JP2005015389A - External preparation for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a preparation which overcomes the problem of a preparation design of a phenolic compound and has a comfortable sense of use. <P>SOLUTION: The external preparation for skin comprises a phenolic compound that is included in an alkylated cyclodextrin as an active ingredient. The external preparation for skin is a preparation having stability with time and excellent compatibility with the skin. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

処方中の数値は重量％を示す
【００３５】
＜使用感評価の基準＞ 試験開始時に対する２ヶ月後の評価
評価Ａ：全く変化がない（外観変化が全くなく，肌へのなじみも良い）
評価Ｂ：殆ど変化がない（外観変化が殆どなく，肌へのなじみも良い）
評価Ｃ：多少変化がある（外観変化が多少あるが，肌へのなじみは良い）
評価Ｄ：かなり変化がある（外観変化がかなりあり、肌へのなじみも悪い）
評価Ｅ：非常に悪い（外観変化が著しく、肌へのなじみも非常に悪い）
【００３６】
＜試験例＞安定性と使用試験（乳化系製剤）
ａ）試験方法
別表のような処方条件で各製剤を調製し、４０℃、７５％ＲＨ（湿度）下で２ヶ月間保存。２ヶ月後に製剤の均一状態（分離の有無・外観）について評価した。また、試験開始前と２ヶ月後に後述の基準で使用感を評価した。
【００３７】
ｂ）試験結果
表２に示したように、本願発明の製剤は、長期間均一性を保持していた。また、使用感についても経時的変化がないことが確認された。
【００３８】
【表２】

処方中の数値は重量％を示す
【００３９】
＜使用感評価の基準＞ 試験開始時に対する２ヶ月後の評価
評価Ａ：全く変化がない（外観変化が全くなく，肌へのなじみも良い）
評価Ｂ：殆ど変化がない（外観変化が殆どなく，肌へのなじみも良い）
評価Ｃ：多少変化がある（外観変化が多少あるが，肌へのなじみは良い）
評価Ｄ：かなり変化がある（外観変化がかなりあり、肌へのなじみも悪い）
評価Ｅ：非常に悪い（外観変化が著しく、肌へのなじみも非常に悪い）
【００４０】
処方例１ 化粧水

【００４１】
処方例２ エッセンス

【００４２】
処方例３ クリーム

【００４３】
処方例４ 乳液

【００４４】
処方例５ クリームパック

これら処方例１乃至５は、いずれも本発明の目的を達成する効果を有していることが確認された。
【００４５】
【発明の効果】
アルキル化シクロデキストリンで包接されたフェノール性化合物を有効成分として使用することで、製剤設計上の制約のない皮膚外用剤が提供され、この皮膚外用剤は、経時的にも安定でべたつきのない極めて使い心地の良い製剤である。[0001]
[Technical field to which the invention belongs]
The present invention relates to a skin external preparation containing a phenolic compound clathrated with an alkylated cyclodextrin as an active ingredient, and more specifically, by increasing the solubility of the phenolic compound by selecting a specific ingredient. Further, the present invention relates to a preparation having improved stability and improved usability.
[0002]
[Prior art]
Generally, various physicochemical means are taken in order to improve the compatibility of the active ingredient and the external preparation base in the external preparation for specific use. For example, it is possible to improve solubility and stability by using a specific solubilizing agent in combination, a charge transfer complex utilizing a substance-specific electronic interaction, hydrogen bonding and inclusion. As for which method is used, the optimum one is selected depending on whether the target active ingredient is hydrophilic or hydrophobic.
[0003] However, even though these one means can solve the solubility problem, on the other hand, it is often accompanied by foreign problems such as formulation problems such as coloring enhancement and poor emulsification.
The phenolic compound, which is the active ingredient targeted in the present invention, is a hydrophobic active ingredient, and thus causes problems such as crystal precipitation and poor emulsification in the design of aqueous preparations. There were development problems such as restrictions on the type.
[0005] In addition, when producing a cream or the like, the active ingredient tends to become yellowish brown due to high temperature or light conditions. As a result, the stability of the active ingredient is lost over time. There were also problems that caused a decline in the value of the product.
Liquiritin, one of the phenolic compounds, is a specific substance derived from licorice and is an active ingredient found by the present applicant for its excellent whitening effect (for example, Patent No. 2501593 and Patent No. 3072768), because it is hydrophobic, it is a material whose formulation conditions are restricted. As a solution to this problem, derivatization has been attempted (Japanese Patent No. 3066989), but although it has been somewhat successful in improving solubility, it has a new problem of being inferior in percutaneous absorption.
Quercetin and rutin are known to have excellent antioxidant power, but the substance is poorly soluble in water, and is well known as a coloring substance particularly in the alkaline region. As a means for solving this problem, a protective group has been introduced into the reaction active site. For example, Japanese Patent Laid-Open No. 55-157580 discloses quercetin fatty acid esters, and Japanese Patent Laid-Open Nos. 3-255013 and 5-32690 disclose glycosides.
According to these prior arts, derivatization of quercetin has achieved some results in water solubility and stability over time, but other problems such as inability to fully exhibit the original function of quercetin. As a result.
The onion bulb extract is a whitening material newly found by the applicant (Japanese Patent Laid-Open No. 2003-95859) and has the same problems as quercetin, but because of the extract, it is chemically synthesized differently from liquiritin and quercetin. We had a problem that the solution by was difficult to plan.
[0010]
SUMMARY OF THE INVENTION The object of the present invention is based on such a current situation, and overcomes the formulation design problems possessed by phenolic compounds and provides a formulation that allows consumers to feel comfortable using. It is to provide.
[0011]
Means for Solving the Problems The present inventor considered the problem of improving the solubility as a priority issue, and decided to solve it by focusing on a method applicable to the extract.
Therefore, as a result of extensive research in view of these circumstances, the present invention was completed by obtaining the knowledge that inclusion by alkylated cyclodextrin is optimal as a method that can solve the above problems at once. It has been made.
That is, according to the present invention, there is provided an external preparation for skin characterized by comprising a phenolic compound encapsulated with an alkylated cyclodextrin as an active ingredient. Hereinafter, the present invention will be described in detail with a focus on embodiments.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
As the inclusion compound, cyclodextrins, which are cyclic oligosaccharides and have α, β, and γ structures depending on the difference in the number of glucose, are generally well known. In the present invention, any of these can improve solubility. A sufficient effect was not obtained. Thus, various other cyclodextrins were examined, and a CD in which a lower alkyl group was introduced into the previous cyclodextrin (hereinafter simply referred to as CD) (hereinafter simply referred to as alkylated CD) achieved the initial object of the present invention. It turns out that you can. Surprisingly, the emulsifying power was improved, and a favorable effect on formulation stability could be obtained.
Alkylated CD is a known substance, and various techniques using this are disclosed. For example, Japanese Patent Application No. 01-195792, Japanese Patent Application No. 01-272325, Japanese Patent Application No. 01-298196, Japanese Patent Application No. 02-77458, Japanese Patent Application No. 02-77459, Japanese Patent Application No. 01-301070, Japanese Patent Application No. 02-86900, Japanese Patent Application No. 04-227733, Japanese Patent Application No. 04-227742, Japanese Patent Application No. 09-52262, and the like. However, there is no example in which the stability of the whole preparation is improved in addition to the improvement of the solubility of the active ingredient itself as in the present invention.
Examples of the alkylated CD include methylated CD, ethylated CD, hydroxymethyl CD, hydroxyethyl CD, hydroxymethyl CD, hydroxypropyl CD, and hydroxybutyl CD. Among them, hydroxypropyl is particularly preferable. -Β-CD.
Examples of phenolic compounds included in alkylated CD include catechin, epicatechin, catechin gallate, epicatechin gallate, liquiritin, quercetin, rutin, caffeic acid, resorcin and resorcin derivatives alkylresorcin, alkoxy Resorcin, lucinol and the like can be mentioned. Among these, one or more selected from liquiritin, quercetin, rutin and onion bulb extract are particularly preferable.
As a method for inclusion of the alkylated CD and the phenolic compound, the alkylated CD and the phenolic compound may be directly kneaded with a small amount of water and oil, but preferably the alkylated CD is a hydrophilic solvent. It can be stably obtained by dispersing and dissolving therein, stirring while gradually adding the phenolic compound thereto, and completely dissolving both.
The blending ratio (weight ratio) of the alkylated CD and the phenolic compound is usually in the range of 0.1 to 100, preferably 10 to 70, more preferably 30 to 50 with respect to the phenolic compound 1. Used in
In addition, during the inclusion, in the course of addition of the phenolic compound, a polyhydric compound such as sugar alcohol such as sorbitol, mannitol, trehalose, polyoxyethylene methyl glucoside, glycerin, 1,3-butylene glycol, etc. Inclusion efficiency can be improved by adding alcohols such as alcohol.
The amount of the clathrate compound prepared as described above varies slightly depending on the type of the selected component and the form of the formulation design, but a high blending amount is possible. 0.0% by weight, preferably 0.01 to 10% by weight, more preferably 0.1 to 5% by weight.
The preparation form of the present invention is used by selecting a generally acceptable base as an external preparation and applying it directly to the affected area. Technically, it is a uniform preparation represented by lotion, essence, etc. General emulsion systems such as O / W and W / O types represented by milk and emulsion, special multilayer emulsions of W / O / W and O / W / O types, and other pastes, ointments, tinctures, etc. As a basic base of a known form such as a coating agent type, an aerosol agent, a spray agent type such as a spray agent, a patch type such as a patch, a plaster agent, etc., it is used for a wide range of uses in combination with other components, There are no particular restrictions.
In the external preparation of the present invention, various known active ingredients that are commonly used, for example, glutathione, hydroquinone and derivatives thereof known as whitening agents, vitamin E, vitamin E nicotinate as peripheral vasodilators, Various vitamins such as nicotinic acid, nicotinic acid amide, benzyl nicotinate, ginger tincture, chili pepper tincture, anti-inflammatory agents such as corticosteroids, ε-aminocaproic acid, lysozyme chloride, glycyrrhizin, allantoin, etc. Various extracts derived from animals and plants / microorganisms such as placenta extract, licorice extract, purple root extract, and lactic acid bacteria culture extract, etc. are used as appropriate according to the purpose of the present invention within a range not impairing the effects of the present invention. be able to.
[0023]
Furthermore, in addition to these known active ingredients, the external preparation of the present invention, in addition to base components such as fats and oils, if necessary, known moisturizers, preservatives, antioxidants, chelating agents, pH adjusters, Various additives, such as a fragrance | flavor and a coloring agent, can be used together in the range which does not impair the effect of this invention.
[0024]
【Example】
Next, the present invention will be described by disclosing experiments and formulation examples, but these disclosures show preferred embodiments of the present invention and do not limit the present invention in any way.
[0025]
Production Example 1)
1 L of purified water is added to 50 g of 2-hydroxypropyl-cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) and gently stirred. Next, 1 g of liquiritin dissolved in 1,3 butylene glycol in advance was added and stirred well until uniform to obtain an inclusion compound.
[0026]
Production Example 2)
1 L of purified water is added to 50 g of 2-hydroxypropyl-cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) and gently stirred. Next, 2 g of quercetin dissolved in sorbitol with heating was added in advance, and the mixture was sufficiently stirred until it was uniform to obtain an inclusion compound.
[0027]
Production Example 3)
The onion bulbs were dried for 1 month during the day tomorrow, the skin surrounding the onion bulbs was peeled up to three layers from the outside, and 20 L of water was added to 1 kg of the scales, followed by boiling for 1 hour for extraction. The liquid from which the onion scale was removed was left to cool, and then 21.8 g of an onion bulb extract that was insolubilized was obtained.
Next, 1 L of purified water is added to 30 g of 2-hydroxypropyl-cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) and gently stirred. To this was added 1 g of the above onion bulb extract (previously heated and dissolved in 1,3-butylene glycol), and the mixture was sufficiently stirred until it was homogeneous to obtain an inclusion compound.
[0028]
Production Example 4)
The onion bulbs were dried for 1 month during the day tomorrow, the skin surrounding the onion bulbs was peeled up to three layers from the outside, and 20 L of water was added to 1 kg of the scales, followed by boiling for 1 hour for extraction. The liquid from which the onion scale was removed was left to cool, and then 21.8 g of an onion bulb extract that was insolubilized was obtained.
Next, 1 L of purified water and 100 g of glycerin are added to 30 g of 2-hydroxypropyl-cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) and gently stirred. To this was added 1 g of the onion bulb extract (previously heated and dissolved in glycerin), and the mixture was sufficiently stirred until it became homogeneous to obtain an inclusion compound.
[0029]
Production Example 5)
1 L of purified water is added to 50 g of 2-hydroxypropyl-cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.) and gently stirred. Next, 1 g of rutin heated and dissolved in 1,3 butylene glycol in advance was added, and the mixture was sufficiently stirred until it was uniform to obtain an inclusion compound.
[0030]
<Test Example 1> Solubility test a) Test method The solubility of liquiritin, onion bulb extract, rutin and quercetin was examined with 0.5% 2-hydroxypropyl-cyclodextrin aqueous solution and purified water.
[0031]
b) Test result (1) Although it was 0.001% or less in purified water of liquiritin, the concentration of 0.001% in 0.5% 2-hydroxypropyl-cyclodextrin aqueous solution was very easily dissolved, 500 times that Even 0.5% concentration of the amount was still transparent.
(2) Onion bulb extract Insoluble in purified water, but still transparent in 0.5% 2-hydroxypropyl-cyclodextrin aqueous solution even at 0.5% concentration.
(3) Although it was insoluble in purified rutin water, it was still transparent at 0.5% concentration in a 0.5% 2-hydroxypropyl-cyclodextrin aqueous solution.
(4) Although it was insoluble in purified quercetin water, it was still transparent at 0.5% concentration in a 0.5% aqueous 2-hydroxypropyl-cyclodextrin solution.
[0032]
<Test Example 2> Stability evaluation test (water-based preparation)
<Test example> Stability and use test a) Test method Each preparation is prepared under the prescription conditions as shown in the attached table, and stored for 2 months at 40 ° C. and 75% RH (humidity). Two months later, the uniform state (deposition and appearance of components) of the preparation was evaluated. In addition, the feeling of use was evaluated according to the criteria described below before the start of the test and after 2 months.
[0033]
b) Test results As shown in Table 1, the preparation of the present invention retained uniformity for a long period of time. It was also confirmed that there was no change over time in the feeling of use.
[0034]
[Table 1]

The numerical value in the prescription indicates% by weight.
<Usage evaluation criteria> Evaluation evaluation 2 months after the start of the test A: No change at all (no change in appearance, good fit to skin)
Evaluation B: Almost no change (almost no change in appearance, good fit to skin)
Evaluation C: Some changes (appearance changes slightly, but familiar to skin is good)
Evaluation D: There is a considerable change (the appearance changes considerably and the familiarity with the skin is also bad)
Evaluation E: very poor (appearance change is remarkable, and familiarity with skin is also very bad)
[0036]
<Test example> Stability and usage test (emulsification)
a) Test method Each preparation is prepared under the prescription conditions as shown in the attached table and stored for 2 months at 40 ° C. and 75% RH (humidity). After 2 months, the uniform state of the preparation (existence of separation / appearance) was evaluated. In addition, the feeling of use was evaluated according to the criteria described below before the start of the test and after 2 months.
[0037]
b) Test results As shown in Table 2, the preparation of the present invention retained uniformity for a long period of time. It was also confirmed that there was no change over time in the feeling of use.
[0038]
[Table 2]

The numerical value in the prescription indicates% by weight. [0039]
<Usage evaluation criteria> Evaluation evaluation 2 months after the start of the test A: No change at all (no change in appearance, good fit to skin)
Evaluation B: Almost no change (almost no change in appearance, good fit to skin)
Evaluation C: Some changes (appearance changes slightly, but familiar to skin is good)
Evaluation D: There is a considerable change (the appearance changes considerably and the familiarity with the skin is also bad)
Evaluation E: very poor (appearance change is remarkable, and familiarity with skin is also very bad)
[0040]
Formulation Example 1 Lotion

[0041]
Formulation Example 2 Essence

[0042]
Formulation Example 3 Cream

[0043]
Formulation Example 4 Latex

[0044]
Formulation Example 5 Cream Pack

It was confirmed that all of these Formulation Examples 1 to 5 have the effect of achieving the object of the present invention.
[0045]
【The invention's effect】
Use of a phenolic compound encapsulated with an alkylated cyclodextrin as an active ingredient provides a skin external preparation that is free from restrictions on formulation design, and this skin external preparation is stable and non-sticky over time. It is an extremely comfortable preparation.

Claims (2)

An external preparation for skin, comprising a phenolic compound encapsulated with an alkylated cyclodextrin as an active ingredient. The topical skin preparation according to claim 1, wherein the phenolic compound is one or more selected from liquiritin, quercetin, rutin and onion bulb extract.