JPWO2013111817A1 - Oil-in-water cream composition containing tacrolimus - Google Patents

Abstract

It is an object of the present invention to provide a tacrolimus-containing pharmaceutical composition which is a creamy external preparation having a good feeling of use and has a high active ingredient stability (residual ratio of active ingredient). The composition according to the present invention is an oil-in-water cream composition comprising (A) tacrolimus, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, (B It is characterized by comprising:) diethyl sebacate and / or diisopropyl sebacate, (C) polyoxyethylene hydrogenated castor oil, (D) a hydrophilic polymer, and (E) an antioxidant.

Description

  The present invention relates to an oil-in-water (O / W) creamy composition containing tacrolimus.

  Tacrolimus topical agent is known to have an excellent therapeutic effect on atopic dermatitis, and currently, Protopic (registered trademark) ointment 0.1% and Protopic (registered trademark) ointment as an oily ointment using an oily base 0.03% for children is commercially available. However, the oily ointment has the merit of excellent skin protection, but it is sticky when applied to the skin and is uncomfortable to use. Is required.

  A creamy external preparation is produced using an emulsion base formed by emulsifying oil and water with an emulsifier. However, since tacrolimus is unstable to water, the use of an emulsion base reduces the residual rate of tacrolimus and maintains its effectiveness (intradermal concentration) compared to the case of using an oil base. However, there is a problem that it is technically difficult.

  On the other hand, the preparation of a creamy pharmaceutical composition has been attempted in the past (see Patent Document 1), and the present applicant has previously filed a creamy pharmaceutical composition containing tacrolimus. (PCT / JP2011 / 066698), but still developed a composition that is easy to use, less irritating, has high stability of the active ingredient in the formulation, and can be easily adjusted to the optimal concentration of tacrolimus in the skin. It is hoped to do.

Special Table 2000-513739

   Therefore, the present invention is a creamy external preparation with a good feeling of use, has little irritation, high stability of tacrolimus in the preparation (main drug residual ratio), and further has a desired transdermal absorbability at the application site. It is an object of the present invention to provide a tacrolimus-containing pharmaceutical composition (external preparation for skin) that can be achieved.

  As a result of repeated studies to solve the above problems, the present inventors adopted a specific solubilizer (hereinafter also referred to as an oil agent) and an emulsifier, dissolved tacrolimus in the solubilizer, and used this as an internal phase. It has been found that the above-mentioned problems can be effectively solved by preparing an oil-in-water composition as (oil phase), and the present invention has been completed.

That is, the present invention is an oil-in-water cream composition,
(A) tacrolimus, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,
(B) diethyl sebacate and / or diisopropyl sebacate,
(C) polyoxyethylene hydrogenated castor oil,
(D) a hydrophilic polymer, and
(E) It contains an antioxidant.

  The cream-like composition according to the present invention is an oil-in-water type having an internal phase as an oil phase, and is the main agent in the oil phase, tacrolimus, a salt thereof, or a solvate thereof (hereinafter, representative of these). (Referred to as tacrolimus), the contact between the active ingredient and the aqueous phase (external phase) can be reduced, and water-unstable tacrolimus can be kept stable. In addition, by using diethyl sebacate and / or diisopropyl sebacate as the oil constituting the oil phase, and further using an antioxidant (preferably dibutylhydroxytoluene), the solubility of tacrolimus, the tacrolimus in the formulation An oil-in-water (O / W type) cream-like composition excellent in all of stability and transdermal absorbability of tacrolimus can be obtained. Moreover, the outstanding dispersibility can be achieved by using a hydrophilic polymer as a thickener and using polyoxyethylene hydrogenated castor oil as an emulsifier.

  According to the present invention, tacrolimus in a preparation can be stably maintained, an excellent medicinal effect can be exhibited, and a cream-like composition with less irritation and good feeling (less sticky) can be provided. .

It is a graph which shows the result of the in vitro skin permeability test regarding tacrolimus, (a) shows the amount of tacrolimus in human stratum corneum, and (b) shows the amount of tacrolimus in mouse skin.

The cream composition according to the present invention preferably contains 0.01 to 0.3% by weight of tacrolimus (A). When the content of tacrolimus is less than 0.01% by weight, the effectiveness is poor, and when it exceeds 0.3% by weight, there is a risk of safety.
As a pharmaceutically acceptable salt of tacrolimus, a non-toxic, pharmaceutically acceptable conventional salt can be used. Examples of such salts include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, amine salts (triethylamine salt, N-benzyl-N-methylamine). Salts with inorganic or organic bases such as salts).
Pharmaceutically acceptable solvates of tacrolimus include hydrates and ethanolates.
A particularly preferred compound as (A) of the present invention is tacrolimus hydrate.

In the creamy composition according to the present invention, diethyl sebacate and / or diisopropyl sebacate (B) is used as the oil agent constituting the oil phase. In the present invention, only diethyl sebacate and / or diisopropyl sebacate may be used as the oil constituting the oil phase, or other oil may be used in combination.
A particularly preferable example of the composition according to the present invention is a composition containing only diethyl sebacate or diisopropyl sebacate as an oil agent constituting the oil phase.

The total content of diethyl sebacate and / or diisopropyl sebacate in the composition is preferably 5 to 50% by weight. If it is less than 5% by weight, the stability and absorbability of tacrolimus are impaired, and if it exceeds 50% by weight, it is difficult to prepare an oil-in-water cream composition. A more preferable content is 5 to 40% by weight, a particularly preferable content is 5 to 25% by weight, and a still more preferable content is 10 to 20% by weight.
In order to achieve a refreshing feeling of use (light smooth feeling with reduced stickiness), the content of diethyl sebacate and / or diisopropyl sebacate is 20 wt% or less (more preferably 15 wt% or less, Particularly preferably, it is preferably 12% by weight or less. In the present invention, even if diethyl sebacate and / or diisopropyl sebacate is 20% by weight or less, a composition having excellent transdermal absorbability can be obtained.

In the present invention, the percutaneous absorbability of tacrolimus can be controlled by increasing or decreasing the amount of diethyl sebacate and / or diisopropyl sebacate.
The control of transdermal absorbability will be described in more detail. As a matter of course, a composition with high transdermal absorbability of tacrolimus is preferable when high drug efficacy is expected. On the other hand, tacrolimus has a strong immunosuppressive effect, and thus the frequency of side effects may increase due to an increase in blood concentration. For example, it is used on skin where the stratum corneum barrier function is reduced and the percutaneous absorption is increased, or on specific patients (for example, children, pregnant women, lactating women, elderly people, patients with liver disorders, etc.) In some cases, preparations with rather low absorbability may be desired.
In the present invention, by adjusting the amount of diethyl sebacate and / or diisopropyl sebacate, it is possible to control the absorbability to the skin while maintaining high formulation stability. Is possible.

The creamy composition according to the present invention contains polyoxyethylene hydrogenated castor oil (C) as an emulsifier (surfactant) for emulsifying and stabilizing an aqueous phase and an oil phase. By using polyoxyethylene hydrogenated castor oil, it is possible to prepare an oil-in-water cream composition having excellent emulsion stability. More preferred polyoxyethylene hydrogenated castor oil is one having an HLB value of 10.5 to 16.5, and particularly preferred polyoxyethylene hydrogenated castor oil is one having an HLB value of 12.5 to 15.0.
The content of polyoxyethylene hydrogenated castor oil in the composition is preferably 0.5 to 10% by weight. If it exceeds 10% by weight, the safety of the preparation may be a concern, and if it is less than 0.5% by weight, it is difficult to produce a stable oil-in-water cream composition. The content of polyoxyethylene hydrogenated castor oil is more preferably 1 to 6% by weight, particularly preferably 1.5 to 5% by weight, and further preferably 2 to 4% by weight.
Polyoxyethylene hydrogenated castor oil may be used alone or in combination. Specific examples of preferable polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil in which the number of addition polymerization of ethylene oxide is 20 to 100. An example of a particularly preferred polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60 (HLB value 14.0).

The cream-like composition according to the present invention contains a hydrophilic polymer (D) in order to increase the viscosity of the composition and ensure the stability as a preparation (prevent separation). The content of the hydrophilic polymer in the composition is preferably 0.1 to 10% by weight. If it exceeds 10% by weight, the preparation may be too hard to use, and if it is less than 0.1% by weight, it is difficult to produce a stable oil-in-water cream composition. A more preferable content of the hydrophilic polymer is 0.2 to 2% by weight.
Specific examples of preferable hydrophilic polymers include carboxyvinyl polymers and water-soluble cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydrophobized hydroxypropylmethylcellulose. These may be used alone or in combination. A particularly preferred hydrophilic polymer is a carboxyvinyl polymer.
Although the viscosity of the cream-like composition according to the present invention is not particularly limited, it is generally preferably 10,000 to 200,000 mPa · s, more preferably 2000 to 100,000 mPa · s. In the present invention, the viscosity means a viscosity when measured with a B-type viscometer (TVB-10H, rotor 7) at a measurement temperature of 25 ° C. and a rotation speed of 20 rpm for 30 seconds.

  The cream-like composition according to the present invention contains an antioxidant (E) in order to suppress the degradation of tacrolimus and increase the stability of the active ingredient. The content of the antioxidant in the composition is preferably 0.01 to 0.20% by weight, and more preferably 0.05 to 0.15% by weight. Whether the amount of antioxidant is too small or too large, the effect of increasing the stability of tacrolimus is weakened.

  Specific examples of the antioxidant (E) include dibutylhydroxytoluene, sodium nitrite, ascorbic acid, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, alphathioglycerin, erythorbic acid, cysteine hydrochloride, and dry sulfite. Sodium, tocopherol acetate, potassium dichloroisocyanurate, soy lecithin, sodium thioglycolate, sodium thiomalate, natural vitamin E, tocopherol, d-δ-tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, sodium pyrosulfite, butyl Hydroxyanisole, benzotriazole, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate], propyl gallate, 2-mercaptobenzimidazole , Carotenoids (astaxanthin, lycopene, etc.), flavonoids (isoflavones), polyphenols (anthocyanins, sesaminol, catechin etc.), and a coenzyme Q10.

  A particularly preferred antioxidant is dibutylhydroxytoluene. When dibutylhydroxytoluene is used as the antioxidant, a composition with very high stability of tacrolimus and very little irritation can be obtained.

  The creamy composition according to the present invention preferably has a pH value in the range of 4-7. When the pH value is less than 4, there is a risk of safety as a preparation, and when the pH value exceeds 7, the hydrolysis of diethyl sebacate and / or diisopropyl sebacate is a concern. Further, the above pH value is an optimum pH in terms of the stability of tacrolimus. A more preferred pH range is 5-6.

  Examples of the pH adjusting agent for adjusting the composition to a pH value in the above range include lactic acid, citric acid, and phosphoric acid, which are used to adjust to the low pH region, and adjust to the high pH region. Examples of those used include sodium hydroxide, potassium hydroxide, sodium lactate, sodium citrate, L-arginine, and diisopropanolamine. A particularly preferred pH adjusting agent is diisopropanolamine.

  The cream-like composition according to the present invention can contain a wetting agent, a preservative, a thickening aid, an emulsification aid and the like in addition to the above components.

  Examples of the wetting agent include 1,3-butylene glycol, glycerin, propylene glycol, dipropylene glycol and the like. A particularly preferred wetting agent is 1,3-butylene glycol. The content of the wetting agent in the composition is preferably in the range of 0.01 to 30% by weight, more preferably 1 to 20% by weight.

  Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, sodium benzoate, phenoxyethanol and the like. The preservative may be used alone or in combination. The content of the preservative in the composition is preferably in the range of 0.01 to 2% by weight, and more preferably in the range of 0.1 to 1.0% by weight. If it exceeds 2% by weight, the safety of the preparation may be a concern, and if it is less than 0.01% by weight, it is difficult to exert a sufficient storage effect.

  Examples of the thickening aid include edetate sodium hydrate, edetate tetrasodium hydrate, edetate tetrasodium tetrahydrate, sodium metaphosphate, and the like. The content of the thickening aid in the composition is preferably in the range of 0.005 to 1% by weight, more preferably in the range of 0.01 to 0.5% by weight. If it exceeds 1% by weight, the safety of the preparation may be a concern, and if it is less than 0.005% by weight, it will provide sufficient thickening support for hydrophilic polymers (thickeners). Is difficult. A particularly preferred thickening aid is sodium edetate hydrate.

  Examples of the emulsification aid include cetanol, stearyl alcohol, cetostearyl alcohol, and behenyl alcohol. A particularly preferred emulsification aid is cetanol. The content of the emulsification aid in the composition is preferably in the range of 0.1 to 5% by weight, more preferably 0.5 to 3% by weight, if necessary.

The cream-like composition according to the present invention contains water (purified water) constituting an aqueous phase. The water content in the composition varies depending on the content of other components, but is preferably about 45 to 85% by weight, more preferably about 55 to 82% by weight.
In addition, it is preferable that the cream-like composition according to the present invention does not contain a lower monohydric alcohol (monohydric alcohol having 1 to 3 carbon atoms) such as ethanol. This is because a lower monohydric alcohol such as ethanol has a high volatility, and there is a concern that the effect on the skin due to the addition to an external preparation is concerned.

  Preferred examples of the composition according to the present invention include tacrolimus hydrate as the main agent, 5 to 25% by weight of diethyl sebacate and / or diisopropyl sebacate (preferably either) as the oil agent, and polyoxyethylene hydrogenated castor as the emulsifier. Examples include oil 60, a composition containing carboxyvinyl polymer as a thickener and dibutylhydroxytoluene as an antioxidant. Examples of more preferable compositions include, in addition to the above, 1,3-butylene glycol as a wetting agent, and / or diisopropanolamine as a pH regulator, and / or sodium edetate as a thickening aid. Examples include compositions containing hydrates.

  In the preceding paragraphs, the names of preferred compounds of the essential components and optional components used in the composition of the present invention have been described. However, the composition of the present invention includes a composition obtained by arbitrarily combining them. Also included are compositions obtained by arbitrarily combining the concentration ranges described for each component. In addition, numerical ranges such as concentration, viscosity, pH value, etc. described in the preceding paragraph can be arbitrarily combined. When multiple numerical ranges are described, the upper limit value or lower limit value of each numerical range can be arbitrarily combined. It is.

  The amount and frequency of application of the composition according to the present invention to the skin may be appropriately adjusted according to skin symptoms, the concentration of tacrolimus in the composition, the age of the patient, and the like. In general, it is appropriate to apply 1 to 2 times a day. The daily dose is 5 mg or less for adults (not the composition, but mg of tacrolimus; the same applies in this paragraph). For children 1.5mg or less is appropriate (Dose as appropriate depending on the age and weight of the child. For example, for children under 20kg, the daily usage is 0.3mg or less, and for children between 20 and 30kg, the daily usage. 0.6 mg or less is appropriate).

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by an Example.
[Example 1] Preparation of O / W type creamy composition containing tacrolimus hydrate An O / W type creamy composition having the composition shown in Table 1 was prepared by the following method.
In advance, the carboxyvinyl polymer was swollen in purified water to obtain an aqueous carboxyvinyl polymer solution. Further, diisopropanolamine was dissolved in purified water to obtain a diisopropanolamine aqueous solution.
According to the formulation, tacrolimus hydrate, dibutylhydroxytoluene (hereinafter referred to as BHT in the examples), propyl paraoxybenzoate and cetanol are dissolved in the oil, polyoxyethylene hydrogenated castor oil is added, and the oil phase part It was. On the other hand, an aqueous carboxyvinyl polymer solution, 1,3-butylene glycol, methyl paraoxybenzoate, sodium edetate hydrate and purified water were combined to form an aqueous phase part.
The oil phase part and the water phase part were each heated to 70 to 90 ° C. and dissolved, and then the water phase part was added to the oil phase part and emulsified using a homomixer. Next, after adding an aqueous solution of diisopropanolamine, the mixture was stirred with a stir bar until the product temperature reached room temperature to prepare a homogeneous cream (viscosity 30000 to 60000 mPa · s).
However, the method for preparing the O / W type creamy composition is not limited to this.

  All of the compositions shown in Table 1 were creamy, and no separation or the like was observed in appearance, and it was possible to prepare a good O / W type creamy composition.

[Example 2] Stability evaluation of O / W type cream-like composition containing tacrolimus hydrate Cream-like compositions No. 2-4, No. 6, No. 8-10 prepared in Example 1 Store for 3 months under specified conditions, and measure tacrolimus hydrate content according to "16th revised Japanese Pharmacopoeia General Test Method Liquid Chromatography <2.01>". The residual rate of hydrate was calculated, and the stability of the active ingredient in the composition was evaluated. The results are shown in Table 2.

  As a result of the stability test of the creamy composition, the composition using No. 2 to No. 4, No. 6, No. 8 as the oil agent was more suitable as the oil agent using diethyl sebacate or diisopropyl sebacate. It showed higher stability of the active ingredient than the compositions using chain fatty acid triglycerides and ethylene glycol salicylate (No. 9 and 10). Further, when comparing compositions using diethyl sebacate or diisopropyl sebacate as an oil agent, composition No. 2 containing an antioxidant (BHT) compared to composition No. 8 containing no antioxidant, No.3, No.4 and No.6 showed higher active ingredient stability.

  Furthermore, Table 3 shows the results of stability tests performed over time for compositions Nos. 2 to 4, No. 6, No. 7, No. 9, and No. 10.

As shown in Table 3, compositions No. 9 and No. 10 were stored for 6 months when the storage conditions were `` 25 ° C., relative humidity 60% '' or `` 30 ° C., relative humidity 65% '' The residual rate of the active ingredient was 95% or more, but when the storage conditions were severe, `` 40 ° C, relative humidity 75% '', the residual rate of active ingredient after 3 months was less than 90% and after 6 months, About 80%. In contrast, compositions No. 2 to 4, No. 6, and No. 7, which are the compositions of the present invention, are main ingredients after 3 months even when the storage conditions are “40 ° C. and relative humidity 75%”. The residual rate was 95% or higher and / or the residual rate of the active ingredient after 6 months was 90% or higher, which proved that it could withstand long-term storage even under harsh conditions.
From the results of this Example, it was found that diethyl sebacate and diisopropyl sebacate are very suitable oil agents for suppressing the decomposition of the main agent over a long period of time.

[Example 3] Effectiveness of O / W type creamy composition (in vitro human skin permeability evaluation)
When the above compositions No. 2, No. 7 and Protopic (registered trademark) ointment 0.1% (hereinafter referred to as P ointment in the examples and figures) were applied to normal human skin (obtained through HAB Research Organization) The stratum corneum content at 24 hours after application was compared.
Human back skin (1.77 cm ² ) was attached to a Franz-type cell, and 10 mg of the composition No. 2, No. 7 or P ointment was hermetically applied. A receptor solution (1 w / v% bovine serum albumin-containing phosphate buffered saline) was collected after a predetermined time, and the amount of tacrolimus in the stratum corneum 24 hours after application was quantified.

  The results are shown in Table 4 and FIG. 1 (a). Composition No. 2 (oil agent: diethyl sebacate) and composition No. 7 (oil agent: diisopropyl sebacate) showed a drug amount in the stratum corneum similar to that of P ointment, which is a commercially available tacrolimus preparation.

[Example 4] Effectiveness of O / W type creamy composition (in vitro mouse skin permeability evaluation)
When the above composition Nos. 1 to 4 and P ointment were applied to hairless mouse skin (obtained through Hoshino test animal breeding house), the amounts in the skin 24 hours after application were compared.
Lab skin (1.77 cm ² ) was attached to a Franz-type cell, and 10 mg of the above composition No. 1 to 4 or P ointment was hermetically applied. A receptor solution (1 w / v% bovine serum albumin-containing phosphate buffered saline) was collected after a predetermined time, and the amount of tacrolimus in the skin 24 hours after application was quantified. The results are shown in Table 5 and FIG. 1 (b).

  As a result of the experiment, the composition No. 1 having a diethyl sebacate content of 5% by weight and the composition No. 2 having a diethyl sebacate content of 20% by weight were more preferable. It was found that the amount of tacrolimus hydrate permeated through the skin was higher than that of Composition No. 4 which was .3 and 40% by weight. Compositions No. 1 and No. 2 showed a higher skin permeation amount than P ointment.

From the results of the present example, it was found that the composition of the present invention can achieve high drug transdermal absorbability exceeding P ointment with a small amount of oil. By suppressing the oil agent to a small amount, a creamy composition with less stickiness and a refreshing feel can be prepared. According to the present invention, a composition having a high medicinal effect and a very good feeling of use is provided. can do.
Further, from the results of this example, according to the present invention, the skin absorbability can be controlled by the amount of oil added, and a safer formulation that exhibits the same medicinal effect even if the tacrolimus content is reduced as compared with P ointment. It turns out that development is possible.

[Example 5] Irritation (evaluation of cumulative skin irritation) of O / W type creamy composition
The cumulative skin irritation of compositions No. 2 and No. 7 was examined using female rabbits (Kbl: NZW).
Four sites of 2.5 × 2.5 cm administration sites (damaged skin) were provided on the back skin of rabbits with hair removal, and 0.05 mL / site of the above composition was administered openly for about 23 hours a day for 14 consecutive days (n = 3). Skin reaction was determined according to the criteria of Draize, JH (Appraisal of the safety of chemicals in foods, drugs and cosmetics, The Association of Food and Drug Officials of the United States, Topeka, Kansas, 46-59, 1965). The degree of cumulative skin irritation was evaluated based on the average value of the administration period of the average score on each judgment day.
The test results are shown in Tables 6 and 7. As can be seen from Table 7, the average value of the administration period of each composition was 0.7 for composition No. 2 and 1.1 for composition No. 7, both of which were classified as “weak stimulants”.

[Example 6] Irritation of O / W cream type composition (Evaluation of primary irritation of ocular mucosa)
The primary irritation of ocular mucosa of compositions No. 2 and No. 7 was examined using female rabbits (Kbl: NZW).
The above composition 0.1 mL / eye was administered once into the conjunctival sac of the rabbit, and eye washing was not performed (n = 3). The ocular reaction was determined by Draize, JH (Appraisal of the safety of chemicals in foods, drugs and cosmetics, Association of Food and Drug Officials of the United States, 49-51, 1959) at 1, 24 and 48 hours after administration. The ocular mucosal irritation intensity was evaluated according to AFNOR evaluation criteria (Association Francaise de Normalisation, Evaluation de I'Irritation et / ou de la Corrosion Oculaires chez le Lapin, NF T03-264, 1982).
The test results are shown in Table 8, and the evaluation criteria are shown in Table 9. As can be seen from Table 8, the highest total average score of each composition was 0.7 for composition No. 2 and 1.3 for composition No. 7, both of which were classified as “irritant”.

Comparing the results of Examples 5 and 6 with P ointment irritation data (for skin irritation, refer to the examination test results ¹⁾ , and for ocular mucosal irritation, refer to P ointment application data ²⁾⁾ . The degree of irritation of No.2 and composition No.7 is the same evaluation category for both compositions as P ointment (skin irritation: `` weak irritant '', ocular mucosa primary irritation: `` irritant '') It was classified into. From this, it was demonstrated that the composition according to the present invention has low irritation and no problem in clinical use.
¹⁾ As a result of a 14-day skin irritation test using rabbits, the average score from day 1 to day 14 of administration of P ointment was 0.2, and the substance was classified as “weak irritant”.
^{2) In} rabbit eye mucosa primary irritation test, no irritating findings of P ointment were observed.

  ADVANTAGE OF THE INVENTION According to this invention, the stability of tacrolimus is favorable, there is little irritation | stimulation, Furthermore, the cream-like composition which can control easily the skin concentration of an active ingredient can be provided. The cream-like composition according to the present invention is particularly suitable as a therapeutic agent for atopic dermatitis.

Claims (4)

(A) tacrolimus, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,
(B) diethyl sebacate and / or diisopropyl sebacate,
(C) polyoxyethylene hydrogenated castor oil,
(D) a hydrophilic polymer, and
(E) An oil-in-water cream composition comprising an antioxidant.   The composition according to claim 1, wherein the total content of diethyl sebacate and / or diisopropyl sebacate (B) is 5 to 25% by weight.   The composition according to claim 1 or 2, characterized in that the antioxidant (E) is dibutylhydroxytoluene.   The hydrophilic polymer (D) is one or more selected from the group consisting of carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and hydrophobized hydroxypropylmethylcellulose, The composition according to any one of claims 1 to 3.

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