WO2021187593A1 - Composition containing betamethasone valerate - Google Patents

Abstract

The present invention provides a composition which contains betamethasone valerate and which has favorable production stability. The composition contains (A) betamethasone valerate, (B) polyoxyethylene alkyl ether, and (C) tocopherol or a derivative thereof.

Description

Betamethasone valerate ester-containing composition

The present invention relates to a betamethasone valerate-containing composition. More specifically, the present invention relates to an external preparation containing betamethasone valerate as an anti-inflammatory agent. The present invention also relates to a method for improving the pharmaceutical stability of a betamethasone valerate-containing composition.

Compounds with a steroid skeleton are known to exhibit high bioactivity in trace amounts. Among them, corticosteroids are effective in improving symptoms such as itching, redness, and swelling of the skin with inflammation, and eczema (including eczema due to atopic dermatitis; the same applies hereinafter) and itching (sweat, buds). It includes pruritus caused by measles, rashes, insect bites, etc. The same shall apply hereinafter), and is widely used for the treatment of dermatitis, psoriasis, and the like. Usually, for external preparations containing corticosteroids, other active ingredients such as non-steroidal anti-inflammatory agents, local anesthetics, blood circulation promoters, bactericides, skin protectants, antibiotics, and refreshing agents are appropriately added. However, depending on the combination of the ingredients, there are problems with the formulation such as difficulty in ensuring the formulation stability, skin irritation, and poor usability. appear.

Therefore, in designing the drug, in addition to the pharmacological action (efficacy / effect), it is necessary to comprehensively consider the physical stability of the drug, the safety of the drug on the living body such as the skin, and the feeling of use.

It has been pointed out that among the above-mentioned corticosteroids, esterified steroids obtained by acetylating or valerylating a steroid having a hydroxyl group at the 17th or 21st position are easily decomposed in the preparation by the compound used in combination. (See Patent Documents 1 and 2 etc.).

Japanese Unexamined Patent Publication No. 2005-343890 Japanese Unexamined Patent Publication No. 2005-343891

An object of the present invention is to provide a betamethasone valerate-containing composition having good pharmaceutical stability. Another object of the present invention is to provide a method for improving the pharmaceutical stability of the betamethasone valerate-containing composition.

The present inventors have found that when a polyoxyethylene alkyl ether is added when designing a preparation containing betamethasone valerate, the pH of the preparation decreases with time. In order to solve this problem, we have been studying diligently. By using betamethasone valerate and polyoxyethylene alkyl ether in combination with tocopherol or a derivative thereof, the above phenomenon is significantly improved and the pH is stabilized. It has been found that a maintained betamethasone valerate-containing preparation can be obtained.

The present invention has been completed by repeating further improvements based on these findings, and includes the following embodiments.

(I) Betamethasone valerate-containing composition (I-1) (A) Betamethasone valerate and
(B) At least one selected from the group consisting of polyoxyethylene alkyl ether and polyoxyethylene aryl phenyl ether, and
(C) A composition containing tocopherol or a derivative thereof.
(I-2) The component (B) is at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetostearyl ether and polyoxyethylene distyrylphenyl ether. , (I-1).
(I-3) The composition according to (I-1) or (I-2), which further contains (D) a pH regulator.
(I-4) The composition according to any one of (I-1) to (I-3), which further contains (E) an external base.
(I-5) The composition according to any one of (I-1) to (I-4), which is a pharmaceutical composition, preferably an external preparation for skin.

(II) Stabilized production method of betamethasone valerate-containing composition (II-1) (A) Selected from the group consisting of betamethasone valerate, (B) polyoxyethylene alkyl ether and polyoxyethylene aryl phenyl ether. A production method in which the stability of a composition containing at least one of these substances is improved.
The production method, which comprises a step of coexisting (C) tocopherol or a derivative thereof in the composition.
(II-2) The production method according to (II-1), wherein the composition further contains (D) a pH adjuster.
(II-3) The component (B) is at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetostearyl ether and polyoxyethylene distyrylphenyl ether. , (II-1) or (II-2).
(II-4) The production method according to any one of (II-1) to (II-3), wherein the improvement in stability is suppression of a decrease in pH.

(III) Method for improving stability of betamethasone valerate-containing composition (III-1) (A) Selected from the group consisting of betamethasone valerate, (B) polyoxyethylene alkyl ether and polyoxyethylene aryl phenyl ether. A method for improving the stability of a composition containing at least one of these.
The method for improving stability, which comprises coexisting (C) tocopherol or a derivative thereof in the composition.
(III-2) The method for improving stability according to (III-1), wherein the composition further contains (D) a pH adjuster.
(III-3) The method for improving stability according to (II-1) or (II-2), wherein the method for improving stability is a method for suppressing a decrease in pH of the composition.
(III-4) The component (B) is at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetostearyl ether and polyoxyethylene distyrylphenyl ether. , (II-1) to (II-3).

According to the present invention, it is possible to provide a betamethasone valerate-containing composition having good pharmaceutical stability. More specifically, according to the present invention, the pH decrease caused by adding polyoxyethylene alkyl ether to the betamethasone valerate-containing composition is significantly suppressed by adding tocopherol or a derivative thereof. It is possible to provide a betamethasone valerate-containing preparation characterized by the above.

The results of comparative evaluation of the pH stability of Samples 1-1 to 1-4 in Experimental Example 1 are shown. The results of comparative evaluation of the pH stability of Samples 1-1 and 1-5 to 1-7 in Experimental Example 1 are shown.

(I) Betamethasone valerate ester-containing composition and method for producing the same The betamethasone valerate ester-containing composition of the present invention (hereinafter, also simply referred to as "the present composition") is the following (A), (B) and ( C) A composition containing a component.
At least one selected from the group consisting of (A) betamethasone valerate (B) polyoxyethylene alkyl ether and polyoxyethylene aryl phenyl ether, and (C) tocopherol or a derivative thereof.

The solid composition may contain the following component (D) in addition to the components (A) and (B).
(D) pH regulator.

Further, the solid composition may contain the following component (E) in addition to the components (A) to (C) or the components (A) to (D).
(E) External base.

Hereinafter, these components will be described.
The component betamethasone valerate is an esterified steroid in which the hydroxyl group at the 17-position is valeryrylized and the hydroxyl group at the 21-position is acetylated. The compound is a strong steroid with anti-inflammatory activity and is known to have the following indications:
Eczema / dermatitis group (including progressive finger palmar keratoderma, female facial lichen planus, Vidal lichen, radiation dermatitis, sunlight dermatitis), dermatitis, pruritus group (lichen-like lichen, strophulus) , Including fixed urticaria), insect bites, psoriasis, palmoplantar pustulosis, lichen planus, glossy lichen planus, pore red erythema, gibelbara erythema, erythema (polymorphic exudative erythema, nodule) Erythema, Darier efferent ring erythema), erythema (including erythema due to malignant lymphoma), chronic discoid erythematosus, drug eczema / toxic eczema, circular alopecia (including malignant), burns (scar, keroid) ), Erythema, lichen groupus, juling herpes dermatitis (including lichen planus), hemorrhoids, tympanic chamber plasty, internal ear fenestration, middle ear radical surgery wound.

The amount of the component (A) contained in the present composition may be an amount that exerts a desired medicinal effect without interfering with the effect of the present invention, and can be appropriately set and adjusted within that range. For example, when this composition is prepared as an external preparation (pharmaceutical preparation) for improving skin diseases (for example, eczema, prurigo, dermatitis or psoriasis) having symptoms such as itching, redness or swelling of the skin with inflammation. As the content of the component (A) in the present composition, the range of 0.0002 to 10% by mass can be exemplified. It is preferably 0.002 to 2% by mass, and more preferably 0.01 to 0.3% by mass.

(B) The component polyoxyethylene alkyl ether and polyoxyethylene arylphenyl ether are nonionic compounds having a surface active action. The polyoxyethylene alkyl ether and polyoxyethylene arylphenyl ether targeted by the present invention can be blended in pharmaceutical products, quasi-drugs or cosmetics.

Specific examples of such polyoxyethylene alkyl ethers include monoethers of polyoxyethylene having an addition molar number of 4 to 200 and an alkyl group having 8 to 22 carbon atoms. Be done. Among these are polyoxyethylene capryl ether, polyoxyethylene caprylyl ether, polyoxyethylene lauryl ether, polyoxyethylene myristyl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and poly. Oxyethylene isosteyl ether, polyoxyethylene cetostearyl ether, polyoxyethylene behenyl ether and the like are included. Preferably, it is polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetostearyl ether, and more preferably polyoxyethylene cetyl ether, and polyoxyethylene stearyl ether.

Specific examples of the polyoxyethylene arylphenyl ether include ethers of polyoxyethylene (EO) having an addition molar number of 4 to 200 and arylphenyl. These include polyoxyethylene distyrylphenyl ether, polyoxyethylene polystyrylphenyl ether and the like. It is preferably polyoxyethylene distyrylphenyl ether.
These components (B) may be used alone or in combination with the component (A), or two or more of them may be arbitrarily combined and used in combination with the component (A). When two or more kinds of the component (B) are used in combination, it is preferable to use the above-mentioned suitable polyoxyethylene alkyl ether as one kind.

The amount of the component (B) contained in the present composition may be an amount that exerts a desired surface-active action without interfering with the effects of the present invention, and can be appropriately set and adjusted within that range. Although not limited, it can be adjusted so as to lower the interfacial tension existing at the interface between the oil component and the water component and exert an action of finely dispersing the oil component in the water component. Although not limited, the content (total amount) of the component (B) in the present composition can be exemplified in the range of 0.1 to 10% by mass. The lower limit amount is preferably 0.15% by mass or more, more preferably 0.2% by mass or more, and further preferably 0.3% by mass or more. The range is preferably 0.25 to 7.5% by mass, more preferably 0.3 to 5% by mass, and further preferably 0.5 to 5% by mass. The ratio of the component (B) to 100 parts by mass of the component (A) is not limited, but is, for example, in the range of 10 to 100,000 parts by mass, preferably 100 to 50,000 parts by mass, and more preferably 500 to 10,000 parts by mass, particularly. Preferably, 1000 to 5000 parts by mass can be exemplified.

(C) Ingredients Tocopherol or a derivative thereof may be a natural product or a synthetic product as long as it can be blended in pharmaceutical products, quasi-drugs or cosmetics. Tocopherols include d-α-tocopherols, dl-α-tocopherols, β-tocopherols, γ-tocopherols, and δ-tocopherols. In addition, tocopherol derivatives include tocopherol acetate (for example, d-α-tocopherol acetate, dl-α-tocopherol acetate), tocopherol nicotinic acid ester, tocopherol succinic acid ester, and tocopherol linolenic acid ester. Esters of: α-tocopheryl acetic acid, α-tocopheryl linolenic acid, α-tocopheryl succinic acid, and salts thereof; tocoretinates such as α-tocoretinate, β-tocoretinate, δ-tocoretinate. The derivative of tocopherol is preferably an ester of tocopherol (vitamin E ester), and more preferably an ester of tocopherol acetate. These components (C) may be used alone or in combination with the components (A) and (B), or two or more of them may be arbitrarily combined and used in combination with the components (A) and (B). May be done.

The component (C) itself is a compound having an antioxidant action, a blood circulation promoting action, and the like, but in the present composition, in addition to at least one of these actions (preferably a blood circulation promoting action), it will be described later. As shown in the examples described above, it exerts an action of suppressing the pH lowering phenomenon of the composition caused by containing the above-mentioned components (A) and (B).

The amount of the component (C) contained in the present composition may be an amount that exhibits the desired medicinal effect and the above-mentioned effect, and can be appropriately set and adjusted within that range. For example, when this composition is prepared as an external preparation (pharmaceutical preparation) for improving skin diseases (for example, eczema, prurigo, dermatitis or psoriasis) having symptoms such as itching, redness or swelling of the skin with inflammation. As the content of the component (C) in the present composition, the range of 0.001 to 10% by mass can be exemplified. It is preferably 0.005 to 10% by mass, and more preferably 0.025 to 5% by mass. The ratio of the component (C) to 100 parts by mass of the component (A) is not limited, but is, for example, in the range of 10 to 10000 parts by mass, preferably 30 to 7000 parts by mass, and more preferably 50 to 5000 parts by mass. can do.

(D) The component pH adjusting agent may be an acid or base or a salt thereof, which can be blended in a drug, a quasi drug or a cosmetic, and is usually used for pH adjusting. Not limited, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or salts thereof; hydroxides of alkali metals or alkaline earth metals; inorganic substances such as carbonates, hydrogen carbonates; acetic acid, methanesulfonic acid, oxalic acid. , Capricic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, levulinic acid, fumaric acid, maleic acid, etc. Organic acids or salts thereof; ethylamine, diethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, lysine, arginine and the like can be exemplified.

Generally, it is said that the pH of human skin (skin, skin membrane) is weakly acidic of about 4.5 to about 6.5, and the pH of healthy skin is about 5.5. Therefore, for example, this composition is used as an external preparation (pharmaceutical preparation) for improving skin diseases (eg, eczema, prurigo, dermatitis, psoriasis, etc.) having symptoms such as itching, redness or swelling of the skin with inflammation. In the case of preparation, the content of the component (D) in the present composition may be any ratio as long as the present composition can be adjusted to the above pH range, preferably pH 5.0 to 6.0. As long as this is not particularly limited, the composition can be appropriately adjusted from the range of 0.01 to 10% by mass in 100% by mass of the present composition. It is preferably 0.05 to 5% by mass, and more preferably 0.1 to 1% by mass.

(E) Component This composition can be prepared as an external preparation by mixing the above-mentioned (A) to (C) components or (A) to (D) components together with (E) an external base. More preferably, it is an external preparation for skin. The dosage form is not limited and may include dosage forms commonly used in pharmaceuticals, quasi-drugs or cosmetics. Examples thereof include liquids (including lotions, emulsions and aerosols), sticks, creams, ointments, plasters, gels, poultices, foams and powders. It is preferably a cream, an ointment, a liquid or a gel.

As the component (E), a conventional external base can be used depending on the shape (dosage form) of the present composition. As long as it does not interfere with the effects of the present invention, it may be a base that can be blended in pharmaceuticals, quasi-drugs or cosmetics, and is not particularly limited.
For example, oils such as white vaseline, cetanol, honeywort, lanolin, paraffin, liquid paraffin; natural rubber, isoprene rubber, polyisobutylene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene. -Rubber such as ethylene / butylene-styrene block copolymer, (meth) acrylic acid alkyl ester (co) polymer, poly (meth) acrylic acid ester, (meth) acrylic acid ester, polyisobutylene, polybutene, liquid polyisoprene, etc. Kind: Water-soluble polymers such as carboxyvinyl polymer, starch acrylate, sodium polyacrylate, sodium carmellose; glycerin; macrogol; silicic anhydride and the like can be exemplified. Further, as a component of the external base, excipients (for example, sugars such as sucrose; starch derivatives such as dextrin; cellulose derivatives such as carmellose sodium; water-soluble polymers such as xanthan gum) can also be used. These can be used alone or in any combination of two or more.
The content of the component (E) in the present composition may be adjusted so that the total amount of the present composition is 100% by mass, and is not limited, but less than 100% by mass, for example, 99.999% by mass. The upper limit range can be exemplified. It is preferably 5 to 99.999% by mass, and more preferably 10 to 99.99% by mass.

(F) Any pharmacologically active ingredient The composition contains the above-mentioned components (A) to (C), components (A) to (D), or (A) as long as the effects of the present invention are not impaired. In addition to the component (E), other pharmacologically active ingredients may be further contained. Non-steroidal anti-inflammatory drugs, local anesthetics, antipruritic agents, blood circulation promoters, fungicides, skin protectants, antibiotics, moisturizers, and / or refreshing agents can be exemplified, but not limited. These may be components that can be blended with external preparations, especially external preparations for skin, but the composition of the present invention may be used for skin diseases (eg, eczema, etc.) having symptoms such as itching, redness or swelling of the skin with inflammation. When prepared as an external preparation (pharmaceutical preparation) for improving pruritus, dermatitis, psoriasis, etc.), it is preferable that the ingredient can be blended in the external preparation.

(G) Arbitrary Carriers / Additives In addition to the above-mentioned components, conventionally known carriers and additives can be arbitrarily blended in the composition as long as the effects of the present invention are not impaired. Examples of these carriers and additives include excipients, thickeners, surfactants, antioxidants, buffers, emulsifiers, pH adjusters, dispersants, solubilizers, fluidizers, colorants, and storage. Agents and / or fragrances and the like can be exemplified without limitation.

In this composition, at least the components (A) to (C) or the components (A) to (D) among the above-mentioned components are mixed with the components (E) and / or (F) as necessary. Then, it can be produced by a production method having a step of coexisting at least the component (C) in the composition containing the component (A) and the component (B), and other than that, it is basically a conventional production method of an external preparation. Therefore, it can be produced in the form of an external preparation.

The composition thus prepared in the form of an external preparation is used externally to improve skin diseases having symptoms such as itching, redness or swelling of the skin with inflammation (for example, eczema, prurigo, dermatitis or psoriasis). It can be suitably used as a preparation (pharmaceutical preparation). The application is not limited and can be widely used on the skin in general, such as hands, feet, fingers, face, head, and body. It can also be applied to areas with thin skin such as the anus and the area around the genital area. The amount and usage of these substances on the skin are not particularly limited, and they should be used by applying an appropriate amount to the outer skin such as the skin once to several times a day depending on the symptoms of the affected area and the content of the active ingredient. Can be done.

(II) Method for improving stability of betamethasone valerate-containing composition The present invention provides a method for improving the stability of a composition containing the above-mentioned component (A) (betamethasone valerate-containing composition). do.
As shown in the experimental example described later, the stability of the composition containing the component (A) is lowered by blending the component (B) described above, and a phenomenon that the pH is lowered with time occurs. This phenomenon may occur beyond the buffering capacity even when the pH adjuster (component (D)) is blended in the composition containing the component (A). The pH lowering phenomenon can be improved by coexisting the above-mentioned component (C) in the composition (composition containing components (A) and (B)). The composition containing the components (A) and (B) may contain the above-mentioned component (D).

For the "improvement of stability of betamethasone valerate-containing composition", which is the subject of the present invention, preferably, the pH decrease over time caused by blending the component (B) with betamethasone valerate-containing composition is suppressed. Includes being done. A composition (measurement target) containing at least the components (A) to (C) or the components (A) to (D) has the same composition as the above except that the component (C) is not contained (comparison target). In comparison, when the pH decrease that occurs over time is small, it is judged that the former composition has the pH decrease phenomenon suppressed by the inclusion of the component (C) and the stability is improved. be able to.
The presence or absence of a decrease in pH over time is determined by storing the composition to be measured and the composition to be compared in a dark place under constant temperature and humidity conditions of 40 ° C. and 75%, respectively, for about 0 to 6 months. It can be evaluated by measuring the pH with a pH meter over time during the period and comparing the degree of the pH decrease. For details, the description of the experimental example described later can be referred to.

As a method for coexisting the component (C) in the composition containing the components (A) and (B) (or the components (A), (B) and (D)), a method capable of obtaining the effect of the present invention is used. All you need is, and there are no restrictions. Although not limited, for example, the component (B) or the component (B) and the component (D) are dissolved in the component (E), the component (C) is mixed therein, and the component (B) and the component (C) are mixed. A method may be used in which a coexistence state with the component or a coexistence state with the (B) component, the (D) component and the (C) component is formed, and the (A) component is dispersed therein. Further, the above-mentioned component (F) and component (G) may be blended as other components as long as the effects of the present invention are not impaired. After mixing each of these components to form a coexistence state with at least the components (A) to (C), if necessary, a liquid agent, a stick agent, a cream agent, an ointment agent, a gel agent, etc. It can also be prepared in the form of a conventional external preparation such as a plaster.
The ratio of each component in the composition, the compounding ratio, and the like are as described in (I) above, and the description can be incorporated herein by reference.

As described above, in the present specification, the terms "including" and "containing" include the meanings of "consisting of" and "consisting of substantially".

Hereinafter, the present invention will be described with reference to experimental examples in order to help understanding the structure and effects of the present invention. However, the present invention is not limited by these experimental examples. The following experiments were performed under room temperature (25 ± 5 ° C.) and atmospheric pressure conditions, unless otherwise noted. Unless otherwise specified, "%" described below means "mass%" and "parts" means "parts by mass".

The compounds used in the following experimental examples are as follows.
Betamethasone Benzoic acid ester: Obtained from Sicor Tocopherol acetate (deer special grade): Obtained from Kanto Chemical Co., Ltd. Polyoxyethylene cetyl ether (BC-TX): Obtained from Nippon Surfartant Polyoxyethylene stearyl ether (220R): Obtained from Nichiyu Co., Ltd. White Vaseline (Snow White V): Obtained from CALUMET Preservatives: Butyl paraixibenzoate, Methyl paraixibenzoate: Obtained from Fuji Film Wako Pure Chemical Industries, Ltd. pH adjuster: 1 sodium phosphate 2 Water salt, phosphoric acid, sodium hydroxide: Obtained from Kanto Chemical Co., Ltd.

[Method for evaluating the stability of betamethasone valerate-containing composition over time]
(1) Preservation method of test composition The betamethasone valerate ester-containing composition (test composition) to be measured is filled in an aluminum tube so as not to create a space, and in this state, under a dark place condition of 75 RH% at 40 ° C. Store statically for 6 months.
(2) Preparation method of sample for pH measurement Take 5 g (± 0.02 g) of the test composition before storage (month: 0) and after storage (month: 1 to June) in a 50 mL beaker and use a measuring pipette. Add 15 mL of distilled water for injection. This is heated in a water bath at 60 ° C. (± 2 ° C.) for 5 minutes, and then stirred for 5 minutes using a stirrer. Then, the sample adjusted so that the product temperature becomes 24.5 ° C to 25.5 ° C is used as a sample for pH measurement.
(3) pH measurement of pH measurement sample The pH of the pH measurement sample (product temperature: 24.5 to 25.5 ° C.) prepared above is measured with a pH meter, and the pH of the test composition before storage is measured. The temporal stability of the test sample is evaluated from the difference (pH change) between the pH of the test composition and the pH of the test composition after storage.

Experimental Example 1 Preparation of betamethasone valerate-containing composition and evaluation of its stability (1) Experimental method According to the compositions shown in Tables 1 and 2, cream-shaped betamethasone valerate-containing compositions (Samples 1-1 to 1-). 7) was prepared and adjusted so that the pH was in the range of 5.0 to 5.5. Specifically, the component (D) and the component (G) are dissolved in the component (E), and the component (B) and / or the component (C) is mixed therein according to the sample to form a coexistence state. , (A) component was dispersed.

Each prepared sample was stored for 6 months under the storage conditions described above. The pH was measured over time during the storage period, and the pH stability was comparatively evaluated between the samples based on the change over time.

(2) Experimental results The results are shown in Tables 3 and 4, and FIGS. 1 and 2.

As shown in Tables 3 and 1, and Tables 4 and 2, the components (A) and (C) are combined with the components (B) to form the components (A) and (C). It was confirmed that the pH decrease of the contained composition (Samples 1-2 and 1-5) was suppressed, and a betamethasone valerate-containing composition having good stability (pH stability) could be obtained (Sample 1). -3, 1-4, 1-6 and 1-7).
Examples 2 to 11: Betamethasone valerate ester-containing composition A book in which the pH decrease over time is suppressed as compared with the betamethasone valerate ester-containing composition (cream) containing no C component (Comparative Examples 2 to 11). The formulations of betamethasone valerate-containing compositions (creams) (Examples 2-11) of the present invention are shown in Tables 5-14.

Claims (13)

1. (A) Betamethasone valerate and
   (B) Polyoxyethylene alkyl ether and
   (C) A composition containing tocopherol or a derivative thereof.
2. The first aspect of the present invention, wherein the component (B) is at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetostearyl ether and polyoxyethylene distyrylphenyl ether. Composition.
3. The composition according to claim 1 or 2, further containing (D) a pH adjuster.
4. The composition according to any one of claims 1 to 3, further containing (E) an external base.
5. The composition according to any one of claims 1 to 4, which is an external preparation for skin.
6. A production method for improving the stability of a composition containing (A) betamethasone valerate and (B) polyoxyethylene alkyl ether.
   The production method, which comprises a step of coexisting (C) tocopherol or a derivative thereof in the composition.
7. The production method according to claim 6, wherein the composition further contains (D) a pH adjuster.
8. The production method according to claim 6 or 7, wherein the improvement in stability is suppression of a decrease in pH of the composition.
9. Claim 6 to claim 6, wherein the component (B) is at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetostearyl ether and polyoxyethylene distyrylphenyl ether. The production method according to any one of 8.
10. A method for improving the stability of a composition containing (A) betamethasone valerate and (B) polyoxyethylene alkyl ether.
    The method for improving stability, which comprises coexisting (C) tocopherol or a derivative thereof in the composition.
11. The method for improving stability according to claim 10, wherein the composition further contains (D) a pH adjuster.
12. The stability improving method according to claim 10 or 11, wherein the stability improving method is a method for suppressing a decrease in pH of the composition.
13. Claim 10 to claim 10, wherein the component (B) is at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetostearyl ether and polyoxyethylene distyrylphenyl ether. The stability improving method according to any one of 12.

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