JP2004339101A - UTILIZATION OF delta-TOCOPHERYL RETINOATE FOR EXTERNAL PREPARATION FOR SKIN - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find a derivative which effectively utilizes the wrinkle-improving effect of retinoic acid, has an excellent skin ageing-improving effect, and does not cause a skin-irritating property and the like. <P>SOLUTION: δ-tocopheryl retinoate is effective for improving wrinkles, exhibits an excellent skin ageing-preventing effect, and has an extremely small skin irritation property. Since the δ-tocopheryl residue has a high anti-oxidizing action as a vitamin E derivative, it can be expected that the δ-tocopheryl retinoate has an extremely effective skin-beautifying action by synergistic effects with the skin ageing-preventing effect and wrinkle-improving effect of the retinoic acid. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

表１に見られるように、ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリルはＤＰＰＨの減少させる効果を示し、レチノイン酸ｄｌ−δ−トコフェリルの活性酸素消去作用の有効性が分かる。
【００１６】
次に、同様にＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリルによる、過酸化脂質が引き起こす細胞障害に対する緩和作用を示す。すなわち、過酸化脂質のモデル物質として通常用いられるｔｅｒｔ−ｂｕｔｙｌｈｙｄｒｏｐｅｒｏｘｉｄｅ（ｔ−ＢＨＰ）による細胞障害に対する緩和作用を以下に示す。
【００１７】
（試験例２）過酸化脂質による細胞障害に対する緩和作用の評価
表２に示す濃度のＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリル、及び比較としてＡＬＬ−ｔｒａｎｓ−レチノイン酸、ｄｌ−δ−トコフェロールを用いて、これらの試料を含有する培地にてＨａＣａｔ ｃｅｌｌを２４時間培養した。その後培地を除去し、１ｍＭのｔ−ＢＨＰにて３７℃で５時間処理した。その後の細胞生存率をＮＲ ａｓｓａｙにより求め、過酸化脂質による細胞障害に対する緩和作用を評価した。
【００１８】
【表２】

表２に見られるようにＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリルは細胞生存率を向上させる効果を示し、レチノイン酸ｄｌ−δ−トコフェリルの過酸化脂質による細胞障害に対する緩和作用の有効性が分かる。
【００１９】
次に、ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリルによる、細胞への紫外線照射に対するコラーゲン分解酵素の生成抑制の効果をそのメッセンジャーレベル、及びコラーゲン分解酵素の生成から示す。
【００２０】
（試験例３）コラーゲン分解酵素のメッセンジャーレベルからの、コラーゲン分解酵素の生成抑制作用の評価
ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリル、及び比較としてＡＬＬ−ｔｒａｎｓ−レチノイン酸を用い、これらの試料を２．５μＭ含有する培地にてＨａＣａｔ ｃｅｌｌを２４時間培養した後、２０Ｊ／ｃｍ^２の紫外線（ＵＶＡ）を６時間照射した。照射後、細胞からｔｏｔａｌ ＲＮＡを抽出し、Ｒｅｖｅｒｓｅ Ｔｒａｎｓｃｒｉｐｔａｓｅ−Ｐｏｌｙｍｅｒａｓｅ Ｃｈａｉｎ Ｒｅａｃｔｉｏｎ（ＲＴ−ＰＣＲ）法によりＭＭＰ−９のｍＲＮＡの発現を観察した。
【００２１】
その結果、ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリルは、ＭＭＰ−９のｍＲＮＡ発現量は約７０％に抑制されたのに対し、ＡＬＬ−ｔｒａｎｓ−レチノイン酸では抑制効果は全く見られなかった。
【００２２】
（試験例４）コラーゲン分解酵素の生成量からの、コラーゲン分解酵素の生成抑制作用の評価
ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリル、及び比較例としてＡＬＬ−ｔｒａｎｓ−レチノイン酸を用い、これらの試料を２．５μＭ含有する培地にてＨａＣａｔ ｃｅｌｌを２４時間培養した後、２０Ｊ／ｃｍ^２の紫外線（ＵＶＡ）を６時間照射した。照射後、ＨａＣａｔ ｃｅｌｌの培養上清を用いてＭＭＰ−２及びＭＭＰ−９のザイモグラフィーを実施した。
【００２３】
その結果、ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄｌ−δ−トコフェリルは、ＭＭＰ−９の発現を約７５％に抑制し、またＭＭＰ−２についても抑制する効果を示した。一方、ＡＬＬ−ｔｒａｎｓ−レチノイン酸では抑制効果は見られなかった。
【００２４】
次に、ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリルによるコラーゲン合成促進を、タイプＩコラーゲンのＥＬＩＳＡによる定量から示す。
【００２５】
（試験例５）コラーゲン合成促進作用の評価
ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリル、及び比較例としてＡＬＬ−ｔｒａｎｓ−レチノイン酸を用い、これらの試料を表３に示す濃度を含有する培地にて、Ｎｏｒｍａｌ Ｈｕｍａｎ Ｄｅｒｍａｌ Ｆｉｂｒｏｂｌａｓｔ（ＮＨＤＦ）を２４時間培養した。培養上清をＥＬＩＺＡプレートに移し、一晩４℃にてコーティングした。０．０５％Ｔｗｅｅｎ２０含有ＰＢＳ（−）（ＰＢＳ−Ｔ）で洗浄した後、１％ｂｏｖｉｎｅ ｓｅｒｕｍ ａｌｂｕｍｉｎ溶液を用いて３７℃にて１時間コーティングした。ＰＢＳ−Ｔにて洗浄後、抗タイプＩコラーゲン抗体溶液と３７℃で１時間反応させ、次いで二次抗体としてＨＩＳＴＯＦＩＮＥ（ｓｉｍｐｌｅ ｓｔａｉｎ ＰＯ（Ｒ））を用いて３７℃で１時間反応させた。２，２’−ａｚｉｎｏｂｉｓ（３−ｅｔｈｙｌｂｅｎｚｏｔｈｉａｚｏｌｉｎｅ−６−ｓｕｌｆｏｎｉｃ ａｃｉｄ（ＡＢＴＳ）を添加し、３０分後の呈色を４０５ｎｍの吸光度により測定した。同時に作成した検量線により培地中に含まれるコラーゲンを定量した。
【００２６】
その結果を表３に示す。
【００２７】
【表３】

表３に示されるようにＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリルは用いた線維芽細胞の培養上清中のコラーゲン量は濃度に依存して増加し、１０μＭにおいてはコントロールと比較して１６８％にまで増大した。
一方、ＡＬＬ−ｔｒａｎｓ−レチノイン酸では増大効果は見られなかった。
【００２８】
次に、実際の皮膚外用剤におけるＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄｌ−δ−トコフェリルのシワ改善効果を示す。
【００２９】
実施例１：シワ改善クリーム
（処方）

（調製法）
水中油型乳化組成物の調製法の定法に従い、ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄｌ−δ−トコフェリルを含有するシワ改善クリームを調製した。
【００３０】
比較例１（シワ改善クリーム比較用のクリームの調製）
実施例１のシワ改善クリームの処方からＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄｌ−δ−トコフェリルを除いた処方により、同様の調製法により比較用のクリームを調製した。
【００３１】
（シワ改善効果の評価）
表４に示す８名の被験者に、実施例１のクリーム、及び比較例１のクリーム約０．１ｇ程度を毎日２回（朝晩）両目尻の一方づつに塗布した。塗布前、及び塗布９０日後に目尻の塗布部分から定法に従ってレプリカを採取し、以下のシワ面積率の測定法、及び最大シワ深さの測定法によりシワ面積率、及び最大シワ深さを求め、塗布前、及び塗布後のシワ面積率、及び最大シワ深さの変化率を求めた。
【００３２】
（シワ面積率の測定法）
目尻から採取したレプリカに、斜め３０°から光を照射し、生じた影の面積を画像解析システムによる２値化法により測定し、下記の式により相対シワ面積率を求めた。
［相対シワ面積率（％）］＝（［シワの影の総面積］／［測定範囲の総面積］）×１００
【００３３】
（最大シワ深さの測定法）
目尻から採取したレプリカに、斜め３０°から光を照射し、生じた影の長さを画像解析システムによる２値化法により測定した。０．２、０．４、０．６、０．８、１．０ｍｍの深さの溝を持つシワ標準板を用いて予め作成してある検量線を用いて、シワ深さを求めた。
【００３４】
塗布前、及び塗布後のシワ面積率の変化率、及び最大シワ深さの変化率を表４に示す。
【００３５】
【表４】

これらの結果の（シワ面積率の変化率）の有効率の平均値は１８．４％、標準偏差は３４．４％であり、また（最大シワ深さの変化率）の有効率の平均値は９．５％、標準偏差は１５．９％で、有意にシワ改善効果が認められることが分かる。
【００３６】
次に、実際の皮膚外用剤及び化粧品処方に、ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄｌ−δ−トコフェリルを添加した例を示す。
【００３７】
実施例２：アイジェル
（処方）

（調製方法）
Ａ相、Ｂ相、Ｃ相の成分をそれぞれ８０℃に加熱し、溶解混合する。Ｃ相にＢ相を加え混合した後に、Ａ相を添加する。撹拌しながら冷却し、３５℃まで撹拌冷却して調製を終了する。
【００３８】
実施例３：アイクリーム１
（処方）

（調製方法）
水相成分、及び油相成分を８０℃に加熱し、予め溶解混合しておく。ホモミキサーにて油相に水相を添加して乳化した後に、３５℃まで撹拌冷却して調製を終了する。
【００３９】
実施例４：アイクリーム２
（処方）

（調製方法）
Ａ相成分、及びＢ相成分を８０℃に加熱し、溶解混合する。Ａ相にＢ相を添加して乳化した後に、５０℃でＣ相を添加し、３５℃まで撹拌冷却して調整を終了する。
【００４０】
実施例５：化粧水
（処方）

（調製方法）
Ａ相成分を７０℃に加温溶解し、Ｂ相成分を室温で均一混合する。Ａ相を撹拌しながらＢ相を徐々に添加し、可溶化して調製を終了する。
【００４１】
（シワ改善効果の評価）
実施例２〜５の化粧料を、実施例１のシワ改善効果の評価と同様の方法で一週間目尻に塗布し、一週間後の皮膚の状態を官能評価により評価を行ったところ、いずれも良好なシワ改善効果が見られた。
【００４２】
【発明の効果】
以上、詳細に説明したように、ＡＬＬ−ｔｒａｎｓ−レチノイン酸ｄ−δ−トコフェリルは、極めて高いシワ改善効果が見られ、ＡＬＬ−ｔｒａｎｓ−レチノイン酸δ−トコフェリルは皮膚刺激性を抑制し、かつ皮膚老化防止効果、シワ改善効果に有効であることが分かる。またδ−トコフェリル残基はビタミンＥ誘導体として高い抗酸化作用を有することから、レチノイン酸の皮膚老化防止効果、シワ改善効果との相乗効果により、極めて有効な美肌作用を有することが期待される。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to the use of a retinoic acid derivative in a skin external preparation for the purpose of improving wrinkles.
[0002]
[Prior art]
The action of retinoic acid on the skin is to maintain the normal structure and function of epithelial tissues and mucous membranes, and is also considered to be related to physiological actions such as growth and development of skin tissues. In addition, retinoic acid is used as a therapeutic agent for acne because of its sebaceous gland atrophy effect, and subsequently its wrinkle-reducing effect has been confirmed. According to studies using hairless mice, it was reported that fibroblast function was normalized, collagen synthesis was increased, and glucosaminoglycan was also increased to improve wrinkles (Journal of the Japan Society of Cosmetic Science, 16 (3), 182p).
[0003]
However, although retinoic acid has these useful effects, various side effects such as skin irritation have been reported and cannot be used in Japan.
[0004]
As a method for improving these, α-tocopherol derivatives of retinoic acid, that is, α-tocopheryl retinoic acid, have been reported (JP-B-59-22684, JP-A-53-15429, etc.). However, there is no report as a retinoic acid derivative of δ-tocopherol having high antioxidant activity as a vitamin E derivative.
[0005]
[Problems to be solved by the invention]
An object of the present invention was to find a derivative that effectively utilizes the skin aging preventing effect and the wrinkle improving effect of retinoic acid and does not cause skin irritation.
[0006]
[Means for Solving the Problems]
The present inventors have conducted intensive studies on various retinoic acid derivatives, and as a result, δ-tocopherol derivative of retinoic acid, that is, δ-tocopheryl retinoic acid, suppresses skin irritation, and is effective in preventing skin aging and improving wrinkles. I found something. In addition, since the δ-tocopheryl residue has a high antioxidant action as a vitamin E derivative, it has been confirmed that retinoic acid has a very effective skin beautiful action due to a synergistic effect with a skin aging prevention effect and a wrinkle improvement effect. Thus, the present invention has been completed.
[0007]
BEST MODE FOR CARRYING OUT THE INVENTION
Δ-Tocopheryl retinoic acid used in the present invention can be synthesized from retinoic acid and δ-tocopherol by a usual esterification reaction.
[0008]
The retinoic acid residue of retinoic acid δ-tocopheryl used in the present invention is not particularly limited as long as it is retinoic acid, and ALL-trans-retinoic acid, 13-cis-retinoic acid, 11-cis-retinoic acid, 9-cis-retinoic acid or any mixture thereof can be used. Among these, ALL-trans-retinoic acid is particularly preferred.
[0009]
The δ-tocopherol residue of retinoic acid δ-tocopheryl used in the present invention is not particularly limited as long as it is δ-tocopherol, and d-δ-tocopherol, 1-δ-tocopherol, and a mixture thereof are used. Certain dl-δ-tocopherols or any mixture thereof can be used. Among these, d-δ-tocopherol is particularly preferred.
[0010]
The amount of δ-tocopheryl retinoic acid used in the present invention in the external preparation for skin is not particularly limited, but is preferably 0.001% by weight or more, more preferably 0.01% by weight or more. The upper limit of the amount is not particularly limited, but is substantially 5% by weight or less, preferably 2% by weight or less.
[0011]
In the skin external preparation of the present invention, in addition to the above-mentioned components, as an ingredient to be added to a skin external preparation such as cosmetics and quasi-drugs as long as the effects of the present invention are not impaired, a hardened oil derived from animal and vegetable oils, a natural wax , Hydrocarbon-based oil phase components, animal and plant-derived oil phase components, silicone-based oil phase components, fluorine-based oil phase components, higher alcohols, thickeners, UV absorbers, powders, pigments, anionic interfaces Contains surfactants, cationic surfactants, nonionic surfactants, polyhydric alcohols, sugars, polymer compounds, physiologically active ingredients, transdermal absorption enhancers, solvents, antioxidants, fragrances, preservatives, etc. can do.
[0012]
【Example】
Hereinafter, the present invention will be described specifically with reference to Examples, but the technical scope of the present invention is not limited thereto.
[0013]
First, using ALL-trans-d-δ-tocopheryl retinoic acid δ-tocopheryl as retinoic acid δ-tocopheryl, the reduction rate of 1,1-diphenyl-2-picryl-hydrazyl (DPPH), which is usually used as a model substance for active oxygen, Shows active oxygen scavenging ability.
[0014]
(Test Example 1) Evaluation of active oxygen scavenging action The active oxygen scavenging action was evaluated using ALL-trans-d-δ-tocopheryl, ALL-trans-retinoic acid, and dl-δ-tocopherol at the concentrations shown in Table 1. An evaluation was performed. After allowing these samples to react with DPPH at 37 ° C. for 2 hours, the reduction rate of DPPH was determined by measuring the absorbance at 516 nm. Table 1 shows the results.
[0015]
[Table 1]

As shown in Table 1, ALL-trans-d-δ-tocopheryl retinoic acid shows an effect of reducing DPPH, and the effectiveness of dl-δ-tocopheryl retinoic acid in scavenging active oxygen can be seen.
[0016]
Next, similarly, the alleviating effect of d-δ-tocopheryl ALL-trans-retinoic acid on cell damage caused by lipid peroxide is shown. That is, the palliative effect on cell damage caused by tert-butylhydroperoxide (t-BHP), which is generally used as a model substance of lipid peroxide, is shown below.
[0017]
(Test Example 2) Evaluation of alleviating action against cell damage caused by lipid peroxide ALL-trans-d-δ-tocopheryl retinoic acid at a concentration shown in Table 2, and ALL-trans-retinoic acid and dl-δ-tocopherol for comparison. HaCat cells were cultured in a medium containing these samples for 24 hours. Thereafter, the medium was removed, and the cells were treated with 1 mM t-BHP at 37 ° C. for 5 hours. Subsequent cell viability was determined by NR assay, and the palliative effect on cell damage due to lipid peroxide was evaluated.
[0018]
[Table 2]

As seen in Table 2, ALL-trans-d-δ-tocopheryl retinoic acid shows an effect of improving cell viability, and the effectiveness of dl-δ-tocopheryl retinoic acid in mitigating the cell injury caused by lipid peroxide is shown. I understand.
[0019]
Next, the effect of inhibiting the production of collagenase by UV-irradiation to cells by ALL-trans-d-δ-tocopheryl retinoic acid will be described based on the messenger level and the production of collagenase.
[0020]
(Test Example 3) Evaluation of collagen-degrading enzyme production inhibitory action from collagen-degrading enzyme messenger level Using ALL-trans-d-δ-tocopheryl retinoic acid and ALL-trans-retinoic acid as a comparison, these samples were used. Was cultured in a medium containing 2.5 μM for 24 hours, and then irradiated with ultraviolet rays (UVA) at 20 J / cm ² for 6 hours. After the irradiation, total RNA was extracted from the cells, and the expression of MMP-9 mRNA was observed by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR).
[0021]
As a result, all-trans-retinoic acid d-δ-tocopheryl suppressed the expression level of MMP-9 mRNA to about 70%, whereas ALL-trans-retinoic acid showed no inhibitory effect. .
[0022]
(Test Example 4) Evaluation of collagen-degrading enzyme production inhibitory action based on collagen-degrading enzyme production amount. Using ALL-trans-retinoic acid d-δ-tocopheryl, and ALL-trans-retinoic acid as a comparative example, these were used. After culturing HaCat cells in a medium containing 2.5 μM of the sample for 24 hours, ultraviolet rays (UVA) at 20 J / cm ² were irradiated for 6 hours. After irradiation, zymography of MMP-2 and MMP-9 was performed using the culture supernatant of HaCat cell.
[0023]
As a result, ALL-trans-dl-δ-tocopheryl retinoic acid showed an effect of suppressing the expression of MMP-9 to about 75% and also suppressing MMP-2. On the other hand, ALL-trans-retinoic acid showed no inhibitory effect.
[0024]
Next, the promotion of collagen synthesis by ALL-trans-d-δ-tocopheryl retinoic acid is shown by quantification of type I collagen by ELISA.
[0025]
(Test Example 5) Evaluation of collagen synthesis promoting action Using ALL-trans-d-δ-tocopheryl retinoic acid and ALL-trans-retinoic acid as a comparative example, these samples were used in a medium containing the concentrations shown in Table 3. Then, Normal Human Dermal Fibroblast (NHDF) was cultured for 24 hours. The culture supernatant was transferred to an ELIZA plate and coated overnight at 4 ° C. After washing with PBS (-) containing 0.05% Tween20 (PBS-T), it was coated with a 1% bovine serum albumin solution at 37 ° C for 1 hour. After washing with PBS-T, the mixture was reacted with an anti-type I collagen antibody solution at 37 ° C. for 1 hour, and then reacted at 37 ° C. for 1 hour using HISTOFINE (simple stain PO®) as a secondary antibody. 2,2′-Azinobis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS)) was added, and the color development after 30 minutes was measured by the absorbance at 405 nm.The collagen contained in the medium was quantified by the calibration curve created at the same time. did.
[0026]
Table 3 shows the results.
[0027]
[Table 3]

As shown in Table 3, all-trans-d-δ-tocopheryl retinoic acid increased the amount of collagen in the culture supernatant of the used fibroblasts in a concentration-dependent manner, and at 10 μM, the amount of collagen was 168 compared to the control. %.
On the other hand, ALL-trans-retinoic acid did not show an increasing effect.
[0028]
Next, the wrinkle improving effect of ALL-trans-dl-δ-tocopheryl in a skin external preparation is shown.
[0029]
Example 1: Wrinkle improving cream (formulation)

(Preparation method)
A wrinkle improving cream containing ALL-trans-dl-δ-tocopheryl was prepared according to a standard method of preparing an oil-in-water emulsion composition.
[0030]
Comparative Example 1 (Preparation of wrinkle improving cream comparison cream)
A cream for comparison was prepared by the same preparation method as in the formulation of the wrinkle improving cream of Example 1 except that ALL-trans-dl-δ-tocopheryl was removed.
[0031]
(Evaluation of wrinkle improvement effect)
About eight grams of the cream of Example 1 and the cream of Comparative Example 1 were applied twice daily (morning and evening) to each of the eight eyes shown in Table 4 twice daily (morning and evening). Before application, and 90 days after application, a replica is collected from the applied portion of the outer corner of the eye according to a standard method, the following wrinkle area ratio measurement method, and the maximum wrinkle depth measurement method, and the maximum wrinkle area is determined, The wrinkle area ratio before and after application and the rate of change in the maximum wrinkle depth were determined.
[0032]
(Method of measuring wrinkle area ratio)
The replica collected from the outer corner of the eye was irradiated with light from an oblique angle of 30 °, the area of the generated shadow was measured by a binarization method using an image analysis system, and the relative wrinkle area ratio was determined by the following equation.
[Relative wrinkle area ratio (%)] = ([total area of wrinkle shadow] / [total area of measurement range]) × 100
[0033]
(Method of measuring maximum wrinkle depth)
The replica taken from the outer corner of the eye was irradiated with light at an oblique angle of 30 °, and the length of the generated shadow was measured by a binarization method using an image analysis system. The wrinkle depth was determined using a calibration curve prepared in advance using a wrinkle standard plate having grooves having a depth of 0.2, 0.4, 0.6, 0.8, and 1.0 mm.
[0034]
Table 4 shows the change rate of the wrinkle area ratio before and after the application and the change rate of the maximum wrinkle depth.
[0035]
[Table 4]

The average value of the effective rate of (change rate of wrinkle area ratio) of these results is 18.4%, the standard deviation is 34.4%, and the average value of the effective rate of (change rate of maximum wrinkle depth) Is 9.5% and the standard deviation is 15.9%, indicating that a significant wrinkle improvement effect is recognized.
[0036]
Next, an example in which ALL-trans-dl-δ-tocopheryl retinoic acid is added to actual skin external preparations and cosmetic formulations will be described.
[0037]
Example 2: Eye gel (formulation)

(Preparation method)
The components of phase A, phase B and phase C are each heated to 80 ° C. and dissolved and mixed. After adding and mixing the phase B and the phase C, the phase A is added. Cool with stirring and stir to 35 ° C. to complete the preparation.
[0038]
Example 3: Eye cream 1
(Prescription)

(Preparation method)
The aqueous phase component and the oil phase component are heated to 80 ° C. and dissolved and mixed in advance. After the aqueous phase is added to the oil phase with a homomixer and emulsified, the mixture is stirred and cooled to 35 ° C. to complete the preparation.
[0039]
Example 4: Eye cream 2
(Prescription)

(Preparation method)
The A-phase component and the B-phase component are heated to 80 ° C. and dissolved and mixed. After adding phase B to phase A and emulsifying, phase C is added at 50 ° C., and the mixture is stirred and cooled to 35 ° C. to complete the adjustment.
[0040]
Example 5: Lotion (Prescription)

(Preparation method)
The phase A component is heated and dissolved at 70 ° C., and the phase B component is uniformly mixed at room temperature. While stirring the phase A, gradually add the phase B, solubilize and finish the preparation.
[0041]
(Evaluation of wrinkle improvement effect)
The cosmetics of Examples 2 to 5 were applied to the outer corner of the first week in the same manner as in the evaluation of the wrinkle improving effect of Example 1, and the state of the skin after one week was evaluated by sensory evaluation. A good wrinkle improving effect was observed.
[0042]
【The invention's effect】
As described above in detail, ALL-trans-d-δ-tocopheryl retinoic acid has an extremely high wrinkle-reducing effect, and ALL-trans-δ-tocopheryl retinoic acid suppresses skin irritation, and It turns out that it is effective in the anti-aging effect and the wrinkle improvement effect. Further, since a δ-tocopheryl residue has a high antioxidant effect as a vitamin E derivative, it is expected that retinoic acid has a very effective skin beautiful effect due to a synergistic effect with a skin aging preventing effect and a wrinkle improving effect.

Claims (2)

A wrinkle improving agent containing δ-tocopheryl retinoic acid as an essential component. A skin external preparation for preventing skin aging using the wrinkle improving agent according to claim 1, and a cosmetic.