Ointment composition containing betamethasone valerate

Abstract

The present invention provides an ointment composition containing betamethasone valerate, which has satisfactory formulation stability. The ointment composition can be prepared by adding a nonionic surfactant having an HLB value of 5.0 or less to betamethasone valerate and a lipophilic base material or betamethasone valerate, a lipophilic base material and crotamiton.

Description

Ointment composition containing betamethasone valerate

[0001] The present invention relates to an ointment composition containing betamethasone valerate, and also to a method for improving the formulation stability of an ointment composition containing betamethasone valerate.

[0002] Compounds with a steroid skeleton are known to exhibit high physiological activity even in trace amounts. Among these, corticosteroids are effective in improving symptoms such as itching, redness, and swelling of inflammatory skin, and are widely used to treat eczema (including eczema caused by atopic dermatitis; the same applies hereinafter), prurigo (including miliaria, urticaria, rashes, and prurigo caused by insect bites; the same applies hereinafter), dermatitis, psoriasis, and the like. External preparations containing corticosteroids typically contain other active ingredients, such as nonsteroidal anti-inflammatory agents, local anesthetics, blood circulation promoters, disinfectants, skin protectants, antibiotics, and cooling agents, in appropriate combinations. However, depending on the combination of ingredients, formulation problems may arise, such as difficulty in ensuring formulation stability, skin irritation, and poor usability.

[0003] For this reason, when designing a formulation, it is necessary to comprehensively consider not only the pharmacological action (efficacy and effect), but also the physical stability of the formulation, safety to the body, such as the skin, and usability.

[0004] Among the above-mentioned adrenocortical hormones, esterified steroids obtained by acetylating or valerylating a steroid having a hydroxyl group at the 17th or 21st position are known to be less stable, for example, being more susceptible to decomposition in formulations depending on the compound used in combination (see Patent Documents 1 and 2).

[0005] JP 2005-343890 A JP 2005-343891 A

[0006] An object of the present invention is to provide a betamethasone valerate-containing ointment composition having good formulation stability, and a method for improving or enhancing the formulation stability of the betamethasone valerate-containing ointment composition.

[0007]

[0003] In designing an ointment containing betamethasone valerate, the present inventors discovered that the coexistence of a lipophilic base with betamethasone valerate causes the liquid components to ooze out over time at room temperature, i.e., causes a bleeding phenomenon. To address this issue, the present inventors conducted extensive research and found that the use of a nonionic surfactant with an HLB of 5.0 or less in combination with betamethasone valerate and a lipophilic base significantly alleviates the bleeding phenomenon, thereby providing a betamethasone valerate-containing ointment with improved or enhanced formulation stability.

[0008] Based on these findings, further improvements were made and the present invention was completed, and includes the following embodiments. (I) Ointment composition containing betamethasone valerate (I-1) An ointment composition containing betamethasone valerate, a lipophilic base, and a nonionic surfactant having an HLB of 5.0 or less, preferably 1.0 to 5.0. (I-2) The ointment composition according to (I-1), further containing crotamiton. (I-3) The ointment composition according to (I-1) or (I-2), wherein the lipophilic base is at least one selected from the group consisting of petrolatum, paraffin, plastibase, lanolin, and beeswax. (I-4) The ointment composition according to any one of (I-1) to (I-3), wherein the nonionic surfactant is at least one selected from the group consisting of sorbitan fatty acid esters and glycerin fatty acid esters. (I-5) An ointment composition according to any one of (I-1) to (I-4), containing betamethasone valerate, a lipophilic base, and a nonionic surfactant having an HLB of 5.0 or less in the following proportions: betamethasone valerate: 0.0002 to 10% by mass, lipophilic base: 10 to 99.79% by mass, nonionic surfactant having an HLB of 5.0 or less: 0.1 to 20% by mass. (I-6) An ointment composition according to any one of (I-2) to (I-5), containing crotamiton in an amount of 0.1 to 20% by mass. (I-7) An ointment composition according to any one of (I-1) to (I-6), characterized in that bleeding is suppressed. (I-8) An ointment composition according to any one of (I-2) to (I-7), which is an ointment containing crotamiton, characterized in that segregation of crotamiton in the ointment composition is suppressed. (I-9) An ointment preparation comprising the ointment composition according to any one of (I-1) to (I-8) filled in a tube container.

[0009] (II) Method for Improving the Formulation Stability of an Ointment Composition Containing Betamethasone Valerate (II-1) A method for improving the formulation stability of an ointment composition containing a lipophilic base and betamethasone valerate, or betamethasone valerate and crotamiton as active ingredients, characterized in that the ointment composition is coexistent with a nonionic surfactant having an HLB of 5.0 or less, preferably an HLB of 1.0 to 5.0. (II-2) The method for improving the formulation stability described in (II-1), wherein the improvement in formulation stability is suppression of bleeding of the ointment composition and / or suppression of segregation of the active ingredient in the ointment composition. (II-3) The method for improving the formulation stability described in (II-1) or (II-2), wherein the lipophilic base is at least one selected from the group consisting of petrolatum, paraffin, plastibase, lanolin, and beeswax. (II-4) The method for improving the stability of a formulation according to any one of (II-1) to (II-3), wherein the nonionic surfactant is at least one selected from the group consisting of sorbitan fatty acid esters and glycerin fatty acid esters. (II-5) The method for improving the stability of a formulation according to any one of (II-1) to (II-4), wherein the formulation contains betamethasone valerate, a lipophilic base, and a nonionic surfactant having an HLB of 5.0 or less, preferably 1.0 to 5.0, in the following proportions: betamethasone valerate: 0.0002 to 10% by mass, lipophilic base: 10 to 99.79% by mass, and nonionic surfactant having an HLB of 5.0 or less: 0.1 to 20% by mass. (II-6) The method for improving the stability of a formulation according to any one of (II-1) to (II-5), wherein the content of crotamiton is 0.1 to 20% by mass.

[0010] According to the present invention, there is provided a betamethasone valerate-containing ointment composition having good formulation stability. More specifically, according to the present invention, there is provided a betamethasone valerate-containing ointment composition in which bleeding that occurs over time due to the incorporation of a lipophilic base is significantly suppressed by the incorporation of a nonionic surfactant having an HLB of 5.0 or less.

[0011] The present invention also provides an ointment composition containing betamethasone valerate and crotamiton, which has good formulation stability. More specifically, the present invention provides an ointment composition in which the segregation of crotamiton that occurs over time when a lipophilic base is added in addition to betamethasone valerate and crotamiton is significantly suppressed by adding a nonionic surfactant with an HLB of 5.0 or less, and crotamiton is stably dispersed in the lipophilic base without separation over time.

[0012] The results of Experimental Example 1 (bleeding evaluation test) are shown. Figure 1A shows the results of measuring the amount of syneresis over time and evaluating the bleeding rate (%) for an ointment containing betamethasone valerate, a lipophilic base, and no nonionic surfactant with an HLB of 5.0 or less (Comparative Example 1), and for ointments containing the nonionic surfactant (Examples 1 and 2). Figure 1B shows the results of measuring the amount of syneresis over time and evaluating the bleeding rate (%) for an ointment containing betamethasone valerate, crotamiton, a lipophilic base, and no nonionic surfactant with an HLB of 5.0 or less (Comparative Example 2), and for ointments containing the nonionic surfactant (Examples 3 and 4).

[0013] (I) Ointment composition containing betamethasone valerate The ointment composition containing betamethasone valerate of the present invention (hereinafter also simply referred to as "the composition") is a composition containing the following components (A), (B), and (C): (A) betamethasone valerate, (B) a lipophilic base, and (C) a nonionic surfactant having an HLB of 5.0 or less.

[0014] In addition to the components (A) and (B), the present composition may contain the following component (D): (D) Crotamiton.

[0015] These ingredients are explained below. (A) Component Betamethasone valerate is an esterified steroid in which the hydroxyl group at position 17 is valerated and the hydroxyl group at position 21 is acetylated. This compound is a strong steroid with anti-inflammatory activity and is known to improve the following symptoms: Eczema / dermatitis (including keratoderma tylodes palmaris progressiva, melasma facialis female, Vidal lichen, radiation dermatitis, and solar dermatitis), cutaneous pruritus, prurigo (including urticarial lichen, strophulus, and urticaria fixedis), insect bites, psoriasis, palmoplantar pustulosis, lichen planus, lichen nitidus, pityriasis rubra pilaris, pityriasis rosea gibertii, erythema (erythema exudativum multiforme, erythema nodosum, and erythema annulare centrifugally Darier), erythroderma (including erythroderma due to malignant lymphoma), chronic discoid lupus erythematosus, drug eruption / toxicosis, alopecia areata (including malignant), burns (including scars and keloids), chilblains, pemphigus, Juhring's herpetiform dermatitis (including pemphigoid), hemorrhoids, and surgical wounds from tympanoplasty, cochlear fenestration, and middle ear radical surgery.

[0016] The amount of component (A) contained in the present composition may be any amount that exerts the desired medicinal effect without interfering with the effects of the present invention, and can be appropriately set and adjusted within that range. For example, when the present composition is prepared as an external preparation (pharmaceutical preparation) for alleviating skin diseases (e.g., eczema, prurigo, dermatitis, psoriasis, etc.) that exhibit symptoms such as itching, redness, or swelling of the skin accompanied by inflammation, the content of component (A) in the present composition can be, for example, in the range of 0.0002 to 10% by mass. It is preferably 0.002 to 2% by mass, and more preferably 0.01 to 0.3% by mass.

[0017] Component (B) Component (B) may be any lipophilic base commonly used in the preparation of ointments. While not particularly limited thereto, examples include petrolatum, paraffin, plastibase, lanolin, and beeswax. Preferred lipophilic bases are those made of hydrocarbon oils such as petrolatum, paraffin, and plastibase. Examples of petrolatum include white petrolatum and yellow petrolatum. Examples of paraffin include liquid paraffin. More preferred examples include white petrolatum, liquid paraffin, and plastibase. These lipophilic bases may be used alone or in any combination of two or more.

[0018] The amount of component (B) contained in the present composition may be any amount that allows the composition to be molded into an ointment without impairing the effects of the present invention, and can be appropriately set and adjusted within that range. For example, the content of component (B) in the present composition can be appropriately selected and adjusted from the range of 10 to 99.79% by mass. It is preferably 80 to 99.7% by mass, and more preferably 90 to 99% by mass.

[0019] Component (C) The nonionic surfactant with an HLB of 5.0 or less to be incorporated as component (C) is one that can be incorporated into topical pharmaceuticals, quasi-drugs, or cosmetics. Examples of such nonionic surfactants include, but are not limited to, sorbitan fatty acid esters and glycerin fatty acid esters. Fatty acids that constitute these surfactants include fatty acids having 5 to 25 carbon atoms. For example, sorbitan fatty acid esters include sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate, as long as their HLB is 5.0 or less. Glycerin fatty acid esters also include glycerin caprylate, glycerin caprate, glycerin laurate, glycerin palmitate, glycerin oleate, glycerin stearate, glycerin dicaprylate, and glycerin tricaprylate, with the HLB limit being 5.0 or less. These sorbitan fatty acid esters and glycerin fatty acid esters may be used alone or in any combination of two or more. The HLB of both the sorbitan fatty acid esters and glycerin fatty acid esters is preferably in the range of 1.0 to 5.0, more preferably in the range of 2.0 to 5.0.

[0020] The amount of component (C) contained in the present composition may be within a range that achieves the effects of the present invention, and can be appropriately set and adjusted within that range. For example, the content of component (C) in the present composition can be appropriately selected and adjusted from a range of 0.1 to 20% by mass. It is preferably 1 to 10% by mass, and more preferably 3 to 8% by mass.

[0021] Component (D) In ​​addition to the aforementioned components (A) to (C), the present composition may contain crotamiton as component (D). The amount of component (D) contained in the present composition may be within a range that does not impair the effects of the present invention, and can be appropriately set and adjusted within that range. For example, the content of component (D) in the present composition can be appropriately selected and adjusted from a range of 0.1 to 20% by mass. It is preferably 1 to 15% by mass, and more preferably 5 to 10% by mass.

[0022] (E) Optional Pharmacologically Active Component The present composition may contain other pharmacologically active components in addition to the components described above, as long as the effects of the present invention are not impaired. Examples of such components include, but are not limited to, nonsteroidal anti-inflammatory agents, local anesthetics, antipruritics, blood circulation promoters, disinfectants, skin protectants, antibiotics, moisturizers, and / or cooling agents. These components may be any components that can be incorporated into topical preparations, particularly topical skin preparations. However, when the present composition is prepared as a topical preparation (pharmaceutical preparation) for ameliorating skin diseases (e.g., eczema, prurigo, dermatitis, psoriasis, etc.) that exhibit symptoms such as itching, redness, or swelling of the skin accompanied by inflammation, it is preferable that the components be components that can be incorporated into such topical preparations.

[0023] (F) Optional Carriers and Additives In addition to the above-mentioned components, the present composition may optionally contain conventionally known carriers and additives used in the manufacture of ointments, as long as the effects of the present invention are not impaired. Examples of such carriers and additives include, without limitation, excipients, thickeners, antioxidants, buffers, emulsifiers, pH adjusters, dispersants, solubilizers, fluidizers, colorants, preservatives, and / or fragrances.

[0024] The present composition can be prepared in the form of an ointment by mixing at least components (A) to (C) or components (A) to (D) among the aforementioned components with component (E) and / or component (F), as needed, according to a conventional method for preparing an ointment. The prepared ointment (paste base) can be filled into a conventional tube container and provided as an ointment formulation.

[0025] The present composition thus prepared in the form of an ointment can be suitably used as an external preparation (pharmaceutical preparation) for alleviating skin diseases (e.g., eczema, prurigo, dermatitis, psoriasis, etc.) exhibiting symptoms such as itching, redness, or swelling of the skin accompanied by inflammation. The application area is not limited, and the composition can be widely used on the skin in general, including the hands, feet, fingers, face, head, and body. It can also be applied to areas with thin keratin, such as the anal region and genital area. The amount and method of application to the skin are also not particularly limited, and the composition can 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. Although not limited, the amount of component (A) contained in a single application (single dose) of the present composition can be in the range of 10 to 1,000 mg. This range can be appropriately selected depending on the type of skin disease and the symptoms of the affected area.

[0026] (II) Method for Improving the Stability of Betamethasone Valerate-Containing Ointment Compositions The present invention provides a method for improving the stability of an ointment composition containing the aforementioned component (A) (a betamethasone valerate-containing ointment composition). As shown in the experimental examples described below, the incorporation of component (B) into component (A) reduces stability and causes bleeding over time, even when stored at 25°C. The bleeding phenomenon refers to the exudation of a liquid component (syringe phenomenon). This phenomenon is more pronounced when component (A) and component (B) are combined with crotamiton (D), a low-melting substance (melting point <25°C). This also causes the problem of segregation of component (D) in the plaster base. These bleeding and segregation problems can be significantly improved by incorporating the aforementioned component (C) into these compositions (compositions containing components (A) and (B), and compositions containing components (A), (B), and (D)) and allowing the coexistence of this component.

[0027] The "improvement of the stability of betamethasone valerate-containing ointment compositions" of the present invention preferably includes the suppression of bleeding over time, which occurs when component (B) is incorporated into a betamethasone valerate-containing composition. When a composition (subject to measurement) containing at least components (A) to (C) or components (A) to (D) exhibits a smaller amount of syneresis over time than a comparison composition (comparison) consisting of the same components as the composition but excluding component (C), the former composition can be determined to have improved stability due to the suppression of bleeding by the incorporation of component (C). The presence or absence of bleeding over time can be evaluated by storing the subject composition and the comparison composition in a dark place under constant temperature and humidity conditions of 25°C and 60% RH for approximately 1 to 4 weeks, measuring the amount of syneresis over time, and comparing the amounts. For details, see Experimental Example 1 below.

[0028] Furthermore, the "improvement of the stability of betamethasone valerate-containing ointment compositions" of the present invention preferably includes suppressing the segregation of component (D) over time, which occurs when components (B) and (D) are blended into a betamethasone valerate-containing composition. When a composition (subject to measurement) containing at least components (A) to (D) exhibits less segregation of component (D) over time than a comparison composition (comparison) consisting of the same components as the composition but excluding component (C), it can be determined that the incorporation of component (C) inhibits the segregation of component (D) in the former composition, thereby improving its stability. The presence or absence of segregation of component (D) over time can be evaluated by storing the subject composition and the comparison composition in a dark place under constant temperature and humidity conditions of 40°C and 75% RH for approximately three months, measuring the segregation of component (D) in the ointment, and comparing the degree of segregation. For details, see Experimental Example 2 below.

[0029] The method for making component (C) coexist in a composition containing components (A) and (B) (or components (A), (B), and (D)) is not limited as long as it achieves the effects of the present invention. For example, the method may involve forming a coexistence state of components (B) and (C) and then sequentially dispersing component (A) or components (A) and (D) into the resulting composition. Furthermore, the aforementioned component (E) and / or component (F) may also be incorporated as other components, provided that the effects of the present invention are not impaired. These components are mixed to form a coexistence state of at least components (A) to (C) or components (A) to (D), and then the resulting composition is formulated into an ointment by a conventional method. The proportions and blending ratios of the components in the composition are as described in (I) above, and the description is incorporated herein by reference.

[0030] As described above, in this specification, the terms "comprise" and "contain" encompass the meanings of "consist of" and "consist essentially of."

[0031] The present invention will be described below using experimental examples to aid in understanding the configuration and effects of the present invention. However, the present invention is not limited by these experimental examples. Unless otherwise specified, the following experiments were carried out at room temperature (25±5°C) and atmospheric pressure. Unless otherwise specified, "%" and "parts" in the following descriptions mean "% by mass" and "parts by mass," respectively.

[0032] The compounds used in the following experimental examples are as follows: Betamethasone valerate (apparent specific gravity (density) 0.16 g / mL): available from Sicor Crotamiton (specific gravity 0.98, melting point 25°C or lower): available from Sumitomo Chemical Co., Ltd. Liquid paraffin (specific gravity 0.88): available from SONNEBORN White petrolatum (specific gravity 0.85): available from CALUMET (trade name: Snow White V) Sorbitan fatty acid ester: NIKKOL SS-15V (HLB 5.0: available from Nikko Chemicals Co., Ltd.) Glycerin fatty acid ester: SY Glystar TS-3S (HLB 4.0: available from Sakamoto Pharmaceutical Co., Ltd.)

[0033] Experimental Example 1 Preparation of Ointment Compositions Containing Betamethasone Valerate and Evaluation Thereof Ointment compositions containing betamethasone valerate were prepared and evaluated for bleeding (syringe, exudation) and spreadability.

[0034] (1) Preparation of Ointments Semi-solid betamethasone valerate-containing ointment compositions (Comparative Examples 1 and 2, Examples 1 to 4) were prepared by mixing the components listed in Table 1. Examples 1 and 2 and Comparative Example 1 were prepared by dissolving component (C) in component (B), adding component (A) to the solution, and mixing. Examples 3 and 4 and Comparative Example 2 were prepared by dissolving component (C) in component (B), and dispersing component (A) and component (D) in that order. The ointments (plaster bases) thus prepared were immediately subjected to the experiments described below after preparation.

[0035] (2) Bleeding Evaluation (a) Test Method 10 g of each ointment (plaster mass) prepared above was filled into the conical tip of a cone mesh (mesh pore size: 45 μm, φ50 mm × H60 mm), and this was placed in a glass beaker and left to stand for 4 weeks under an environment of 25°C / 60% RH, and the amount of liquid (low-melting point substance) dripping from the tip of the wire mesh of the cone mesh was measured over time. The bleeding rate (%), which is an index of the ease of bleeding of the liquid portion, was calculated from the drip amount (g) measured after 1 week and 4 weeks.

[0036] The bleeding rates (%) after 1 week and 4 weeks were calculated by measuring the mass of the glass beaker that had received the liquid dripping from the cone mesh after 1 week and 4 weeks of static storage, and then calculating the bleeding rates (%) based on the following formula.

[0037] <Formula> Bleeding rate (%) = ([A-B] / C) x 100 A: Mass (g) of glass beaker (including contents) after test B: Mass (g) of empty glass beaker C: Amount of plaster filled (g) (10g).

[0038] (b) Test Results The results are shown in Figure 1. Figure 1A shows the results of Comparative Example 1 and Examples 1 and 2, and Figure 1B shows the results of Comparative Example 2 and Examples 3 and 4. As shown in Figure 1, when betamethasone valerate was present in the presence of a lipophilic base, a liquid oozed out over time (bleeding phenomenon) (Comparative Example 1). While not intended to be limiting, the oozed liquid is thought to be derived from low-melting-point substances in the liquid paraffin and white petrolatum. Furthermore, it was confirmed that the bleeding phenomenon was further increased by the presence of crotamiton, a low-melting-point substance, in the presence of betamethasone valerate (Comparative Example 2). The bleeding phenomenon observed in the betamethasone valerate-containing ointments of Comparative Examples 1 and 2 was significantly improved by the presence of a nonionic surfactant with an HLB of 5 or less, confirming that the storage stability of the ointment (storage stability of betamethasone valerate and crotamiton in the lipophilic base) was improved.

[0039] (3) Evaluation of Spreadability (a) Test Method The ointments (plaster bases) prepared above (Comparative Examples 1 and 2, Examples 3 and 4) were stored in an environment of 25°C / 60% RH for 8 weeks, and then the spreadability (ease of spreading) was evaluated by measuring the fluidity at 23 to 25°C using a spread meter (manufactured by Imoto Machinery Co., Ltd.). (b) Test Results The results are shown in Table 2. Table 2 also shows the bleeding rate (%) measured after the same 8-week storage.

[0040] As shown in Table 2, it was confirmed that the incorporation of a nonionic surfactant with an HLB of 5 or less in addition to betamethasone valerate, crotamiton, and a lipophilic base (Examples 3 and 4) slightly reduced the spreadability (ease of spreading the ointment); in other words, slightly increased the viscosity of the ointment base, compared with the incorporation of no nonionic surfactant (Comparative Examples 1 and 2). A characteristic of nonionic surfactants with an HLB of 5 or less is that they dissolve in a lipophilic base and then form a gel structure in the base without crystallizing upon cooling. Therefore, without being bound by theory, it is believed that the bleeding phenomenon is significantly reduced in the ointment composition of the present invention by stably dispersing crotamiton in a lipophilic base containing a gelled nonionic surfactant.

[0041] Experimental Example 2: Evaluation of Segregation of Components in Betamethasone Valerate-Containing Ointment Compositions To evaluate the storage stability of betamethasone valerate-containing ointment compositions, the content segregation of the component (crotamiton) was measured using the betamethasone valerate-containing ointment compositions (Comparative Example 2, Examples 3 and 4) prepared in Experimental Example 1 above. Specifically, betamethasone valerate-containing ointment compositions (Comparative Example 2, Examples 3 and 4) were prepared by the method described in Experimental Example 1, and 5 g of each was filled into a tubular aluminum container (φ: 13.8 mm, length: 75 mm) and stored in a sealed state under an environment of 40°C / 75% RH for 3 months. After storage, the container was opened so as not to lose the shape of the ointment mass filled inside the tubular container, and the approximately cylindrical ointment mass was divided into three equal parts (fractions 1 to 3). The crotamiton content in each fraction was measured by liquid chromatography.

[0042] From the measured values, the percentage was determined with the initial crotamiton content (5% by mass in the ointment) taken as 100, and the standard deviation was calculated for fractions 1 to 3. The results are shown in Table 3.

[0043] As shown in Table 3, the ointment containing no nonionic surfactant (Comparative Example 2) was found to experience segregation of crotamiton during storage, whereas this phenomenon was significantly improved by adding a nonionic surfactant with an HLB of 5 or less (Examples 3 and 4). This demonstrates that the incorporation of a nonionic surfactant with an HLB of 5 or less in an ointment containing betamethasone valerate, crotamiton, and a lipophilic base stabilizes the formulation and inhibits segregation of crotamiton, a low-melting substance.

Claims

1. an ointment composition comprising betamethasone valerate, a lipophilic base, a nonionic surfactant having an HLB of 5.0 or less, and crotamiton; However, this does not include ointment compositions containing betamethasone valerate, diphenhydramine or a salt thereof, dibutylhydroxytoluene, and menthol.

2. 2. The ointment composition according to claim 1, wherein the lipophilic base is at least one selected from the group consisting of petrolatum, paraffin, plastibase, lanolin, and beeswax.

3. 3. The ointment composition according to claim 1, wherein the nonionic surfactant is at least one selected from the group consisting of sorbitan fatty acid esters and glycerin fatty acid esters.

4. The ointment composition according to any one of claims 1 to 3, comprising betamethasone valerate, a lipophilic base, and a nonionic surfactant having an HLB of 5.0 or less in the following proportions: Betamethasone valerate: 0.0002 to 10% by mass, Lipophilic base: 10 to 99.79% by mass, Nonionic surfactants with an HLB of 5.0 or less: 0.1 to 20% by mass.

5. 5. The ointment composition according to claim 1, wherein the content of crotamiton is 0.1 to 20% by mass.

6. 6. The ointment composition according to claim 1, wherein bleeding is suppressed.

7. An ointment composition described in any one of claims 1 to 6, characterized in that segregation of crotamiton in the ointment composition is suppressed.

8. An ointment preparation comprising the ointment composition according to any one of claims 1 to 7 packed in a tube container.

9. A method for improving the formulation stability of an ointment composition containing a lipophilic base and, as active ingredients, betamethasone valerate and crotamiton, characterized in that a nonionic surfactant having an HLB of 5.0 or less is coexisted in the ointment composition; However, the ointment compositions exclude ointment compositions containing betamethasone valerate, diphenhydramine or a salt thereof, dibutylhydroxytoluene, and menthol.

10. 10. The method for improving the stability of a formulation according to claim 9, wherein the improvement of the stability of a formulation is suppression of bleeding of an ointment composition and / or suppression of segregation of an active ingredient of an ointment composition.

11. 11. The method for improving the stability of a formulation according to claim 9 or 10, wherein the lipophilic base is at least one selected from the group consisting of petrolatum, paraffin, plastibase, lanolin, and beeswax.

12. The method for improving the stability of a formulation according to any one of claims 9 to 11, wherein the nonionic surfactant is at least one selected from the group consisting of sorbitan fatty acid esters and glycerin fatty acid esters.

13. The method for improving the stability of a formulation according to any one of claims 9 to 12, comprising the following proportions of betamethasone valerate, a lipophilic base, and a nonionic surfactant having an HLB of 5.0 or less: Betamethasone valerate: 0.0002 to 10% by mass, Lipophilic base: 10 to 99.79% by mass, Nonionic surfactants with an HLB of 5.0 or less: 0.1 to 20% by mass.

14. The method for improving the stability of a formulation according to any one of claims 9 to 13, wherein the content of crotamiton is 0.1 to 20% by mass.