Betamethasone valerate-containing ointment composition

Abstract

The present invention provides a betamethasone valerate-containing ointment composition having good formulation stability. [Solution] The above ointment composition can be prepared by combining betamethasone valerate and a lipophilic base, or betamethasone valerate, a lipophilic base, and crotamiton with a nonionic surfactant with an HLB of 5.0 or less.

Description

Technical Field

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

Background Art

[0002] Compounds having a steroid skeleton are known to exhibit high physiological activity even in trace amounts. Among them, adrenocortical hormones are effective in ameliorating symptoms such as inflammatory pruritus, redness, and swelling of the skin, and are widely used for the treatment of eczema (including eczema due to atopic dermatitis; the same applies hereinafter), prurigo (including prurigo caused by miliaria, urticaria, contact dermatitis, insect bites, etc.; the same applies hereinafter), dermatitis, psoriasis and the like. Usually, in external preparations containing adrenocortical hormones, other active ingredients such as non-steroidal anti-inflammatory agents, local anesthetics, blood circulation promoters, bactericides, skin protectants, antibiotics, refreshing agents and the like are appropriately combined and incorporated. However, depending on the combination of the incorporated components, formulation problems may arise, such as difficulty in ensuring formulation stability, induction of skin irritation, and poor feeling upon use.

[0003] For this reason, in the design of formulations, it is necessary to comprehensively consider not only the pharmacological action (efficacy and effects) but also the physical stability of the formulation, safety to living bodies such as the skin, and feeling upon use.

[0004] Among the aforementioned adrenocortical hormones, esterified steroids obtained by acetylating or valerylating steroids having a hydroxyl group at the 17-position or 21-position are known to have reduced stability, such as being more prone to degradation in the formulation depending on the co-used compound (see Patent Documents 1 and 2).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

[0006] The present invention aims to provide a betamethasone valerate-containing ointment composition having good formulation stability. Furthermore, the present invention aims to provide a method for improving or enhancing the formulation stability of the betamethasone valerate-containing ointment composition. [Means for solving the problem]

[0007] The present inventors, in designing an ointment containing betamethasone valerate, discovered that when a lipophilic base is present with betamethasone valerate, liquid components seep out over time under room temperature conditions, i.e., a bleeding phenomenon occurs. Therefore, in order to resolve this, they diligently conducted research and found that by further using a nonionic surfactant with an HLB of 5.0 or less in combination with betamethasone valerate and a lipophilic base, the bleeding phenomenon is significantly improved, and a betamethasone valerate-containing ointment with improved formulation stability can be obtained.

[0008] The present invention has been completed through further improvements based on these findings and includes the following embodiments. (I) Betamethasone valerate-containing ointment composition (I-1) An ointment composition containing betamethasone valerate, a lipophilic base, and a nonionic surfactant with an HLB of 5.0 or less, preferably 1.0 to 5.0. (I-2) The ointment composition described in (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 with an HLB of 5.0 or less in the following proportions: Betamethasone valerate: 0.0002-10% by mass, Lipophilic base: 10~99.79% by mass, Nonionic surfactants with an HLB of 5.0 or less: 0.1 to 20% by mass. (I-6) An ointment composition according to any one of items (I-2) to (I-5), wherein the crotamiton content is 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 containing crotamiton, characterized in that segregation of crotamiton in the ointment composition is suppressed, as described in any one of (I-2) to (I-7). An ointment preparation comprising an ointment composition described in any one of items (I-9), (I-1), to (I-8), filled into a tube container.

[0009] (II) Method for improving the formulation stability of a betamethasone valerate-containing ointment composition (II-1) A method for improving the formulation stability of an ointment composition comprising a lipophilic base and betamethasone valerate, or betamethasone valerate and crotamiton as active ingredients, characterized in that a nonionic surfactant with an HLB of 5.0 or less, preferably 1.0 to 5.0, is present in the ointment composition. (II-2) The method for improving formulation stability as described in (II-1), wherein the improvement in formulation stability is the suppression of bleeding of the ointment composition and / or the suppression of segregation of the active ingredient of the ointment composition. (II-3) The method for improving the stability of a pharmaceutical formulation according to (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) A method for improving the stability of a pharmaceutical 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) A method for improving the stability of a formulation as described in any one of (II-1) to (II-4), comprising betamethasone valerate, a lipophilic base, and a nonionic surfactant with an HLB of 5.0 or less, preferably 1.0 to 5.0, in the following proportions: Betamethasone valerate: 0.0002-10% by mass, Lipophilic base: 10~99.79% by mass, Nonionic surfactants with an HLB of 5.0 or less: 0.1 to 20% by mass. (II-6) A method for improving the stability of a pharmaceutical product as described in any one of items (II-1) to (II-5), wherein the crotamiton content is 0.1 to 20% by mass. [Effects of the Invention]

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

[0011] Furthermore, according to the present invention, it is possible to provide an ointment composition containing betamethasone valerate and crotamiton and having excellent formulation stability. More specifically, according to the present invention, segregation of crotamiton that occurs over time due to the addition of a lipophilic base to betamethasone valerate and crotamiton is significantly suppressed by adding a nonionic surfactant with an HLB of 5.0 or lower, making it possible to provide an ointment composition in which crotamiton is stably dispersed in the lipophilic base without separating over time. [Brief Description of Drawings]

[0012] [Figure 1] 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 not formulated with a nonionic surfactant having an HLB of 5.0 or lower (Comparative Example 1) in addition to betamethasone valerate and a lipophilic base, as well as for ointments formulated with said 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 not formulated with a nonionic surfactant having an HLB of 5.0 or lower (Comparative Example 2) in addition to betamethasone valerate, crotamiton and a lipophilic base, as well as for ointments formulated with said nonionic surfactant (Examples 3 and 4). [Modes for Carrying Out the Invention]

[0013] (I) Betamethasone valerate-containing ointment composition The betamethasone valerate-containing ointment composition of the present invention (hereinafter also simply referred to as "the present composition") is a composition containing the following components (A), (B) and (C). (A) Betamethasone valerate (B) Lipophilic base, and (C) Nonionic surfactant with an HLB of 5.0 or lower.

[0014] The present composition may contain the following component (D) in addition to the aforementioned components (A) and (B). (D) Crotamiton.

[0015] The following explains these ingredients. (A) component Betamethasone valerate is an esterified steroid in which the hydroxyl group at position 17 is valerylated and the hydroxyl group at position 21 is acetylated. This compound is a strong steroid with anti-inflammatory properties and is known to improve the following symptoms: Eczema and dermatitis (including progressive palmar and plantar keratoderma, female facial melanosis, lichen simplex chronicus, radiation dermatitis, and photodermatitis), pruritus, prurigo (including lichen urticarialis, strophulus, and fixed urticaria), insect bites, psoriasis, palmoplantar pustulosis, lichen planus, lichen patella, pityriasis rubra pilaris, pityriasis rosea, erythema (erythema multiforme, erythema nodosum, erythema annulare centrifugal), erythroderma (including erythroderma due to malignant lymphoma), chronic discoid lupus erythematosus, drug eruptions and toxicoderma, alopecia areata (including malignant), burns (including scars and keloids), chilblains, pemphigus, dermatitis herpetiformis (including bullous pemphigoid), hemorrhoids, surgical wounds from tympanoplasty, inner ear fenestration, and radical middle ear surgery.

[0016] The amount of component (A) contained in this composition may be any amount that exhibits the desired pharmacological effect without hindering the effects of the present invention, and can be appropriately set and adjusted within that range. For example, when this composition is prepared as a topical preparation (pharmaceutical preparation) to improve skin diseases (e.g., eczema, prurigo, dermatitis, or psoriasis) that have symptoms such as itching, redness, or swelling of the skin accompanied by inflammation, the content of component (A) in this composition can be exemplified as being in the range of 0.0002 to 10% by mass. Preferably, it is 0.002 to 2% by mass, and more preferably 0.01 to 0.3% by mass.

[0017] (B) Component (B) The component may be any lipophilic base commonly used in the preparation of ointments. In this respect, it is not particularly limited, but examples include petrolatum, paraffin, Plastibase, lanolin, and beeswax. Preferably, it is a lipophilic base consisting of hydrocarbon oils such as petrolatum, paraffin, and Plastibase. The petrolatum includes white petrolatum and yellow petrolatum. The paraffin includes liquid paraffin. More preferably, white petrolatum, liquid paraffin, and Plastibase can be used. These lipophilic bases may be used individually or in any combination of two or more.

[0018] The amount of component (B) contained in this composition is sufficient to allow the composition to be formed into an ointment without hindering the effects of the present invention, and can be appropriately set and adjusted within that range. For example, the content of component (B) in this composition can be appropriately selected and adjusted from the range of 10 to 99.79% by mass. Preferably it is 80 to 99.7% by mass, and more preferably 90 to 99% by mass.

[0019] (C) Component (C) The nonionic surfactants to be included as components have an HLB of 5.0 or less and are suitable for inclusion in topical pharmaceuticals, quasi-drugs, or cosmetics. Examples of such nonionic surfactants, though not limited, include sorbitan fatty acid esters and glycerin fatty acid esters. The fatty acids constituting these surfactants may include fatty acids with 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, sorbitan penta-2-ethylhexyl diglycerol sorbitan, and tetra-2-ethylhexyl diglycerol sorbitan, with an HLB of 5.0 or less. Glycerin fatty acid esters also include caprylic acid glycerin, capric acid glycerin, laurate glycerin, palmitate glycerin, oleate glyceryl, stearate glyceryl, dicaprylate glyceryl, and tricaprylate glyceryl, with an HLB of 5.0 or less. These sorbitan fatty acid esters and glycerol fatty acid esters may be used individually or in any combination of two or more types. The HLB of both the sorbitan fatty acid ester and the glycerol fatty acid ester is preferably in the range of 1.0 to 5.0, and more preferably in the range of 2.0 to 5.0.

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

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

[0022] (E) Any pharmacologically active ingredient The composition may contain other pharmacologically active ingredients in addition to the ingredients described above, to the extent that they do not interfere with the effects of the present invention. Examples of such ingredients, though not limited to them, include nonsteroidal anti-inflammatory agents, local anesthetics, antipruritics, blood circulation promoters, bactericides, skin protectants, antibiotics, moisturizers, and / or cooling agents. These may be any ingredients that can be incorporated into topical preparations, particularly topical skin preparations. However, when the composition is prepared as a topical formulation (pharmaceutical preparation) to improve skin diseases with symptoms such as itching, redness, or swelling of the inflamed skin (e.g., eczema, prurigo, dermatitis, or psoriasis), it is preferable that the ingredients be those that can be incorporated into the topical formulation.

[0023] (F) Any carrier / additive In addition to the components described above, this composition may optionally contain conventionally known carriers and additives used in the manufacture of ointments, to the extent that they do not interfere with the effects of the present invention. Examples of these carriers and additives include, without limitation, excipients, thickeners, antioxidants, buffers, emulsifiers, pH adjusters, dispersants, solubilizers, fluidizers, colorants, preservatives, and / or fragrances.

[0024] This composition can be manufactured in the form of an ointment by mixing at least components (A) to (C) or components (A) to (D) from the aforementioned components with components (E) and / or (F) as needed, according to conventional methods for manufacturing ointments. The manufactured ointment (paste) can then be filled into conventional tube containers and provided as an ointment formulation.

[0025] The composition thus prepared in the form of an ointment can be suitably used as a topical preparation (pharmaceutical preparation) to improve skin diseases (e.g., eczema, prurigo, dermatitis, or psoriasis) that have symptoms such as itching, redness, or swelling of the skin accompanied by inflammation. The application area is not limited and can be broadly used on the skin in general, including the hands, feet, fingers, face, head, and body. It can also be applied to areas where the stratum corneum of the skin is thin, such as around the anus and genitals. The amount and method of application to these areas of skin are not particularly limited and can be used by applying an appropriate amount to the skin or other external surface 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 amount (single dose) of this composition can be exemplified as being in the range of 10 to 1000 mg. Within this range, it 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) (an ointment composition containing betamethasone valerate). As shown in the experimental examples described later, when component (B) is combined with component (A), stability decreases and bleeding occurs over time, even when stored at 25°C. The bleeding phenomenon refers to the phenomenon of liquid components seeping out (syneresis). This phenomenon becomes even more pronounced when component (A) and component (B) are combined with (D) crotamiton (melting point < 25°C), which is a low-melting-point substance. In this case, the problem of component (D) segregation in the ointment also arises. These problems of bleeding and segregation can be significantly improved by combining these compositions (compositions containing components (A) and (B), and compositions containing components (A), (B), and (D)) with the aforementioned component (C).

[0027] The "improvement of the stability of betamethasone valerate-containing ointment compositions" targeted by the present invention preferably includes suppressing the time-dependent bleeding phenomenon that occurs when component (B) is incorporated into the betamethasone valerate-containing composition. If a composition containing at least components (A) to (C) or components (A) to (D) (the subject of measurement) produces less syneresis over time compared to a composition consisting of the same components as above except for the absence of component (C) (the comparison subject), then it can be determined that the former composition has improved stability because the bleeding phenomenon is suppressed due to the inclusion of component (C). The presence or absence of bleeding over time can be evaluated by storing the composition to be measured and the comparison composition under constant temperature and humidity conditions of 25°C and 60%RH in the dark for about 1 to 4 weeks, measuring the amount of syneresis over time during that period, and comparing the amounts of syneresis. For details, please refer to the description in Experimental Example 1 below.

[0028] Furthermore, the "improvement of the stability of betamethasone valerate-containing ointment compositions" targeted by the present invention preferably includes suppressing the time-dependent segregation of component (D) that occurs when components (B) and (D) are blended into the betamethasone valerate-containing composition. If a composition containing at least components (A) to (D) (the subject of measurement) exhibits less time-dependent segregation of component (D) compared to a composition consisting of the same components as above except for the absence of component (C) (the comparison subject), then it can be determined that the former composition has improved stability because the segregation of component (D) is suppressed due to the inclusion of component (C). The presence or absence of segregation of component (D) over time can be evaluated by storing the composition to be measured and the comparison composition under constant temperature and humidity conditions of 40°C and 75%RH in the dark for about 3 months, and then measuring the segregation of component (D) content in the ointment and comparing the degree of segregation. For details, please refer to the description in Experimental Example 2 below.

[0029] The method for introducing component (C) into a composition containing components (A) and (B) (or components (A), (B), and (D)) is not limited to any method that yields the effects of the present invention. However, for example, a method may be used in which a coexistence state of component (B) and component (C) is formed, and component (A) or component (A) and component (D) are dispersed sequentially in this coexistence state. Furthermore, to the extent that it does not hinder the effects of the present invention, component (E) and / or component (F) described above may also be incorporated as other components. After mixing these components to form a coexistence state with at least components (A) to (C) or components (A) to (D), the mixture is prepared in the form of an ointment by conventional methods. The proportions of each component in the composition and the mixing ratios are as described in (I) above, and that description can be incorporated herein by reference.

[0030] In this specification, the terms “contains” and “includes” include the meanings of “consisting of” and “substantially consisting of.” [Examples]

[0031] The present invention will be described below using experimental examples to aid in understanding its structure and effects. However, the present invention is not limited in any way by these experimental examples. Unless otherwise specified, the following experiments were conducted at room temperature (25±5℃) and under atmospheric pressure conditions. Unless otherwise specified, "%" below means "mass percent" and "parts" means "parts by mass".

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

[0033] Experimental Example 1: Preparation and evaluation of a betamethasone valerate-containing ointment composition. Ointment compositions containing betamethasone valerate were prepared, and their bleeding (seizing, exudation) and spreadability were evaluated.

[0034] (1) Preparation of ointment Semi-solid betamethasone valerate-containing ointment compositions (Comparative Examples 1-2, Examples 1-4) 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) and then adding and mixing component (A). Examples 3 and 4 and Comparative Example 2 were prepared by dissolving component (C) in component (B) and then sequentially dispersing component (A) and component (D) in this mixture. The ointments thus prepared were immediately subjected to the experiments described later. [Table 1]

[0035] (2) Breeding evaluation (a) Test method Ten g of each ointment (paste) prepared as described above was filled into the cone tip of a cone mesh (mesh pore size: 45 μm, φ50 mm × H60 mm). This was then placed in a glass beaker and left to stand for four weeks at 25°C / 60% RH. The amount of liquid (low melting point substance) dripping from the wire mesh tip of the cone mesh was measured over time. The bleeding rate (%), an indicator of how easily the liquid seeps out, was calculated from the dripping amount (g) measured after one week and four weeks.

[0036] The bleeding rate (%) after one week and four weeks was calculated by measuring the mass of the glass beaker that received liquid dripping from the cone mesh one week and four weeks after static storage, and using the following formula.

[0037] <expression> Breeding rate (%) = ([A - B] / C) × 100 A: Mass (g) of the glass beaker (including contents) after the test. B: Mass of the empty glass beaker (g) C: Amount of plaster filling (g) (10g).

[0038] (b) Test results The results are shown in Figure 1. Figure 1A shows the results for Comparative Example 1 and Examples 1-2, and Figure 1B shows the results for Comparative Example 2 and Examples 3-4. As shown in Figure 1, when betamethasone valerate was present with a lipophilic base, it was observed that liquid seeped out over time (bleeding phenomenon) (Comparative Example 1). Although not constrained, the seeped-out liquid is thought to originate from low-melting-point substances in the liquid paraffin and white petrolatum. Furthermore, it was confirmed that this bleeding phenomenon was amplified when crotamiton, a low-melting-point substance, was present with 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, and it was confirmed that the storage stability of the ointment (storage stability of betamethasone valerate and crotamiton in a lipophilic base) was improved.

[0039] (3) Evaluation of ductility (a) Test method The ointments (pastes) prepared as described above (Comparative Examples 1 and 2, Examples 3 and 4) were stored for 8 weeks at 25°C / 60%RH. After storage, their spreadability (ease of spreading) was evaluated by measuring the fluidity under 23-25°C conditions using a spread meter (manufactured by Imoto Seisakusho). (b) Test results The results are shown in Table 2. Table 2 also includes the bleeding rate (%) measured after 8 weeks of storage. [Table 2]

[0040] As shown in Table 2, when a nonionic surfactant with an HLB of 5 or less was added to betamethasone valerate, crotamiton, and a lipophilic base (Examples 3 and 4), it was confirmed that the spreadability (ease of spreading of the ointment) was slightly reduced, or in other words, the viscosity of the ointment was slightly increased, compared to when this was not added (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, upon cooling, form a gel structure in the base without crystallization. Therefore, although not bound by theory, it is thought that the bleeding phenomenon was significantly reduced in the ointment composition of the present invention because crotamiton was stably dispersed in a lipophilic base containing a gelled nonionic surfactant.

[0041] Experimental Example 2: Evaluation of segregation of components in a betamethasone valerate-containing ointment composition. To evaluate the storage stability of the betamethasone valerate-containing ointment composition, the segregation of the component (crotamiton) was measured using the betamethasone valerate-containing ointment composition prepared in Experimental Example 1 (Comparative Example 2, Examples 3 and 4). Specifically, betamethasone valerate-containing ointment compositions (Comparative Example 2, Examples 3 and 4) were prepared using the method described in Experimental Example 1. 5 g of these compositions were filled into a tube-shaped aluminum container (φ: 13.8 mm, length: 75 mm), sealed, and stored at 40°C / 75% RH for 3 months. After storage, the container was opened carefully to avoid damaging the shape of the ointment inside the tube, and the roughly cylindrical ointment was divided into three equal parts (fractions 1-3). The crotamiton content in each fraction was measured by liquid chromatography.

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

[0043] As shown in Table 3, in the ointment without a nonionic surfactant (Comparative Example 2), crotamiton segregation was observed during storage. However, this was significantly improved by incorporating a nonionic surfactant with an HLB of 5 or less (Examples 3 and 4). From this, it was confirmed that by adding a nonionic surfactant with an HLB of 5 or less to an ointment containing betamethasone valerate, crotamiton, and a lipophilic base, the formulation is stabilized and segregation of crotamiton, a low-melting-point substance, can be suppressed.

Claims

1. Betamethasone valerate, Lipophilic base, and An ointment composition containing at least one nonionic surfactant with an HLB of 4.0 or higher and 5.0 or lower, selected from the group consisting of sorbitan fatty acid esters and glycerin fatty acid esters, and without water. The following ointment composition has the following proportions of each component per 100% by mass of the ointment composition: Betamethasone valerate: 0.01-0.3% by mass, Lipophilic base: 90% by mass or more, The aforementioned nonionic surfactant: 3 to 8% by mass.

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. An ointment composition according to claim 1 or 2, characterized in that bleeding is suppressed.

4. An ointment formulation comprising an ointment composition according to any one of claims 1 to 3, filled into a tube container.

5. A method for improving the formulation stability of an ointment composition containing 90 to 99.79% by mass of a lipophilic base and betamethasone valerate as an active ingredient, without water, The improvement in formulation stability is achieved by suppressing bleeding of the ointment composition. The ointment composition is characterized by containing at least one nonionic surfactant with an HLB of 4.0 or more and 5.0 or less, selected from the group consisting of sorbitan fatty acid esters and glycerin fatty acid esters. The method for improving the stability of the aforementioned pharmaceutical formulation.

6. The method for improving the stability of a pharmaceutical formulation according to claim 5, wherein the lipophilic base is at least one selected from the group consisting of petrolatum, paraffin, Plastibase, lanolin, and beeswax.

7. A method for improving the stability of a formulation according to claim 5 or 6, comprising betamethasone valerate and the nonionic surfactant in the following proportions: Betamethasone valerate: 0.0002 to 10% by mass, The aforementioned nonionic surfactant: 0.1 to 20% by mass.

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