JP2004115451A - Biosynthesis promoter and activity promoter of epidermal transglutaminase - Google Patents
Biosynthesis promoter and activity promoter of epidermal transglutaminase Download PDFInfo
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- JP2004115451A JP2004115451A JP2002282404A JP2002282404A JP2004115451A JP 2004115451 A JP2004115451 A JP 2004115451A JP 2002282404 A JP2002282404 A JP 2002282404A JP 2002282404 A JP2002282404 A JP 2002282404A JP 2004115451 A JP2004115451 A JP 2004115451A
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- Prior art keywords
- transglutaminase
- biosynthesis
- promoter
- vitamin
- activity
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、表皮におけるトランスグルタミナーゼの生合成及び活性を促進することにより、表皮角質細胞を正常化し、乾燥肌やアトピー性皮膚炎症状の軽減、及び肌荒れの改善に有効な、表皮トランスグルタミナーゼ生合成促進剤，活性促進剤に関する。さらに詳しくは、ビタミンＤ及びその関連化合物から選択される１種又は２種以上を有効成分とする、表皮トランスグルタミナーゼ生合成促進剤，及び活性促進剤に関する。
【０００２】
【従来の技術】
皮膚は、外部刺激を緩和し、水分等の体内成分の逸失を制御する働きをしており、その最前線にあたるのが、表皮である。表皮は、基底層，有棘層，顆粒層及び角質層から構成されている。基底層で分裂，増殖した細胞は、有棘層、顆粒層を通過しながら分化し、強固な架橋結合をもったケラチン蛋白線維で構成された角質層になり、最終的には落屑する、というターンオーバーを繰り返している。
【０００３】
特に、顆粒層では、細胞膜が肥厚して肥厚細胞膜を形成すると共に、トランスグルタミナーゼの作用により、蛋白分子間がグルタミル−リジン架橋され、強靭なケラチン蛋白線維が形成される。さらに、その一部にセラミド等が共有結合し、疎水的な構造をとることで、細胞間脂質のラメラ構造の土台を供給し、角質バリアー機能の基礎を形成する。
【０００４】
このような、表皮のターンオーバーのサイクルは、正常な皮膚では約４週間と言われており、一般に年齢と共に衰えて長くなる傾向にはある。しかし、一方では、年齢に関係なく、擦る，掻く等の外部からの軽度な反復刺激によっても、さらには住環境の高温高湿化によるダニの多発、食生活の変化による食品添加物の過剰摂取、窒素酸化物等による大気汚染等の要因による反復刺激によっても、角化機能が亢進され、角質層が肥厚する場合も多い。この現象は、表皮の防御機能の現れではあるが、肥厚化が早すぎると角質層バリアー機能の基礎となるグルタミル−リジン架橋が十分に行われないため、角質層組織が粗膨化し、かえって感作性物質や有害微生物の侵入を許す結果となる。掻痒を伴う乾皮症やアトピー性皮膚炎は、表皮組織でこのような悪循環を繰り返していると言える。
【０００５】
このような問題を解決するために、対症療法的に皮膚の乾燥を防ぎ、保湿機能を高める目的で、水溶性ポリマー，多価アルコール類，ヒアルロン酸等のムコ多糖類等の保湿剤、セラミドなどのラメラ構造を形成する油脂類等を配合した外用剤が市販されている。しかしながら、これらの保湿剤の効果は、一時的なもので、肌状態の根本的な解決にならないことが多く、またセラミドのみの利用では効果が不十分なことが報告されている。
【０００６】
また、トランスグルタミナーゼの活性を促進する効果を有する成分の皮膚外用剤への配合も試みられており、エピダーマルトランスグルタミナーゼの活性促進効果を有するパントテインスルホン酸カルシウム，パントテン酸カルシウム，グルコン酸カルシウム及びグリセロリン酸カルシウムよりなる群から選ばれる１種以上を含有する皮膚外用剤についても、開示されている（特許文献１）が、さらなるトランスグルタミナーゼ活性促進成分の開発が求められてきた。
【０００７】
また、ビタミンＤ及びその関連化合物を含有することを特徴とする皮膚老化予防化粧料（特許文献２）、美肌化粧料（特許文献３）、タンニング皮膚化粧料（特許文献４）等が提案されている。また、ビタミンＤ及びその関連化合物と他の有効成分を併用した皮膚外用剤に関しても多くの検討が為されてきており、紫外線吸収剤と併用することにより日焼け後の肌の状態を整える皮膚外用剤（特許文献５）、ビタミンＣ類との併用による皮膚老化防止、美肌、タンニング効果の強化（特許文献６）、マイカイカ、モッカ、イクリニン及びアスパラガス抽出物との併用による、過酸化物生成抑制効果（特許文献７，特許文献８）、ヨモギ属植物抽出物との併用による老化防止効果、（特許文献９）等が既に開示されている。しかしながら、ビタミンＤ及びその関連化合物が、トランスグルタミナーゼの生合成及び活性を促進することは、これまで全く知られていなかった。
【０００８】
【特許文献１】
特開平１１−１００３２０号公報
【特許文献２】
特開昭６２−２６３１１０号公報
【特許文献３】
特開昭６３−５１３１２号公報
【特許文献４】
特開平２−１７８２１８号公報
【特許文献５】
特開平５−２４６８３５
【特許文献６】
特開平５−２９４８２０号公報
【特許文献７】
特開平６−６５０４４号公報
【特許文献８】
特開平６−１２８１４２号公報
【特許文献９】
特開平１０−２５１１３３号公報
【０００９】
【発明が解決しようとする課題】
そこで本発明においては、表皮におけるトランスグルタミナーゼの生合成及び活性を促進することにより、表皮角質細胞を正常化し、乾燥肌やアトピー性皮膚炎症状の軽減、及び肌荒れの改善に有効な、表皮トランスグルタミナーゼ生合成促進剤、及び活性促進剤（以下両剤をあわせてトランスグルタミナーゼ賦活剤と略す）を得ることを目的とした。
【００１０】
【課題を解決するための手段】
先に述べた課題を解決するべく種々検討したところ、本発明者らは、ビタミンＤ及びその関連化合物から選択される１種又は２種以上物が、高い表皮トランスグルタミナーゼ生合成及び活性を促進作用を有することを見いだし、本発明を完成するに至った。
【００１１】
【発明の実施の形態】
本発明の実施の形態を説明する。
【００１２】
本発明のトランスグルタミナーゼ賦活剤は、ビタミンＤ及びその関連化合物から選択される１種又は２種以上を有効成分とする。本発明に用いられるビタミンＤ及びその関連化合物としては、ビタミンＤ２、ビタミンＤ３、それらの誘導体が挙げられる。具体的にはエルゴカルシフェロール、コレカルシフェロール、プレエルゴカルシフェロール、５，６−ｔｒａｎｓ−エルゴカルシフェロール、イソエルゴカルシフェロール、イソピロエルゴカルシフェロール、プレコレカルシフェロール、５，６−ｔｒａｎｓ−コレカルシフェロール、２５−ヒドロキシコレカルシフェロール、１α−ヒドロキシコレカルシフェロール、１，２５−ジヒドロキシコレカルシフェロール等が挙げられ、本発明の効果の点から、コレカルシフェロールを用いることが最も好ましい。
【００１３】
本発明におけるトランスグルタミナーゼ賦活剤は、ビタミンＤ及びその関連化合物はそのままでもトランスグルタミナーゼ賦活剤として用いることができるが、各種基剤又は担体に含有させて、トランスグルタミナーゼ賦活剤としてもよい。トランスグルタミナーゼ賦活剤全量に対する添加量としては、用いるビタミンＤ及びその関連化合物により異なるが、０．０１〜５．０重量％程度とするのが適切である。
【００１４】
本発明に係るトランスグルタミナーゼ賦活剤は、液剤，乳剤，ゲル剤，クリーム剤，軟膏剤，粉剤，顆粒剤，丸剤等、種々の剤型で提供することができる。また、本発明に係るトランスグルタミナーゼ賦活剤には、トランスグルタミナーゼ生合成促進作用及びトランスグルタミナーゼ活性促進作用を損なわない範囲で、油性成分，界面活性剤，保湿剤，賦形剤，紫外線吸収剤，抗酸化剤，香料，防菌防黴剤等の一般的な医薬品，化粧料及び食品用添加剤を含有させることができる。
【００１５】
【実施例】
さらに本発明の特徴について、実施例により詳細に説明する。
【００１６】
まず、ビタミンＤ及びその関連化合物の１種であるコレカルシフェロールの表皮トランスグルタミナーゼ生合成及び活性促進作用を示す。
【００１７】
［トランスグルタミナーゼ生合成促進作用］
正常ヒト表皮角化細胞を１ウェル当たり２．０×１０４個となるように９６穴マイクロプレートに播種した。播種培地には、市販のクラボウ社製Ｈｕｍｅｄｉａ−ＫＧ２を用いた。３７℃で２４時間培養後、牛胎仔血清等を添加した分化誘導培地に交換し、コレカルシフェロールを所定の濃度添加し、さらに３７℃で２４時間培養した。その際、コレカルシフェロールを添加せずに培養したサンプルをブランクとした。培養した細胞を掻き取り、８Ｍの尿素，０．１ｍＭのジチオスレイトール，２ｍＭのエチレンジアミン三ナトリウムを添加したトリス塩酸緩衝液（ｐＨ７．５）を加えて、超音波処理を施してタンパク質を分散させて、粗酵素画分とした。粗酵素画分のタンパク質量は、ビオチンコニネート法（ＢＣＡ法）を用いて定量した。タンパク質量が１０μｇになるように粗酵素画分を分取し、ＳＤＳ−ポリアクリルアミドゲル電気泳動により分離し、さらにグリシン含有２０容量％エタノール水溶液（ｐＨ１０．０）雰囲気下で、０．２μｍのポリフッ化ビニリデン膜に転写した。０．１重量％モノパルミチン酸ポリオキシエチレンソルビタン（２０Ｅ．Ｏ．），１容量％牛胎仔血清を含有する１００ｍＭ，トリス塩酸、１５０ｍＭ，塩化ナトリウム緩衝液（以下ＴＢＳＴと略す）（ｐＨ７．５）を用いて室温で９０分ブロッキングを行った。抗ヒト表皮トランスグルタミナーゼ１，マウスＩｇＧ２ａモノクローナル抗体を添加した０．５容量％牛胎仔血清含有ＴＢＳＴにて、３７℃で９０分間反応させ、さらにＴＢＳＴにて３回ゲルを洗浄した。次いで、ホースラディッシュペルオキシダーゼ標識ラット抗マウスＩｇＧ１モノクローナル抗体を添加した０．５容量％牛胎仔血清含有ＴＢＳＴにて、室温で６０分間反応させ、さらにＴＢＳＴにて３回ゲルを洗浄した。０．３ｍｇ／ｍＬ２，２’−アジノビス（３−エチルベンゾチアゾリン−６−スルホン酸）ジアンモニウム塩，０．００３容量％過酸化水素含有リン酸−クエン酸緩衝液（ｐＨ４．０）にて３７℃３０分間反応させた後、４０５ｎｍの吸光度を測定することにより定量した。結果をコレカルシフェロールを無添加の場合のトランスグルタミナーゼ蛋白質量を１００とした場合の相対値で表１に示した。
【００１８】
【表１】
表１に示したとおり、コレカルシフェロールを添加して表皮角化細胞を培養することにより、トランスグルタミナーゼ生合成が有意に活性化された。
【００２０】
［トランスグルタミナーゼ活性促進作用］
正常ヒト表皮角化細胞を１ウェル当たり２．０×１０４個となるように９６穴マイクロプレートに播種した。播種培地には、市販のクラボウ社製Ｈｕｍｅｄｉａ−ＫＧ２を用いた。３７℃で２４時間培養後、コレカルシフェロールを所定の濃度添加し、さらに３７℃で２４時間培養した。その際、コレカルシフェロールを添加せずに培養したサンプルをブランクとした。２ｍＭ５ー（ビオチンアミド）ペンチルアミンを添加して３７℃で１時間培養することによりラベリングし、２００μＬのＰＢＳＴにて３回洗浄した。冷メタノールを添加し２分後に２００μＬのＰＢＳＴにて洗浄することにより細胞を固定した。次いで５容量％牛胎仔血清含有ＰＢＳＴを添加して３７℃で２時間培養した後ＰＢＳＴで洗浄することによりブロッキングを行った。ホースラディッシュペルオキシダーゼ標識ストレプトアビジンを添加した、０．３牛胎仔血清含有ＰＢＳＴ溶液にて室温で１時間反応させた後、ＰＢＳＴにて３回洗浄した。０．３ｍｇ／ｍＬ２，２’−アジノビス（３−エチルベンゾチアゾリン−６−スルホン酸）ジアンモニウム塩，０．００３容量％過酸化水素含有リン酸−クエン酸緩衝液（ｐＨ４．０）にて３７℃で３０分間反応させた後、４０５ｎｍの吸光度を測定することにより定量した。結果をコレカルシフェロールを無添加の場合のトランスグルタミナーゼ活性を１００とした場合の相対値で表２に示した。
【００２１】
【表２】
表２に示した、コレカルシフェロールを添加して表皮角化細胞を培養することにより、トランスグルタミナーゼ活性が有意に上昇した。
【００２３】
続いて、本発明に係るトランスグルタミナーゼ生合成促進剤及び活性促進剤についての実施例の処方を示す。
【００２４】
［実施例１］乳剤型トランスグルタミナーゼ賦活剤
（１）ベヘニルアルコール １．００（重量％）
（２）モノステアリン酸ソルビタン ３．００
（３）ポリオキシエチレン（２０ＥＯ）モノステアリン酸ソルビタン２．００
（４）流動パラフィン １０．００
（５）１，２５−ジヒドロキシコレカルシフェロール ０．０５
（６）１，２−ペンタンジオール ５．００
（７）ヒドロキシエチルセルロース ０．２０
（８）精製水 ７８．７５
製法：（１）〜（５）の油相及び（６）〜（８）の水相をそれぞれ均一に溶解して７０℃に加熱する。水相を油相に添加してホモミキサーで乳化後、冷却する。
【００２５】
［実施例２］乳剤型トランスグルタミナーゼ賦活剤
（１）セチルアルコール ０．５０（重量％）
（２）モノステアリン酸ソルビタン ３．００
（３）ポリオキシエチレン（２０ＥＯ）モノステアリン酸ソルビタン２．００
（４）イソステアリン酸セチル ２５．００
（５）エルゴカルシフェロール ０．５０
（６）１，２−ペンタンジオール ８．００
（７）精製水 ６１．００
製法：（１）〜（５）の油相及び（６）〜（７）の水相をそれぞれ均一に溶解して７０℃に加熱する。油相を水相に添加してホモミキサーで乳化後、冷却する。
【００２６】
［実施例３］軟膏状トランスグルタミナーゼ賦活剤
（１）セタノール １．００（重量％）
（２）ミツロウ ５．００
（３）ポリオキシエチレン（２０ＥＯ）モノステアリン酸ソルビタン２．００
（４）モノステアリン酸ソルビタン ３．００
（５）スクワラン ２０．００
（６）コレカルシフェロール ０．０５
（７）１，２−ペンタンジオール ８．００
（８）キサンタンガム ０．２０
（９）精製水 ６０．７５
製法：（１）〜（６）の油相及び（７）〜（９）の水相をそれぞれ均一に溶解して７０℃に加熱する。油相を水相に添加してホモミキサーで乳化後、冷却する。
【００２７】
［実施例４］ 油中水型乳剤状トランスグルタミナーゼ賦活剤
（１）流動パラフィン ３０．０（重量％）
（２）マイクロクリスタリンワックス ２．０
（３）ワセリン ５．０
（４）コレカルシフェロール ０．１
（５）ジグリセリンオレイン酸エステル ５．０
（６）Ｌ−グルタミン酸ナトリウム １．６
（７）Ｌ−セリン ０．４
（８）プロピレングリコール ３．０
（９）１，３−ブチレングリコール ５．０
（１０）パラオキシ安息香酸メチル ０．１
（１１）精製水 ４４．７
（１２）香料 ０．１
製法：（６），（７）を（１１）の一部に溶解して５０℃とし、５０℃に加熱した（５）に撹拌しながら徐々に添加する。これをあらかじめ混合し、７０℃に加熱溶解した（１）〜（４）に均質に分散し、これに（８）〜（１０）を（１１）の残部に溶解して７０℃に加熱したものを撹拌しながら添加し、ホモミキサーにて乳化する。冷却後、４０℃にて（１２）の成分を添加，混合する。
【００２８】
［実施例５］ 油状トランスグルタミナーゼ賦活剤
（１）スクワラン ９８．９（重量％）
（２）エルゴカルシフェロール １．０
（３）ｄ−デルタ−トコフェロール ０．１
製法：（１）〜（３）の成分を、混合，溶解する。
【００２９】
本発明の実施例１〜実施例５について使用試験を行った。同時に実施例１〜実施例５に配合しているビタミンＤ及びその関連化合物を配合せずに、トランスグルタミナーゼ生合成促進及び活性促進剤を調製し、比較例１〜比較例５として、同様に使用試験を行った。
【００３０】
使用試験は、２０才〜５０才の乾燥肌若しくはアトピー性皮膚炎症状を呈する女性パネラー２０名を一群として、ブラインドにて、１日１回２ヶ月間、実施例若しくは比較例を使用させた。評価は、使用試験前後の角質層の状態評価、及び乾燥肌，アトピー性皮膚炎症状、肌荒れの改善状況の聞き取り調査により行った。なお、角質層の状態は次に示す方法により評価した。聞き取り調査は、「改善した〜どちらかといえば改善した」若しくは「変化無し〜悪化した」の２段階で聞き取りを行い、「改善した〜どちらかといえば改善した」と評価したパネラーの数にて結果を示した。
【００３１】
［角質層の状態評価］
洗顔後の油分の少ない状態で、市販のセロファンテープを被験者の頬に貼り付け、しばらく抑えた後、これを剥がし、予め固着剤を塗布したスライドガラスに貼り付ける。次いで、このスライドガラスを１時間キシレンに浸漬し、テープを静かに剥がした後再度、キシレンに１時間浸漬する。その後、スライドガラスを取り出し、風乾させた後、１０分間１％ゲンチアナバイオレットＢ水溶液に浸漬する。次いでスライドガラスを取り出し、水洗，乾燥後バルサム封入して角質層標本を得る。得られた角質層標本を顕微鏡を用いて目視で観察し、角質細胞の形状，剥離密度，有核細胞数について、それぞれ表３〜表５に示した基準にてスコア化した。また、角質の剥離多重度については、得られた角質層の画像をコンピュータに取り込み、画像解析ソフトを用いて、以下のようにスコア化した。使用試験前後のスコアを比較し、スコアが２以上向上したパネラーの数にて、結果を示した。
【００３２】
［角質の剥離多重度］
画像として取り込んだ角質細胞の占める部分の面積Ｓ、及びｎ枚の角層の重なっている部分の面積Ｓｎを、画像解析ソフトを用いて求める。この値により下記式（１）を用いて角質剥離多重度を算出し、得られた角質剥離多重度の値を表６に示す基準でスコア化した。
角質剥離多重度＝Σｎ・Ｓｎ／ｓ （１）
【００３３】
【表３】
【表４】
【表５】
【表６】
【表７】
表７に示したとおり、本発明の実施例は、ビタミンＤ及びその関連化合物を含有していない比較例に比べ、高い、表皮角質細胞正常化効果、乾燥肌やアトピー性皮膚炎症状の軽減、肌荒れの改善効果を示した。
【００３９】
【発明の効果】
以上詳述したように、表皮におけるトランスグルタミナーゼの生合成及び活性を促進することにより、表皮角質細胞を正常化し、乾燥肌やアトピー性皮膚炎症状の軽減、及び肌荒れの改善に有効な、表皮トランスグルタミナーゼ生合成促進剤，活性促進剤を得ることができた。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention promotes transglutaminase biosynthesis and activity in the epidermis, normalizes epidermal keratinocytes, reduces dry skin and atopic dermatitis symptoms, and is effective in improving skin roughness, epidermal transglutaminase biosynthesis It relates to an accelerator and an activity accelerator. More specifically, the present invention relates to an epidermal transglutaminase biosynthesis promoter and an activity promoter comprising one or more selected from vitamin D and its related compounds as active ingredients.
[0002]
[Prior art]
The skin acts to relieve external stimuli and control the loss of internal components such as water, and the epidermis is at the forefront. The epidermis is composed of the basal, spinous, granular and stratum corneum. Cells that divide and proliferate in the basal layer differentiate while passing through the spinous layer and granular layer, become a stratum corneum composed of keratin protein fibers with strong cross-links, and eventually desquamate. Repeated turnover.
[0003]
In particular, in the granular layer, the cell membrane is thickened to form a thickened cell membrane, and glutamyl-lysine is cross-linked between protein molecules by the action of transglutaminase to form strong keratin protein fibers. Further, ceramide or the like is covalently bonded to a part of the liposome to form a hydrophobic structure, thereby providing a basis for a lamellar structure of intercellular lipids and forming a basis for a keratin barrier function.
[0004]
Such a cycle of epidermal turnover is said to be about 4 weeks in normal skin, and generally tends to decline with age and become longer. However, on the other hand, irrespective of age, even mild repeated external stimuli such as rubbing and scratching, frequent occurrence of mites due to high temperature and high humidity in the living environment, and excessive intake of food additives due to changes in dietary habits In addition, the keratinization function is enhanced by the repeated stimulation caused by factors such as air pollution by nitrogen oxides and the like, and the stratum corneum often becomes thick. This phenomenon is a manifestation of the protective function of the epidermis.However, if the hypertrophy is too early, the glutamyl-lysine cross-linking, which is the basis of the stratum corneum barrier function, is not sufficiently performed, and the stratum corneum tissue coarsens and conversely senses. This results in the entry of sensitizing substances and harmful microorganisms. It can be said that xerosis and atopic dermatitis accompanied by pruritus repeat such a vicious cycle in epidermal tissue.
[0005]
To solve such problems, humectants such as water-soluble polymers, polyhydric alcohols, mucopolysaccharides such as hyaluronic acid, ceramides, etc. are used symptomatically to prevent drying of the skin and enhance the moisturizing function. An external preparation containing a fat or oil that forms a lamellar structure is commercially available. However, the effects of these humectants are temporary and often do not fundamentally solve the skin condition, and it has been reported that use of ceramide alone is insufficient.
[0006]
Attempts have also been made to incorporate a component having an effect of promoting the activity of transglutaminase into an external preparation for skin, and to provide calcium pantothein sulfonate, calcium pantothenate, calcium gluconate and calcium pantothein having the effect of promoting epidermal transglutaminase activity. An external preparation for skin containing at least one member selected from the group consisting of calcium glycerophosphate has also been disclosed (Patent Document 1), but development of a further transglutaminase activity promoting component has been demanded.
[0007]
Also, a skin aging preventive cosmetic (Patent Document 2), a beautiful skin cosmetic (Patent Document 3), a tanning skin cosmetic (Patent Document 4), etc., characterized by containing vitamin D and its related compounds have been proposed. I have. In addition, many studies have been made on skin external preparations using vitamin D and its related compounds in combination with other active ingredients, and skin external preparations that regulate the condition of the skin after sunburn by being used in combination with ultraviolet absorbers. (Patent Literature 5), Prevention of skin aging, combination with vitamin Cs, enhancement of beautiful skin and tanning effect (Patent Literature 6), Peroxide generation inhibitory effect by combined use with Maikaika, Mokka, Ichinin and asparagus extract (Patent Literature 7, Patent Literature 8), an anti-aging effect by combined use with Artemisia plant extracts, and (Patent Literature 9) have already been disclosed. However, it has never been known that vitamin D and its related compounds promote the biosynthesis and activity of transglutaminase.
[0008]
[Patent Document 1]
JP-A-11-100320 [Patent Document 2]
JP-A-62-263110 [Patent Document 3]
JP-A-63-51312 [Patent Document 4]
JP-A-2-178218 [Patent Document 5]
JP-A-5-246835
[Patent Document 6]
JP-A-5-294820 [Patent Document 7]
JP-A-6-65044 [Patent Document 8]
JP-A-6-128142 [Patent Document 9]
JP-A-10-251133
[Problems to be solved by the invention]
Therefore, in the present invention, by promoting the biosynthesis and activity of transglutaminase in the epidermis, it normalizes epidermal keratinocytes, reduces dry skin and atopic dermatitis, and is effective in improving skin roughness, epidermal transglutaminase. The purpose was to obtain a biosynthesis promoter and an activity promoter (hereinafter, both agents are abbreviated as a transglutaminase activator).
[0010]
[Means for Solving the Problems]
After conducting various studies to solve the above-mentioned problems, the present inventors have found that one or more selected from vitamin D and related compounds promotes high epidermal transglutaminase biosynthesis and activity. Have been completed, and the present invention has been completed.
[0011]
BEST MODE FOR CARRYING OUT THE INVENTION
An embodiment of the present invention will be described.
[0012]
The transglutaminase activator of the present invention contains, as an active ingredient, one or more selected from vitamin D and its related compounds. Vitamin D and its related compounds used in the present invention include vitamin D 2 , vitamin D 3 , and derivatives thereof. Specifically, ergocalciferol, cholecalciferol, preergocalciferol, 5,6-trans-ergocalciferol, isoergocalciferol, isopiroergocalciferol, plecoreccalciferol, 5,6-trans-chole Examples thereof include calciferol, 25-hydroxycholecalciferol, 1α-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol. From the viewpoint of the effects of the present invention, it is most preferable to use cholecalciferol.
[0013]
The transglutaminase activator in the present invention can be used as a transglutaminase activator, even if vitamin D and its related compounds are used as they are, but may be contained in various bases or carriers to form a transglutaminase activator. The amount added to the total amount of the transglutaminase activator varies depending on the vitamin D used and its related compounds, but it is appropriate to be about 0.01 to 5.0% by weight.
[0014]
The transglutaminase activator according to the present invention can be provided in various dosage forms, such as a liquid, emulsion, gel, cream, ointment, powder, granule, and pill. In addition, the transglutaminase activator according to the present invention includes an oily component, a surfactant, a humectant, an excipient, an ultraviolet absorber, an antibacterial agent as long as the transglutaminase biosynthesis promoting action and the transglutaminase activity promoting action are not impaired. It can contain general pharmaceutical, cosmetic and food additives such as oxidizing agents, fragrances, fungicides and fungicides.
[0015]
【Example】
Further, features of the present invention will be described in detail with reference to examples.
[0016]
First, the action of vitamin C and one of its related compounds, cholecalciferol, to promote epidermal transglutaminase biosynthesis and activity is shown.
[0017]
[Transglutaminase biosynthesis promoting action]
Normal human epidermal keratinocytes were seeded in a 96-well microplate at 2.0 × 10 4 cells per well. As the seeding medium, commercially available Humedia-KG2 manufactured by Kurabo Industries was used. After culturing at 37 ° C. for 24 hours, the medium was replaced with a differentiation-inducing medium supplemented with fetal calf serum and the like, cholecalciferol was added at a predetermined concentration, and the cells were further cultured at 37 ° C. for 24 hours. At that time, a sample cultured without adding cholecalciferol was used as a blank. The cultured cells were scraped off, tris-HCl buffer (pH 7.5) containing 8 M urea, 0.1 mM dithiothreitol, and 2 mM trisodium ethylenediamine was added, and sonication was performed to disperse the protein. Was used as a crude enzyme fraction. The protein amount of the crude enzyme fraction was quantified using the biotin coninate method (BCA method). The crude enzyme fraction was collected to give a protein amount of 10 µg, separated by SDS-polyacrylamide gel electrophoresis, and further subjected to a 0.2 µm polyhedral solution in a 20% by volume glycine-containing aqueous ethanol solution (pH 10.0). Transferred to a vinylidene fluoride film. 0.1% by weight of polyoxyethylene sorbitan monopalmitate (20 EO), 100 mM, Tris-HCl, 150 mM, sodium chloride buffer containing 1% by volume of fetal calf serum (hereinafter abbreviated as TBST) (pH 7.5) For 90 minutes at room temperature. Reaction was carried out at 37 ° C. for 90 minutes with TBST containing 0.5% by volume of fetal calf serum supplemented with anti-human epidermal transglutaminase 1 and mouse IgG2a monoclonal antibody, and the gel was washed three times with TBST. Next, the mixture was reacted at room temperature with TBST containing 0.5% by volume of fetal calf serum supplemented with horseradish peroxidase-labeled rat anti-mouse IgG1 monoclonal antibody at room temperature for 60 minutes, and the gel was washed three times with TBST. 0.3 mg / mL 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, 37% in a phosphate-citrate buffer (pH 4.0) containing 0.003% by volume of hydrogen peroxide. After reacting at 30 ° C. for 30 minutes, quantification was performed by measuring the absorbance at 405 nm. The results are shown in Table 1 as relative values when the amount of the transglutaminase protein when cholecalciferol was not added was taken as 100.
[0018]
[Table 1]
As shown in Table 1, by adding cholecalciferol and culturing epidermal keratinocytes, transglutaminase biosynthesis was significantly activated.
[0020]
[Transglutaminase activity promoting action]
Normal human epidermal keratinocytes were seeded in a 96-well microplate at 2.0 × 10 4 cells per well. As the seeding medium, commercially available Humedia-KG2 manufactured by Kurabo Industries was used. After culturing at 37 ° C. for 24 hours, cholecalciferol was added at a predetermined concentration, and the cells were further cultured at 37 ° C. for 24 hours. At that time, a sample cultured without adding cholecalciferol was used as a blank. Labeling was performed by adding 2 mM 5- (biotinamide) pentylamine and culturing at 37 ° C. for 1 hour, followed by washing three times with 200 μL of PBST. The cells were fixed by adding cold methanol and washing 2 minutes later with 200 μL of PBST. Subsequently, blocking was performed by adding PBST containing 5% by volume of fetal calf serum, culturing at 37 ° C. for 2 hours, and washing with PBST. After a reaction with a PBST solution containing 0.3 fetal bovine serum containing a horseradish peroxidase-labeled streptavidin at room temperature for 1 hour, the plate was washed three times with PBST. 0.3 mg / mL 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, 37% in a phosphate-citrate buffer (pH 4.0) containing 0.003% by volume of hydrogen peroxide. After reacting at 30 ° C. for 30 minutes, it was quantified by measuring the absorbance at 405 nm. The results are shown in Table 2 as relative values when the transglutaminase activity when no cholecalciferol was added was taken as 100.
[0021]
[Table 2]
By culturing epidermal keratinocytes with addition of cholecalciferol shown in Table 2, transglutaminase activity was significantly increased.
[0023]
Next, formulas of Examples of the transglutaminase biosynthesis promoter and the activity promoter according to the present invention will be described.
[0024]
[Example 1] Emulsion type transglutaminase activator (1) behenyl alcohol 1.00 (wt%)
(2) Sorbitan monostearate 3.00
(3) Polyoxyethylene (20EO) sorbitan monostearate 2.00
(4) Liquid paraffin 10.00
(5) 1,25-dihydroxycholecalciferol 0.05
(6) 1,2-pentanediol 5.00
(7) Hydroxyethyl cellulose 0.20
(8) Purified water 78.75
Production method: The oil phase of (1) to (5) and the aqueous phase of (6) to (8) are each dissolved uniformly and heated to 70 ° C. The aqueous phase is added to the oil phase, emulsified with a homomixer, and then cooled.
[0025]
[Example 2] Emulsion type transglutaminase activator (1) Cetyl alcohol 0.50 (% by weight)
(2) Sorbitan monostearate 3.00
(3) Polyoxyethylene (20EO) sorbitan monostearate 2.00
(4) Cetyl isostearate 25.00
(5) Ergocalciferol 0.50
(6) 1,2-pentanediol 8.00
(7) Purified water 61.00
Production method: The oil phase of (1) to (5) and the aqueous phase of (6) to (7) are each dissolved uniformly and heated to 70 ° C. The oil phase is added to the aqueous phase, emulsified with a homomixer, and then cooled.
[0026]
[Example 3] Ointment-like transglutaminase activator (1) cetanol 1.00 (% by weight)
(2) Beeswax 5.00
(3) Polyoxyethylene (20EO) sorbitan monostearate 2.00
(4) Sorbitan monostearate 3.00
(5) Squalane 20.00
(6) Cholecalciferol 0.05
(7) 1,2-pentanediol 8.00
(8) Xanthan gum 0.20
(9) Purified water 60.75
Production method: The oil phase of (1) to (6) and the aqueous phase of (7) to (9) are each uniformly dissolved and heated to 70 ° C. The oil phase is added to the aqueous phase, emulsified with a homomixer, and then cooled.
[0027]
Example 4 Water-in-oil emulsion transglutaminase activator (1) Liquid paraffin 30.0 (% by weight)
(2) Microcrystalline wax 2.0
(3) Vaseline 5.0
(4) Cholecalciferol 0.1
(5) Diglycerin oleate 5.0
(6) L-sodium glutamate 1.6
(7) L-serine 0.4
(8) Propylene glycol 3.0
(9) 1,3-butylene glycol 5.0
(10) Methyl paraoxybenzoate 0.1
(11) Purified water 44.7
(12) Fragrance 0.1
Production method: (6) and (7) are dissolved in a part of (11) to 50 ° C., and gradually added to (5) heated to 50 ° C. with stirring. This was previously mixed and dispersed homogeneously in (1) to (4) heated and melted at 70 ° C, and (8) to (10) were dissolved in the remainder of (11) and heated to 70 ° C. Is added with stirring and emulsified with a homomixer. After cooling, the component (12) is added and mixed at 40 ° C.
[0028]
[Example 5] Oily transglutaminase activator (1) squalane 98.9 (% by weight)
(2) Ergocalciferol 1.0
(3) d-delta-tocopherol 0.1
Production method: Components (1) to (3) are mixed and dissolved.
[0029]
A use test was performed on Examples 1 to 5 of the present invention. At the same time, transglutaminase biosynthesis promoting and activity promoting agents were prepared without blending vitamin D and its related compounds blended in Examples 1 to 5 and used similarly as Comparative Examples 1 to 5. The test was performed.
[0030]
In the use test, a group of 20 female panelists exhibiting dry skin or atopic dermatitis symptoms of 20 to 50 years old was allowed to use the examples or comparative examples once a day for 2 months in a blind. The evaluation was performed by evaluating the condition of the stratum corneum before and after the use test, and by hearing the improvement of dry skin, atopic dermatitis and skin roughness. The state of the stratum corneum was evaluated by the following method. Interview surveys were conducted in two stages: "Improved-Somewhat improved" or "No change-Deteriorated", and the number of panelists who rated "Improved-Somewhat improved" was evaluated. The results are shown.
[0031]
[Evaluation of stratum corneum condition]
After washing the face, a commercially available cellophane tape is applied to the cheek of the subject in a state where the amount of oil is small, and after being held down for a while, the adhesive is peeled off and attached to a slide glass to which a fixing agent has been applied in advance. Next, the slide glass is immersed in xylene for 1 hour, the tape is gently peeled off, and then immersed again in xylene for 1 hour. Thereafter, the slide glass is taken out, air-dried, and then immersed in a 1% gentian violet B aqueous solution for 10 minutes. Next, the slide glass is taken out, washed with water, dried, and sealed with balsam to obtain a stratum corneum specimen. The obtained stratum corneum specimen was visually observed using a microscope, and the shape, exfoliation density, and number of nucleated cells of the stratum corneum were scored based on the criteria shown in Tables 3 to 5, respectively. Regarding the exfoliation degree of the stratum corneum, the obtained image of the stratum corneum was taken into a computer, and scored as follows using image analysis software. The scores before and after the use test were compared, and the results were indicated by the number of panelists whose scores improved by 2 or more.
[0032]
[Keratin exfoliation multiplicity]
The area S of the portion occupied by the keratinocytes captured as an image and the area Sn of the overlapping portion of the n stratum corneum are determined using image analysis software. Based on this value, the keratin exfoliation multiplicity was calculated using the following equation (1), and the obtained value of the keratin exfoliation multiplicity was scored based on the criteria shown in Table 6.
Exfoliation multiplicity = Σn · Sn / s (1)
[0033]
[Table 3]
[Table 4]
[Table 5]
[Table 6]
[Table 7]
As shown in Table 7, the Example of the present invention has a higher normalizing effect on epidermal keratinocytes, a reduction in dry skin and atopic dermatitis symptoms as compared with Comparative Examples not containing vitamin D and its related compounds, The effect of improving rough skin was shown.
[0039]
【The invention's effect】
As described in detail above, by promoting transglutaminase biosynthesis and activity in the epidermis, it normalizes epidermal keratinocytes, reduces dry skin and atopic inflammatory conditions, and is effective in improving skin roughness. Glutaminase biosynthesis promoter and activity promoter were obtained.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002282404A JP2004115451A (en) | 2002-09-27 | 2002-09-27 | Biosynthesis promoter and activity promoter of epidermal transglutaminase |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002282404A JP2004115451A (en) | 2002-09-27 | 2002-09-27 | Biosynthesis promoter and activity promoter of epidermal transglutaminase |
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|---|---|
| JP2004115451A true JP2004115451A (en) | 2004-04-15 |
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| JP2002282404A Pending JP2004115451A (en) | 2002-09-27 | 2002-09-27 | Biosynthesis promoter and activity promoter of epidermal transglutaminase |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1781302A4 (en) * | 2004-07-28 | 2010-02-17 | Lipopeptide Ab | New use |
| WO2011027048A1 (en) | 2009-09-04 | 2011-03-10 | Isp Investments Inc. | Transglutaminase-activating peptide, and cosmetic or pharmaceutical composition containing same |
| FR2949781A1 (en) * | 2009-09-04 | 2011-03-11 | Isp Investments Inc | New peptide hydrolyzate enriched in bioactive peptide capable of activating the human transglutaminase useful e.g. to enhance the barrier function of the epidermis and stimulate the epidermal regeneration and differentiation |
| JPWO2022138866A1 (en) * | 2020-12-24 | 2022-06-30 |
-
2002
- 2002-09-27 JP JP2002282404A patent/JP2004115451A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1781302A4 (en) * | 2004-07-28 | 2010-02-17 | Lipopeptide Ab | New use |
| WO2011027048A1 (en) | 2009-09-04 | 2011-03-10 | Isp Investments Inc. | Transglutaminase-activating peptide, and cosmetic or pharmaceutical composition containing same |
| FR2949781A1 (en) * | 2009-09-04 | 2011-03-11 | Isp Investments Inc | New peptide hydrolyzate enriched in bioactive peptide capable of activating the human transglutaminase useful e.g. to enhance the barrier function of the epidermis and stimulate the epidermal regeneration and differentiation |
| FR2949782A1 (en) * | 2009-09-04 | 2011-03-11 | Isp Investments Inc | TRANSGLUTAMINASE ACTIVATOR PEPTIDE AND COSMETIC OR PHARMACEUTICAL COMPOSITION CONTAINING SAME. |
| US8933035B2 (en) | 2009-09-04 | 2015-01-13 | Isp Investments Inc. | Transglutaminase-activating peptide and cosmetic or pharmaceutical composition containing same |
| JPWO2022138866A1 (en) * | 2020-12-24 | 2022-06-30 | ||
| WO2022138866A1 (en) * | 2020-12-24 | 2022-06-30 | アスパック企業株式会社 | Agent for improving atopic dermatitis |
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