External preparation composition

Abstract

Provided is a stable oil-in-water emulsified composition containing three components: urea, an ester steroid, and allantoin.　An oil-in-water emulsified composition containing the following components (A)-(D) and having a pH of 5-6. (A) Urea: 0.5-10 mass%, (B) an ester steroid: 0.05-0.3 mass%, (C) allantoin: 0.1-1 mass%, and (D) an amino acid or a salt thereof: 1-10 mass%

Description

[Technical field]

[0001] The present invention relates to an external preparation composition containing urea, an ester steroid and allantoin. [Background technology]

[0002] Urea has excellent effects of increasing the moisture retention of stratum corneum, improving the decrease in the moisture retention of the stratum corneum in dry keratosis, and dissolving and peeling keratin, and is used to treat ichthyosis, senile xerosis, atopic skin, progressive palmar keratosis, footplantar keratosis, palmoplantar keratosis, lichen pilaris, etc. However, urea is easily decomposed by acid, alkali, heat, etc. in the presence of water to generate ammonia, and it is known that, particularly in creams containing water, the product value decreases due to the generation of an ammonia odor and an increase in pH. As means for stabilizing such urea-containing preparations, the addition of allantoin (Patent Document 1), amino acids (Patent Documents 2 and 3), and lactic acid (Patent Document 4) have been reported.

[0003] On the other hand, ester steroids, typified by prednisolone valerate acetate, are widely used by external application to the skin as a treatment for skin diseases such as eczema / dermatitis, prurigo, insect bites, psoriasis, palmoplantar pustulosis, etc. The ester steroids are also susceptible to hydrolysis and have stability problems, and a technique for stabilizing the ester steroids by blending them with a basic local anesthetic and citric acid, lactic acid or malic acid (Patent Document 5), and a technique for blending menthol, camphor, or the like and a pH adjuster with the ester steroids (Patent Document 6) have been reported.

[0004] Allantoin is also used as a skin protective agent in cosmetics and the like because it has a tissue recovery effect, etc. Since allantoin also has a property of being easily hydrolyzed, a technique for stabilizing it by blending lactic acid has been reported (Patent Document 7). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 52-109487 [Patent Document 2] Japanese Patent Application Publication No. 59-134707 [Patent Document 3] Japanese Patent Publication No. 61-30509 [Patent Document 4] Special Publication No. 47-47662 [Patent Document 5] JP 2001-72603 A [Patent Document 6] JP 2005-350379 A [Patent Document 7] JP 2013-1651 A Summary of the Invention [Problem to be solved by the invention]

[0006] As described above, urea, ester-based steroids, and allantoin are each susceptible to hydrolysis, and therefore no topical composition containing these three ingredients simultaneously has been commercialized. Therefore, an object of the present invention is to provide an external preparation composition which contains these three components and is stable and has an excellent feel when used. [Means for solving the problem]

[0007] Therefore, the present inventors produced an oil-in-water emulsion composition containing the above-mentioned three components and conducted extensive research into its stability. As a result, they found that the three components could be stably maintained by adding a specific amount of an amino acid or a salt thereof to the above-mentioned three components and adjusting the pH to 5 to 6, thereby completing the present invention.

[0008] That is, the present invention provides the following [1] to [6].

[0009] [1] An oil-in-water emulsion composition containing the following components (A) to (D) and having a pH of 5 to 6: (A) Urea 0.5-10% by mass, (B) 0.05 to 0.3 mass% of an ester steroid, (C) 0.1 to 1% by mass of allantoin, and (D) Amino acid or its salt 1 to 10% by mass [2] The oil-in-water emulsion composition according to [1], further comprising (E) a hydroxy acid or a salt thereof. [3] The oil-in-water emulsion composition according to [1] or [2], further comprising (F) a local anesthetic. [4] The oil-in-water emulsion composition according to any one of [1] to [3], further comprising (G) a chelating agent. [5] The oil-in-water emulsion composition according to any one of [1] to [4], further comprising (H) a tocopherol selected from tocopherol, tocopherol acetate, and tocopherol nicotinate. [6] The oil-in-water emulsion composition according to any one of [1] to [5], further comprising one or more selected from a bactericide, an oily base, a polyhydric alcohol, an emulsifier, and water. Effect of the Invention

[0010] The present invention provides an external preparation composition that contains three ingredients, namely, urea, an ester-based steroid, and allantoin, which are useful for treating skin diseases but each of which has stability problems, and in which the stability of these three ingredients is maintained. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The oil-in-water emulsion composition of the present invention is characterized by containing the following components (A) to (D) and having a pH of 5 to 6. (A) Urea 0.5-10% by mass, (B) 0.05 to 0.3 mass% of an ester steroid, (C) 0.1 to 1% by mass of allantoin, and (D) 1 to 10% by mass of an amino acid or a salt thereof.

[0012] Component (A) is urea. The content of component (A) in the composition of the present invention is 0.5 to 10 mass%, preferably 0.5 to 8 mass%, more preferably 1 to 8 mass%, and further preferably 2 to 7 mass%, from the viewpoints of the action effect and stability of urea.

[0013] The ester steroid of component (B) may be any ester steroid used as an external preparation, and examples thereof include clobetasol propionate, diflorasone acetate, mometasone furoate, betamethasone butyrate propionate, fluocinonide, difluprednate, amcinonide, diflucortolone valerate, hydrocortisone butyrate propionate, deprodone propionate, dexamethasone acetate, betamethasone valerate, beclomethasone propionate, prednisolone acetate, prednisolone valerate acetate, alclometasone propionate, clobetasone butyrate, hydrocortisone butyrate, hydrocortisone acetate, and cortisone acetate. Of these, dexamethasone acetate, prednisolone acetate, prednisolone valerate acetate, hydrocortisone butyrate, hydrocortisone acetate, cortisone acetate, and betamethasone valerate are preferred, prednisolone valerate acetate, hydrocortisone butyrate, and betamethasone valerate are more preferred, and prednisolone valerate acetate is even more preferred. The content of component (B) in the composition of the present invention is 0.05 to 0.3 mass %, preferably 0.1 to 0.3 mass %, and more preferably 0.1 to 0.25 mass %, from the viewpoints of the action effect and stability of the ester steroid.

[0014] Component (C) allantoin has the chemical name 5-ureidohydantoin, and from the viewpoint of the action effect and stability of allantoin, the amount used in the composition of the present invention is 0.1 to 1 mass%, preferably 0.1 to 0.8 mass%, and more preferably 0.1 to 0.5 mass%.

[0015] The amino acid of component (D) may be an α-amino acid, specifically glycine, glutamic acid, aspartic acid, arginine, alanine, or a salt thereof. Of these, glycine, glutamic acid, and alanine are preferred in terms of the stability of components (A) to (C), and glycine and alanine are more preferred. As the salt of the amino acid, in the case of an acidic amino acid, an alkali metal salt such as a sodium salt or a potassium salt is used. In the case of a basic amino acid, a hydrochloride salt or the like is used. As these amino acids, any of the L-, D-, and DL-forms may be used. Furthermore, one or more of these amino acids may be used in combination. The content of component (D) in the composition of the present invention is 1 to 10 mass%, preferably 2 to 8 mass%, more preferably 3 to 7 mass%, and even more preferably 4 to 6 mass%, from the viewpoint of the stability of components (A) to (C).

[0016] In order to ensure the stability of the components (A) to (C), the composition of the present invention preferably further contains (E) a hydroxy acid or a salt thereof. As the hydroxy acid, aliphatic hydroxy acids such as lactic acid, citric acid, malic acid, and tartaric acid are preferred, lactic acid, citric acid, and malic acid are more preferred, and lactic acid and citric acid are even more preferred. As salts of these hydroxy acids, alkali metal salts such as sodium salts and potassium salts can be mentioned. These hydroxy acids or salts thereof can be used alone or in combination of two or more. These hydroxy acids or salts thereof also act as pH adjusters. The content of component (E) in the composition of the present invention is 0.5 to 3 mass %, preferably 0.5 to 2 mass %, and more preferably 0.5 to 1.5 mass %, from the viewpoint of the stability of components (A) to (C).

[0017] The composition of the present invention preferably contains (F) a local anesthetic from the viewpoints of the stability of the components (A) to (C) and suppressing itching, pain, hot flashes, irritation, etc. of the skin. Examples of local anesthetics include lidocaine, dibucaine, tetracaine, oxydibucaine, bupivacaine, mepivacaine, propitocaine, diethylaminoethyl p-butylaminobenzoate, etc., of which lidocaine and dibucaine are preferred, and lidocaine is more preferred. Hydrochlorides of these lidocaine, dibucaine, tetracaine, etc. may also be used. The content of component (F) in the composition of the present invention is 0.1 to 4 mass%, preferably 0.2 to 3 mass%, more preferably 0.5 to 3 mass%, and even more preferably 1 to 3 mass%, from the viewpoints of the stability of components (A) to (C) and the local anesthetic effect.

[0018] From the viewpoint of the stability of the components (A) to (C), the composition of the present invention preferably contains a chelating agent (G). As the chelating agent (G), edetic acid and sodium edetate are preferable. The content of the chelating agent (G) in the composition of the present invention is 0.1 to 2 mass%, preferably 0.2 to 1 mass%, and more preferably 0.2 to 0.8 mass%, from the viewpoint of stabilizing the components (A) to (C).

[0019] From the viewpoint of the stability of the components (A) to (C), the composition of the present invention preferably contains (H) a tocopherol selected from tocopherol, tocopherol acetate, and tocopherol nicotinate. Of these components (H), it is preferable to use tocopherol acetate. The content of component (H) in the composition of the present invention is from 0.1 to 2 mass %, and preferably from 0.1 to 1 mass %, from the viewpoint of stabilizing components (A) to (C).

[0020] From the viewpoint of the stability of the components (A) to (C), the composition of the present invention preferably contains (I) one or more selected from a bactericide, an oily base, a polyhydric alcohol, an emulsifier and water. Here, examples of the bactericide include isopropylmethylphenol, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium dehydroacetate, p-cresol, etc. These bactericides are preferably contained in the composition of the present invention in an amount of 0.05 to 0.8% by mass, more preferably 0.05 to 0.3% by mass.

[0021] Examples of oily bases include petrolatum, plastibase, paraffin, liquid paraffin, white beeswax, behenyl alcohol, stearyl alcohol, cetanol, cetostearyl alcohol, stearic acid, behenic acid, silicone oil, etc. These oily bases are contained in the composition of the present invention preferably in an amount of 10 to 40% by mass, more preferably 10 to 35% by mass, and even more preferably 15 to 30% by mass.

[0022] Examples of polyhydric alcohols include glycerin, 1,3-butylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol, etc. These polyhydric alcohols are preferably contained in the composition of the present invention in an amount of 10 to 40% by mass, more preferably 10 to 30% by mass.

[0023] Examples of the emulsifier include nonionic surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyoxyethylene polyoxypropylene glycol, etc., and ionic surfactants such as sodium lauryl sulfate, sodium cetyl sulfate, etc. The content of the emulsifier in the composition of the present invention is preferably 1 to 15% by mass, more preferably 2 to 10% by mass.

[0024] The content of water in the composition of the present invention is preferably from 30 to 60% by mass, and more preferably from 35 to 55% by mass.

[0025] Furthermore, the composition of the present invention may contain thickeners such as polyvinylpyrrolidone, carboxymethylcellulose, colloidal hydrated aluminum silicate, xanthan gum, locust bean gum, tragacanth gum, guar gum, gelatin, gum arabic, alginic acid, and albumin.

[0026] The composition of the present invention has a pH of 5 to 6 in order to ensure the stability of components (A) to (C). If the pH is less than 5 or more than 6, the stability of any of components (A) to (C) becomes insufficient. The pH is preferably 5.1 to 5.9, and more preferably 5.1 to 5.6. The pH is preferably adjusted to within these ranges by adding the above-mentioned (E) hydroxy acid or a salt thereof. Here, the pH is the pH of the final oil-in-water emulsion composition.

[0027] The composition of the present invention is an oil-in-water emulsion composition containing the above-mentioned components, and has a good feel when applied to the skin as an external preparation. The composition is preferably produced by dissolving the lipophilic component and hydrophilic component to which an emulsifier has been added separately in a lipophilic base or water by heating, adding the latter to the former, stirring the mixture with a homomixer or the like to emulsify the mixture, and then cooling the mixture to room temperature.

[0028] In the composition of the present invention, the components (A) to (C) are stably maintained for a long period of time, and therefore the excellent effects of the components (A) to (C) are exhibited even after long-term storage. EXAMPLES

[0029] The present invention will now be described in detail with reference to examples, but the present invention is not limited thereto.

[0030] Examples 1 to 23 and Comparative Examples 1 to 4 The oil-in-water emulsion compositions shown in Tables 1 to 6 were produced according to a conventional method and stored at a humidity of 60% and 25°C for 12 months, and the stability, usability, etc. of each component were evaluated. The results are shown in Tables 1 to 6. Among these, the usability, expansion of the container, and irritation were evaluated by a panel of five people.

[0031] (1) Evaluation of urea The residual rate after storage at 25°C for 12 months was measured by liquid chromatography. ◎: Residual rate of 97% or more after 12 months at 25℃ 〇: Survival rate of 95% or more after 12 months at 25℃ △: Residual rate 93% or more after 12 months at 25℃ ×: Less than 93% survival rate after 12 months at 25℃ (2) Evaluation of ester-based steroids The residual rate after storage at 25°C for 12 months was measured by liquid chromatography. ◎: Residual rate of 97% or more after 12 months at 25℃ 〇: Survival rate of 95% or more after 12 months at 25℃ △: Residual rate 93% or more after 12 months at 25℃ ×: Less than 93% survival rate after 12 months at 25℃ (3) Evaluation of allantoin The residual rate after storage at 25°C for 12 months was measured by liquid chromatography. ◎: Residual rate of 97% or more after 12 months at 25℃ 〇: Survival rate of 95% or more after 12 months at 25℃ △: Residual rate 93% or more after 12 months at 25℃ ×: Less than 93% survival rate after 12 months at 25℃ (4)pH buffering property After storage at 25°C for 12 months, the pH was measured and the increase in pH was evaluated. ◎: Less than 0.1 ○: 0.1 or more and less than 0.2 △: 0.2 or more and less than 0.3 ×: 0.3 or more (5) The feeling of use was evaluated according to the following criteria. ◎: Very easy to apply 〇: Easy to apply △: A little difficult to apply ×: Difficult to apply (6) Container expansion was evaluated according to the following criteria. ◎: Not acceptable at all ○: Hardly recognized △: Slightly noticeable ×: Accepted (7) Irritation was evaluated according to the following criteria. ◎: Not felt at all ○: Almost not noticeable △: Slightly noticeable ×: Feeling (8) The overall evaluation was based on the following criteria. ◎: ◎ rating in all the above evaluation items ○: There are no items rated as ×, and there are four or more items rated as ○ or higher. △: There are no × evaluation items and there are three or less evaluation items with 〇 or higher. ×: There is at least one item with an × rating.

[0032] [Table 1]

[0033] [Table 2]

[0034] [Table 3]

[0035] [Table 4]

[0036] [Table 5]

[0037] [Table 6]

[0038] As shown in Tables 1 to 6, the results were as follows. As shown in the table, low pH increases irritation, while high pH accelerates decomposition of ester steroids and allantoin, which is not preferred. In addition, when the amount of (D) amino acid added is small, the pH rises and decomposition of ester steroids and allantoin accelerates, which is not preferred, while too much accelerates decomposition of urea, which is not preferred. When (A) urea is added in an amount of more than 10% by mass, irritation increases and the container expands due to the decomposition of urea, which is not preferred. On the other hand, the oil-in-water emulsion composition shown in the examples gave better results than the comparative examples.

Claims

1. An oil-in-water type emulsion skin topical composition containing the following components (A) to (E) and having a pH of 5 to 6: (A) Urea 0.5 to 8% by mass, (B) 0.05 to 0.3 mass% of an ester steroid, (C) allantoin 0.1 to 1 mass%, (D) 1 to 10% by mass of an amino acid or a salt thereof, and (E) Hydroxy acid or its salt

2. An oil-in-water emulsion skin topical composition as described in claim 1, wherein (E) the hydroxy acid or its salt is one or more selected from lactic acid, citric acid, malic acid, tartaric acid and salts thereof.

3. The oil-in-water emulsion skin topical composition according to claim 1 or 2, further comprising (F) a local anesthetic.

4. The oil-in-water emulsion skin topical composition according to any one of claims 1 to 3, further comprising (G) a chelating agent.

5. The oil-in-water emulsified skin external preparation composition according to any one of claims 1 to 4, further comprising (H) a tocopherol selected from tocopherol, tocopherol acetate and tocopherol nicotinate.

6. The oil-in-water emulsion skin external preparation composition according to any one of claims 1 to 5, further comprising one or more selected from the group consisting of a bactericide, an oily base, a polyhydric alcohol, an emulsifier and water.

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