JP3660656B2 - Topical skin preparation - Google Patents

Description

表２より明らかなように、Ｒ^１，Ｒ^２の両者の炭素数が１〜４の場合（化合物２，３，４）には、いずれも優れた保湿効果、使用感が得られた。
【００６０】
これに対し、Ｒ^１，Ｒ^２が水素であった場合（化合物１）には、べたつき感が強く、またＲ^１がＣ１２であった場合（化合物６）には、保湿性、使用感ともに好ましくないものとなった。一方、Ｒ^１，Ｒ^２の炭素数の和が７であり、化合物４よりも少ない場合にも、Ｒ^１がＣ６となる（化合物５）とやはり保湿感が落ちる傾向にあった。
以上のことから、本発明にかかる基剤には、Ｒ^１，Ｒ^２ともに炭素数が１〜４のアルキル基であることが必要である。
【００６１】
なお、実際の製造にあたってはＲ^１，Ｒ^２のすべてがアルキル基により置換されるとは限らないため、その未置換（Ｈ）の化合物の許容存在割合について検討を行った。なお、未置換の割合は、アルキル基の数（Ｘ）に対する水素原子の数（Ｙ）の割合Ｙ／Ｘで表わす。なお、下記表３中、１：２＝５：９５は、化合物１と化合物２を５：９５の割合で混合し、所定のＹ／Ｘを調整したことを意味する。
【００６２】
【表３】

前記表３より明らかなように、Ｒ^１，Ｒ^２について未反応のものが存在しても、その量が少なければ（Ｙ／Ｘ＝０．０５３）大きな影響はないが、Ｙ／Ｘが０．２０２になると明らかにべたつき感を生じる。さらに本発明者等の詳細な検討の結果、Ｙ／Ｘは０．１５以下であることが必要であることが明らかとなった。
【００６３】
［オキシアルキレン基、オキシエチレン基］
次に本発明者等はオキシアルキレン基、オキシエチレン基の存在と皮膚外用剤（前記基本組成に対して５重量％配合）としての適性について検討を行った。
結果を次の表４に示す。なお、化合物７〜１１については、Ｒ^１，Ｒ^２がＣＨ_３のものを用いている。
【００６４】
【表４】

【００６５】
【化５】

【００６６】
表４より明らかなように、オキシアルキレン基及びオキシエチレン基の両者の存在が本発明の保湿性、使用性に不可欠であり、化５に示す化合物１２も効果が低いことから、単に親水性、疎水性の調整効果ではないものと考えられる。本発明者等のさらに詳細な検討によりオキシアルキレン基及びオキシエチレン基の合計に対するオキシエチレン基の好適な割合は２０〜８０重量％であることが明らかとなった。
さらに本発明者等は同一アルキレン基数、オキシエチレン基数でブロックポリマー、ランダムポリマーを製造し、その比較を行った。
【００６７】
【表５】

前記表５より明らかなように、ブロックポリマーであってもランダムポリマーであっても本発明の効果を奏することができるが、特にランダムポリマーの場合に優れた使用感を得ることができる。
［皮膚外用剤への配合量］
次に本発明者等は本発明にかかるアルキレンオキシド誘導体の皮膚外用剤（前記基本処方）への配合量についてさらに検討を行った。
【００６８】
【表６】
化合物８ ０ ０．０１ ０．５ ５．０ ４０．０ ７０．０
評価１ × ○ ◎ ◎ ◎ ◎
評価２ × ○ ◎ ◎ ◎ ○
評価３ × ○ ◎ ◎ ◎ ◎
評価４ × ○ ◎ ◎ ◎ ◎
評価５ × ○ ◎ ◎ ◎ ◎
表６に示す結果より、本発明にかかる化合物の添加効果は、０.０１重量％程度から認められるが、特に顕著に認められるのは０．５重量％以上である。但し、７０重量％となると、ややべたつきを生じはじめるので、４０重量％程度までの配合が好ましい。
【００６９】
[べたつき改善効果]
さらに本発明者等は、本発明にかかるアルキレンオキシド誘導体に関し、各種配合を検討する過程で、アルキレンオキシド誘導体にグリセリンなどの保湿剤に見られるべたつきの改善効果があることを見出した。すなわち、表６において、アルキレンオキシド誘導体無配合の試験区においても、グリセリンなどに起因するべたつきが認められる。これに対し、アルキレンオキシド誘導体を加えると、単にべたつき感が増悪するのを抑制するのではなく、他の保湿剤に起因するべたつきを改善できるのである。
【００７０】
［経皮吸収促進効果］
下記表７のように、アルキレンオキシド誘導体(I)やグリセリンはそれ自体が保湿効果、肌荒れ改善効果を有するが、他の保湿剤との併用系においては、その保湿効果、肌荒れ改善効果が相乗的に著しく改善される。
【表７】

【００７１】
そこで、本発明者等はアルキレンオキシド誘導体の作用をさらに詳細に検討した。その結果、本発明にかかるアルキレンオキシド誘導体にグリセリンなどの他の保湿剤の角質浸透促進作用があることも判明した。すなわち、図１のように、グリセリン単独の場合（コントロール）に比べて本発明のアルキレンオキシド誘導体を併用した場合（試料２）の方がグリセリンの浸透量が約４０％増大した。図１の試験方法は次の通りであった。
（１）被験試料
【表８】

【００７２】
（２）試験方法
試験は、テープストリッピング法により行った。テープストリッピング法は、薬物を塗布後、角層をテープで剥離し、角層内の薬物濃度を求める手法であり、ヒト皮膚の薬物吸収量を見積もる手段として一般的に用いられている方法である。具体的には、下記(1)〜(7)の手順で操作を行い、テープで剥離した角層からのグリセリン回収量から、グリセリンの浸透性を調べた。なお、試験は４名のパネルにより行い、その平均値で評価した。
(1)パネルの両腕前腕内側部を石けん洗浄。
(2)試料塗布（２０ｍｌ／２０ｃｍ²）。前腕内側部において、右腕は手首に近い方に試料１、肘関節に近い方に試料２を塗布する。左腕は試料１，２が右腕と逆の位置になるよう塗布する。
(3)４時間放置。
(4)両腕前腕内側部石けん洗浄。
(5)角層テープストリッピング（８層）。
(6)テープからイオン交換水でグリセリンを抽出。
(7)グリセリン定量（ＨＰＬＣ）。
【００７３】
さらに、本発明者等は保湿剤としてグリセリンの代わりにキシリトールを用いて同様に検討を行った。なお、試験方法は、(3)放置時間を６時間とした以外は前記グリセリンにおけるテープストリッピング法と同じであった。用いた試料は下記表９の通りであった。
【表９】

【００７４】
結果を図２に示す。図２からわかるように、何れの４名のパネルＡ〜Ｄの何れにおいても、アルキレンオキシド誘導体無配合の試料３（コントロール）に比べてアルキレンオキシド誘導体を配合した場合（試料４）の方が角層へのキシリトール浸透量が増加していた。
以上のことから、アルキレンオキシド誘導体(I)は、グリセリンやキシリトール等の保湿剤などに対して経皮吸収を促進することが示唆された。
さらに、本発明者等は保湿剤以外の親水性薬剤に対するアルキレンオキシド誘導体の効果を調べるため、アルブチン（ハイドロキノン−β−Ｄ−グルコピラノシド）を用いて同様に検討を行った。なお、試験方法は前記グリセリンにおけるテープストリッピング法に準じた。用いた試料とその結果を下記表１０に示す。
【表１０】

表１０からわかるように、アルキレンオキシド誘導体無配合の試料５（コントロール）に比べてアルキレンオキシド誘導体を配合した場合（試料６）の方が、アルブチン、グリセリン共に角層への浸透量が増加していた。
以上のことから、アルキレンオキシド誘導体(I)は、アルブチン等の美白剤などに対しても経皮吸収を促進することが示唆された。
【００７５】
本発明のアルキレンオキシド誘導体の経皮吸収促進効果を発揮する作用機作は明らかではないが、本発明のアルキレンオキシド誘導体が保湿剤や美白剤などの親水性薬剤と基剤との親和性を低下させることにより経皮吸収を促進しているのではないかと推察される。
すなわち、理論的には、薬剤の基剤中における活量が大きいほど薬物の皮膚透過速度は大きくなるので、薬剤の飽和溶解度以下の領域では、薬剤と基剤との親和性を低下させる（薬剤と基剤との溶解度パラメータの値の差を広げる）ことにより、皮膚への分配を大きくすることが可能である。
【００７６】
本発明のアルキレンオキシド誘導体(I)の特徴として、高い水溶性（水への溶解度１００％以上）とともに、高い脂溶性も有する（エステル油への溶解度１００％以上）ことが挙げられる。このような溶解特性はアルキレンオキシド誘導体(I)の化学構造に由来している。そして、このように水溶性と脂溶性とを兼ね備えた水性基剤で、水性基剤に配合して基剤の溶解度パラメータを大きく変化させることができる機能を有し、且つ皮膚外用剤の基剤として優れた適性を持つものはこれまでほとんどなかった。
従って、このようなアルキレンオキシド誘導体(I)を水性基剤に添加することにより、基剤の溶解度パラメータが大きく変化して保湿剤のような親水性薬剤と基剤と親和性が著しく低下し、その結果角質浸透性が高まるものと推察される。よって、親水性薬剤として、保湿剤のように水溶性でかつ皮膚に浸透して効果を発揮する薬剤、例えば、水溶性ビタミンやアミノ酸、美白剤等を用いれば、その効果の向上が期待できる。経皮吸収促進が期待できる薬剤としては親水性の高いものが望ましく、これに限定されるものではないが、水溶性、脂溶性を表す水/オクタノール分配係数（logP値）を一つの指標とすれば、０以下のものが有効であり、さらに好ましくは−１以下である。logP値−１．０以下の水溶性薬剤としては、例えば、ハイドロキノン配糖体及び誘導体、アスコルビン酸及びその誘導体、サリチル酸誘導体等が挙げられる。logP値とは、Chemical Reviews vol71(6), 525 (1971)などで定義されている水とオクタノールへの物質の分配のしやすさにより、極性をあらわす係数である。
【００７７】
一方、比較的角質透過性が高い脂溶性薬剤に対しては、逆にアルキレンオキシド誘導体を配合することにより、経皮吸収を抑制することが可能であると考えられる。例えば、脂溶性薬剤が水性基剤中に可溶化あるいは分散されている場合、アルキレンオキシド誘導体の添加により、基剤と薬剤との溶解度パラメータの差が縮小し、薬物と基剤との親和性が高くなって角質浸透性が抑制される。従って、できるだけ皮膚に浸透しないことが望ましい脂溶性薬剤（例えば防腐剤、紫外線吸収剤など）に対しては、アルキレンオキシド誘導体の配合により経皮吸収の抑制が期待できる。経皮吸収の抑制が期待できる薬剤としては、これに限定されるものではないが、水/オクタノール分配係数（logP値）が０．５以上のものが有効であり、さらに好ましくは１．０以上である。logP値１．０以上の脂溶性薬剤としては、例えば、メチルパラベン、エチルパラベン、ブチルパラベン、フェノキシエタノール、オクチルメトキシシンナメート等が挙げられる。
【００７８】
以上のように、本発明のアルキレンオキシド誘導体(I)は水性基剤中に配合することにより、保湿剤や美白剤のような親水性薬剤に対しては経皮吸収促進作用を発揮することができる。一方、防腐剤や紫外線吸収剤のような脂溶性薬剤に対しては経皮吸収抑制作用が期待される。また、油性基剤中においては、アルキレンオキシド誘導体はこれらと逆の作用を発揮すると推察できる。よって、本発明のアルキレンオキシド誘導体は、経皮吸収コントロール剤として機能することが可能である。
本発明のアルキレンオキシド誘導体(I)はＥＯ鎖とＡＯ鎖の数や割合により、その性質を調整できるので、対象とする薬剤に合わせて適正を容易にコントロールすることができるという利点も有する。
【００７９】
以下、本発明にかかる皮膚外用剤の好適な配合例について説明する。
配合例１ クリーム
Ａ．油相
ステアリン酸 １０．０ 重量％
ステアリルアルコール ４．０
ステアリン酸ブチル ８．０
ステアリン酸モノグリセリンエステル ２．０
ビタミンＥアセテート ０．５
ビタミンＡパルミテート ０．１
マカデミアナッツ油 １．０
茶実油 ３．０
香料 ０．４
防腐剤 適 量
Ｂ．水相
化合物１３ ５．０
グリセリン ４．０
１，２ペンタンジオール ３．０
ヒアルロン酸ナトリウム １．０
水酸化カリウム ２．０
アスコルビン酸リン酸マグネシウム ０．１
Ｌ−アルギニン塩酸塩 ０．０１
エデト酸三ナトリウム ０．０５
精製水 残 余
【００８０】
（製法及び評価）
Ａの油相部とＢの水相部をそれぞれ７０℃に加熱し完全溶解する。Ａ相をＢ相に加えて、乳化機で乳化する。乳化物を、熱交換機を用いて冷却してクリームを得た。得られたクリームはなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００８１】
配合例２ クリーム
Ａ．油相
セタノール ４．０ 重量％
ワセリン ７．０
イソプロピルミリステート ８．０
スクワラン １５．０
ステアリン酸モノグリセリンエステル ２．２
ＰＯＥ（20）ソルビタンモノステアレート ２．８
ビタミンＥニコチネート ２．０
香料 ０．３
酸化防止剤 適 量
防腐剤 適 量
Ｂ．水相
化合物２ １０．０
グリセリン １０．０
ヒアルロン酸ナトリウム ０．０２
ジプロピレングリコール ４．０
ピロリドンカルボン酸ナトリウム １．０
エデト酸二ナトリウム ０．０１
精製水 残 余
（製法及び評価）
配合例１に準じてクリームを得た。得られたクリームはなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００８２】
配合例３ 乳液
Ａ．油相
スクワラン ５．０ 重量％
オレイルオレート ３．０
ワセリン ２．０
ソルビタンセスキオレイン酸エステル ０．８
ポリオキシエチレンオレイルエーテル（20EO） １．２
月見草油 ０．５
香料 ０．３
防腐剤 適 量
Ｂ．水相
化合物９ ８．０
１，３ブチレングリコール ４．５
エタノール ３．０
カルボキシビニルポリマー ０．２
水酸化カリウム ０．１
Ｌ−アルギニンＬ−アスパラギン酸塩 ０．０１
エデト酸塩 ０．０５
精製水 残 余
（製法及び評価）
配合例１に準じて乳液を得た。得られた乳液はなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００８３】

（製法及び評価）
配合例１に準じてファンデーションを得た。得られたファンデーションはなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００８４】

（製法及び評価）
Ａのアルコール相をＢの水相に添加し、可溶化して化粧水を得た。得られた化粧水はなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００８５】
配合例６ Ｗ／Ｏ乳化型サンスクリーン剤
（１）エチルセルロース ０．５重量％
（２）エチルアルコール ４．０
（３）化合物２ ２．０
（４）パラメトキシケイ皮酸オクチル ５．０
（５）コハク酸ジ２−エチルヘキシルアルコール ２２．０
（６）メチルハイドロジェンポリシロキサン処理二酸化チタン ６．０
（７）カルボキシメチルセルロース １．０
（８）香料 適 量
（９）防腐剤 適 量
（1０）精製水 残 余
（製法及び評価）
（１）に（２）〜（３）を加え十分に膨潤させたのち、（４）〜（６）を加え加熱混合し十分に分散及び溶解した。この分散液を７０℃に保ち、（７）、（８）〜（１０）を混合した溶液を徐々に加えながらホモミキサーで乳化し、Ｗ／Ｏ乳化型サンスクリーン剤を得た。得られたＷ／Ｏ乳化型サンスクリーン剤はなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００８６】
配合例７ Ｗ／Ｏ乳化型サンスクリーン剤
Ａ成分
オクチルメトキシシンナメート ２．０ 重量％
デカメチルシクロペンタシロキサン ３０．５
トリメチルシロキシシリケイト ２．５
ジメチルシリコン ５．０
ＰＯＥポリメチルシロキサンコポリマー １．０
ジメチルステアリルアンモニウムヘクトライト ０．７
デキストリン脂肪酸処理酸化亜鉛（平均粒径６０ｎｍ） １０．０
Ｂ成分
１，３−ブタンジオール ５．０
化合物８ １．０
精製水 残 余
（製法及び評価）
Ａ成分をホモミキサーで攪拌しながら、Ｂ成分を徐々に添加することによって乳化し、Ｗ／Ｏ乳化型サンスクリーン剤を得た。得られたＷ／Ｏ乳化型サンスクリーン剤はなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００８７】
配合例８ Ｏ／Ｗ乳化型サンスクリーン剤
（１）ベヘニン酸 ０．７ 重量％
（２）イソステアリン酸 ０．７
（３）セタノール １．０
（４）流動パラフィン ６．０
（５）ジメチルポリシロキサン ２．０
（６）グリセリルモノステアレート ２．０
（７）パラメトシキケイ皮酸オクチル ３．０
（８）ポリエチレングリコール１５００ ５．０
（９）ジプロピレングリコール ５．０
（１０）二酸化チタン粉末 ２．０
（１１）水酸化カリウム ０．１
（１２）カルボキシビニルポリマー １．０
（１３）ヘキサメタリン酸ソーダ ０．０５
（１４）化合物１１ ２．０
（１５）香料 適 量
（１６）防腐剤 適 量
（１７）精製水 残 余
（製法及び評価）
（１）〜（７）、（１５）をそれぞれ混合し８０℃に加熱溶解して油相部とする。（８）〜（１４）、（１６）〜（１７）を７０〜７５℃にて加熱、分散させ水相部とする。油相部を水相部に徐々に添加し、ホモミキサーを用いて乳化する。
乳化物を熱交換機を用いて３０℃まで冷却し、Ｏ／Ｗ乳化型サンスクリーン剤を得た。得られたＯ／Ｗ乳化型サンスクリーン剤はなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００８８】
配合例９ 日焼け止めオイル
（１）パラメトキシケイ皮酸オクチル ３．０ 重量％
（２）化合物３ １．５
（３）疎水化処理二酸化チタン ２．０
（４）疎水化処理酸化亜鉛 １．０
（５）流動パラフィン ５１．０
（６）セチルオクタノエート ４０．０
（７）酸化防止剤 適 量
（８）香料 適 量
（製法及び評価）
（１）〜（８）の各成分を加熱攪拌したのち冷却し、日焼け止めサンスクリーンオイルを得た。得られた日焼け止めサンスクリーンオイルはなめらかさに優れ、
べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００８９】
配合例１０ Ｗ／Ｏ乳化型サンスクリーン剤
（１）エチルセルロース ０．５ 重量％
（２）エチルアルコール ４．０
（３）化合物２ ２．０
（４）パラメトキシケイ皮酸オクチル ５．０
（５）コハク酸ジ２−エチルヘキシルアルコール ２２．０
（６）疎水化処理微粒子二酸化チタン（平均粒径３０ｎｍ） ６．０
（７）カルボキシメチルセルロース １．０
（８）香料 適 量
（９）防腐剤 適 量
（１０）精製水 残 余
（製法及び評価）
（１）に（２）〜（３）を加え十分に膨潤させたのち、（４）〜（６）を加え加熱混合し十分に分散及び溶解した。この分散液を７０℃に保ち、（７）、（８）〜（１０）を混合した溶液を徐々に加えながらホモミキサーで乳化し、Ｗ／Ｏ乳化型サンスクリーン剤を得た。得られたＷ／Ｏ乳化型サンスクリーンはなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００９０】
配合例１１ ローションマスク
Ａ．アルコール相
エチルアルコール １０．０ 質量％
ＰＰＧ−１３ デシルテトラデセス−２４ ０．３
乳酸メンチル ０．００４
防腐剤 適 量
香料 適 量
Ｂ．水相
グリセリン ２．０
化合物９ ３．０
ジプロピレングリコール ４．０
トレハロース ２．０
苛性カリ 適 量
精製水 残 余
（製法及び評価）
Ａのアルコール相を、Ｂの水相に添加し、化粧水を得た。さらにこれを不織布などに含浸させてローションマスクを得た。得られたローションマスクはなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００９１】
配合例１２ 乳液
Ａ．油相
スクワラン ７．０ 質量％
オレイルオレート ２．０
ワセリン １．０
ソルビタンセスキオレイン酸エステル ０．８
ＰＯＥ（２０）オレイルエーテル １．２
香料 適 量
防腐剤 適 量
Ｂ．水相
化合物１４ ３．０
１，３−ブチレングリコール １．０
エタノール ４．０
カルボキシビニルポリマー ０．２
水酸化カリウム ０．１
エデト酸塩 ０．０５
精製水 残 余
（製法及び評価）
配合例１に準じて乳液を得た。得られた乳液はなめらかさに優れ、べたつき感がなく、且つ保湿効果、肌荒れ改善効果が認められた。
【００９２】
【発明の効果】
本発明の皮膚外用剤は、アルキレンオキシド誘導体を配合することにより、使用感触、特になめらかさに優れ、べたつき感がなく、且つ保湿効果・肌荒れ改善効果を有するものである。また、他の保湿剤を併用すると、アルキレンオキシド誘導体がその保湿剤の角質浸透性を促進し、保湿効果、肌荒れ改善効果が著しく向上する。さらに、美白剤など対しても経皮吸収を促進する。
【図面の簡単な説明】
【図１】本発明のアルキレンオキシド誘導体の、グリセリンに対する経皮吸収促進効果を示す図である。
【図２】本発明のアルキレンオキシド誘導体の、キシリトールに対する経皮吸収促進効果を示す図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an external preparation for skin, and particularly to an external preparation for skin containing an alkylene oxide derivative as an active ingredient.
[0002]
[Prior art]
Moisture retention is indispensable for maintaining healthy skin, and many external preparations for the purpose of moisturizing have been developed. Further, as a feeling of use of the external preparation for skin, there is a demand for a smooth and non-sticky feeling.
Research on moisturizers is actively conducted, and glycerin is used as a moisturizer used for various purposes such as lotion and emulsion. This glycerin has an effect of improving rough skin in addition to the moisturizing effect.
However, glycerin has to increase the blending amount in order to increase the moisturizing effect and skin roughening effect. As a result, the system becomes unstable, the usability deteriorates, and when applied to the skin, There were problems to be solved, such as being repelled by sebum and becoming less familiar to skin.
[0003]
As humectants other than glycerin, polyols such as 1,3-butylene glycol, propylene glycol, polyethylene glycol, sorbitol, and xylitol are known.
However, these polyols have less feel when used, for example, less sticky than glycerin, but are less moisturizing and less rough skin, and like glycerin, when applied to the skin, they are repelled by sebum and are familiar to the skin. There was a problem to be solved such as getting worse.
[0004]
On the other hand, a (poly) ethylene glycol dialkyl ether having a good usability and a skin care effect has been reported (see Patent Document 1). However, this (poly) ethylene glycol dialkyl ether is an oily base, and although it can exert effects such as barrier ability by forming a hydrophobic film and suppression of transdermal water loss as an oil component, it has low water solubility and is itself a humectant. It did not have the function as.
[0005]
[Patent Document 1]
JP-A-10-259112
[0006]
[Problems to be solved by the invention]
This invention is made | formed in view of the subject of the said prior art, The objective is to provide the skin external preparation which aimed at coexistence of a moisturizing and rough skin improvement effect, and a usability | use_condition.
[0007]
[Means for Solving the Problems]
As a result of intensive studies by the present inventors to achieve the above-mentioned object, when a specific alkylene oxide derivative is blended with an external preparation for skin, it is excellent in use feeling, particularly smooth, has no sticky feeling, has a moisturizing effect, and improves rough skin. It discovered that the skin external preparation which has an effect was obtained. In addition, when an alkylene oxide derivative is used in combination with a humectant such as glycerin, percutaneous absorption of the humectant is promoted, the moisturizing effect and the rough skin improving effect are synergistically improved, and the stickiness caused by the humectant is also improved. I found out. Furthermore, it has been found that the alkylene oxide derivative exerts a percutaneous absorption promoting action on a whitening agent such as arbutin, and the present invention has been completed.
That is, the external preparation for skin according to the present invention is characterized by containing an alkylene oxide derivative represented by the following general formula (I).
[0008]
[Chemical 2]
R¹O-[(AO)_m(EO)_n] -R²          (I)
(In the formula, AO is an oxyalkylene group having 3 to 4 carbon atoms, EO is an oxyethylene group, m and n are average addition moles of the oxyalkylene group and oxyethylene group, respectively, 1 ≦ m ≦ 70, 1 ≦ n ≦ 70 The ratio of the oxyethylene group to the total of the oxyalkylene group having 3 to 4 carbon atoms and the oxyethylene group is 20 to 80% by weight, and the oxyalkylene group and oxyethylene group having 3 to 4 carbon atoms. May be added in blocks or randomly.¹, R²Are the same or different and have 1 to 4 carbon atomsAlkyl groupOr a hydrogen atom and R¹And R²ofAlkyl groupThe ratio of the number of hydrogen atoms to the number is 0.15 or less. )
  In the present invention, it is preferable that oxyalkylene groups and oxyethylene groups are randomly added.
[0009]
In the external preparation of the present invention, it is preferable to blend 0.01 to 70% by weight of the alkylene oxide derivative (I).
The humectant according to the present invention contains an alkylene oxide derivative represented by the general formula (I) as an active ingredient.
Further, the rough skin improving agent according to the present invention contains an alkylene oxide derivative represented by the general formula (I) as an active ingredient.
Moreover, the stickiness improving agent according to the present invention contains an alkylene oxide derivative represented by the general formula (I) as an active ingredient.
Further, the percutaneous absorption enhancer according to the present invention contains an alkylene oxide derivative represented by the general formula (I) as an active ingredient.
Further, the external preparation for skin of the present invention comprises an alkylene oxide derivative represented by the general formula (I) and a hydrophilic drug, and the alkylene oxide derivative is a transdermal absorption enhancer of a hydrophilic drug. To do.
The hydrophilic drug is preferably a humectant, and the humectant is preferably glycerin or xylitol.
In addition, it is preferable that the hydrophilic drug is at least one selected from hydroquinone derivatives and ascorbic acid derivatives.
Moreover, the percutaneous absorption control agent according to the present invention comprises an alkylene oxide derivative represented by the general formula (I) as an active ingredient.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
In the alkylene oxide derivative represented by the general formula (I) characteristic in the present invention, AO is an oxyalkylene group having 3 to 4 carbon atoms, specifically, an oxypropylene group, an oxybutylene group, an oxyisobutylene group, Examples thereof include an oxytrimethylene group and an oxytetramethylene group. Preferably, an oxypropylene group and an oxybutylene group are mentioned.
m is the average number of added moles of the oxyalkylene group having 3 to 4 carbon atoms, and 1 ≦ m ≦ 70, preferably 2 ≦ m ≦ 20. n is the average number of added moles of oxyethylene groups, and 1 ≦ n ≦ 70, preferably 2 ≦ n ≦ 20. When the oxyalkylene group or oxyethylene group having 3 to 4 carbon atoms is 0, the moist feeling is lowered, and when it exceeds 70, a sticky feeling is produced, and the smooth feeling is not sufficiently obtained. In addition, as (m + n), Preferably it is 8-100. If (m + n) is too large, stickiness may occur.
Moreover, it is preferable that the ratio of the oxyethylene group with respect to the sum total of a C3-C4 oxyalkylene group and an oxyethylene group is 20 to 80 weight%. When the proportion of the oxyethylene group is less than 20% by weight, the moist feeling tends to be inferior, and when it exceeds 80% by weight, the smooth feeling tends to be inferior.
[0011]
  The order of adding ethylene oxide and alkylene oxide having 3 to 4 carbon atoms is not particularly specified. Further, the oxyethylene group and the oxyalkylene group having 3 to 4 carbon atoms may be added in a block shape or in a random shape. The block shape includes not only two-stage blocks but also three or more stages. Preferably, those added randomly are listed.
  R¹And R²Has 1 to 4 carbon atomsAlkyl groupOr a hydrogen atom,Alkyl groupExamples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and a tert-butyl group. A methyl group and an ethyl group are preferred. Hydrocarbon groups having 5 or more carbon atoms are less hydrophilic and less moist. R¹, R²May be the same or different.
  R¹And R²Each of which has only 1 type,Alkyl groupEven if hydrogen atoms are mixed,Alkyl groupMay be mixed. However, R¹And R²ofAlkyl groupOut ofAlkyl groupThe proportion of hydrogen atoms present isAlkyl groupThe ratio Y / X of the number of hydrogen atoms (Y) to the number of (X) is 0.15 or less, preferably 0.06 or less. When the ratio of Y / X exceeds 0.15, a sticky feeling comes out.
[0012]
The alkylene oxide derivative of the present invention can be produced by a known method. For example, it can be obtained by subjecting a compound having a hydroxyl group to addition polymerization of ethylene oxide and an alkylene oxide having 3 to 4 carbon atoms, and then subjecting an alkyl halide to an ether reaction in the presence of an alkali catalyst.
Although the compounding quantity of the alkylene oxide derivative to the skin external preparation of this invention is not specifically limited, Usually, about 0.01 to 70 weight%, Preferably about 0.5 to 40 weight% is mix | blended. If it is less than 0.01% by weight, the effect of the blending may not be sufficiently exhibited. If it exceeds 70% by weight, stickiness may be felt after use.
[0013]
The alkylene oxide derivative according to the present invention exhibits a moisturizing effect and a rough skin improving effect when blended with an external preparation for skin. Furthermore, when other humectants such as glycerin are further blended, an effect of suppressing the stickiness is recognized. Examples of humectants that can coexist include polyethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, carolinic acid, atelocollagen, cholesteryl-12- Examples thereof include hydroxystearate, sodium lactate, bile salt, dl-pyrrolidone carboxylate, short-chain soluble collagen, diglycerin (EO) PO adduct, Izayoi rose extract, yarrow extract, and merirot extract.
The alkylene oxide derivative (I) according to the present invention also has an action of promoting keratin permeability of other moisturizing agents. Therefore, when the alkylene oxide derivative (I) and another moisturizing agent are used in combination in the external preparation for skin, it is possible to obtain extremely high moisturizing effect and rough skin improving effect due to the synergistic effect. Examples of such a humectant include those described above, and glycerin and xylitol are particularly preferable.
Although the compounding quantity of a moisturizer is not specifically limited, Preferably it is 0.001-20.00 weight% in a skin external preparation whole quantity, More preferably, it is 0.1-10.0 weight%.
Further, the alkylene oxide derivative (I) according to the present invention has an action of promoting keratin permeability even for hydrophilic agents other than the humectant, for example, whitening agents such as arbutin.
[0014]
The skin external preparation of this invention is adjusted by mix | blending said essential component with the existing skin external preparation base. In addition to the essential components described above, the skin external preparation of the present invention is usually used for other skin external preparations such as cosmetics and pharmaceuticals, for example, powder components, liquid fats, solid fats, waxes, hydrocarbons, higher fatty acids. Higher alcohols, esters, silicones, anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, water-soluble polymers, thickeners, film agents, UV absorbers, sequestering agents, Lower alcohol, polyhydric alcohol, sugar, amino acid, organic amine, polymer emulsion, pH adjuster, skin nutrient, vitamin, antioxidant, antioxidant aid, fragrance, water, etc., as needed, It can be produced by a conventional method according to the intended dosage form. Specific ingredients that can be blended are listed below, but the skin external preparation of the present invention can be prepared by blending the above essential blending ingredients and any one or more of the following ingredients.
[0015]
Examples of the powder component include inorganic powders (for example, talc, kaolin, mica, sericite, muscovite, phlogopite, synthetic mica, saucite, biotite, permiculite, magnesium carbonate, calcium carbonate, silicic acid. Aluminum, barium silicate, calcium silicate, magnesium silicate, strontium silicate, metal tungstate, magnesium, silica, zeolite, barium sulfate, calcined calcium sulfate (baked gypsum), calcium phosphate, fluorine apatite, hydroxyapatite, ceramic powder , Metal soap (eg, zinc myristate, calcium palmitate, aluminum stearate), boron nitride, etc .; organic powder (eg, polyamide resin powder (nylon powder), polyethylene powder, polymethyl methacrylate powder, polystyrene Powder, copolymer resin powder of styrene and acrylic acid, benzoguanamine resin powder, polytetrafluoroethylene powder, cellulose powder, etc.); inorganic white pigment (eg, titanium dioxide, zinc oxide, etc.); inorganic red pigment (eg, Iron oxide (Bengara), iron titanate, etc .; Inorganic brown pigments (eg, γ-iron oxide, etc.); Inorganic yellow pigments (eg, yellow iron oxide, loess, etc.); Inorganic black pigments (eg, black oxide) Iron, low-order titanium oxide, etc.); inorganic purple pigments (eg, mango violet, cobalt violet, etc.); inorganic green pigments (eg, chromium oxide, chromium hydroxide, cobalt titanate, etc.); inorganic blue pigments (eg, Pearl pigments (eg titanium oxide coated mica, titanium oxide coated bismuth oxychloride, titanium oxide coated talc, colored oxidation) Tan-coated mica, bismuth oxychloride, fish scale foil, etc.); metal powder pigments (eg, aluminum powder, copper powder, etc.); organic pigments such as zirconium, barium or aluminum lake (eg, red 201, red 202, red 204) No., red 205, red 220, red 226, red 228, red 405, orange 203, orange 204, yellow 205, yellow 401, and blue 404, organic pigments such as red 3 , Red 104, Red 106, Red 227, Red 230, Red 401, Red 505, Orange 205, Yellow 4, Yellow 5, Yellow 202, Yellow 203, Green 3 and Blue No. 1 etc.); natural pigments (for example, chlorophyll, β-carotene, etc.) and the like.
[0016]
Examples of liquid oils include avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, persic oil, wheat germ oil, southern castor oil, castor oil, linseed oil , Safflower oil, cottonseed oil, eno oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, cinnagiri oil, Japanese kiri oil, jojoba oil, germ oil, triglycerin and the like.
[0017]
Examples of the solid fat include cacao butter, palm oil, horse fat, hydrogenated palm oil, palm oil, beef tallow, sheep fat, hydrogenated beef tallow, palm kernel oil, pork fat, beef bone fat, owl kernel oil, hydrogenated oil, cattle Leg fats, moles, hydrogenated castor oil and the like.
[0018]
Examples of waxes include beeswax, candelilla wax, cotton wax, carnauba wax, bayberry wax, ibota wax, whale wax, montan wax, nuka wax, lanolin, kapok wax, lanolin acetate, liquid lanolin, sugar cane wax, lanolin fatty acid isopropyl, hexyl laurate, and reduced lanolin. , Jojoballow, hard lanolin, shellac wax, POE lanolin alcohol ether, POE lanolin alcohol acetate, POE cholesterol ether, lanolin fatty acid polyethylene glycol, POE hydrogenated lanolin alcohol ether, and the like.
[0019]
Examples of the hydrocarbon oil include liquid paraffin, ozokerite, squalane, pristane, paraffin, ceresin, squalene, petrolatum, microcrystalline wax, and the like.
Examples of the higher fatty acid include lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, undecylenic acid, toluic acid, isostearic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid ( DHA) and the like.
[0020]
Examples of higher alcohols include linear alcohols (eg, lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, cetostearyl alcohol); branched chain alcohols (eg, monostearyl glycerin ether (batyl alcohol) ), 2-decyltetradecinol, lanolin alcohol, cholesterol, phytosterol, hexyl decanol, isostearyl alcohol, octyldodecanol and the like.
[0021]
Synthetic ester oils include isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyl decyl dimethyloctanoate, cetyl lactate, myristyl lactate Lanolin acetate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene glycol di-2-ethylhexanoate, dipentaerythritol fatty acid ester, monoisostearate N-alkyl glycol, neopentyl glycol dicaprate, apple Acid diisostearyl, di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, triisostearic acid trimethylo Propane, tetra-2-ethylhexanoate pentaerythritol, glycerol tri-2-ethylhexanoate, glycerol trioctanoate, glycerol triisopalmitate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, 2-ethylhexyl palmi Tate, glyceryl trimyristate, glyceride tri-2-heptylundecanoate, castor oil fatty acid methyl ester, oleyl oleate, acetoglyceride, 2-heptylundecyl palmitate, diisobutyl adipate, N-lauroyl-L-glutamic acid-2 -Octyldodecyl ester, di-2-heptylundecyl adipate, ethyl laurate, di-2-ethylhexyl sebacate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, 2-hexyldecyl adipate Le, diisopropyl sebacate, 2-ethylhexyl succinate, and triethyl citrate.
[0022]
Examples of the silicone oil include linear polysiloxanes (for example, dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane, etc.); cyclic polysiloxanes (for example, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexyl). And silicone resins that form a three-dimensional network structure, various modified polysiloxanes (amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, fluorine-modified polysiloxane, etc.) It is done.
[0023]
Anionic surfactants include, for example, fatty acid soaps (eg, sodium laurate, sodium palmitate, etc.); higher alkyl sulfates (eg, sodium lauryl sulfate, potassium lauryl sulfate, etc.); alkyl ether sulfates (eg, POE-lauryl sulfate triethanolamine, POE-sodium lauryl sulfate, etc.); N-acyl sarcosine acids (eg, sodium lauroyl sarcosine, etc.); higher fatty acid amide sulfonates (eg, sodium N-myristoyl-N-methyl taurate, palm Oil fatty acid methyl tauride sodium, lauryl methyl tauride sodium, etc .; phosphate ester salt (POE-oleyl ether sodium phosphate, POE-stearyl ether phosphate, etc.); sulfosuccinate (eg, di-2-ethylhexyl sulfo) Sodium succinate, monolauroyl monoethanolamide sodium polyoxyethylene sulfosuccinate, sodium lauryl polypropylene glycol sulfosuccinate, etc.); alkyl benzene sulfonates (eg, sodium linear dodecyl benzene sulfonate, triethanol amine linear dodecyl benzene sulfonate, linear dodecyl) Higher fatty acid ester sulfates (eg, hydrogenated coconut oil fatty acid sodium glycerol sulfate); N-acyl glutamate (eg, monosodium N-lauroyl glutamate, disodium N-stearoyl glutamate, N-myristoyl) -L-glutamic acid monosodium, etc.); sulfated oil (eg funnel oil); POE-alkyl ether carboxylic acid; POE-alkyl allyl ether Α-olefin sulfonates; higher fatty acid ester sulfonates; secondary alcohol sulfates; higher fatty acid alkylolamide sulfates; lauroyl monoethanolamide sodium succinate; N-palmitoyl aspartate ditriethanolamine ; Sodium caseinate and the like.
[0024]
Examples of the cationic surfactant include alkyltrimethylammonium salts (eg, stearyltrimethylammonium chloride, lauryltrimethylammonium chloride, etc.); alkylpyridinium salts (eg, cetylpyridinium chloride, etc.); distearyldimethylammonium dialkyldimethylammonium chloride; Poly (N, N'-dimethyl-3,5-methylenepiperidinium chloride); alkyl quaternary ammonium salt; alkyldimethylbenzylammonium salt; alkylisoquinolinium salt; dialkyl morpholinium salt; POE-alkylamine; Examples include alkylamine salts; polyamine fatty acid derivatives; amyl alcohol fatty acid derivatives; benzalkonium chloride; benzethonium chloride and the like.
[0025]
Examples of amphoteric surfactants include imidazoline-based amphoteric surfactants (eg, 2-undecyl-N, N, N- (hydroxyethylcarboxymethyl) -2-imidazoline sodium, 2-cocoyl-2-imidazolinium hydroxide). Side-1-carboxyethyloxy disodium salt, etc.); betaine surfactants (for example, 2-heptadecyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, lauryldimethylaminoacetic acid betaine, alkylbetaine, amide betaine) , Sulfobetaine, etc.).
[0026]
Examples of the lipophilic nonionic surfactant include sorbitan fatty acid esters (for example, sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, Sorbitan trioleate, diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate); glycerin polyglycerin fatty acids (eg mono cottonseed oil fatty acid glycerin, monoerucic acid glycerin, sesquioleate glycerin, monostearin) Glycerin acid, α, α'-oleic acid pyroglutamate glycerin, monostearic acid glycerin malic acid, etc.); propylene glycol fatty acid esters (eg monostearies) Propylene glycolate, etc.); hardened castor oil derivative; glycerin alkyl ether, etc.
[0027]
Examples of hydrophilic nonionic surfactants include POE-sorbitan fatty acid esters (for example, POE-sorbitan monooleate, POE-sorbitan monostearate, POE-sorbitan monooleate, POE-sorbitan tetraoleate). POE sorbite fatty acid esters (eg, POE-sorbite monolaurate, POE-sorbite monooleate, POE-sorbite pentaoleate, POE-sorbite monostearate, etc.); POE-glycerin fatty acid esters (eg, POE- POE-monooleate such as glycerol monostearate, POE-glycerol monoisostearate, POE-glycerol triisostearate); POE-fatty acid esters (eg POE-distearate, POE-monodiolate, ethylene glycol distearate, etc.) POE-alkyl ethers (eg POE- Lauryl ether, POE-oleyl ether, POE-stearyl ether, POE-behenyl ether, POE-2-octyldodecyl ether, POE-cholestanol ether, etc.); Pluronic type (eg, Pluronic, etc.); POE / POP-alkyl ether (For example, POE / POP-cetyl ether, POE / POP-2-decyltetradecyl ether, POE / POP-monobutyl ether, POE / POP-hydrogenated lanolin, POE / POP-glycerin ether, etc.); Tetra POE / Tetra POP-ethylenediamine condensates (eg Tetronic, etc.); POE-castor oil hardened castor oil derivatives (eg POE-castor oil, POE-hardened castor oil, POE-hardened castor oil monoisostearate, POE-hardened castor Oil triisostearate, POE-hardened castor oil monopyroglutamic acid monoisostearic acid diester, POE-hardened castor oil maleic acid, etc.) POE-beeswax lanolin derivatives (eg POE-sorbite beeswax); alkanolamides (eg coconut oil fatty acid diethanolamide, lauric acid monoethanolamide, fatty acid isopropanolamide, etc.); POE-propylene glycol fatty acid ester; POE-alkylamine POE-fatty acid amide; sucrose fatty acid ester; alkyl ethoxydimethylamine oxide; trioleyl phosphate and the like.
[0028]
Examples of natural water-soluble polymers include plant-based polymers (for example, gum arabic, gum tragacanth, galactan, guar gum, carob gum, caraya gum, carrageenan, pectin, agar, quince seed (malmello), alge colloid (guckweed extract), starch (Rice, corn, potato, wheat), glycyrrhizic acid); microbial polymers (eg, xanthan gum, dextran, succinoglucan, bullulan, etc.); animal polymers (eg, collagen, casein, albumin, gelatin, etc.), etc. Is mentioned.
[0029]
Semi-synthetic water-soluble polymers include, for example, starch polymers (eg, carboxymethyl starch, methylhydroxypropyl starch, etc.); cellulose polymers (methylcellulose, ethylcellulose, methylhydroxypropylcellulose, hydroxyethylcellulose, sodium cellulose sulfate) Hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, cellulose powder and the like); alginic acid polymers (for example, sodium alginate, propylene glycol alginate, etc.) and the like.
[0030]
Synthetic water-soluble polymers include, for example, vinyl polymers (eg, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone, carboxyvinyl polymer); polyoxyethylene polymers (eg, polyethylene glycol 20,000, 40,000, 60,000). Polyoxyethylene polyoxypropylene copolymer, etc.); acrylic polymers (for example, sodium polyacrylate, polyethyl acrylate, polyacrylamide, etc.); polyethyleneimine; cationic polymers, and the like.
[0031]
Examples of the thickener include gum arabic, carrageenan, caraya gum, gum tragacanth, carob gum, quince seed (malmello), casein, dextrin, gelatin, sodium pectate, sodium alginate, methylcellulose, ethylcellulose, CMC, hydroxyethylcellulose, hydroxypropyl Cellulose, PVA, PVM, PVP, sodium polyacrylate, carboxyvinyl polymer, locust bean gum, guar gum, tamarind gum, cellulose dialkyldimethylammonium sulfate, xanthan gum, magnesium aluminum silicate, bentonite, hectorite, silicate A1Mg (vee gum), Examples thereof include laponite and silicic anhydride.
[0032]
Examples of UV absorbers include benzoic acid UV absorbers (eg, paraaminobenzoic acid (hereinafter abbreviated as PABA), PABA monoglycerin ester, N, N-dipropoxy PABA ethyl ester, N, N-diethoxy PABA ethyl ester. N, N-dimethyl PABA ethyl ester, N, N-dimethyl PABA butyl ester, N, N-dimethyl PABA ethyl ester, etc.); anthranilic acid-based UV absorbers (for example, homomenthyl-N-acetyl anthranilate, etc.); Salicylic acid ultraviolet absorbers (for example, amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate, etc.); cinnamic acid ultraviolet absorbers (for example, octylcinnamate, ethyl- 4-isopropyl cinnamate, meth -2,5-diisopropylcinnamate, ethyl-2,4-diisopropylcinnamate, methyl-2,4-diisopropylcinnamate, propyl-p-methoxycinnamate, isopropyl-p-methoxycinnamate, isoamyl-p-methoxy Cinnamate, octyl-p-methoxycinnamate (2-ethylhexyl-p-methoxycinnamate), 2-ethoxyethyl-p-methoxycinnamate, cyclohexyl-p-methoxycinnamate, ethyl-α-cyano-β-phenyl Cinnamate, 2-ethylhexyl-α-cyano-β-phenylcinnamate, glyceryl mono-2-ethylhexanoyl-diparamethoxycinnamate, etc.); benzophenone UV absorbers (for example, 2,4-dihydroxybenzophenone, 2 , 2'-Dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone 2,2 ', 4,4'-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfone Acid salt, 4-phenylbenzophenone, 2-ethylhexyl-4′-phenyl-benzophenone-2-carboxylate, 2-hydroxy-4-n-octoxybenzophenone, 4-hydroxy-3-carboxybenzophenone, etc.); 3- ( 4'-methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l-camphor; 2-phenyl-5-methylbenzoxazole; 2,2'-hydroxy-5-methylphenylbenzotriazole; (2'-hydroxy-5'-t-octylphenyl) benzotriazole; 2- (2'-hydroxy-5'-methylphenylbenzotriazole; dibenzalazine; dianisoylmethane; 4-methoxy-4'-t-butyldiben Irumetan; 5- (3,3-dimethyl-2-norbornylidene) -3-pentan-2-one, and the like.
[0033]
Examples of the sequestering agent include 1-hydroxyethane-1,1-diphosphonic acid, 1-hydroxyethane-1,1-diphosphonic acid tetrasodium salt, disodium edetate, trisodium edetate, tetrasodium edetate Sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, phosphoric acid, citric acid, ascorbic acid, succinic acid, edetic acid, trisodium ethylenediaminehydroxyethyl triacetate and the like.
[0034]
Examples of the lower alcohol include ethanol, propanol, isopropanol, isobutyl alcohol, t-butyl alcohol and the like.
[0035]
Examples of the polyhydric alcohol include divalent alcohols (for example, ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, tetramethylene glycol, 2,3-butylene glycol, Pentamethylene glycol, 2-butene-1,4-diol, hexylene glycol, octylene glycol, etc.); trivalent alcohol (eg, glycerin, trimethylolpropane, etc.); tetravalent alcohol (eg, 1,2,6) Pentaerythritol such as hexanetriol); pentahydric alcohol (eg, xylitol, etc.); hexavalent alcohol (eg, sorbitol, mannitol, etc.); polyhydric alcohol polymer (eg, diethylene glycol, dipropylene glycol, triethylene glycol, polypropylene Glycol, tetraethylene glycol, diglycerin, polyethylene glycol, triglycerin, tetraglycerin, polyglycerin, etc.); divalent alcohol alkyl ethers (for example, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene) Glycol monophenyl ether, ethylene glycol monohexyl ether, ethylene glycol mono 2-methylhexyl ether, ethylene glycol isoamyl ether, ethylene glycol benzyl ether, ethylene glycol isopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, etc.) ; Dihydric alcohol alkyl ester Tellurium (for example, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol butyl ether, diethylene glycol methyl ethyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, propylene glycol monomethyl ether , Propylene glycol monoethyl ether, propylene glycol monobutyl ether, propylene glycol isopropyl ether, dipropylene glycol methyl ether, dipropylene glycol ethyl ether, dipropylene glycol butyl ether, etc.); divalent alcohol Ether esters (eg, ethylene glycol monomethyl ether acetate, ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether acetate, ethylene glycol monophenyl ether acetate, ethylene glycol diazinate, ethylene glycol disuccinate, diethylene glycol monoethyl ether acetate, diethylene glycol) Monobutyl ether acetate, propylene glycol monomethyl ether acetate, propylene glycol monoethyl ether acetate, propylene glycol monopropyl ether acetate, propylene glycol monophenyl ether acetate, etc .; glycerin monoalkyl ether (for example, xyl alcohol, ceralkyl alcohol) Sugar alcohol (for example, sorbitol, maltitol, maltotriose, mannitol, sucrose, erythritol, glucose, fructose, amylolytic sugar, maltose, xylitolose, amylolytic sugar reducing alcohol, etc.); Solid; Tetrahydrofurfuryl alcohol; POE-Tetrahydrofurfuryl alcohol; POP-Butyl ether; POP / POE-Butyl ether; Tripolyoxypropylene glycerin ether; POP-glycerin ether; POP-glycerin ether phosphate; POP / POE-pentane erythritol Examples include ether and polyglycerin.
[0036]
Monosaccharides include, for example, tricarbon sugars (eg, D-glyceryl aldehyde, dihydroxyacetone, etc.); tetracarbon sugars (eg, D-erythrose, D-erythrulose, D-treose, erythritol, etc.); pentose sugars (eg, , L-arabinose, D-xylose, L-lyxose, D-arabinose, D-ribose, D-ribulose, D-xylulose, L-xylulose, etc .; hexose (eg, D-glucose, D-talose, D) -Bucicose, D-galactose, D-fructose, L-galactose, L-mannose, D-tagatose, etc.); pentose sugar (eg, aldheptose, heproose, etc.); octose sugar (eg, octulose, etc.); For example, 2-deoxy-D-ribose, 6-deoxy-L-galactose, 6-deoxy-L-mannose, etc .; amino sugar (eg, D-glucosamine, D-galactosamine, shea Acid, Aminouron acid, muramic acid); uronic acid (e.g., D- glucuronic acid, D- mannuronic acid, L- guluronic acid, D- galacturonic acid, L- iduronic acid) and the like.
[0037]
Examples of the oligosaccharides include sucrose, gnocyanose, umbelliferose, lactose, planteose, isoliquinoses, α, α-trehalose, raffinose, lycnose, umbilicin, stachyose verbus courses and the like.
[0038]
Examples of the polysaccharide include cellulose, quince seed, chondroitin sulfate, starch, galactan, dermatan sulfate, glycogen, gum arabic, heparan sulfate, hyaluronic acid, tragacanth gum, keratan sulfate, chondroitin, xanthan gum, mucoitin sulfate, guar gum, dextran, kerato sulfate. , Locust bean gum, succinoglucan, caronic acid and the like.
[0039]
Examples of amino acids include neutral amino acids (eg, threonine, cysteine, etc.); basic amino acids (eg, hydroxylysine, etc.) and the like. Examples of amino acid derivatives include acyl sarcosine sodium (lauroyl sarcosine sodium), acyl glutamate, acyl β-alanine sodium, glutathione, and pyrrolidone carboxylic acid.
[0040]
Examples of organic amines include monoethanolamine, diethanolamine, triethanolamine, morpholine, triisopropanolamine, 2-amino-2-methyl-1,3-propanediol, and 2-amino-2-methyl-1-propanol. Is mentioned.
Examples of the polymer emulsion include an acrylic resin emulsion, a polyethyl acrylate emulsion, an acrylic resin liquid, a polyacryl alkyl ester emulsion, a polyvinyl acetate resin emulsion, and a natural rubber latex.
[0041]
Examples of the pH adjusting agent include buffers such as lactic acid-sodium lactate, citric acid-sodium citrate, and succinic acid-sodium succinate.
Examples of vitamins include vitamins A, B1, B2, B6, C, E and derivatives thereof, pantothenic acid and derivatives thereof, biotin and the like.
Examples of the antioxidant include tocopherols, dibutylhydroxytoluene, butylhydroxyanisole, gallic acid esters and the like.
[0042]
Examples of the antioxidant assistant include phosphoric acid, citric acid, ascorbic acid, maleic acid, malonic acid, succinic acid, fumaric acid, kephalin, hexametaphosphate, phytic acid, and ethylenediaminetetraacetic acid.
[0043]
Other ingredients that can be blended include, for example, preservatives (ethyl paraben, butyl paraben, etc.); anti-inflammatory agents (eg, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc.); Extract, placenta extract, saxifrage extract, arbutin, etc.); various extracts (eg, buckwheat, auren, shikon, peonies, assembly, birch, sage, loquat, carrot, aloe, mallow), iris, grape, yokuinin, loofah, lily , Saffron, nematode, ginger, hypericum, onionis, garlic, capsicum, chimney, red snapper, seaweed, etc.), activator (eg, royal jelly, photosensitizer, cholesterol derivative, etc.); blood circulation promoter (eg, nonyl acid wallenylamide, nicotine) Acid Gyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, gingerone, cantalis tincture, ictamol, tannic acid, α-borneol, nicotinic acid tocopherol, inositol hexanicotinate, cyclandrate, cinnarizine, trazoline, acetylcholine, verapamil, cephalanthin , Γ-oryzanol, etc.); antiseborrheic agents (eg, sulfur, thianthol, etc.);
[0044]
The dosage form of the external preparation for skin of the present invention is arbitrary, solution system, solubilization system, emulsification system, powder dispersion system, water-oil two-layer system, water-oil-powder three-layer system, gel, mist, spray, Any dosage form such as mousse, roll-on, stick, etc. may be used. A preparation impregnated or coated on a sheet such as a nonwoven fabric is also possible. Further, the product form of the external preparation for skin of the present invention is also optional, such as facial cosmetics such as lotion, emulsion, cream and pack; makeup cosmetics such as foundation, lipstick and eye shadow; sunscreen cosmetics (sunscreen agent) ); Body cosmetics; aromatic cosmetics; skin cleansing agents such as make-up removers, body shampoos;
[0045]
【Example】
Examples of the present invention will be described below.
Prior to the description of the examples of the present invention, an evaluation method is shown below.
"Test method by conductance measurement"
Using the forearm of 10 panelists, skin conductance was measured before application, 30 minutes, 60 minutes, and 120 minutes after application, and the moisturizing effect was evaluated from the rate of change. The change rate of skin conductance can be obtained by the following formula (II), and it is possible to examine the effect of the stratum corneum on water absorption and water retention ability. It can be evaluated that the moisturizing effect is high.
Formula (II)
Conductance change rate = (conductance before application) / (conductance after application)
[0046]
The evaluation criteria for the “test by conductance measurement” are as follows.
◎… Average conductance change rate of 10 panelists: 0 or more and less than 0.1
○… Average of conductance change rate of 10 panelists: 0.1 or more and less than 0.2
Δ: Average conductance change rate of 10 panelists: 0.2 or more and less than 0.5
×… Average of conductance change rate of 10 panelists: 0.5 or more
[0047]
"Evaluation (1): Smooth skin"
An actual use test was conducted by 10 expert panelists on the smoothness of the skin during and after use. The evaluation criteria are as follows.
◎ ... More than 8 professional panelists recognized that the skin was smooth during and after use.
○… More than 6 panelists recognized that the skin was smooth during and after use.
Δ: 3 or more and less than 6 professional panelists recognized that the skin was smooth during and after use.
X: Less than 3 professional panelists recognized that the skin was smooth during use and after use.
[0048]
"Evaluation (2): No stickiness on the skin"
An actual use test was conducted by 10 expert panelists on the non-stickiness of the skin during and after use. The evaluation criteria are as follows.
◎… 8 or more professional panelists recognized that there was no stickiness on the skin during and after use.
○… More than 6 panelists and less than 8 panelists recognized that there was no stickiness on the skin during and after use.
Δ: 3 or more and 6 less than 6 panelists recognized that there was no stickiness on the skin during and after use.
X: Less than 3 professional panelists recognized that there was no stickiness on the skin during and after use.
[0049]
"Evaluation (3): Moisturizing effect"
An actual use test was conducted by 10 expert panelists to determine whether there was a moisturizing effect after 120 minutes of use. The evaluation criteria are as follows.
◎ ... More than 8 professional panelists recognized that there was a moisturizing effect.
○ ... 6 or more and less than 8 expert panelists recognized that there was a moisturizing effect.
Δ: 3 or more and less than 6 specialist panelists recognized that there was a moisturizing effect.
X: Less than 3 professional panelists recognized that there was a moisturizing effect.
[0050]
"Evaluation (4): Rough skin improvement effect test"
A skin roughness improvement effect test was conducted by a panel of 10 people who had rough skin on their faces (parts: cheeks). In the test method, different lotions were applied to the left and right cheeks for one week, and the determination was made the next day after the period. The evaluation criteria are as follows.
◎… 8 or more panelists recognized that rough skin was improved.
○: 6 or more panelists and less than 8 panelists recognized that rough skin was improved.
Δ: 3 or more and less than 6 panelists recognized that the rough skin was improved.
X: Less than 3 panelists recognized that rough skin was improved.
[0051]
"Evaluation (5): Skin irritation test"
The obstruction patch for 24 hours was applied to the inner arm of the panel of 10 people, and then the average value was calculated according to the following criteria.
0… No abnormality is observed.
1… Slight redness is observed.
2… Redness is recognized.
3… Redness and papules are observed.
Evaluation criteria for the “skin irritation test” are as follows.
◎… Average of 10 panelists: 0 or more and less than 0.1
○… Average value of 10 panelists: 0.1 or more and less than 0.15
Δ: Average value of 10 panelists: 0.15 or more and less than 0.2
×… Average value of 10 panelists: 0.2 or more
First, the present inventors evaluated conductance according to the above criteria for each 10% aqueous solution of each of the humectants.
[0052]
[Table 1]
Compound 30 minutes later 60 minutes later 120 minutes later
CH_ThreeO [(EO)₆/ (PO)_{1 4}] CH_Three         ◎ ◎ ◎
CH_ThreeO [(EO)₁₅/ (PO)₅] CH_Three        ◎ ◎ ◎
CH_ThreeO [(EO)₂₅/ (PO)₂₅] CH_Three       ◎ ◎ ◎
Ion exchange water △ × ×
1,3-butylene glycol △ △ △
Glycerin ◎ ○ ○
  As a result, compared to general moisturizers such as 1,3-butylene glycol or glycerin,Alkyl groupIt was revealed that the EO / PO derivative bonded with is excellent in moisture retention.
  Therefore, the present inventors proceeded with investigations on alkylene oxide derivatives. Each alkylene oxide derivative used in the test was produced according to Synthesis Examples 1 and 2 below. In the present invention, EO represents an oxyethylene group, PO represents an oxypropylene group, and [(EO) / (PO)] represents a random bond.
[0053]
Synthesis Example 1 Random polymer synthesis example
Polyoxyethylene (10 mol) Polyoxypropylene (10 mol) Dimethyl ether
[Chemical 3]
CH₃O [(EO)₁₀/ (PO)₁₀] CH₃
[0054]
76 g of propylene glycol and 3.1 g of potassium hydroxide as a catalyst were charged into an autoclave. After the air in the autoclave was replaced with dry nitrogen, the catalyst was completely dissolved at 140 ° C. with stirring. Next, a mixture of 440 g of ethylene oxide and 522 g of propylene oxide was dropped with a dropping device and stirred for 2 hours. Next, 224 g of potassium hydroxide was charged and the inside of the system was replaced with dry nitrogen, and then 188 g of methyl chloride was injected at a temperature of 80 to 130 ° C. and reacted for 5 hours. Thereafter, the reaction composition was taken out from the autoclave, neutralized with hydrochloric acid to pH 6 to 7, and treated at a reduced pressure of -0.095 MPa (50 mmHg) at 100 ° C for 1 hour in order to remove the contained water. Further, filtration was performed to remove the salt generated after the treatment, and an alkylene oxide derivative of Chemical Formula 3 was obtained.
Samples that were sampled and reacted before the reaction with methyl chloride had a hydroxyl value of 107, the compound of formula 3 obtained had a hydroxyl value of 0.4, and the ratio of the number of hydrogen atoms to the number of terminal methyl groups was 0.004. The hydrogen atom is completely converted to a methyl group.
[0055]
Synthesis Example 2 Synthesis of block polymer
Polyoxyethylene (10 mol) Polyoxypropylene (10 mol) Dimethyl ether
[Formula 4]
CH₃O (EO)₅(PO)₁₀(EO)₅CH₃
[0056]
76 g of propylene glycol and 3.1 g of potassium hydroxide as a catalyst were charged into an autoclave. After the air in the autoclave was replaced with dry nitrogen, the catalyst was completely dissolved at 140 ° C. with stirring. Next, 522 g of propylene oxide was dropped with a dropping device and stirred for 2 hours. 440 g of ethylene oxide was dropped with a dripping device, and stirred for 2 hours. Next, 224 g of potassium hydroxide was charged and the inside of the system was replaced with dry nitrogen, and then 188 g of methyl chloride was injected at a temperature of 80 to 130 ° C. and reacted for 5 hours. Thereafter, the reaction composition was taken out from the autoclave, neutralized with hydrochloric acid to pH 6 to 7, and treated at a reduced pressure of -0.095 MPa (50 mmHg) at 100 ° C for 1 hour in order to remove the contained water. Further, filtration was performed to remove the salt generated after the treatment, and an alkylene oxide derivative of Chemical Formula 4 was obtained.
Samples that were sampled and reacted before the reaction with methyl chloride had a hydroxyl value of 110, the compound of formula 4 obtained had a hydroxyl value of 0.3, and the ratio of the number of hydrogen atoms to the number of terminal methyl groups was 0.003. The hydrogen atom is completely converted to a methyl group.
[0057]
According to the above synthesis examples, various alkylene oxide derivatives were prepared and evaluated as external preparations for skin using the following basic composition for testing.
Basic composition for testing
2% ethanol
Glycerin 5
1,3-butylene glycol 5
Nicotinamide 0.3
Sodium pyrrolidonecarboxylate 0.5
Purified water residue
[0058]
[R¹, R²Decision]
First, the inventors¹, R²The relationship between the drug and its suitability as a topical skin preparation was examined. The results are shown in Table 2 below. All compounds have EO and PO parts.
[(EO)₁₀/ (PO)₁₀]
Is used. Moreover, the compounding quantity of each compound is 5 weight% with respect to the said basic composition.
[0059]
[Table 2]

As is clear from Table 2, R¹, R²In the case where the number of carbon atoms of each was 1 to 4 (compounds 2, 3, and 4), an excellent moisturizing effect and usability were obtained.
[0060]
  In contrast, R¹, R²When is a hydrogen (compound 1), the sticky feeling is strong, and R¹When C was C12 (Compound 6), both the moisture retention and the usability were unfavorable. On the other hand, R¹, R²In the case where the sum of the carbon number of 7 is 7 and less than that of Compound 4, R¹When C6 was C6 (Compound 5), the moisturizing feeling tended to decrease.
  From the above, the base according to the present invention includes R¹, R²Both have 1 to 4 carbon atomsAlkyl groupIt is necessary to be.
[0061]
  In actual production, R¹, R²All ofAlkyl groupTherefore, the permissible abundance ratio of the unsubstituted (H) compound was examined. In addition, the ratio of unsubstituted isAlkyl groupThe ratio Y / X of the number of hydrogen atoms (Y) to the number of (X). In Table 3 below, 1: 2 = 5: 95 means that Compound 1 and Compound 2 were mixed at a ratio of 5:95 to adjust a predetermined Y / X.
[0062]
[Table 3]

As apparent from Table 3, R¹, R²Even if there is an unreacted substance for Y, if the amount is small (Y / X = 0.053), there is no significant effect, but when Y / X becomes 0.202, a sticky feeling is clearly produced. Furthermore, as a result of detailed studies by the present inventors, it has become clear that Y / X needs to be 0.15 or less.
[0063]
[Oxyalkylene group, oxyethylene group]
Next, the present inventors examined the presence of oxyalkylene groups and oxyethylene groups and their suitability as a skin external preparation (containing 5% by weight based on the basic composition).
The results are shown in Table 4 below. In addition, about compounds 7-11, R¹, R²Is CH₃Is used.
[0064]
[Table 4]

[0065]
[Chemical formula 5]

[0066]
As is clear from Table 4, the presence of both an oxyalkylene group and an oxyethylene group is indispensable for the moisture retention and usability of the present invention, and the compound 12 shown in Chemical formula 5 is also less effective. This is not considered to be a hydrophobic adjustment effect. Further detailed studies by the present inventors have revealed that a suitable ratio of oxyethylene groups to the total of oxyalkylene groups and oxyethylene groups is 20 to 80% by weight.
Furthermore, the present inventors produced block polymers and random polymers with the same number of alkylene groups and the same number of oxyethylene groups, and compared them.
[0067]
[Table 5]

As can be seen from Table 5, the effect of the present invention can be obtained with either a block polymer or a random polymer, but an excellent feeling in use can be obtained particularly in the case of a random polymer.
[Amount to be added to external preparation for skin]
Next, the inventors further examined the blending amount of the alkylene oxide derivative according to the present invention into the external preparation for skin (the above-mentioned basic formulation).
[0068]
[Table 6]
Compound 8 0 0.01 0.5 5.0 5.0 40.0 70.0
Evaluation 1 × ○ ◎ ◎ ◎ ◎
Evaluation 2 × ○ ◎ ◎ ◎ ○
Evaluation 3 × ○ ◎ ◎ ◎ ◎
Evaluation 4 × ○ ◎ ◎ ◎ ◎
Evaluation 5 × ○ ◎ ◎ ◎ ◎
From the results shown in Table 6, the effect of addition of the compound according to the present invention is recognized from about 0.01% by weight, but particularly remarkable is 0.5% by weight or more. However, since it becomes somewhat sticky when it becomes 70% by weight, the blending up to about 40% by weight is preferable.
[0069]
 [Stickness improvement effect]
Furthermore, the inventors of the present invention have found that the alkylene oxide derivative according to the present invention has an effect of improving the stickiness found in humectants such as glycerin in the course of studying various formulations. That is, in Table 6, stickiness due to glycerin and the like is observed even in the test section without the alkylene oxide derivative. On the other hand, when an alkylene oxide derivative is added, the stickiness caused by other moisturizing agents can be improved rather than simply suppressing the stickiness.
[0070]
[Percutaneous absorption promotion effect]
As shown in Table 7 below, the alkylene oxide derivative (I) and glycerin itself have a moisturizing effect and a rough skin improving effect, but in a combination system with other moisturizing agents, the moisturizing effect and rough skin improving effect are synergistic. Is significantly improved.
[Table 7]

[0071]
Therefore, the present inventors examined the action of alkylene oxide derivatives in more detail. As a result, it was also found that the alkylene oxide derivative according to the present invention has a keratin penetration promoting action of other humectants such as glycerin. That is, as shown in FIG. 1, when the alkylene oxide derivative of the present invention was used in combination (sample 2), the amount of glycerin permeation increased by about 40% compared to the case of glycerin alone (control). The test method of FIG. 1 was as follows.
(1) Test sample
[Table 8]

[0072]
(2) Test method
The test was conducted by a tape stripping method. The tape stripping method is a method for peeling the stratum corneum with a tape after applying a drug and obtaining the drug concentration in the stratum corneum, and is a method generally used as a means for estimating the amount of drug absorbed by human skin. . Specifically, the procedure of the following (1) to (7) was performed, and the permeability of glycerin was examined from the amount of glycerin recovered from the stratum corneum peeled off with the tape. The test was performed by a panel of 4 people, and the average value was evaluated.
(1) Wash the inside of the forearm of the panel with soap.
(2) Sample application (20ml / 20cm²). On the inner side of the forearm, the right arm is coated with sample 1 closer to the wrist and sample 2 closer to the elbow joint. The left arm is applied so that the samples 1 and 2 are in the opposite positions to the right arm.
(3) Leave for 4 hours.
(4) Soap washed on the inner forearm of both arms.
(5) Square layer tape stripping (8 layers).
(6) Extract glycerin from the tape with ion-exchanged water.
(7) Glycerin quantification (HPLC).
[0073]
Furthermore, the present inventors similarly examined using xylitol instead of glycerin as a humectant. The test method was the same as the tape stripping method in glycerin except that (3) the standing time was 6 hours. The samples used were as shown in Table 9 below.
[Table 9]

[0074]
The results are shown in FIG. As can be seen from FIG. 2, in any of the four panels A to D, when the alkylene oxide derivative was blended (sample 4), the corner was better than the sample 3 (control) without the alkylene oxide derivative. The amount of xylitol permeating into the layer increased.
From the above, it was suggested that the alkylene oxide derivative (I) promotes percutaneous absorption with respect to humectants such as glycerin and xylitol.
Furthermore, the present inventors similarly examined using arbutin (hydroquinone-β-D-glucopyranoside) in order to investigate the effect of the alkylene oxide derivative on hydrophilic drugs other than the humectant. The test method was in accordance with the tape stripping method in glycerin. The samples used and the results are shown in Table 10 below.
[Table 10]

As can be seen from Table 10, the amount of penetration of arbutin and glycerin into the stratum corneum increased when the alkylene oxide derivative was blended (sample 6) compared to sample 5 (control) without the alkylene oxide derivative. It was.
From the above, it was suggested that the alkylene oxide derivative (I) promotes percutaneous absorption even for whitening agents such as arbutin.
[0075]
Although the mechanism of action for promoting the percutaneous absorption promotion effect of the alkylene oxide derivative of the present invention is not clear, the alkylene oxide derivative of the present invention decreases the affinity between the hydrophilic agent such as a moisturizer and a whitening agent and the base. It is presumed that percutaneous absorption may be promoted by the treatment.
That is, theoretically, the greater the activity of the drug in the base, the higher the rate of drug permeation through the skin. Therefore, in the region below the saturation solubility of the drug, the affinity between the drug and the base decreases (drugs) By widening the difference in solubility parameter values between the base and the base), it is possible to increase the distribution to the skin.
[0076]
The characteristics of the alkylene oxide derivative (I) of the present invention include high water solubility (solubility in water of 100% or more) and high fat solubility (solubility in ester oil of 100% or more). Such solubility characteristics are derived from the chemical structure of the alkylene oxide derivative (I). And, it is an aqueous base that has both water-solubility and fat-solubility in this way, has a function that can be mixed in an aqueous base and can greatly change the solubility parameter of the base, and is a base for skin external preparations There have been few things that have excellent aptitude as ever.
Therefore, by adding such an alkylene oxide derivative (I) to the aqueous base, the solubility parameter of the base is greatly changed, and the affinity between the hydrophilic agent such as a humectant and the base is significantly reduced, As a result, it is presumed that keratin permeability increases. Therefore, if a drug that is water-soluble and permeates the skin and exerts an effect, such as a water-soluble vitamin, an amino acid, a whitening agent, or the like, is used as a hydrophilic drug, an improvement in the effect can be expected. Drugs that are expected to promote transdermal absorption are preferably highly hydrophilic and are not limited to these, but water / octanol partition coefficient (log P value) indicating water solubility and fat solubility should be used as one index. For example, 0 or less is effective, and more preferably -1 or less. Examples of water-soluble drugs having a log P value of −1.0 or less include hydroquinone glycosides and derivatives, ascorbic acid and derivatives thereof, salicylic acid derivatives, and the like. The logP value is a coefficient representing polarity depending on the ease of distribution of substances into water and octanol as defined in Chemical Reviews vol71 (6), 525 (1971).
[0077]
On the other hand, it is considered that percutaneous absorption can be suppressed by adding an alkylene oxide derivative to a fat-soluble drug having a relatively high keratin permeability. For example, when a fat-soluble drug is solubilized or dispersed in an aqueous base, the addition of an alkylene oxide derivative reduces the solubility parameter difference between the base and the drug, and the affinity between the drug and the base is reduced. It becomes high and keratin permeability is suppressed. Therefore, for fat-soluble drugs that do not penetrate the skin as much as possible (for example, preservatives, ultraviolet absorbers, etc.), suppression of percutaneous absorption can be expected by blending alkylene oxide derivatives. The drug that can be expected to suppress transdermal absorption is not limited to this, but those having a water / octanol partition coefficient (log P value) of 0.5 or more are effective, and more preferably 1.0 or more. It is. Examples of the fat-soluble drug having a log P value of 1.0 or more include methyl paraben, ethyl paraben, butyl paraben, phenoxyethanol, octyl methoxycinnamate, and the like.
[0078]
As described above, by blending the alkylene oxide derivative (I) of the present invention in an aqueous base, it can exert a transdermal absorption promoting action on hydrophilic drugs such as humectants and whitening agents. it can. On the other hand, a transdermal absorption inhibitory effect is expected for fat-soluble drugs such as preservatives and ultraviolet absorbers. Moreover, in an oil-based base, it can be guessed that an alkylene oxide derivative exhibits an effect | action contrary to these. Therefore, the alkylene oxide derivative of the present invention can function as a transdermal absorption control agent.
Since the properties of the alkylene oxide derivative (I) of the present invention can be adjusted by the number and ratio of the EO chain and the AO chain, there is also an advantage that the appropriateness can be easily controlled according to the target drug.
[0079]
Hereinafter, the suitable formulation example of the external preparation for skin concerning this invention is demonstrated.
Formulation Example 1 Cream
A. Oil phase
Stearic acid 10.0% by weight
Stearyl alcohol 4.0
Butyl stearate 8.0
Stearic acid monoglycerin ester 2.0
Vitamin E acetate 0.5
Vitamin A palmitate 0.1
Macadamia nut oil 1.0
Tea oil 3.0
Fragrance 0.4
Preservative appropriate amount
B. Water phase
Compound 13 5.0
Glycerin 4.0
1,2 pentanediol 3.0
Sodium hyaluronate 1.0
Potassium hydroxide 2.0
Magnesium ascorbate phosphate 0.1
L-arginine hydrochloride 0.01
Edetate trisodium 0.05
Purified water residue
[0080]
(Manufacturing method and evaluation)
The oil phase part of A and the aqueous phase part of B are heated to 70 ° C. and completely dissolved. Add Phase A to Phase B and emulsify with an emulsifier. The emulsion was cooled using a heat exchanger to obtain a cream. The obtained cream was excellent in smoothness, had no stickiness, and was confirmed to have a moisturizing effect and a rough skin improving effect.
[0081]
Formulation Example 2 Cream
A. Oil phase
Cetanol 4.0 wt%
Vaseline 7.0
Isopropyl myristate 8.0
Squalane 15.0
Stearic acid monoglycerol ester 2.2
POE (20) sorbitan monostearate 2.8
Vitamin E Nicotinate 2.0
Fragrance 0.3
Antioxidant appropriate amount
Preservative appropriate amount
B. Water phase
Compound 2 10.0
Glycerin 10.0
Sodium hyaluronate 0.02
Dipropylene glycol 4.0
Sodium pyrrolidonecarboxylate 1.0
Edetate disodium 0.01
Purified water residue
(Manufacturing method and evaluation)
A cream was obtained according to Formulation Example 1. The obtained cream was excellent in smoothness, had no stickiness, and was confirmed to have a moisturizing effect and a rough skin improving effect.
[0082]
Formulation Example 3 Latex
A. Oil phase
Squalane 5.0 wt%
Oleil Olate 3.0
Vaseline 2.0
Sorbitan sesquioleate 0.8
Polyoxyethylene oleyl ether (20EO) 1.2
Evening primrose oil 0.5
Fragrance 0.3
Preservative appropriate amount
B. Water phase
Compound 9 8.0
1,3 Butylene glycol 4.5
Ethanol 3.0
Carboxyvinyl polymer 0.2
Potassium hydroxide 0.1
L-arginine L-aspartate 0.01
Edetate 0.05
Purified water residue
(Manufacturing method and evaluation)
An emulsion was obtained according to Formulation Example 1. The obtained emulsion was excellent in smoothness, had no stickiness, and was found to have a moisturizing effect and a rough skin improving effect.
[0083]

(Manufacturing method and evaluation)
A foundation was obtained according to Formulation Example 1. The obtained foundation was excellent in smoothness, had no stickiness, and was confirmed to have a moisturizing effect and a rough skin improving effect.
[0084]

(Manufacturing method and evaluation)
The alcohol phase of A was added to the aqueous phase of B and solubilized to obtain a lotion. The obtained lotion was smooth and free from stickiness, and a moisturizing effect and an effect of improving skin roughness were recognized.
[0085]
Formulation Example 6 W / O emulsion sunscreen agent
(1) Ethylcellulose 0.5% by weight
(2) Ethyl alcohol 4.0
(3) Compound 2 2.0
(4) Octyl paramethoxycinnamate 5.0
(5) Di-2-ethylhexyl alcohol succinate 22.0
(6) Titanium dioxide treated with methyl hydrogen polysiloxane 6.0
(7) Carboxymethylcellulose 1.0
(8) Perfume appropriate amount
(9) Preservative appropriate amount
(10) Purified water residue
(Manufacturing method and evaluation)
After (2) to (3) was added to (1) and sufficiently swollen, (4) to (6) were added and mixed by heating to sufficiently disperse and dissolve. This dispersion was kept at 70 ° C. and emulsified with a homomixer while gradually adding a solution prepared by mixing (7) and (8) to (10) to obtain a W / O emulsion type sunscreen agent. The obtained W / O emulsified sunscreen agent was excellent in smoothness, had no stickiness, and was confirmed to have a moisturizing effect and a rough skin improving effect.
[0086]
Formulation Example 7 W / O emulsion sunscreen agent
A component
Octyl methoxycinnamate 2.0 wt%
Decamethylcyclopentasiloxane 30.5
Trimethylsiloxysilicate 2.5
Dimethyl silicon 5.0
POE polymethylsiloxane copolymer 1.0
Dimethylstearyl ammonium hectorite 0.7
Dextrin fatty acid-treated zinc oxide (average particle size 60 nm) 10.0
B component
1,3-butanediol 5.0
Compound 8 1.0
Purified water residue
(Manufacturing method and evaluation)
While stirring component A with a homomixer, component B was gradually added to emulsify to obtain a W / O emulsion type sunscreen agent. The obtained W / O emulsified sunscreen agent was excellent in smoothness, had no stickiness, and was confirmed to have a moisturizing effect and a rough skin improving effect.
[0087]
Formulation Example 8 O / W emulsion type sunscreen agent
(1) Behenic acid 0.7% by weight
(2) Isostearic acid 0.7
(3) Cetanol 1.0
(4) Liquid paraffin 6.0
(5) Dimethylpolysiloxane 2.0
(6) Glyceryl monostearate 2.0
(7) Octyl paramethoxycinnamate 3.0
(8) Polyethylene glycol 1500 5.0
(9) Dipropylene glycol 5.0
(10) Titanium dioxide powder 2.0
(11) Potassium hydroxide 0.1
(12) Carboxyvinyl polymer 1.0
(13) Sodium hexametaphosphate 0.05
(14) Compound 11 2.0
(15) Perfume appropriate amount
(16) Preservative appropriate amount
(17) Purified water residue
(Manufacturing method and evaluation)
(1) to (7) and (15) are mixed and dissolved by heating to 80 ° C. to obtain an oil phase part. (8) to (14) and (16) to (17) are heated and dispersed at 70 to 75 ° C. to form an aqueous phase part. The oil phase part is gradually added to the aqueous phase part and emulsified using a homomixer.
The emulsion was cooled to 30 ° C. using a heat exchanger to obtain an O / W emulsion type sunscreen agent. The obtained O / W emulsified sunscreen agent was excellent in smoothness, had no stickiness, and was confirmed to have a moisturizing effect and a rough skin improving effect.
[0088]
Formulation Example 9 Sunscreen Oil
(1) Octyl paramethoxycinnamate 3.0% by weight
(2) Compound 3 1.5
(3) Hydrophobized titanium dioxide 2.0
(4) Hydrophobized zinc oxide 1.0
(5) Liquid paraffin 51.0
(6) Cetyl octanoate 40.0
(7) Antioxidant appropriate amount
(8) Perfume appropriate amount
(Manufacturing method and evaluation)
The components (1) to (8) were heated and stirred and then cooled to obtain a sunscreen sunscreen oil. The obtained sunscreen sunscreen oil is excellent in smoothness,
There was no stickiness, and a moisturizing effect and a rough skin improving effect were recognized.
[0089]
Formulation Example 10 W / O emulsion sunscreen agent
(1) Ethylcellulose 0.5% by weight
(2) Ethyl alcohol 4.0
(3) Compound 2 2.0
(4) Octyl paramethoxycinnamate 5.0
(5) Di-2-ethylhexyl alcohol succinate 22.0
(6) Hydrophobized fine particle titanium dioxide (average particle size 30 nm) 6.0
(7) Carboxymethylcellulose 1.0
(8) Perfume appropriate amount
(9) Preservative appropriate amount
(10) Purified water residue
(Manufacturing method and evaluation)
After (2) to (3) was added to (1) and sufficiently swollen, (4) to (6) were added and mixed by heating to sufficiently disperse and dissolve. This dispersion was kept at 70 ° C. and emulsified with a homomixer while gradually adding a solution prepared by mixing (7) and (8) to (10) to obtain a W / O emulsion type sunscreen agent. The obtained W / O emulsified sunscreen was excellent in smoothness, had no stickiness, and was found to have a moisturizing effect and a rough skin improving effect.
[0090]
Formulation Example 11 Lotion Mask
A. Alcohol phase
Ethyl alcohol 10.0% by mass
PPG-13 Decyltetradeceth-24 0.3
Lactic acid menthyl 0.004
Preservative appropriate amount
Perfume appropriate amount
B. Water phase
Glycerin 2.0
Compound 9 3.0
Dipropylene glycol 4.0
Trehalose 2.0
Caustic potash appropriate amount
Purified water residue
(Manufacturing method and evaluation)
The alcohol phase of A was added to the aqueous phase of B to obtain a skin lotion. Further, this was impregnated into a nonwoven fabric or the like to obtain a lotion mask. The obtained lotion mask was excellent in smoothness, had no stickiness, and was confirmed to have a moisturizing effect and a rough skin improving effect.
[0091]
Formulation Example 12 Latex
A. Oil phase
Squalane 7.0% by mass
Oleyl oleate 2.0
Vaseline 1.0
Sorbitan sesquioleate 0.8
POE (20) oleyl ether 1.2
Perfume appropriate amount
Preservative appropriate amount
B. Water phase
Compound 14 3.0
1,3-butylene glycol 1.0
Ethanol 4.0
Carboxyvinyl polymer 0.2
Potassium hydroxide 0.1
Edetate 0.05
Purified water residue
(Manufacturing method and evaluation)
An emulsion was obtained according to Formulation Example 1. The obtained emulsion was excellent in smoothness, had no stickiness, and was found to have a moisturizing effect and a rough skin improving effect.
[0092]
【The invention's effect】
The skin external preparation of the present invention is blended with an alkylene oxide derivative, has excellent use feeling, particularly smoothness, has no stickiness, and has a moisturizing effect and a rough skin improving effect. When other moisturizing agents are used in combination, the alkylene oxide derivative promotes the keratin permeability of the moisturizing agent, and the moisturizing effect and the rough skin improving effect are remarkably improved. Furthermore, transdermal absorption is also promoted for whitening agents.
[Brief description of the drawings]
FIG. 1 is a graph showing the percutaneous absorption promoting effect on glycerin of an alkylene oxide derivative of the present invention.
FIG. 2 is a graph showing the percutaneous absorption promoting effect on xylitol of the alkylene oxide derivative of the present invention.

Claims (12)

A skin external preparation containing an alkylene oxide derivative represented by the following general formula (I).

(In the formula, AO is an oxyalkylene group having 3 to 4 carbon atoms, EO is an oxyethylene group, m and n are average addition moles of the oxyalkylene group and oxyethylene group, respectively, 1 ≦ m ≦ 70, 1 ≦ n ≦ 70 The ratio of the oxyethylene group to the total of the oxyalkylene group having 3 to 4 carbon atoms and the oxyethylene group is 20 to 80% by weight, and the oxyalkylene group and oxyethylene group having 3 to 4 carbon atoms. is also be added in a block form may also be added to the random form .R ^1, R ² are identical or different alkyl group or a hydrogen atom of good 1 to 4 carbon atoms and, R ¹ and R ratio of the number of hydrogen atoms of ² for the alkyl group having 0.15 or less.)   The external preparation according to claim 1, wherein oxyalkylene groups and oxyethylene groups are randomly added.   The external preparation for skin according to claim 1 or 2, wherein 0.01 to 70% by weight of the alkylene oxide derivative (I) is blended.   A humectant comprising an alkylene oxide derivative represented by the general formula (I) as an active ingredient.   A rough skin improving agent comprising an alkylene oxide derivative represented by the general formula (I) as an active ingredient.   Stickiness improver comprising an alkylene oxide derivative represented by the general formula (I) as an active ingredient.   A transdermal absorption enhancer comprising an alkylene oxide derivative represented by the general formula (I) as an active ingredient.   An external preparation for skin comprising an alkylene oxide derivative represented by the general formula (I) and a hydrophilic drug, wherein the alkylene oxide derivative is a percutaneous absorption enhancer of the hydrophilic drug.   The external preparation according to claim 8, wherein the hydrophilic drug is a humectant.   The external preparation according to claim 9, wherein the humectant is glycerin or xylitol.   The external preparation according to claim 8, wherein the hydrophilic drug is at least one selected from hydroquinone derivatives and ascorbic acid derivatives.   A transdermal absorption control agent comprising an alkylene oxide derivative represented by the general formula (I) as an active ingredient.

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