JP4046426B2 - Ceramide derivative and skin cosmetic containing the same - Google Patents

Description

【００１０】
（但し、式中、Ｒ₁は炭素数１１〜３５の直鎖又は分岐鎖状の、飽和又は不飽和の、ヒドロキシル基を有する又は有さない脂肪族炭化水素基、Ｒ₂は炭素数６〜２６の直鎖又は分岐鎖状の、飽和又は不飽和の、ヒドロキシル基を有する又は有さない脂肪族炭化水素基、Ｒ₃はＨ、グルコシル基又はガラクトシル基である。）で示されるセラミド誘導体にある。
【００１１】
また、本発明は、一般式（２）
【００１２】
【化５】

【００１３】
（但し、式中、Ｒ₄は炭素数１１〜３５の直鎖又は分岐鎖状の、飽和又は不飽和の脂肪族炭化水素基、Ｒ₅は炭素数６〜２６の直鎖又は分岐鎖状の、飽和又は不飽和の脂肪族炭化水素基、Ｒ₆はＨ、グルコシル基又はガラクトシル基である。）で示されるセラミド誘導体にある。
【００１４】
更に、本発明は Ｒ₁又はＲ₄が、置換基として一般式−ＣＯＯＲ_Ｘ(Ｒ_Ｘは炭素数１１〜３５である脂肪族炭化水素基である）で表される脂肪族オキシカルボニル基を更に有する脂肪族炭化水素基であることを特徴とする請求項１または２のセラミド誘導体にある。なお、かかるセラミド誘導体とは、すなわち請求項１および請求項２にかかるセラミド誘導体のうち、Ｒ₁又はＲ₄基中にヒドロキシル基を有する化合物の、Ｒ_ＸＣＯＯＨの一般式で表される脂肪酸エステル誘導体である。
【００１５】
更に、本発明は、上記一般式（１）又は（２）で示されるセラミド誘導体の少なくとも１種を有効成分として含有することを特徴とする皮膚化粧料にある。そして特に好ましくは、一般式（２）で示されるセラミド誘導体の少なくとも１種を有効成分として含有することを特徴とする皮膚化粧料にある。
【００１６】
また、更に本発明は、上記一般式（１）又は（２）で示されるセラミド誘導体の少なくとも１種及び一般式（３）
【００１７】
【化６】

【００１８】
（但し、式中、Ｒ₇は炭素数１１〜３５の直鎖又は分岐鎖状の、飽和又は不飽和のヒドロキシル基を有する脂肪族炭化水素基、Ｒ₈は炭素数８〜２８の直鎖又は分岐鎖状の、飽和又は不飽和の脂肪族炭化水素基、Ｒ₉はＨ、グルコシル基又はガラクトシル基である。）で示されるセラミド誘導体の少なくとも１種とを有効成分として含有することを特徴とする皮膚化粧料にある。そして特に好ましくは、一般式（２）で示されるセラミド誘導体の少なくとも１種ならびに一般式（３）で示されるセラミド誘導体の少なくとも１種を有効成分として含有することを特徴とする皮膚化粧料にある。
【００１９】
【発明の実施の形態】
前記一般式（１）
【００２０】
【化７】

【００２１】
（但し、式中、Ｒ₁は炭素数１１〜３５の直鎖又は分岐鎖状の、飽和もしくは不飽和の、ヒドロキシル基を有する又は有さない脂肪族炭化水素基、Ｒ₂は炭素数６〜２６の直鎖又は分岐鎖状の、飽和又は不飽和の、ヒドロキシル基を有する又は有さない脂肪族炭化水素基、Ｒ₃はＨ、グルコシル基又はガラクトシル基である。）、又は一般式（２）
【００２２】
【化８】

【００２３】
（但し、式中、Ｒ₄は炭素数１１〜３５の直鎖又は分岐鎖状の、飽和又は不飽和の脂肪族炭化水素基、Ｒ₅は炭素数６〜２６の直鎖又は分岐鎖状の、飽和又は不飽和の脂肪族炭化水素基、Ｒ₆はＨ、グルコシル基又はガラクトシル基である。）で示される本発明のセラミド誘導体、並びにＲ₁又はＲ₄が、置換基として一般式−ＣＯＯＲ_Ｘ(Ｒ_Ｘは炭素数１１〜３５である脂肪族炭化水素基である）で表される脂肪族オキシカルボニル基を更に有する脂肪族炭化水素基である上記のセラミド誘導体は、合成又は天然物よりの抽出によって得ることができ、その方法は特に限定されるものではなく、例えば、次の方法により得ることができる。
【００２４】
（１）抽出法：前記一般式（１）又は一般式（２）で示されるセラミド誘導体は天然物からの抽出、例えば、ヒト角質細胞間脂質やヒト新生児の皮表に存在する胎脂からの抽出により得られる。その方法には特に制限がなく、通常の抽出法が採用されるが、好ましくは以下の抽出及び精製法である。胎脂を例に挙げて説明する。
【００２５】
出生直後の新生児の体表面に付着している胎脂を、ガーゼを用いて採取し、そこからクロロホルム／メタノール（１：２）を用いて脂質画分を抽出する。イアトロビーズ（６RS-8060、Iatron Laboratories社製）を充填したクロマトグラフ管を用い、クロロホルム／メタノール混液系で溶出させ、前記一般式（１）又は一般式（２）のセラミド誘導体画分の粗分画を行なう。続いて、薄層板（シリカゲル６０，２０×２０ｃｍ，厚さ０．２５ｍｍ，濃縮ゾーン付き，Ｍｅｒｃｋ社製）の下部に横長の帯状に粗画分を滴下し、クロロホルム／メタノール混液系で上端まで２回ないしは３回展開し、風乾後、０．０１％プリムリン−メタノール溶液を噴霧して前記一般式（１）のセラミド誘導体を検出し、シリカゲルごと掻き取り、クロロホルム／メタノール（２：１）で溶出させる。その後、カラムクロマトグラフィーを用いて、吸着剤及びプリムリンを除去し、前記一般式（１）又は一般式（２）のセラミド誘導体を単離する。
【００２６】
（２）合成法：前記一般式（１）で示されるセラミド誘導体の合成方法には特に制限がなく、通常の合成法が採用されるが、好ましくは以下の方法である。触媒存在下で、一般式（４）
【００２７】
【化９】

【００２８】
（但し、式中、Ｒ₁₀は炭素数１１〜３５の直鎖もしくは分岐鎖状の、飽和もしくは不飽和の、ヒドロキシル基を有する又は有さない脂肪族炭化水素基、Ｒ₁₁は炭素数６〜２６の直鎖もしくは分岐鎖状の、飽和もしくは不飽和の、ヒドロキシル基を有する又は有さない脂肪族炭化水素基、Ｒ₁₂はＨ、グルコシル基又はガラクトシル基である。）で示されるセラミド誘導体を酸化、精製する。触媒としては二酸化セレンを用い、ジクロロメタン中、２５℃で４８時間反応させて、一般式（４）のＲ₁₁に結合している炭素原子に水酸基を付加する。それを、有機溶媒で抽出し、１０％水酸化カリウム溶液で洗浄して前記一般式（１）で示されるセラミド誘導体を得る。尚、一般式（４）で示されるセラミド誘導体はシグマ社より入手可能である。
【００２９】
前記一般式（２）で示されるセラミド誘導体の合成方法には特に制限がなく、通常の合成法が採用されるが、好ましくは以下の方法である。触媒存在下で、一般式（５）
【００３０】
【化１０】

【００３１】
（但し、式中、Ｒ₁₃は炭素数１１〜３５の直鎖もしくは分岐鎖状の、飽和又は不飽和の脂肪族炭化水素基、Ｒ₁₄は炭素数６〜２６の直鎖もしくは分岐鎖状の、飽和又は不飽和の脂肪族炭化水素基、Ｒ₁₅はＨ、グルコシル基又はガラクトシル基である。）で示されるセラミド誘導体を酸化、精製する。触媒としては二酸化セレンを用い、ジクロロメタン中、２５℃で４８時間反応させて、一般式（５）のＲ₁₄に結合している炭素原子に水酸基を付加する。それを、有機溶媒で抽出し、１０％水酸化カリウム溶液で洗浄して前記一般式（２）で示されるセラミド誘導体を得る。
【００３２】
前記一般式（３）で示されるセラミド誘導体は例えば特開平２−２４１３２９号公報に記載されている方法に従って合成することができる。つまり、化１１で示されるスフィンゲニン誘導体と、化１２で示されるカルボン酸誘導体を塩基の存在下、アミド化反応させることにより得られる。
【００３３】
【化１１】

【００３４】
（但し、上記式中、Ｒ₁₆は炭素数８〜２８の直鎖もしくは分岐鎖状の、飽和又は不飽和の脂肪族炭化水素基、Ｒ₁₇はＨ、グルコシル基又はガラクトシル基である。）
【００３５】
【化１２】

【００３６】
（但し、上記式中、Ｒ₁₈は炭素数１１〜３５の直鎖もしくは分岐鎖状の、飽和又は不飽和のヒドロキシル基を有する脂肪族炭化水素基、Ｒ₁₉は、ｐ−ニトロフェノール基である。）
【００３７】
次に、本発明に係る皮膚化粧料について説明をする。本発明に係る皮膚化粧料は前記一般式（１）又は（２）で示されるセラミド誘導体の少なくとも１種を有効成分として含有する。ここで、本発明の皮膚化粧料とは、人体の頭皮を含む表皮に適用する組成物を指し、例えばクリーム類、乳液類、ローション類、パック類、美容液等、また錠剤、粉末、顆粒、液状等の入浴剤等、種々の剤形にすることができる。
【００３８】
本発明の皮膚化粧料には、前記一般式（１）又は（２）で示されるセラミド誘導体の少なくとも１種を有効成分として含有していればよく、その配合量は、最終製剤の総量を基準として、大略０．０１〜３０．０ｗｔ％が好ましい。配合量がこの範囲より少ないと本発明の効果が十分に達成されない場合があり、３０．０ｗｔ％を越えて配合してもその増加分に見合った効果の向上は望めない場合がある。
【００３９】
本発明の皮膚化粧料には、前記一般式（１）又は（２）で示されるセラミド誘導体の少なくとも１種と、一般式（３）で示されるセラミド誘導体の少なくとも１種とを有効成分として含有すると更に好ましく、その配合量は、最終製剤の総量を基準として、それぞれ大略０．０１〜３０．０ｗｔ％が好ましい。配合量がこの範囲より少ないと本発明の効果が十分に達成されない場合があり、これらが上限量を越えて配合してもその増加分に見合った効果の向上は望めない場合がある。また、本発明の前記一般式（１）又は（２）で示されるセラミド誘導体と、一般式（３）で示されるセラミド誘導体の配合比率は０．０１：１〜１００：１が更に好ましい。
【００４０】
本発明の皮膚化粧料には、上記必須成分の他に、必要に応じて油脂、色素、香料、防腐剤、界面活性剤、顔料、酸化防止剤等を本発明の目的を達成する範囲内で適宜配合することができる。
【００４１】
【実施例】
以下、実施例について説明する。実施例中で使用した一般式（１）又は一般式（２）で示されるセラミド誘導体は以下の通りである。これらは前述した抽出又は合成方法によって得た。
【００４２】
Ｎ−アシル−６−ヒドロキシ−４−スフィンゲニン
【００４３】
【化１３】

【００４４】
（但し、上記式中、Ｒ₂₀は炭素数１１〜３５の飽和又は不飽和の脂肪族炭化水素基である。）
【００４５】
Ｎ−α−ヒドロキシアシル−６−ヒドロキシ−４−スフィンゲニン
【００４６】
【化１４】

【００４７】
（但し、上記式中、Ｒ₂₁は炭素数１０〜３４の飽和又は不飽和の脂肪族炭化水素基である。）
【００４８】
Ｎ−ω−ヒドロキシアシル−６−ヒドロキシ−４−スフィンゲニン
【００４９】
【化１５】

【００５０】
（但し、上記式中、Ｒ₂₂は炭素数１１〜３５の飽和又は不飽和の脂肪族炭化水素基である。）
【００５１】
Ｎ−ω−アシルオキシアシル−６−ヒドロキシ−４−スフィンゲニン
【００５２】
【化１６】

【００５３】
（但し、上記式中、Ｒ₂₃及びＲ₂₄は炭素数１１〜３５の飽和又は不飽和の脂肪族炭化水素基である。）
【００５４】
１−Ｏ−β−グルコシル−Ｎ−アシル−６−ヒドロキシ−４−スフィンゲニン
【００５５】
【化１７】

【００５６】
（但し、上記式中、Ｒ₂₅は炭素数１１〜３５の飽和又は不飽和の脂肪族炭化水素基であり、Ｇｌｕはグルコース残基である。）
【００５７】
１−Ｏ−β−ガラクトシル−Ｎ−アシル−６−ヒドロキシ−４−スフィンゲニン
【００５８】
【化１８】

【００５９】
（但し、上記式中、Ｒ₂₆は炭素数１１〜３５の飽和又は不飽和の脂肪族炭化水素基であり、Ｇａｌはガラクトース残基である。）
【００６０】
実施例中で使用した一般式（３）で示されるセラミド誘導体は以下の通りである。
【００６１】
Ｎ−α−ヒドロキシアシルフィトスフィンゴシン
【００６２】
【化１９】

【００６３】
（但し、上記式中、Ｒ₂₇は炭素数１０〜３４の飽和又は不飽和の脂肪族炭化水素基である。）
【００６４】
１−Ｏ−β−ガラクトシル−Ｎ−α−ヒドロキシアシルフィトスフィンゴシン
【００６５】
【化２０】

【００６６】
（但し、上記式中、Ｒ₂₈は炭素数１０〜３４の飽和又は不飽和の脂肪族炭化水素基であり、Ｇａｌはガラクトース残基である。）
【００６７】
本発明の皮膚化粧料を評価するために用いた荒れ肌改善効果試験、角質層改善効果試験、保湿効果試験（ＴＷＬ値低減率）、美肌効果試験（実用テスト）は下記の通りである。
【００６８】
（１）荒れ肌改善効果試験
両下脚に荒れ肌を有する中高年被験者２０名を対象として４週間連続塗布効果を調べた。被験者の左側下脚試験部位に１日１回約１ｇの試料を塗布し、試験開始前及び終了翌日の皮膚の状態を下記の判定基準により肉眼判定した。右側下脚は試料を塗布せず対照とした。
【００６９】
判定基準（皮膚乾燥度の判定基準）
− ：正常
± ：軽微乾燥、落屑なし
＋ ：乾燥、落屑軽度
＋＋ ：乾燥、落屑中等度
＋＋＋ ：乾燥、落屑顕著
【００７０】
試験前後の試験部位と対照部位の判定結果を比較し、皮膚乾燥度が２段階以上改善された場合（例えば、＋→−、＋＋→±）を有効、１段階改善された場合をやや有効、変化がなかった場合を無効とした。試験結果は有効、やや有効となった被験者の人数で示した。
【００７１】
（２）角質層改善効果試験
前述の荒れ肌改善効果試験開始前及び終了翌日の被験者皮膚にニチバンメンディングテープを接着し、これを剥離した時テープに付着した角質細胞の状態を走査型電子顕微鏡によって詳細に調べ、下記の基準によって皮膚角質細胞抗剥離性を解析し、角質層改善効果（角質細胞抗剥離性増大効果）を求めた。
【００７２】
判定基準（角質層改善効果の判定基準）
評価点１：スケールを認めず
評価点２：小スケール点在
評価点３：小〜中スケール顕著
評価点４：大スケール顕著
【００７３】
評価は、４週間連続塗布後の試験部位の評価点と対照部位のそれとの差が２点以上の場合を有効、１点の場合をやや有効、０点の場合を無効とした。試験結果は、２０人中有効、やや有効となった被験者の人数で示した。
【００７４】
（３）保湿効果試験（ＴＷＬ値低減率）
前述の荒れ肌改善効果試験開始前及び終了翌日の被験者皮膚を対照として４週間連続塗布前及び塗布後のＴＷＬ値及びＴＷＬ値の低減率（水分保持機能亢進効果）を下記の如く算出して、保湿効果を調べた。
【００７５】
▲１▼ＴＷＬ値
密閉した皮表上の空気の一定時間内における温度変化を電気抵抗にて測定する方法を用いた。即ち、被試験者の皮表を測定用セルで密閉し、セルに強制乾燥した空気を通気してセル内を乾燥空気で充分置換した後、乾燥空気の通気を停止してその時点でのセル内の相対湿度ＲＨｓ（％）を求め、次いで１０分間放置して再びセル内の相対湿度ＲＨ10（％）を測定し、この時の湿度変化から下記の式によりＴＷＬ値（ｍｇ／ｃｍ²／ｈｒ）を算出した。
ＴＷＬ値＝〔（ＲＨ10−ＲＨｓ）×Ｄｔ×Ｖ×６〕／Ｓ×１００
但し、Ｄｔ：測定温度下（ｔ℃）での空気中の飽和水蒸気の密度（ｍｇ／ｌ）
Ｖ ：セルの容積（ｌ）
Ｓ ：測定面積（ｃｍ²）
【００７６】
▲２▼ＴＷＬ値の低減率
ＴＷＬ値の低減率は、試料塗布前後のＴＷＬ値、ＴＷＬＡ（試料塗布前のＴＷＬ値）及びＴＷＬＢ（試料塗布後のＴＷＬ値）を下記の式に代入して算出した。
ＴＷＬ値低減率＝（１−ＴＷＬＢ／ＴＷＬＡ）×１００（％）
ＴＷＬ値の低減率が２０％以上の場合を「有効」、低減率が２０％未満の場合を「無効」、とした。試験結果は、２０人中の「有効」であった被験者の人数で表示した。
【００７７】
（４）美肌効果試験（実用テスト）
荒れ肌，小皺，乾燥肌等を訴える女子被験者（３５〜５５才）２０人に試料を１日２回（朝・夕）連続３ケ月後の効果を評価した。試験結果は、皮膚の湿潤性，平滑性，弾力性の各項目に対して、「皮膚に潤いが生じた」，「皮膚が滑らかになった」，「皮膚に張りが生じた」と回答した人数で示した。
【００７８】
実施例１〜５，比較例１〜５（スキンクリーム）
表１の組成にて、スキンクリームを調製し、前記諸試験を実施した。
【００７９】
【表１】

【００８０】
スキンクリーム中に配合した本発明の成分を表２に示す。
【００８１】
【表２】

【００８２】
（１）調製法
表１中（Ｃ）及び（Ｄ）成分を（Ａ）成分中に８０℃にて加温溶解した後、（Ｂ）成分を８０℃にて加温溶解したものを加えて混合し、ホモミキサーにて分散した。次いで撹拌しつつ３０℃まで冷却して各スキンクリームを調製した。
【００８３】
（２）特性
下記表３に示す如く、本発明の皮膚化粧料である実施例１〜５のスキンクリームは、セラミド誘導体未配合化粧料である比較例１、一般式（１）又は（２）で示されるセラミド誘導体以外のセラミド誘導体配合化粧料である比較例２、比較例３及び比較例４、一般式（１）又は（２）で示されるセラミド誘導体以外のセラミド誘導体と一般式（３）で示されるセラミド誘導体とを含有する化粧料である比較例５と比較して、諸特性の全てに亘って優れており、その中で、実施例５の一般式（１）又は（２）で示されるセラミド誘導体の１種と、一般式（３）で示されるセラミド誘導体の１種とを配合している皮膚化粧料は特に良好なる結果が認められた。また、配合特性においても異常は認められなかった。
【００８４】
【表３】

【００８５】
実施例６〜１０、比較例６〜１０（美容液）
表４の組成にて、美容液を調製し、前記諸試験を実施した。
【００８６】
【表４】

【００８７】
美容液中に配合した本発明の成分を表５に示す。
【００８８】
【表５】

【００８９】
（１）調製法
表４中（Ｃ）及び（Ｄ）成分を（Ａ）成分中に８０℃にて加温溶解したものを、８０℃に加熱した（Ｂ）成分に添加して混合し、ホモミキサーにて分散した。次いで撹拌しつつ３０℃まで冷却して各美容液を調製した。
【００９０】
（２）特性
各美容液の諸試験を実施した結果を下記表６に示した。
セラミド誘導体未配合化粧料である比較例６、一般式（１）又は（２）で示されるセラミド誘導体以外のセラミド誘導体配合化粧料である比較例７及び比較例９、一般式（３）で示されるセラミド誘導体のみ含有する化粧料である比較例８、
一般式（１）又は（２）で示されるセラミド誘導体以外のセラミド誘導体と一般式（３）で示されるセラミド誘導体とを含有する化粧料である比較例１０と比較して、実施例６〜１０の本発明の皮膚化粧料は諸試験の全てに亘って良好なる結果が認められた。実施例９及び実施例１０の一般式（１）又は（２）で示されるセラミド誘導体の１種と一般式（３）で示されるセラミド誘導体の１種とを配合した皮膚化粧料は、特に優れていた。
【００９１】
【表６】

【００９２】
【発明の効果】
以上記載の如く、本発明の皮膚化粧料は、皮膚が本来備えている水分保持機能を亢進、維持することによって皮膚を健常な状態に改善又は修復して、かつ美肌作用を有する優れた皮膚化粧料を提供することが明らかである。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a ceramide derivative effective for improving or restoring the skin to a healthy state by enhancing and maintaining the moisture retention function of the skin, and a skin cosmetic containing the ceramide derivative.
[0002]
[Prior art]
The moisture of the skin always moves from the inside of the skin to the outer layer along the gradient of the moisture content that decreases from the dermis to the basal cell layer of the epidermis and further to the stratum corneum, and transpirations to the outside through the stratum corneum. However, this water transpiration is controlled mainly by a protective function (barrier function) consisting of a dense cellular tissue of the stratum corneum, and the transpiration amount (transdermal water loss, hereinafter abbreviated as TWL). ], For example healthy range 0.2~0.3mg / cm ² / hr in the forearm skin surface in a normal condition of the skin, which is usually kept below about 0.25mg / cm ² / hr.
[0003]
On the other hand, in dry skin usually found in dry skin or dry skin found in aging skin, the TWL value shows an upper limit value in the above range or a larger value depending on the degree, and the moisture content of the skin. It can be seen that the retention function is reduced. In the case of these dry skins, they are in a state where the normal control limit by the protective function of the stratum corneum is exceeded, or the protective function is deteriorated.
[0004]
Conventionally, a method of applying sphingolipids such as ceramide (derivatives), fatty acids, cholesterol and the like to the skin as a method for preventing a decrease in the keratin water content and maintaining normal skin function has been reported (Japanese Patent Publication No. 4). No. 57641, JP 61-260008, JP 62-29508, JP 62-56414, JP 63-192703). When applied to the skin, these lipid components form a liquid state containing water on the skin, prevent moisture transpiration from the skin, improve water retention, and maintain skin function normally. .
[0005]
[Problems to be solved by the invention]
However, when these lipid components were applied, the skin could be temporarily kept healthy, but the dry skin was not improved or repaired. In other words, in order for these lipid components to form a liquid crystal structure on the skin, a certain amount of water is required in the structure, and when applied to the skin by blending with a skin external base or cosmetic base Temporarily, the liquid crystal structure can be formed or maintained on the skin by the water in the base, but the structure cannot be maintained over time due to water evaporation from the coating surface. For these reasons, even though the skin can be temporarily kept healthy, it has been difficult to maintain that state and to improve or repair dry skin.
[0006]
Therefore, an object of the present invention is to provide a novel substance effective for maintaining the skin in a healthy state by restoring the protective function of the damaged stratum corneum and maintaining the normal protective function. It is in the provision of the skin cosmetics containing this.
[0007]
[Means for Solving the Problems]
As a result of intensive studies to overcome the above problems, a specific ceramide derivative has an action of enhancing the water retention function inherent in the skin, and the skin cosmetic containing the same has a damaged horny layer Was found to be effective in essentially restoring the protective function of the skin and maintaining the skin in a normal state.
[0008]
The present invention relates to the following general formula (1)
[0009]
[Formula 4]

[0010]
(In the formula, R ₁ is a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having or not having a hydroxyl group having 11 to 35 carbon atoms, and R ₂ is having 6 to 6 carbon atoms. 26 linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having or not having a hydroxyl group, and R ₃ is H, a glucosyl group or a galactosyl group). is there.
[0011]
Further, the present invention provides a compound represented by the general formula (2)
[0012]
[Chemical formula 5]

[0013]
(However, in the formula, R ₄ is a linear or branched aliphatic hydrocarbon group having 11 to 35 carbon atoms, or a saturated or unsaturated aliphatic hydrocarbon group, and R ₅ is a linear or branched chain having 6 to 26 carbon atoms. A saturated or unsaturated aliphatic hydrocarbon group, and R ₆ is H, a glucosyl group, or a galactosyl group).
[0014]
Furthermore, the present invention further provides an aliphatic oxycarbonyl group in which R ₁ or R ₄ is represented by the general formula —COOR _X (R _X is an aliphatic hydrocarbon group having 11 to 35 carbon atoms) as a substituent. The ceramide derivative according to claim 1, wherein the ceramide derivative is an aliphatic hydrocarbon group. The ceramide derivative is a fatty acid ester represented by the general formula R _X COOH of a compound having a hydroxyl group in R ₁ or R ₄ among the ceramide derivatives according to claim 1 and claim 2. Is a derivative.
[0015]
Furthermore, the present invention is a skin cosmetic comprising at least one ceramide derivative represented by the above general formula (1) or (2) as an active ingredient. Particularly preferred is a skin cosmetic comprising at least one ceramide derivative represented by the general formula (2) as an active ingredient.
[0016]
Furthermore, the present invention provides at least one ceramide derivative represented by the above general formula (1) or (2) and the general formula (3).
[0017]
[Chemical 6]

[0018]
(In the formula, R ₇ is a linear or branched aliphatic hydrocarbon group having a saturated or unsaturated hydroxyl group having 11 to 35 carbon atoms, and R ₈ is a straight chain having ₈ to 28 carbon atoms or A branched or saturated aliphatic hydrocarbon group, R ₉ is H, a glucosyl group or a galactosyl group)) and contains as an active ingredient at least one ceramide derivative. To be in skin cosmetics. Particularly preferably, the skin cosmetic contains at least one ceramide derivative represented by the general formula (2) and at least one ceramide derivative represented by the general formula (3) as an active ingredient. .
[0019]
DETAILED DESCRIPTION OF THE INVENTION
General formula (1)
[0020]
[Chemical 7]

[0021]
(However, in the formula, R ₁ is a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having or not having a hydroxyl group having 11 to 35 carbon atoms, and R ₂ is having 6 to 6 carbon atoms. 26 linear or branched, saturated or unsaturated, aliphatic hydrocarbon groups with or without hydroxyl groups, R ₃ is H, glucosyl group or galactosyl group), or general formula (2 )
[0022]
[Chemical 8]

[0023]
(However, in the formula, R ₄ is a linear or branched aliphatic hydrocarbon group having 11 to 35 carbon atoms, or a saturated or unsaturated aliphatic hydrocarbon group, and R ₅ is a linear or branched chain having 6 to 26 carbon atoms. , aliphatic saturated or unsaturated hydrocarbon group, R ₆ is H, ceramide derivatives of the present invention represented by it.) a glucosyl group or a galactosyl group, and R ₁ or R _4, the general formula -COOR as a substituent _The above-mentioned ceramide derivative, which is an aliphatic hydrocarbon group further having an aliphatic oxycarbonyl group represented by _X (R _X is an aliphatic hydrocarbon group having 11 to 35 carbon atoms) is obtained from a synthetic or natural product. The method is not particularly limited, and for example, it can be obtained by the following method.
[0024]
(1) Extraction method: The ceramide derivative represented by the general formula (1) or the general formula (2) is extracted from a natural product, for example, from human keratinocyte lipids or vernix present in the skin surface of a human newborn. Obtained by extraction. The method is not particularly limited, and a normal extraction method is adopted, but the following extraction and purification methods are preferred. An explanation will be given using vernix as an example.
[0025]
The vernix adhering to the body surface of the newborn immediately after birth is collected using gauze, and the lipid fraction is extracted therefrom using chloroform / methanol (1: 2). Using a chromatograph tube packed with Iatrobeads (6RS-8060, manufactured by Iatron Laboratories), eluting with a chloroform / methanol mixture system, crude fraction of the ceramide derivative fraction of the above general formula (1) or general formula (2) To do. Subsequently, a crude fraction was dropped in the form of a horizontally long strip at the bottom of a thin-layer plate (silica gel 60, 20 × 20 cm, thickness 0.25 mm, with a concentration zone, manufactured by Merck) to the top with a chloroform / methanol mixture system. Developed twice or three times, air-dried, sprayed with 0.01% primulin-methanol solution to detect the ceramide derivative of the general formula (1), scraped together with silica gel, and chloroform / methanol (2: 1) Elute. Thereafter, the adsorbent and primulin are removed using column chromatography, and the ceramide derivative of the general formula (1) or the general formula (2) is isolated.
[0026]
(2) Synthesis method: The method for synthesizing the ceramide derivative represented by the general formula (1) is not particularly limited, and a usual synthesis method is adopted, but the following method is preferable. In the presence of a catalyst, general formula (4)
[0027]
[Chemical 9]

[0028]
(In the formula, R ₁₀ is a linear or branched, saturated or unsaturated aliphatic hydrocarbon group having or not having a hydroxyl group having _{11 to} 35 carbon atoms, and R ₁₁ is having 6 to 6 carbon atoms. 26 linear or branched, saturated or unsaturated, aliphatic hydrocarbon groups with or without hydroxyl groups, R ₁₂ is H, glucosyl group or galactosyl group). Oxidize and purify. As a catalyst, selenium dioxide is used and reacted in dichloromethane at 25 ° C. for 48 hours to add a hydroxyl group to the carbon atom bonded to R ₁₁ in the general formula (4). It is extracted with an organic solvent and washed with a 10% potassium hydroxide solution to obtain a ceramide derivative represented by the general formula (1). The ceramide derivative represented by the general formula (4) is available from Sigma.
[0029]
There is no particular limitation on the method for synthesizing the ceramide derivative represented by the general formula (2), and a usual synthesis method is adopted, but the following method is preferable. In the presence of a catalyst, the general formula (5)
[0030]
Embedded image

[0031]
(In the formula, R ₁₃ is a linear or branched aliphatic hydrocarbon group having 11 to 35 carbon atoms, or a saturated or unsaturated aliphatic hydrocarbon group, and R ₁₄ is a linear or branched chain having 6 to 26 carbon atoms. A saturated or unsaturated aliphatic hydrocarbon group, and R ₁₅ is H, a glucosyl group, or a galactosyl group.) Is oxidized and purified. As a catalyst, selenium dioxide is used and reacted in dichloromethane at 25 ° C. for 48 hours to add a hydroxyl group to the carbon atom bonded to R ₁₄ in the general formula (5). It is extracted with an organic solvent and washed with a 10% potassium hydroxide solution to obtain a ceramide derivative represented by the general formula (2).
[0032]
The ceramide derivative represented by the general formula (3) can be synthesized, for example, according to the method described in JP-A-2-241329. That is, it can be obtained by subjecting the sphingenin derivative represented by Chemical Formula 11 and the carboxylic acid derivative represented by Chemical Formula 12 to an amidation reaction in the presence of a base.
[0033]
Embedded image

[0034]
(In the above formula, R ₁₆ is a linear or branched, saturated or unsaturated aliphatic hydrocarbon group having 8 to 28 carbon atoms, and R ₁₇ is H, a glucosyl group, or a galactosyl group.)
[0035]
Embedded image

[0036]
(In the above formula, R ₁₈ is a linear or branched aliphatic hydrocarbon group having a saturated or unsaturated hydroxyl group having 11 to 35 carbon atoms, and R ₁₉ is a p-nitrophenol group. .)
[0037]
Next, the skin cosmetic according to the present invention will be described. The skin cosmetic according to the present invention contains at least one ceramide derivative represented by the general formula (1) or (2) as an active ingredient. Here, the skin cosmetic of the present invention refers to a composition applied to the epidermis including the scalp of the human body, such as creams, emulsions, lotions, packs, cosmetic liquids, tablets, powders, granules, Various dosage forms such as a liquid bathing agent can be used.
[0038]
The skin cosmetic of the present invention only needs to contain at least one ceramide derivative represented by the general formula (1) or (2) as an active ingredient, and the blending amount is based on the total amount of the final preparation. About 0.01 to 30.0 wt% is preferable. If the blending amount is less than this range, the effect of the present invention may not be sufficiently achieved, and even if the blending amount exceeds 30.0 wt%, an improvement in the effect commensurate with the increase may not be expected.
[0039]
The skin cosmetic of the present invention contains at least one ceramide derivative represented by the general formula (1) or (2) and at least one ceramide derivative represented by the general formula (3) as active ingredients. More preferably, the blending amount is preferably about 0.01 to 30.0 wt% based on the total amount of the final preparation. If the blending amount is less than this range, the effects of the present invention may not be sufficiently achieved, and even if these blending exceeds the upper limit amount, improvement in the effect commensurate with the increase may not be expected. Further, the blending ratio of the ceramide derivative represented by the general formula (1) or (2) of the present invention and the ceramide derivative represented by the general formula (3) is more preferably 0.01: 1 to 100: 1.
[0040]
In the skin cosmetic of the present invention, in addition to the above essential components, oils, dyes, fragrances, preservatives, surfactants, pigments, antioxidants and the like are included within the scope of achieving the object of the present invention as necessary. It can mix | blend suitably.
[0041]
【Example】
Examples will be described below. The ceramide derivatives represented by the general formula (1) or the general formula (2) used in the examples are as follows. These were obtained by the extraction or synthesis method described above.
[0042]
N-acyl-6-hydroxy-4-sphingenin
Embedded image

[0044]
(However, in the above formula, R ₂₀ represents a saturated or unsaturated aliphatic hydrocarbon group having 11 to 35 carbon atoms.)
[0045]
N-α-hydroxyacyl-6-hydroxy-4-sphingenin
Embedded image

[0047]
(In the above formula, R ₂₁ is a saturated or unsaturated aliphatic hydrocarbon group having 10 to 34 carbon atoms.)
[0048]
N-ω-hydroxyacyl-6-hydroxy-4-sphingenin
Embedded image

[0050]
(In the above formula, R ₂₂ is a saturated or unsaturated aliphatic hydrocarbon group having 11 to 35 carbon atoms.)
[0051]
N-ω-acyloxyacyl-6-hydroxy-4-sphingenin
Embedded image

[0053]
(However, in the above formula, R ₂₃ and R ₂₄ are a saturated or unsaturated aliphatic hydrocarbon group having 11 to 35 carbon atoms.)
[0054]
1-O-β-glucosyl-N-acyl-6-hydroxy-4-sphingenin
Embedded image

[0056]
(In the above formula, R ₂₅ is a C11-35 saturated or unsaturated aliphatic hydrocarbon group, and Glu is a glucose residue.)
[0057]
1-O-β-galactosyl-N-acyl-6-hydroxy-4-sphingenin
Embedded image

[0059]
(However, in the above formula, R ₂₆ is a saturated or unsaturated aliphatic hydrocarbon group having 11 to 35 carbon atoms, and Gal is a galactose residue.)
[0060]
The ceramide derivatives represented by the general formula (3) used in the examples are as follows.
[0061]
N-α-hydroxyacyl phytosphingosine
Embedded image

[0063]
(However, in the above formula, R ₂₇ is an aliphatic saturated or unsaturated hydrocarbon group of 10-34 carbon atoms.)
[0064]
1-O-β-galactosyl-N-α-hydroxyacyl phytosphingosine
Embedded image

[0066]
(In the above formula, R ₂₈ is a saturated or unsaturated aliphatic hydrocarbon group having 10 to 34 carbon atoms, and Gal is a galactose residue.)
[0067]
The rough skin improving effect test, the stratum corneum improving effect test, the moisturizing effect test (TWL value reduction rate), and the skin beautifying effect test (practical test) used for evaluating the skin cosmetic of the present invention are as follows.
[0068]
(1) Rough skin improvement effect test For 20 middle-aged subjects having rough skin on both lower legs, the application effect for 4 weeks was examined. About 1 g of a sample was applied to the subject's left lower leg test site once a day, and the skin condition on the day before the start of the test and the day after the end of the test was visually determined according to the following criteria. The lower right leg was used as a control with no sample applied.
[0069]
Judgment criteria (judgment criteria for skin dryness)
−: Normal ±: Lightly dry, no desquamation +: Dry, desquamation mild ++: Dry, moderate desquamation +++: Dry, desquamation prominent
Compare the test results of the test site before and after the test and the control site, and when the skin dryness is improved by 2 or more levels (for example, + → −, ++ → ±) is effective, 1 level is improved slightly, The case where there was no change was invalidated. The test results were shown as the number of subjects who became effective or slightly effective.
[0071]
(2) stratum corneum improvement effect test Nichiban mending tape was adhered to the subject skin before and after the rough skin improvement effect test described above, and the state of the stratum corneum attached to the tape was peeled off by scanning electron microscope. The skin keratinocyte anti-peeling property was analyzed in detail according to the following criteria, and the stratum corneum improvement effect (keratinocyte anti-peeling property increasing effect) was determined.
[0072]
Criteria (Criteria for stratum corneum improvement effect)
Evaluation point 1: No scale allowed Evaluation point 2: Small scale interspersed evaluation point 3: Small to medium scale remarkable evaluation point 4: Large scale remarkable
The evaluation was effective when the difference between the evaluation score of the test site after 4 weeks of continuous application and that of the control site was 2 points or more, with 1 point being slightly effective, and 0 being invalid. The test result was shown by the number of subjects who were effective in 20 people and slightly effective.
[0074]
(3) Moisturizing effect test (TWL value reduction rate)
Using the test subject skin before and after the rough skin amelioration effect test described above as a control, the TWL value and the reduction rate of the TWL value (moisture retention function enhancement effect) before and after continuous application for 4 weeks were calculated as shown below. The effect was investigated.
[0075]
(1) TWL value A method of measuring the temperature change of the air on the sealed skin surface within a predetermined time by electric resistance was used. That is, the skin surface of the subject is sealed with a measurement cell, forced air is passed through the cell and the inside of the cell is sufficiently replaced with dry air, and then the dry air is stopped and the cell at that time is stopped. The relative humidity RHs (%) in the inside was determined, and then left for 10 minutes to again measure the relative humidity RH10 (%) in the cell. From the change in humidity at this time, the TWL value (mg / cm ² / hr ) Was calculated.
TWL value = [(RH10−RHs) × Dt × V × 6] / S × 100
Where Dt: density of saturated water vapor in air at the measurement temperature (t ° C.) (mg / l)
V: Cell volume (l)
S: Measurement area (cm ² )
[0076]
(2) Reduction rate of TWL value The reduction rate of TWL value is calculated by substituting TWL value before and after sample application, TWLA (TWL value before sample application) and TWLB (TWL value after sample application) into the following formula. did.
TWL value reduction rate = (1−TWLB / TWLA) × 100 (%)
The case where the reduction rate of the TWL value is 20% or more is “effective”, and the case where the reduction rate is less than 20% is “invalid”. The test result was displayed as the number of subjects who were “effective” out of 20 subjects.
[0077]
(4) Skin beautiful effect test (practical test)
Samples were given to 20 female subjects (35 to 55 years old) who complained of rough skin, small wrinkles, dry skin, etc., twice a day (morning / evening) after 3 months. The test results indicated that the skin was moisturized, smooth, and elastic, that the skin was moistened, the skin became smooth, and that the skin became stretched. Shown in number of people.
[0078]
Examples 1-5, Comparative Examples 1-5 (skin cream)
Skin cream was prepared with the composition shown in Table 1, and the above tests were performed.
[0079]
[Table 1]

[0080]
Table 2 shows the components of the present invention blended in the skin cream.
[0081]
[Table 2]

[0082]
(1) Preparation method In Table 1, the components (C) and (D) were dissolved in the component (A) by heating at 80 ° C, and then the component (B) was dissolved by heating at 80 ° C. Mix and disperse with a homomixer. Next, each skin cream was prepared by cooling to 30 ° C. with stirring.
[0083]
(2) Characteristics As shown in Table 3 below, the skin creams of Examples 1 to 5 which are skin cosmetics of the present invention are Comparative Example 1, General Formula (1) or (2) which is a ceramide derivative-free cosmetic. Comparative Example 2, Comparative Example 3 and Comparative Example 4, which are cosmetics containing a ceramide derivative other than the ceramide derivative represented by formula (1) or a ceramide derivative other than the ceramide derivative represented by formula (1) or (2) and formula (3) Compared with Comparative Example 5 which is a cosmetic containing a ceramide derivative represented by the formula (1), it is superior over all the characteristics, and among them, in general formula (1) or (2) of Example 5 Particularly good results were observed for skin cosmetics containing one of the ceramide derivatives shown and one of the ceramide derivatives shown by general formula (3). Also, no abnormality was found in the blending characteristics.
[0084]
[Table 3]

[0085]
Examples 6 to 10, Comparative Examples 6 to 10 (Cosmetic liquid)
A serum was prepared with the composition shown in Table 4, and the above tests were performed.
[0086]
[Table 4]

[0087]
Table 5 shows the components of the present invention blended in the cosmetic liquid.
[0088]
[Table 5]

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(1) Preparation method In Table 4, the components (C) and (D), which are heated and dissolved in the component (A) at 80 ° C, are added to the component (B) heated to 80 ° C and mixed. Dispersed with a homomixer. Next, each cosmetic solution was prepared by cooling to 30 ° C. with stirring.
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(2) Characteristics Table 6 below shows the results of various tests on each cosmetic liquid.
Comparative Example 6 which is a ceramide derivative-free cosmetic, Comparative Example 7 and Comparative Example 9 which are ceramide derivative-containing cosmetics other than the ceramide derivative represented by the general formula (1) or (2), and a general formula (3) Comparative Example 8, which is a cosmetic containing only a ceramide derivative
Examples 6-10 compared with Comparative Example 10 which is a cosmetic containing a ceramide derivative other than the ceramide derivative represented by the general formula (1) or (2) and the ceramide derivative represented by the general formula (3) In the skin cosmetics of the present invention, good results were observed throughout all the tests. Skin cosmetics comprising one of the ceramide derivatives represented by general formula (1) or (2) of Example 9 and Example 10 and one of the ceramide derivatives represented by general formula (3) are particularly excellent. It was.
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[Table 6]

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【The invention's effect】
As described above, the skin cosmetic of the present invention is an excellent skin cosmetic that improves or repairs the skin to a healthy state by enhancing and maintaining the moisture retention function inherent in the skin and has a skin beautifying effect. It is clear to provide a fee.

Claims (6)

Ceramide derivative represented by the following general formula.

(However, in the above formula, R ₂₀ Is a saturated or unsaturated aliphatic hydrocarbon group having 11 to 35 carbon atoms. ) Ceramide derivative represented by the following general formula.

(However, in the above formula, R _{twenty three} And R _{twenty four} Is a saturated or unsaturated aliphatic hydrocarbon group having 11 to 35 carbon atoms. ) Ceramide derivative represented by the following general formula.

(However, in the above formula, R _{twenty five} Is a C11-35 saturated or unsaturated aliphatic hydrocarbon group, and Glu is a glucose residue. ) Ceramide derivative represented by the following general formula.

(However, in the above formula, R ₂₆ Is a saturated or unsaturated aliphatic hydrocarbon group having 11 to 35 carbon atoms Gal is a galactose residue. ) Skin cosmetic which is characterized by containing at least one as an active ingredient of claims 1 to 4 ceramide derivative according. Skin cosmetic and at least one of claims 1 to 4 ceramide derivative according, characterized in that it contains as an active ingredient and at least one ceramide derivatives represented by the following general formula.

(However, in the above formula, R ₂₇ is an aliphatic saturated or unsaturated hydrocarbon group of 10-34 carbon atoms.)

(In the above formula, R ₂₈ is a saturated or unsaturated aliphatic hydrocarbon group having 10 to 34 carbon atoms, and Gal is a galactose residue.)