (Cream)
A semi-solid composition containing the following components and amounts per 100 g is produced by a conventional method, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the cream of Production Example 21. got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, Sorbitan monostearate and purified water appropriate amount

Production Example 22 (Cream)
By a conventional method, a semi-solid composition containing the following components and amounts per 100 g was produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the cream of Production Example 22 was prepared. got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Glycol salicylate 1g
l-menthol 3.5g
dl-camphor 1 g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, Sorbitan monostearate and purified water appropriate amount

Production Example 23 (Cream)
By a conventional method, a semi-solid composition containing the following components and amounts per 100 g was produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and cream of Production Example 23. got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
Glycyrrhetinic acid 0.2g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, Sorbitan monostearate and purified water appropriate amount

Production Example 24 (Cream)
A semi-solid composition containing the following components and amounts per 100 g was produced by a conventional method, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the cream of Production Example 24 was prepared. got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
dl-camphor 1g
Glycyrrhetinic acid 0.2g
Allantoin 0.2g
Tannic acid 0.06g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, Sorbitan monostearate and purified water appropriate amount

Production Example 25 (Cream)
By a conventional method, a semi-solid composition containing the following components and amounts per 100 g was produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and cream of Production Example 25. got
Betamethasone Valerate 0.12g
Diphenhydramine 1g
l-menthol 3.5g
dl-camphor 1g
5g crotamiton
Glycyrrhetinic acid 0.2g
Isopropylmethylphenol 0.1g
Allantoin 0.2g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, Sorbitan monostearate and purified water appropriate amount

Production Example 26 (Cream)
A semi-solid composition containing the following components and amounts per 100 g was produced by a conventional method, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the cream of Production Example 26 was prepared. got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
l-menthol 3.5g
5g crotamiton
Isopropylmethylphenol 0.1g
1g panthenol
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, Sorbitan monostearate and purified water appropriate amount

Production Example 27 (Cream)
A semi-solid composition containing the following components and amounts per 100 g was produced by a conventional method, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and cream preparation of Production Example 27. got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
5g crotamiton
Hypromellose, sodium edetate, citric acid, benzyl alcohol, ethanol and methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, sorbitan monostearate and purified water appropriate amount

Production Example 28 (Ointment)
A semi-solid composition containing the following components and amounts in 100 g is produced by a conventional method, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the ointment of Production Example 28 got
Betamethasone Valerate 0.12g
Diphenhydramine 1g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Allantoin 0.2g
1g panthenol
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, liquid paraffin appropriate amount

Production Example 29 (ointment)
By a conventional method, a semi-solid composition containing the following components and amounts in 100 g is produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the ointment of Production Example 29 got
Betamethasone Valerate 0.12g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
Isopropylmethylphenol 0.1g
Glycol salicylate 1g
2g eucalyptus oil
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, liquid paraffin appropriate amount

Production Example 30 (Ointment)
By a conventional method, a semi-solid composition containing the following components and amounts in 100 g is produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the ointment of Production Example 30 got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, liquid paraffin appropriate amount

Production Example 31 (Ointment)
By a conventional method, a semi-solid composition containing 100 g of the following components and amounts is produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the ointment of Production Example 31 got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Glycol salicylate 1g
l-menthol 3.5g
dl-camphor 1 g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, liquid paraffin appropriate amount

Production Example 32 (ointment)
By a conventional method, a semi-solid composition containing the following components and amounts in 100 g is produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the ointment of Production Example 32 got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Glycyrrhetinic acid 0.2g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, liquid paraffin appropriate amount

Production Example 33 (Ointment)
By a conventional method, a semi-solid composition containing the following components and amounts in 100 g is produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the ointment of Production Example 33 got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
dl-camphor 1g
Glycyrrhetinic acid 0.2g
Allantoin 0.2g
Tannic acid 0.06g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, liquid paraffin appropriate amount

Production Example 34 (ointment)
By a conventional method, a semi-solid composition containing the following components and amounts in 100 g is produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the ointment of Production Example 34 got
Betamethasone Valerate 0.12g
Diphenhydramine 1g
l-menthol 3.5g
dl-camphor 1g
5g crotamiton
Glycyrrhetinic acid 0.2g
Isopropylmethylphenol 0.1g
Allantoin 0.2g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, liquid paraffin appropriate amount

Production Example 35 (ointment)
By a conventional method, a semi-solid composition containing 100 g of the following components and amounts is produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the ointment of Production Example 35 got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
l-menthol 3.5g
5g crotamiton
Isopropylmethylphenol 0.1g
1g panthenol
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, liquid paraffin appropriate amount

Production Example 36 (Ointment)
By a conventional method, a semi-solid composition containing the following components and amounts in 100 g is produced, placed in a container (cap: polyethylene, tube: aluminum-epoxy resin inner surface coating), and the ointment of Production Example 36 got
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
5g crotamiton
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, liquid paraffin appropriate amount

Production Example 37 (emulsion lotion)
A liquid composition containing the following components and amounts per 100 g was produced by a conventional method, and placed in a container (cap: polyethylene, inner plug: polyethylene, bottle: ethylene) to obtain the lotion of Production Example 37. Ta.
Betamethasone Valerate 0.12g
Diphenhydramine 1g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Allantoin 0.2g
1g panthenol
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, carboxy Vinyl polymer, sorbitan sesquioleate and purified water appropriate amount

Production Example 38 (emulsion lotion)
By a conventional method, a liquid composition containing 100 g of the following components and amounts was produced and placed in a container (cap: polyethylene, inner plug: polyethylene, bottle: ethylene) to obtain the lotion of Production Example 38. Ta.
Betamethasone Valerate 0.12g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
Isopropylmethylphenol 0.1g
Glycol salicylate 1g
2g eucalyptus oil
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, carboxy Vinyl polymer, sorbitan sesquioleate and purified water appropriate amount

Production Example 39 (emulsion lotion)
A liquid composition containing the following components and amounts in 100 g was produced by a conventional method, and placed in a container (cap: polyethylene, inner plug: polyethylene, bottle: ethylene) to obtain the lotion of Production Example 39. Ta.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, carboxy Vinyl polymer, sorbitan sesquioleate and purified water appropriate amount

Production Example 40 (emulsion lotion)
A liquid composition containing 100 g of the following components and amounts was produced by a conventional method, and placed in a container (cap: polyethylene, inner plug: polyethylene, bottle: ethylene) to obtain the lotion of Production Example 40. Ta.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Glycol salicylate 1g
l-menthol 3.5g
dl-camphor 1 g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, carboxy Vinyl polymer, sorbitan sesquioleate and purified water appropriate amount

Production Example 41 (emulsion lotion)
A liquid composition containing the following components and amounts per 100 g was produced by a conventional method, and placed in a container (cap: polyethylene, inner plug: polyethylene, bottle: ethylene) to obtain the lotion of Production Example 41. Ta.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1g
Glycyrrhetinic acid 0.2g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, carboxy Vinyl polymer, sorbitan sesquioleate and purified water appropriate amount

Production Example 42 (emulsion lotion)
A liquid composition containing the following components and amounts in 100 g was produced by a conventional method, and placed in a container (cap: polyethylene, inner plug: polyethylene, bottle: ethylene) to obtain the lotion of Production Example 42. Ta.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
dl-camphor 1 g
Glycyrrhetinic acid 0.2g
Allantoin 0.2g
Tannic acid 0.06g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, carboxy Vinyl polymer, sorbitan sesquioleate and purified water appropriate amount

Production Example 43 (emulsion lotion)
A liquid composition containing the following components and amounts in 100 g was produced by a conventional method, and placed in a container (cap: polyethylene, inner plug: polyethylene, bottle: ethylene) to obtain the lotion of Production Example 43. Ta.
Betamethasone Valerate 0.12g
Diphenhydramine 1g
l-menthol 3.5g
dl-camphor 1g
5g crotamiton
Glycyrrhetinic acid 0.2g
Isopropylmethylphenol 0.1g
Allantoin 0.2g
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, carboxy Vinyl polymer, sorbitan sesquioleate and purified water appropriate amount

Production Example 44 (emulsion lotion)
A liquid composition containing the following components and amounts in 100 g was produced by a conventional method and placed in a container (cap: polyethylene, inner plug: polyethylene, bottle: ethylene) to obtain the lotion of Production Example 44. Ta.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
l-menthol 3.5g
5g crotamiton
Isopropylmethylphenol 0.1g
1g panthenol
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, carboxy Vinyl polymer, sorbitan sesquioleate and purified water appropriate amount

Production Example 45 (emulsion lotion)
A liquid composition containing the following components and amounts in 100 g was produced by a conventional method, and placed in a container (cap: polyethylene, inner plug: polyethylene, bottle: ethylene) to obtain a lotion of Production Example 45. Ta.
Betamethasone Valerate 0.12g
Diphenhydramine hydrochloride 2g
Lidocaine 1g
l-menthol 3.5g
dl-camphor 1 g
5g crotamiton
Methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum, light liquid paraffin, cetanol, stearyl alcohol, polyoxyethylene hydrogenated castor oil, polysorbate 60, sodium edetate hydrate, citric acid hydrate, sodium hydroxide, carboxy Vinyl polymer, sorbitan sesquioleate and purified water appropriate amount

Production example 46
Sugar-coated tablets of 600 mg each containing the following ingredients were produced according to a conventional method. Two of the obtained tablets were SP-packaged in a sheet made of aluminum foil by a conventional method to obtain a drug of Production Example 46.
Benfotiamine 6.915mg
Pyridoxine hydrochloride 5 mg
L-sodium ascorbate 100 mg
Nicotinamide 6mg
Gamma oryzanol 5mg
Anhydrous caffeine 25mg
Oxoamidine end 30mg
Lycium dry extract 40mg (100mg equivalent of crude drug)
Gum arabic, carnauba wax, crospovidone, magnesium stearate, gelatin, talc, hydroxypropyl cellulose, hypromellose, polyoxyethylene polyoxypropylene glycol, sodium hydrogen phosphate, cellulose, anhydrous silicic acid, titanium oxide, sucrose, calcium carbonate

Production Example 47
Sugar-coated tablets of 500 mg each containing the following ingredients were produced according to a conventional method. Two of the obtained tablets were SP-packaged in a sheet made of aluminum foil by a conventional method to obtain a drug of Production Example 47.
Benfotiamine 6.915mg
Riboflavin 5.9mg
Pyridoxine hydrochloride 5 mg
Magnesium and potassium L-aspartate 100mg
Gamma oryzanol 5mg
Anhydrous caffeine 25mg
Oxoamidine end 30mg
Lycium dry extract 40mg (100mg equivalent of crude drug)
Gum arabic, carnauba wax, crospovidone, magnesium stearate, gelatin, talc, hydroxypropyl cellulose, hypromellose, polyoxyethylene polyoxypropylene glycol, sodium hydrogen phosphate, cellulose, anhydrous silicic acid, titanium oxide, sucrose, calcium carbonate

Production example 48
Sugar-coated tablets of 500 mg each containing the following ingredients were produced according to a conventional method. Two of the obtained tablets were SP-packaged in a sheet made of aluminum foil by a conventional method to obtain a drug of Production Example 48.
Benfotiamine 6.915mg
Tocopherol succinate 25.895mg
Cyanocobalamin 0.03 mg
L-sodium ascorbate 100 mg
Calcium pantothenate 15mg
Anhydrous caffeine 25mg
Oxoamidine end 30mg
Guarana dry extract 13.35mg (100mg equivalent of crude drug)
Gum arabic, carnauba wax, crospovidone, magnesium stearate, gelatin, talc, hydroxypropyl cellulose, hypromellose, polyoxyethylene polyoxypropylene glycol, sodium hydrogen phosphate, cellulose, anhydrous silicic acid, titanium oxide, sucrose, calcium carbonate

Production example 49
Sugar-coated tablets of 550 mg each containing the following ingredients were produced according to a conventional method. Two of the obtained tablets were SP-packaged in a sheet made of aluminum foil by a conventional method to obtain a drug of Production Example 49.
Benfotiamine 6.915mg
Riboflavin 5.9mg
Cyanocobalamin 0.03 mg
Magnesium and potassium L-aspartate 100mg
Gamma oryzanol 5mg
Anhydrous caffeine 25mg
Oxoamidine end 30mg
Lycium dry extract 40mg (100mg equivalent of crude drug)
Gum arabic, carnauba wax, crospovidone, magnesium stearate, gelatin, talc, hydroxypropyl cellulose, hypromellose, polyoxyethylene polyoxypropylene glycol, sodium hydrogen phosphate, cellulose, anhydrous silicic acid, titanium oxide, sucrose, calcium carbonate

Production example 50
Sugar-coated tablets of 500 mg each containing the following ingredients were produced according to a conventional method. Two of the obtained tablets were SP-packaged in a sheet made of aluminum foil by a conventional method to obtain a drug of Production Example 50.
Benfotiamine 6.915mg
Pyridoxine hydrochloride 5 mg
Calcium pantothenate 15mg
Magnesium and potassium L-aspartate 100mg
Gamma oryzanol 5mg
Anhydrous caffeine 25mg
Oxoamidine end 30mg
Guarana dry extract 13.35mg (100mg equivalent of crude drug)
Gum arabic, carnauba wax, crospovidone, magnesium stearate, gelatin, talc, hydroxypropyl cellulose, hypromellose, polyoxyethylene polyoxypropylene glycol, sodium hydrogen phosphate, cellulose, anhydrous silicic acid, titanium oxide, sucrose, calcium carbonate

Production example 51
Sugar-coated tablets of 500 mg each containing the following ingredients were produced according to a conventional method. Two of the obtained tablets were SP-packaged in a sheet made of aluminum foil by a conventional method to obtain a drug of Production Example 51.
Benfotiamine 6.915mg
Riboflavin 5.9mg
Pyridoxine hydrochloride 5 mg
Cyanocobalamin 0.03 mg
Nicotinamide 6mg
Magnesium and potassium L-aspartate 100mg
Anhydrous caffeine 25mg
Oxoamidine end 30mg
Guarana dry extract 13.35mg (100mg equivalent of crude drug)
Gum arabic, carnauba wax, crospovidone, magnesium stearate, gelatin, talc, hydroxypropyl cellulose, hypromellose, polyoxyethylene polyoxypropylene glycol, sodium hydrogen phosphate, cellulose, anhydrous silicic acid, titanium oxide, sucrose, calcium carbonate

Production Examples 52-57
Pharmaceuticals of Production Examples 52 to 57 were obtained in the same manner as in Production Examples 46 to 51, except that 30 tablets were bottle-packaged in a glass container instead of SP packaging two tablets each.

Production Examples 58-63
Pharmaceuticals of Production Examples 52 to 57 were obtained in the same manner as in Production Examples 46 to 51, except that 30 tablets were bottle-wrapped in a polyethylene container instead of SP packaging two tablets each.

Production Examples 64-69
Pharmaceuticals of Production Examples 64 to 69 were obtained in the same manner as in Production Examples 46 to 51, except that 80 tablets were bottle-wrapped in a polypropylene container instead of SP packaging two tablets each.

Production Examples 70-75
Pharmaceuticals of Production Examples 70 to 75 were obtained in the same manner as in Production Examples 46 to 51, except that 10 tablets were PTP-packaged and then pillow-packaged instead of SP packaging two tablets each.

Production Examples 76-81
Pharmaceuticals of Production Examples 76-81 were obtained in the same manner as in Production Examples 46-51, except that instead of SP packaging 2 tablets each, 30 tablets were sealed in a self-supporting aluminum bag.

According to the present invention, it is possible to provide a pharmaceutical composition that contains a betamethasone ester, has a suppressed odor change during high-temperature storage, and has good storage stability. Therefore, the present invention can be used, for example, in the pharmaceutical industry.

Claims (4)

The following components (A) and (B):
(A) betamethasone ester;
(B) terpenes;
A packaging-filled composition comprising a pharmaceutical composition containing 2. The packaging composition according to claim 1, wherein component (A) is one or more selected from the group consisting of betamethasone valerate, betamethasone dipropionate and betamethasone butyrate propionate. 3. The packaging body stuffing composition according to claim 1 or 2, wherein component (B) is one or more selected from the group consisting of menthol, camphor and borneol. The packaging composition according to any one of claims 1 to 3, which is in a dosage form selected from lotions, ointments, creams and gels.