Method for stabilizing allantoin and / or its derivatives

Abstract

To provide a formulation technique whereby, in an external composition containing allantoin and / or a derivative thereof, and urea, the decomposition of the allantoin and / or derivative thereof can be suppressed, to improve the storage stability.SOLUTION: An external composition contains allantoin and / or a derivative thereof, and urea, together with glycine and / or alanine. The external composition can suppress the decomposition of the allantoin and / or derivative thereof, so that the storage stability of the allantoin and / or derivative thereof is significantly improved.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for improving the storage stability of a topical composition containing allantoin and / or a derivative thereof and urea by suppressing the decomposition of allantoin and / or a derivative thereof. [Background technology]

[0002] Allantoin has tissue repair activating, anti-inflammatory, antipruritic, etc. effects and is used in external compositions, while urea has moisture retention in the stratum corneum, cell activating, antibacterial, antipruritic, etc. effects and is used in external compositions such as skin medicines and cosmetics.

[0003] In recent years, there has been a strong demand for improved functionality in topical compositions, and topical compositions have been proposed that focus on the functionality of allantoin and / or its derivatives, and urea, and that use these ingredients in combination to improve functionality. For example, Patent Document 1 discloses that a topical composition containing predetermined amounts of allantoin, urea, 1,3-butylene glycol, polyglycerin, and deep-sea water is effective in preventing and treating atopic dermatitis.

[0004] On the other hand, allantoin has the disadvantage of being easily decomposed at pH 6 or higher. Furthermore, urea exhibits alkalinity even when decomposed even slightly, which facilitates the decomposition of allantoin. Therefore, topical compositions containing allantoin and / or its derivatives, and urea, require formulation techniques that suppress the decomposition of allantoin and improve storage stability. However, such formulation techniques have not been thoroughly investigated to date. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 9-67258 Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have conducted various studies to develop a topical composition containing allantoin and / or its derivatives, and urea, and have found that topical compositions containing allantoin and / or its derivatives, and urea have extremely poor storage stability because the pH increases during storage, causing allantoin to decompose.

[0007] Therefore, an object of the present invention is to provide a formulation technology that can suppress the decomposition of allantoin and / or its derivatives and improve the storage stability in an external composition containing allantoin and / or its derivatives, and urea. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above-mentioned problems and have found that by adding glycine and / or alanine to a topical composition containing allantoin and / or its derivatives and urea, the decomposition of allantoin and / or its derivatives can be suppressed and the storage stability of allantoin and / or its derivatives can be improved. The present invention was completed through further research based on this finding.

[0009] That is, the present invention provides the following aspects. Item 1. A method for stabilizing allantoin and / or a derivative thereof in a topical composition containing allantoin and / or a derivative thereof and urea, comprising: A stabilization method comprising incorporating (A) allantoin and / or its derivatives, and (B) urea, together with (C) glycine and / or alanine, into a topical composition. Item 2. The stabilization method according to Item 1, wherein the component (C) comprises glycine and alanine. Item 3. The stabilization method according to Item 1 or 2, wherein the component (A) is allantoin. Item 4. The stabilization method according to any one of Items 1 to 3, wherein the topical composition further contains water. [Effects of the Invention]

[0010] According to the present invention, in a topical composition containing allantoin and / or a derivative thereof and urea, the decomposition of allantoin and / or a derivative thereof can be inhibited, and excellent storage stability can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0011] The stabilization method of the present invention is a method for stabilizing allantoin and / or its derivatives in a topical composition containing allantoin and / or its derivatives and urea, characterized in that the topical composition contains (A) allantoin and / or its derivatives, (B) urea, and (C) glycine and / or alanine. The stabilization method of the present invention is described in detail below.

[0012] (A) Allantoin and / or its derivatives In the stabilization method of the present invention, the topical composition contains allantoin as a target component for preservation stabilization. Allantoin is a compound also known as 5-ureidohydantoin, and is a known component known to have tissue repair activating effects, anti-inflammatory effects, antipruritic effects, etc.

[0013] The allantoin derivatives are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, and specific examples include allantoin chlorohydroxyaluminum, allantoin hydroxyaluminum, allantoin dihydroxyaluminum, allantoin chlorohydroxyaluminum, etc. These allantoin derivatives may be used alone or in combination of two or more.

[0014] In the stabilization method of the present invention, either allantoin or a derivative thereof may be used alone as component (A), or a combination of these may be used. Among components (A), allantoin is preferred from the viewpoint of further improving the stabilizing effect.

[0015] In the stabilization method of the present invention, the amount of component (A) to be contained in the topical composition is not particularly limited and is set appropriately depending on the medicinal effect to be imparted to the topical composition, the form of the topical composition, etc., but is, for example, 0.05 to 2% by weight, preferably 0.1 to 2% by weight, and more preferably 0.2 to 1.5% by weight.

[0016] [(B) Urea] In the stabilization method of the present invention, the topical composition contains urea, a known ingredient known to have moisturizing, cell-activating, antibacterial, and antipruritic effects.

[0017] In the stabilization method of the present invention, the amount of component (B) to be contained in the topical composition is appropriately determined depending on the medicinal effect to be imparted to the topical composition, the form of the topical composition, etc., but is, for example, 1 to 30% by weight, preferably 2.5 to 25% by weight, and more preferably 5 to 20% by weight.

[0018] In the stabilization method of the present invention, the ratio of component (B) to component (A) contained in the topical composition is determined depending on the content of each of these components, but for example, the ratio of component (B) is 0.5 to 600 parts by weight, preferably 1.5 to 250 parts by weight, and more preferably 5 to 200 parts by weight per part by weight of component (A).

[0019] [(C) Glycine and / or Alanine] In the stabilization method of the present invention, the topical composition contains glycine and / or alanine. In topical compositions containing allantoin or its derivatives and urea, decomposition of allantoin and / or its derivatives occurs during storage, resulting in poor storage stability. However, in the stabilization method of the present invention, by adding glycine and / or alanine to the topical composition in addition to these components, decomposition of allantoin and / or its derivatives can be suppressed, thereby improving storage stability. Glycine and alanine are known amino acids.

[0020] In the stabilization method of the present invention, at least one of glycine and alanine may be used as component (C). From the viewpoint of more effectively suppressing the decomposition of allantoin and / or its derivatives, preferred is glycine, or a combination of glycine and alanine, and more preferred is a combination of glycine and alanine.

[0021] When glycine and alanine are used in combination in the stabilization method of the present invention, the ratio between them is not particularly limited, but for example, 0.05 to 20 parts by weight, preferably 0.1 to 20 parts by weight, and more preferably 0.5 to 10 parts by weight of alanine per 1 part by weight of glycine.

[0022] In the stabilization method of the present invention, the amount of component (C) contained in the topical composition is appropriately set depending on the form of the topical composition, etc., but can be, for example, 0.5 to 20 wt %, preferably 1 to 10 wt %, and more preferably 1 to 6 wt % of the total amount of component (C).

[0023] Furthermore, in the stabilization method of the present invention, the ratio of component (C) to component (A) contained in the topical composition is determined depending on the content of each of these components, but for example, the total amount of component (C) per 1 part by weight of component (A) is 0.25 to 400 parts by weight, preferably 0.5 to 200 parts by weight, and more preferably 0.5 to 100 parts by weight.

[0024] [water] In the stabilization method of the present invention, the topical composition may contain water as a base, etc. In topical compositions containing water as well as allantoin or a derivative thereof and urea, decomposition of allantoin and / or its derivatives tends to become significant during storage. However, in the stabilization method of the present invention, even if the topical composition contains water as a base, etc., the decomposition of allantoin and / or its derivatives can be effectively suppressed.

[0025] In the stabilization method of the present invention, when water is contained in the topical composition, the content thereof is appropriately set depending on the form of the topical composition, etc., but may be, for example, 25 to 98.5% by weight, preferably 30 to 90% by weight, and more preferably 35 to 85% by weight.

[0026] [Polyhydric alcohol] In the stabilization method of the present invention, the topical composition may contain a polyhydric alcohol, if necessary, for the purpose of enhancing the moisturizing effect, etc.

[0027] The polyhydric alcohol is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and examples thereof include 1,3-butylene glycol, ethylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, glycerin, etc. Among these polyhydric alcohols, propylene glycol and glycerin are preferred. These polyhydric alcohols may be used alone or in combination of two or more.

[0028] In the stabilization method of the present invention, when a polyhydric alcohol is contained in the topical composition, the content thereof may be appropriately set depending on the type of polyhydric alcohol used, the form of the topical composition, etc., but may be, for example, 1 to 20% by weight, preferably 1.5 to 15% by weight, and more preferably 2 to 10% by weight.

[0029] [Thickener] In the stabilization method of the present invention, the topical composition may contain, in addition to the above-mentioned components, a thickener, if necessary, for adjusting viscosity, etc.

[0030] The thickener is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and examples thereof include xanthan gum, guar gum, locust bean gum, carrageenan, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, acrylate-alkyl methacrylate copolymer, sodium polyacrylate bentonite, dextrin fatty acid ester, pectin, etc. Among these thickeners, carboxyvinyl polymer is preferred. These thickeners can be used alone or in combination of two or more.

[0031] In the stabilization method of the present invention, when a thickener is contained in the topical composition, the content thereof may be appropriately set depending on the type of thickener used, the viscosity to be imparted, the form of the topical composition, etc., but may be, for example, 0.01 to 1.5 wt %, preferably 0.05 to 1 wt %, and more preferably 0.1 to 1.0 wt %.

[0032] [Chelating agent] In the stabilization method of the present invention, the topical composition may contain a chelating agent in addition to the above-mentioned components, if necessary.

[0033] The chelating agent is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and examples thereof include edetic acid, citric acid, succinic acid, and salts thereof. Examples of salt forms include alkali metal salts such as sodium salts and potassium salts. Among these chelating agents, edetic acid and its salts are preferred, and sodium edetate is more preferred. These chelating agents may be used alone or in combination of two or more.

[0034] In the stabilization method of the present invention, when a chelating agent is contained in the topical composition, the content thereof may be appropriately set depending on the type of chelating agent used, the form of the topical composition, etc., but may be, for example, 0.01 to 2 wt %, preferably 0.01 to 1 wt %, and more preferably 0.02 to 0.5 wt %.

[0035] [Other ingredients] In the stabilization method of the present invention, the topical composition may contain, in addition to the above-mentioned components, other commonly used additives as needed. Examples of such additives include surfactants, monohydric lower alcohols, vegetable oils, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, higher alcohols, pH adjusters, buffers, solubilizers, antiseptics, preservatives, antioxidants, stabilizers, fragrances, colorants, etc. When these additives are contained in the topical composition, the content thereof may be appropriately determined depending on the type of additive used, etc.

[0036] In the stabilization method of the present invention, the topical composition may contain pharmacological ingredients in addition to the above-mentioned ingredients. Examples of such pharmacological ingredients include steroids, antihistamines, local anesthetics, anti-inflammatory agents other than allantoin and its derivatives, moisturizers other than urea, disinfectants, antibacterial agents, antipruritics, skin protectants, blood circulation promoters, vitamins, mucopolysaccharides, etc. These pharmacological ingredients may be used alone or in combination of two or more. Furthermore, when these pharmacological ingredients are contained in the topical composition, their concentration may be appropriately determined depending on the type of pharmacological ingredient used, the desired effect, etc.

[0037] [pH] In the stabilization method of the present invention, the pH of the topical composition may be within a range in which allantoin and / or its derivatives are stably maintained, for example, 2 to 9, preferably 3 to 8.5, more preferably 4 to 8.5, and immediately after preparation, 2 to 5.5.

[0038] [Dosage form / preparation type] In the stabilization method of the present invention, the dosage form of the topical composition is not particularly limited as long as it is applicable transdermally, and may be any of liquid, semi-solid (cream, gel, ointment, paste), solid, etc., but liquid or semi-solid is preferred. The topical composition may also be an emulsified preparation such as an oil-in-water emulsion preparation or a water-in-oil emulsion preparation, or a non-emulsified preparation such as a solubilized preparation or an aqueous ointment.

[0039] Furthermore, in the stabilization method of the present invention, the topical composition may be in any formulation, such as a topical skin drug (including quasi-drugs), a cosmetic, or a skin cleanser, as long as it is applied to the skin.

[0040] Specific formulation forms of the topical composition include topical skin medicines such as creams, lotions, gels, emulsions, liquids, poultices, patches, liniments, aerosols, aqueous ointments, and packs; cosmetics such as aqueous ointments, creams, emulsions, lotions, lotions, packs, and gels; skin cleansers such as body shampoos, hair shampoos, and rinses. Among these, topical skin medicines are preferred.

[0041] The topical composition stabilized during storage by the stabilization method of the present invention can exhibit tissue repair activating effects, anti-inflammatory effects, antipruritic effects, etc. based on component (A), and can also exhibit moisturizing effects, cell activating effects, antibacterial effects, antipruritic effects, etc. based on the component (B) it contains. Therefore, the composition is suitable for use in moisturizing, improving rough skin, and preventing or treating dry skin diseases, inflammatory skin diseases, hypertrophic scars, keloids, etc. [Example]

[0042] The present invention will be explained in more detail below by showing examples, but the present invention is not limited to these examples.

[0043] Test Example 1 A topical composition (liquid) was prepared by blending the ingredients shown in Table 1. The obtained topical composition was stored at 50°C for two weeks or one month under light-shielded conditions at 50°C. The pH and allantoin content of the topical composition were measured immediately after production and after storage. pH was measured using a pH meter (HORIBA, Horiba Ltd.). The allantoin content was measured by high-performance liquid chromatography. The allantoin content (relative value when the amount charged is taken as 100%) (%) was calculated from the measured allantoin content.

[0044] The results are shown in Table 1. When allantoin and urea were contained (Comparative Examples 1 and 2), the pH increased significantly and the allantoin residual rate decreased significantly upon storage. In contrast, when glycine was added in addition to allantoin and urea (Examples 1 and 2), the increase in pH after storage was suppressed and an improvement in the allantoin residual rate was observed compared to Comparative Examples 1 and 2. Furthermore, when glycine and alanine were added in addition to allantoin and urea (Example 3), a significantly higher allantoin residual rate was observed.

[0045] [Table 1]

[0046] Prescription example Topical compositions having the compositions shown in Tables 2 and 3 (Formulation Examples 1 to 6 are gels, Formulation Example 7 is a liquid, and Formulation Example 8 is an oil-in-water emulsion preparation) were prepared. The storage stability of the obtained topical compositions was evaluated in the same manner as in Test Example 1, and all of them had a high rate of allantoin remaining after storage and excellent storage stability.

[0047] [Table 2]

[0048] [Table 3]

Claims

1. A method for stabilizing allantoin and / or a derivative thereof in a topical composition containing allantoin and / or a derivative thereof and urea (excluding those containing an ester steroid), comprising: A stabilization method comprising adding (A) allantoin and / or a derivative thereof, and (B) urea, together with (C) glycine and alanine, to a topical composition (excluding those containing an ester-based steroid), and adjusting the pH of the topical composition immediately after preparation to 4 to 5.

5.

2. The stabilization method according to claim 1, wherein the component (A) is allantoin.

3. The stabilization method according to claim 1 or 2, wherein the topical composition further contains water.

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