JP5423002B2 - Collagen synthesis promoter containing zinc as an active ingredient - Google Patents
Collagen synthesis promoter containing zinc as an active ingredient Download PDFInfo
- Publication number
- JP5423002B2 JP5423002B2 JP2008522615A JP2008522615A JP5423002B2 JP 5423002 B2 JP5423002 B2 JP 5423002B2 JP 2008522615 A JP2008522615 A JP 2008522615A JP 2008522615 A JP2008522615 A JP 2008522615A JP 5423002 B2 JP5423002 B2 JP 5423002B2
- Authority
- JP
- Japan
- Prior art keywords
- collagen synthesis
- zinc salt
- zinc
- composition
- ubiquinone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Images
Description
【技術分野】
【0001】
本発明はしわを防止するのに有用な、亜鉛を有効成分として含有するコラーゲン合成促進剤、およびこれを含有する組成物に関する。
【背景技術】
【0002】
皮膚のしわを予防あるいは改善する物質は多く見出されているが、完全に予防や改善が実感できる安全な物質はなく、未だ多くの研究がなされている。しわの形成が起きる原因は種々報告されているが、その一つに肌の乾燥があげられる。皮膚角層中の水分量が減少することで、皮膚の小じわは現れることは良く知られた事実である。このことから、皮膚角層中の水分量を高く維持するため保湿成分が利用されている。我々自身の皮膚角層が持っている保湿成分としてNMF(Natural Moisturizing Factor)が有名であるが、その構成要素であるアミノ酸自身にも角層中の水分を高く保持するものも見出されている。また、プラセンタエキスやビタミン類などの細胞賦活成分により皮膚角化細胞のターンオーバーを促進し、しわの予防・改善を行おうとする提案もなされている。
【0003】
乾燥とは異なる原因として、皮膚の老化に伴うしわやたるみの大きな原因として、真皮中のコラーゲン量の減少が関係していると考えられる。皮膚中のコラーゲンは真皮の細胞外マトリックスの成分であり結合組織として重要な役割を果たしている。コラーゲン量は皮膚の柔らかさや張りを構成する重要な要因である。
【0004】
皮膚組織におけるコラーゲン量を増加させるためには、UV照射により誘導されるコラーゲナーゼ活性を阻害し、コラーゲンの分解を抑制すること、および、コラーゲン合成を促進することが重要である。コラーゲン合成はビタミンやホルモン、サイトカインなどが作用することで促進することが知られている。
【0005】
コラーゲン合成を促す製品としてコラーゲンタンパクやコラーゲン組成アミノ酸組成物などが市販されているが、そのコラーゲン合成促進効果は明確でない。
【0006】
また、レチノイド、レチノール、レチノイン酸がコラーゲンの合成を促進させることが知られているが、催奇性、副作用も報告されており、より安全で、効果の高いコラーゲン合成促進剤が求められている。
【0007】
ユビキノンは1957年にウシの心臓の細胞内ミトコンドリアから単離・発見された化合物で、コエンザイムQ10、補酵素Q10、あるいは単にCoQ10とも呼ばれる。ユビキノンは体内で作り出され、多くの臓器に存在する。その働きの1つに細胞内ミトコンドリアでのエネルギーの産生がある。ミトコンドリア内において、糖や脂質などを利用し電子伝達系、TCAサイクルを介して、ATPという高エネルギー分子を産生する。すなわち、ユビキノンは電子伝達系で働き、ATP産生に寄与する。心臓でのユビキノンは40歳を過ぎると20歳時の約半分までその生成量が減少すると言われている。皮膚においては、いまだユビキノンに関する詳しいデータは少ないが、他の臓器と同様に加齢と共にユビキノン濃度は減少すると考えられる。
【0008】
また、ユビキノンのもう1つの働きは抗酸化効果である。皮膚は紫外線などに暴露される機会が多いため、皮膚内での酸化反応が常に引き起こされている。この酸化反応を防ぐため、多くのユビキノンが生成され利用されていると考えられる。2004年には、化粧品としてユビキノンが利用可能となり、多くの化粧品に使われるようになってきたが、エネルギー産生促進による肌のターンオーバーの促進や、抗酸化効果以外では、ユビキノンの皮膚に対する具体的な効果については未だ不明な点も多い。
【0009】
一方、亜鉛については、無機亜鉛塩の一種である酸化亜鉛が、おむつかぶれを抑制すると報告されている(例えば、FEBS Letters,384巻,92〜96ページ、1996年)。しかしながら、この化合物は水にも油性成分にも難溶で、化粧品や皮膚外用剤の成分として用いることが難しい。
【0010】
有機亜鉛塩の一種であるグリシン亜鉛塩について、メタロチオネインの誘導促進作用を有することが知られている(特開2005−247729号公報)。これは抗酸化効果やラジカル補足能などの経路により、メラニン合成阻害や細胞毒性阻害などのUVによる皮膚損傷の抑制作用である。しかしながらグリシン亜鉛塩のコラーゲン合成に対する影響は知られていない。
【0011】
同じく有機亜鉛塩の一種であるピロリドンカルボン酸亜鉛塩やアシルアミノ酸亜鉛塩について、UVにより惹起されるAP−1やNF−κBなどの炎症因子を抑制することが知られている(特開2006−022090号公報、国際公開WO2005/123062号パンフレット)。しかしながらピロリドンカルボン酸亜鉛塩やアシルアミノ酸亜鉛塩のコラーゲン合成に関する作用は知られていない。
【0012】
その他、有機亜鉛塩や無機亜鉛塩について、収れん作用、消炎作用、白色顔料、紫外線防御剤、消臭・殺菌剤の用途で化粧料組成物に配合することが知られているが、効果を期待できる濃度領域近傍での利用は皮膚に対する刺激性から、化粧品としての利用が難しかった。また低濃度での利用では、皮膚への上記有効性を見出せず、亜鉛塩の化粧料への配合は進んでいないのが現状である。
【発明の開示】
【0013】
本発明者らは、保湿や、肌のターンオーバーの促進によるしわの改善ではなく、コラーゲン合成によるしわの改善を目的として鋭意検討を重ねた結果、亜鉛をヒト真皮繊維芽細胞に導入することにより、アスコルビン酸トランスポーターの発現促進効果を有することを見出し、これに伴いコラーゲン合成促進効果が得られることを見出した。
【0014】
アスコルビン酸トランスポーターは、細胞へのアスコルビン酸の取り込みを促進する膜タンパク質であり(Hiroyasu Tsukaguchi etc (1999)Nature 399,70−75を参照せよ)、アスコルビン酸トランスポーターの発現増強により、真皮繊維芽細胞においてコラーゲン合成に必須なアスコルビン酸の細胞内への取り込みが増加し、コラーゲン合成が促進される。
【0015】
さらに、驚くべきことに、従来コラーゲン合成促進効果が知られていなかったユビキノンに、亜鉛塩の一つであるピロリドンカルボン酸亜鉛塩を添加することにより、極めて顕著にコラーゲン合成が相乗的に促進されることを見出した。
【0016】
本発明の目的は、上記の知見に基づき、優れたコラーゲン合成作用を有するコラーゲン合成促進剤、およびこれを含有する化粧料組成物を得ることにある。
【課題を解決するための手段】
【0017】
すなわち、本発明は、亜鉛を有効成分として含有することを特徴とするコラーゲン合成促進用組成物、およびユビキノンとピロリドンカルボン酸亜鉛塩を有効成分として含有することを特徴とするコラーゲン合成促進用組成物に関する。
【0018】
皮膚刺激性、細胞内への導入効率などの観点から、現実的に実施可能な亜鉛の導入方法としては、亜鉛を亜鉛塩にして、一定濃度、皮膚に塗布することが必要であり、具体的には以下の発明を含む。
【0019】
(1)亜鉛を有効成分として含有するコラーゲン合成促進剤。
(2)亜鉛が、ピロリドンカルボン酸亜鉛塩、グルコン酸亜鉛塩、フェノールスルホン酸亜鉛、乳酸亜鉛塩、各種アミノ酸亜鉛塩、アシルアミノ酸亜鉛塩、硫酸亜鉛、塩化亜鉛および酸化亜鉛からなる群より選択される化合物である、(1)記載のコラーゲン合成促進剤。
(3)亜鉛が、ピロリドンカルボン酸亜鉛塩である(1)記載のコラーゲン合成促進剤。
(4)ピロリドンカルボン酸亜鉛塩とユビキノンを有効成分として含有するコラーゲン合成促進剤。
(5)コラーゲン合成が、ヒト繊維芽細胞のアスコルビン酸トランスポーターの発現増強を介してされるものである、上記(1)から(4)に記載のコラーゲン合成促進剤。
(6)亜鉛を、有効成分として配合することを特徴とする、コラーゲン合成促進用組成物。
(7)亜鉛が、ピロリドンカルボン酸亜鉛塩、グルコン酸亜鉛塩、フェノールスルホン酸亜鉛、乳酸亜鉛塩、各種アミノ酸亜鉛塩、アシルアミノ酸亜鉛塩、硫酸亜鉛、塩化亜鉛および酸化亜鉛からなる群より選択される化合物である、(6)記載のコラーゲン合成促進用組成物。
(8)亜鉛が、ピロリドンカルボン酸亜鉛塩である(6)記載のコラーゲン合成促進用組成物。
(9)ピロリドンカルボン酸亜鉛塩とユビキノンを有効成分として配合することを特徴とする、コラーゲン合成促進用組成物。
(10)亜鉛を、組成物中に1μM〜100mMの濃度で存在するように配合することを特徴とする、上記(6)〜(9)に記載のコラーゲン合成促進用組成物。
(11)さらに、N−アシル酸性アミノ酸エステル、またはアミノ酸誘導体が配合される、上記(6)〜(10)に記載のコラーゲン合成促進用組成物。
(12)軟膏、化粧水、ローション、クリーム、乳液、美容液、パック、ファンデーション、液体ハンドソープ、シャンプー、または毛髪用化粧水である上記(6)〜(11)に記載のコラーゲン合成促進用組成物。
(13)亜鉛を、有効成分として配合することを特徴とする、しわの予防剤または治療剤。
(14)亜鉛が、ピロリドンカルボン酸亜鉛塩、グルコン酸亜鉛塩、フェノールスルホン酸亜鉛、乳酸亜鉛塩、各種アミノ酸亜鉛塩、アシルアミノ酸亜鉛塩、硫酸亜鉛、塩化亜鉛および酸化亜鉛からなる群より選択される化合物である、(13)記載のしわの予防剤または治療剤。
(15)亜鉛が、ピロリドンカルボン酸亜鉛塩である(13)記載のしわの予防剤または治療剤。
(16)ピロリドンカルボン酸亜鉛塩とユビキノンを有効成分として配合することを特徴とする、しわの予防剤または治療剤。
(17)コラーゲン合成促進のための亜鉛の使用。
(18)コラーゲン合成促進のための、ピロリドンカルボン酸亜鉛塩、グルコン酸亜鉛塩、フェノールスルホン酸亜鉛、乳酸亜鉛塩、各種アミノ酸亜鉛塩、アシルアミノ酸亜鉛塩、硫酸亜鉛、塩化亜鉛および酸化亜鉛からなる群より選択される亜鉛塩の使用。
(19)コラーゲン合成促進のためのピロリドンカルボン酸亜鉛塩の使用。
(20)コラーゲン合成促進のためのピロリドンカルボン酸亜鉛塩とユビキノンの併用。
(21)上記(6)〜(12)に記載の組成物を皮膚に塗布することを特徴とするコラーゲン合成を促進する方法。
(22)ユビキノンとピロリドンカルボン酸亜鉛塩が、50:1〜0.1:1の重量比率で含有される、上記(4)に記載のコラーゲン合成促進剤。
(23)0.0001重量%〜10重量%のユビキノンおよび0.000035重量%〜3.5重量%のピロリドンカルボン酸亜鉛塩を含有することを特徴とするコラーゲン合成促進用組成物。
(24)0.0001重量%〜10重量%のユビキノンおよび0.000035重量%〜3.5重量%のピロリドンカルボン酸亜鉛塩を含有することを特徴とするしわの予防剤または治療剤。
(25)0.0001重量%〜10重量%のユビキノンおよび0.000035重量%〜3.5重量%のピロリドンカルボン酸亜鉛塩を含有する組成物を皮膚に塗布することを特徴とするコラーゲン合成を促進する方法。
【図面の簡単な説明】
【0020】
図1は、ヒト真皮繊維芽細胞を用いた亜鉛塩のコラーゲン合成促進効果を確認した図である。
図2は、ヒト真皮繊維芽細胞を用いたピロリドンカルボン酸亜鉛塩によるコラーゲン合成促進効果を確認した図である。
図3は、ピロリドンカルボン酸亜鉛塩によるアスコルビン酸トランスポーターmRNA発現増強効果を確認した図である。
図4は、ヒト真皮繊維芽細胞を用いたピロリドンカルボン酸亜鉛塩およびユビキノンによるコラーゲン合成促進効果を確認した図である。
図5は、ピロリドンカルボン酸亜鉛塩配合処方による三次元培養ヒト皮膚におけるコラーゲン合成促進効果を確認した図である。
【発明の詳細な説明】
【発明を実施するための最良の形態】
【0021】
以下、本発明の詳細を説明する。
【0022】
本発明に用いられる亜鉛は、皮膚刺激性、細胞への導入効率などの観点から、現実的に亜鉛を亜鉛塩にして、一定濃度、皮膚に塗布することが必要である。この場合有機亜鉛塩および無機亜鉛塩のいずれも使用することができる。有機亜鉛塩としては、ピロリドンカルボン酸亜鉛塩、グルコン酸亜鉛塩、フェノールスルホン酸亜鉛、乳酸亜鉛塩、各種アミノ酸亜鉛塩、アシルアミノ酸亜鉛塩、などが含まれる。無機亜鉛塩としては、硫酸亜鉛、塩化亜鉛、酸化亜鉛などが含まれる。
【0023】
アミノ酸亜鉛塩としては、グリシン亜鉛塩、アラニン亜鉛塩、バリン亜鉛塩、ロイシン亜鉛塩、イソロイシン亜鉛塩、フェニルアラニン亜鉛塩、メチオニン亜鉛塩、トリプトファン亜鉛塩、アスパラギン亜鉛塩、グルタミン亜鉛塩、セリン亜鉛塩、スレオニン亜鉛塩、システイン亜鉛塩、チロシン亜鉛塩、アスパラギン酸亜鉛塩、グルタミン酸亜鉛塩、リジン亜鉛塩、アルギニン亜鉛塩、若しくはヒスチジン亜鉛塩などの各種アミノ酸亜鉛塩が挙げられる。
【0024】
アシルアミノ酸亜鉛塩とは、アミノ酸のアミノ基にアシル基が結合した化合物の亜鉛塩であるが、例えば、アシルアミノ酸としては以下の構造式を有する化合物が挙げられる。
【0025】
【化1】
【0026】
(上記(I)中、R1は炭素原子数2〜22のアシル基、R2は水素原子または、炭素数1〜6の直鎖または分岐鎖アルキル基を、R3はアミノ酸であるバリン、ロイシン、イソロイシン、フェニルアラニン、メチオニン、トリプトファン、アスパラギン、グルタミン、セリン、スレオニン、システイン、チロシン、アスパラギン酸、グルタミン酸、リジン、アルギニン、ヒスチジン、アラニンの側鎖または、水素原子を表し、nは0または1の整数を表す。)
【0027】
コラーゲン合成促進効果を高めるという観点において、血流促進効果を持つピロリドンカルボン酸の亜鉛塩は、血管内のアスコルビン酸などの有用物質を塗布部位に集めることが期待されるため、アスコルビン酸トランスポーターの発現促進効果がより顕著にコラーゲン合成促進効果に反映される亜鉛塩である。
【0028】
ピロリドンカルボン酸亜鉛塩(以下、PCA亜鉛塩、PCAZn塩ともいう)とは、2−ピロリドン−5−カルボン酸の亜鉛塩であって、各種水和物であってもよい。実施例において使用したピロリドンカルボン酸亜鉛塩は2水和物であり、以下の構造を有する。
【0029】
【化2】
【0030】
ピロリドンカルボン酸亜鉛塩は、D体、L体もしくはDL体(D体とL体の混合物)のいずれを用いてもよい。例えば、L−PCA亜鉛塩やDL−PCA亜鉛塩を用いることができる。これらを単独あるいは混合して用いることが可能であり、DL体を用いる場合、D体とL体の比率は特に限定されない。
【0031】
本発明のコラーゲン合成促進剤は、化粧料や皮膚外用剤などの組成物に配合して使用される。この際、その配合量を1μM〜100mM(PCA亜鉛塩として0.000035重量%〜3.5重量%)、好ましくは、1μM〜10mM(PCA亜鉛塩として0.000035重量%〜0.35重量%)、更に好ましくは、1μM〜1mM(PCA亜鉛塩として0.000035重量%〜0.035重量%)程度のごく少量配合することが重要である。3.5重量%以上の配合では皮膚に対して刺激感が生じる、あるいは、きしみ感などが発生する問題があり、また、培養皮膚細胞を用いた検討によれば、高濃度ではコラーゲン合成促進効果は起こらなくなり、好ましくない。
【0032】
本発明のコラーゲン合成促進剤を化粧料や皮膚外用剤などの組成物に配合するとき、これらの成分以外に、一般に化粧料あるいは皮膚外用剤として使用される成分を本発明の効果を阻害しない範囲で添加することができる。
【0033】
本発明の第二の態様として、ユビキノンとピロリドンカルボン酸亜鉛塩を有効成分として含有するコラーゲン合成促進剤に関する。今まで説明したように、ピロリドンカルボン酸亜鉛塩を単独でコラーゲン合成促進剤として使用することができるが、ユビキノンと併用して用いると、驚くべき相乗効果を有するコラーゲン合成促進剤として使用することができる。これにより、肌のターンオーバーの促進や、抗酸化効果による、しわの改善ではなく、コラーゲン合成によるしわの改善が期待できる。
【0034】
本発明においてユビキノンとは、2,3−ジメトキシ−5−メチル−6−ポリプレニル−1,4−ベンゾキノンの側鎖のイソプレン単位が10のユビキノン類であり、本発明の効果を適切に発現させるためには、ユビキノンの配合量は0.0001重量%以上にすることが好ましく、0.01重量%以上にすることがより好ましく、0.03重量%以上にすることがさらに好ましい。また、ユビキノンの配合量を必要以上に多くすると、結晶化したり、製品の色が黄変するおそれがあるので、10重量%以下にすることが好ましく、1重量%以下にすることがより好ましく、0.1重量%以下にすることがさらに好ましい。ピロリドンカルボン酸亜鉛塩は、その効果を適切に発現させるためには、ユビキノンとピロリドンカルボン酸亜鉛塩の配合比率が、50:1〜0.1:1の比率で含有されることが好ましい。
【0035】
また、本発明の更なる態様として、本発明のコラーゲン合成促進剤と、N−アシル酸性アミノ酸エステル、アミノ酸およびアミノ酸誘導体からなる群より選択される1種また2種以上が同時に配合されてなる組成物に関する。
【0036】
本発明の組成物に配合することができるN−アシル酸性アミノ酸エステルは、次の構造で表されるものであって、
【0037】
【化3】
【0038】
(式中のXおよびYは双方が同じでも異なっていてもよいが、XおよびYはステロールのエステル生成残基、炭素数8〜30の直鎖もしくは分岐の液状高級アルキルアルコールもしくはアルケニルアルコール、または炭素数12〜38の固形状直鎖もしくは分岐の高級アルコールのエステル生成残基から選ばれる少なくとも1種である。そして、窒素原子に結合するCORは炭素数8〜22の直鎖アシル基である。nは1または2である。a、bは0〜10であり、bは0〜10である。)
【0039】
特にN−アシル酸性ジエステルが好ましく、その好適な具体例としては、例えば、N−ラウロイルグルタミン酸ジ(コレステリルベヘニルオクチルドデシル)、N−ラウロイルグルタミン酸ジ(コレステリルオクチルドデシル)、N−ラウロイルグルタミン酸ジ(フィトステリル2−オクチルドデシル)、N−ラウロイルグルタミン酸ジ(オクチルドデシルフィトステリルベヘニル)などが挙げられ、それらは、味の素株式会社から、それぞれ、「エルデュウCL−301」、「エルデュウCL−202」、「エルデュウPS−203」、「エルデュウPS−304」の商品名で市販されている。
【0040】
そして、本発明において、このN−アシル酸性アミノ酸エステルは、保湿力や整肌性の向上に寄与し、また、安定性の向上にも寄与するが、その効果を適切に発現させるためには、その配合量は、0.01重量%以上にすることが好ましく、0.1重量%以上にすることがより好ましく、0.5重量%以上にすることがさらに好ましく、また、N−アシル酸性アミノ酸エステルの配合量を必要以上に多くすると、べたつくおそれがあるので、20重量%以下にすることが好ましく、10重量%以下にすることがより好ましく、5重量%以下にすることがさらに好ましい。
【0041】
アミノ酸またはアミノ酸誘導体は、保湿効果の向上に寄与させるために組成物中に配合されるが、そのアミノ酸としては、例えば、アラニン、アルギニン、アスパラギン、アスパラギン酸、シトルリン、システイン、シスチン、グルタミン、グルタミン酸、グリシン、ヒスチジン、オキシプロリン、イソロイシン、ロイシン、リジン、メチオニン、オルニチン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン、バリンなどが挙げられ、それらのL体、D体またはDL体のいずれであってもよいし、また、それらの塩であってもよい。そのような塩としては、例えば、ナトリウム塩、カリウム塩、トリエタノールアミン塩などが挙げられる。
【0042】
また、アミノ酸誘導体としては、前述のアミノ酸を環化、アシル化またはエステル化したものであって、例えば、アセチルグルタミン酸、アセチルメチオニン、アセチルシステイン、N,N−ジアセチル−L−シスチンジメチルエステル、アシルグルタミン酸塩、アシルグリシン塩、アシルアラニン塩、アシルアルギニンエチルエステル塩などが挙げられる。ただし、N−アシル酸性アミノ酸エステルは含まない。
【0043】
一般に化粧料あるいは皮膚外用剤に使用されている成分としては、抗酸化剤、抗炎症剤、紫外線吸収剤、美白剤、細胞賦活剤、保湿剤、金属キレート剤、油性原料、界面活性剤、溶剤、高分子物質、粉体物質、色素類、香料、経皮吸収促進剤及びステロイドホルモン等を挙げることができる。
【0044】
上記亜鉛塩を含有する組成物の形態には特に制限はなく、溶液状、ペースト状、ゲル状、固体状、粉末状等任意の形態をとることができる。また、本発明の組成物は、オイル、ローション、クリーム、乳液、ゲル、シャンプー、ヘアリンス、ヘアコンディショナー、エナメル、ファンデーション、リップスティック、おしろい、パック、軟膏、錠剤、注射液、顆粒、カプセル、香水、パウダー、オーデコロン、歯磨、石鹸、エアゾル、クレンジングフォーム等の他、皮膚老化防止改善剤、皮膚炎症防止改善剤、浴用剤、養毛剤、皮膚美容液、日焼け防止剤、色素性乾皮症・日光蕁麻疹等の光線過敏症の防止改善剤、光アレルギーの防止改善剤、光免疫抑制の防止改善剤あるいは、外傷・あかぎれ・ひびわれ等による肌荒れの防止改善剤、消毒剤、抗菌剤、殺虫剤、害虫駆除剤、角質溶解剤、表皮剥離剤、ニキビの防止改善剤、角化症・乾皮症・魚鱗癬・乾癬等の各種皮膚疾患の防止改善剤等に用いることができる。
【0045】
更にその他の常用成分を、組成物に本発明の効果を阻害しない範囲で添加することができる。本発明の組成物におけるその他の常用成分としては、防腐剤、褪色防止剤、緩衝剤、にきび用薬剤、ふけ・かゆみ防止剤、制汗防臭剤、熱傷用薬剤、抗ダニ・シラミ剤、角質軟化剤、乾皮症用薬剤、抗ウイルス剤、ホルモン類、ビタミン類、アミノ酸・ペプチド類、タンパク質類、収れん剤、清涼・刺激剤、動植物由来成分、抗生物質、抗真菌剤、育毛剤等を挙げることができる。
【実施例】
【0046】
以下、本発明を実施例(合成例、試験例および配合例)により更に具体的に説明するが、本発明はこれら実施例に限定されるものではない。尚、これらの実施例において、配合量は重量%で表した。
【0047】
試験例1.亜鉛塩のコラーゲン合成促進効果
亜鉛塩のコラーゲン合成促進効果を確認するため、2種類の亜鉛塩と、同じくナトリウム塩を調製し、正常ヒト真皮繊維芽細胞からのコラーゲン合成促進効果を評価した。コンフルエント状態になった正常ヒト真皮繊維芽細胞を剥がし、D−MEM(10%FBS含有)中、96ウェルプレートに播種し、24時間、飽和水蒸気下、37℃、5%CO2にて無菌的に培養した。24時間後、培地を取り除き、各サンプルを所定の濃度(50μM。250μMアスコルビン酸Na塩及び2%FBS含有)に調製したD−MEMを添加した。48時間、飽和水蒸気下、37℃、5%CO2にて無菌的に培養した。48時間後、その培養上澄みを採取し、その液中のヒト真皮繊維芽細胞から放出されたI型プロコラーゲン量をELISAにて定量評価した。
結果を図1に示す。グラフから分かるように、2種類の亜鉛塩はともに、コントロールに比べ48時間での培地中へのコラーゲン合成量が増加した。しかし、対応するナトリウム塩では、培地中のコラーゲン合成量の増加は認められなかった。
【0048】
試験例2.PCAZn塩の血流促進効果
PCAZn塩とその他のZn塩との違いを血流促進効果(血液量増加)から確認した。各サンプルのZn塩及び、Na塩を調製し、ヒト前腕に塗布し血流促進効果を目視にて評価した。サンプルは、(1)PCAZn塩、(2)PCANa塩、(3)グルコン酸Zn塩、(4)グルコン酸Na塩、(5)硫酸Zn塩、(6)硫酸Na2塩を用いた。濃度は5wt%とし、pHは5.5〜6.5の間に調製した。上記サンプルを80μl、前腕に半閉塞パッチし、30分後パッチを除去し、目視評価を行った。さらに、30分後、50分後に目視観察を行い、表1に従い評点を付した。結果を表2に示す。結果は得られた評点の平均である。
【0049】
【表1】
【0050】
【表2】
【0051】
サンプル(1)及び(2)では一過性の血流促進効果が確認された。しかし、その他のサンプルにおいては、どの評価時間帯においても血流促進効果は認められなかった。この結果から、PCAZn塩はその他のZn塩に比べ、皮膚に塗布することで一時的な血流促進効果を誘導することが判明した。
これにより、血管内のアスコルビン酸などの有用物質を塗布部位に集めることで、PCAZn塩はその他のZn塩に比べ、よりコラーゲン産生促進効果を高めることが期待される。
【0052】
試験例3.ピロリドンカルボン酸亜鉛塩のヒト真皮繊維芽細胞コラーゲン合成促進効果
正常ヒト真皮繊維芽細胞を6ウェルプレートにDMEM(ダルベッコ改変イーグル培地、FBS10%含有)にて播種した。5%CO2、飽和水蒸気下、37℃のインキュベータで24時間培養した。24時間後、サンプル(PCA亜鉛塩など)を10μMの濃度で添加したDMEM(FBS10%含有、アスコルビン酸500μM含有)に、6ウェルプレートの培地を交換した。サンプルの交換は毎日行い、計5回サンプル交換(8日間)を行った。最後のサンプルを交換した後、24時間後、培地を吸引除去しPBSにてウェルをリンスした。得られたコラーゲンシートを酵素的に分解し可溶化させ、ELISAにてI型コラーゲン量を定量評価した。
図2に示したように、ピロリドンカルボン酸亜鉛塩を10μM添加したI型コラーゲン量はコントロール(ピロリドンカルボン酸亜鉛塩無添加)に比べ、180%の増加を示した。
【0053】
試験例4.ピロリドンカルボン酸亜鉛塩のアスコルビン酸トランスポーターmRNA発現増強効果
正常ヒト真皮繊維芽細胞をシャーレにD−MEM(ダルベッコ改変イーグル培地、FBS10%含有)にて播種した。5%CO2、飽和水蒸気下、37℃のインキュベータで1日、培養した。シャーレにサンプル(PCA亜鉛塩など)を1μM、50μMの濃度で添加し、インキュベータにて24時間培養した。培養後、培地を吸引除去し、PBSでリンスした。細胞はRN easy Mini Kit(Quiagen製)のプロトコールに従って、細胞内中のRNAの抽出を行った。得られたRNAから、定法に従いc−DNAを合成し、文献既知の方法にて(Christopher P.Corpe etc(2005)J.Biol.Chem.280、5211−5220)、アスコルビン酸トランスポーター;SVCTのRT−PCRを行った(プライマー:センスプライマー;5’−CTGAGCTCATGGCGATCTAC−3’(配列番号1)、アンチセンス;5’−CATGTCAGGTAGTGCTGTAGCCCCA−3’(配列番号2))。得られたDNAを電気泳動し、サンプルの有無によるSVCTのRNAの発現量を評価した。電気泳動のバンドの評価は、ルミノ・イメージアナライザー(LAS−3000/富士フィルム製)を用い、G3PDHにて規格化した数値にて行った。
図3に示すように、ピロリドンカルボン酸亜鉛塩を1μM、50μM添加することで、無添加のコントロールに比べ1μMで150%、50μM添加で200%のアスコルビン酸トランスポーターのRNA発現量の増加が確認された。これにより、NHDFでのアスコルビン酸トランスポーターが増加し細胞内のアスコルビン酸濃度の増加、これに伴いNHDFのコラーゲン合成量が増加したと考えられる。
【0054】
試験例5.ピロリドンカルボン酸亜鉛塩とユビキノンのヒト真皮繊維芽細胞コラーゲン合成促進効果
正常ヒト真皮繊維芽細胞を6ウェルプレートにD−MEM(ダルベッコ改変イーグル培地、FBS10%含有)にて播種した。5%CO2、飽和水蒸気下、37℃のインキュベータで24時間培養した。24時間後、サンプル(1)PCA亜鉛塩(30μM)+ユビキノン(30μM)、サンプル(2)PCA亜鉛塩(30μM)、サンプル(3)ユビキノン(30μM)を添加したDMEM(FBS10%含有、アスコルビン酸500μM含有)に、6ウェルプレートの培地を交換した。サンプルの交換は毎日行い、計5回サンプル交換(8日間)を行った。最後のサンプルを交換した後、24時間後、培地を吸引除去しPBSにてウェルをリンスした。得られたコラーゲンシートを酵素的に分解し可溶化させ、ELISAにてI型コラーゲン量を定量評価した。
図4に示したように、ピロリドンカルボン酸亜鉛塩単独ではコントロール(サンプル無添加)に比べ約300%のコラーゲンマトリックス生成促進効果を示し、ユビキノン単独では250%の促進効果を示した。さらに、ピロリドンカルボン酸亜鉛塩とユビキノンを併用投与した場合、コラーゲン合成促進は約400%まで上昇し、ピロリドンカルボン酸亜鉛塩単独の場合よりも強いコラーゲン合成促進効果が確認された。
これにより従来知られていなかったユビキノンおよびピロリドンカルボン酸亜鉛塩の組み合わせにコラーゲン合成促進効果があることが示され、さらに、ユビキノンのエネルギー産生促進効果をピロリドンカルボン酸亜鉛塩がコラーゲン合成促進につなげ、両者を併用することで、コラーゲン合成促進を相乗的に増加させることに成功した。
【0055】
試験例6.ピロリドンカルボン酸亜鉛塩配合処方による三次元培養ヒト皮膚におけるコラーゲン合成促進効果
角層、表皮層、真皮層を持ちコラーゲンマトリックスを形成している三次元培養ヒト皮膚モデルを用い、PCA亜鉛塩(0.001wt%)、ユビキノン、N,N’−ジアセチルシスチンジメチルエステル(DACDM)、アミノ酸数種類を配合したクリームA(表7および表8を参照)を角層表面に100μl塗布した。さらに、比較対象としてクリームAから上記4種類(PCA亜鉛塩、ユビキノン、DACDM、アミノ酸群)を除いたクリームBを、コントロールとしてはリン酸バッファー(PBS)を同様に、それぞれ100μl角層表面に塗布した。皮膚モデルの真皮層側には皮膚モデル用培地を張り、培地は毎日交換した。サンプルを塗布後、皮膚モデルは、5%CO2、飽和水蒸気下、37℃のインキュベータにて培養した。サンプル塗布後3日目に、上層のサンプル、下層の培地を取り除き、水でリンス後、皮膚を凍結乾燥した。凍結乾燥後、真皮層のみを水に1日浸潤させた。1日後、浸潤した真皮層を上記試験例2.で行った方法を用い、コラーゲンマトリックスを酵素的に分解可溶化し、ELISAにてI型コラーゲン量を定量評価した。
図5に示すように、ピロリドンカルボン酸亜鉛塩を含んだクリームAを塗布した三次元培養ヒト皮膚モデルは、コントロール、及びクリームBに比較し、真皮層のコラーゲンマトリックス中のI型コラーゲン量が170%程度増加した。
【0056】
合成例1.ピロリドンカルボン酸亜鉛塩の合成
DL−PCA亜鉛塩は特開平3−168240号公報記載の方法に準じ、DL−PCAと酸化亜鉛を水中100℃で2時間反応させた後、室温下5時間攪拌を続け、析出した結晶をろ別することにより合成した。L−PCA亜鉛塩は以下の方法で合成した。オートクレーブ中にて、L−グルタミン酸ナトリウム1水和物(61.1g)の水溶液を180℃で2時間加熱し、50wt%のピロリドンカルボン酸ナトリウム塩溶液を得た。50wt%のピロリドンカルボン酸ナトリウム塩溶液100.0g(0.33mol、pH7.7、光学純度84%、L/D比率=92/8)に、硝酸(純度 60wt%)2.7gを添加し、pH5.2に調整した。硫酸亜鉛7水和物47.6g(0.17mol)を水34.2gに溶解した水溶液を、ピロリドンカルボン酸ナトリウム塩溶液(pH4.1)に添加した。この溶液を30分間室温(pH3.7)で結晶を得るまで混和し、ろ過した。得られた結晶は水(21.9g)で洗浄し、32.0g(0.09mol、収率55%)のピロリドンカルボン酸亜鉛二水和物を得た。光学純度は99.8%(L/D比率99.9/0.1)であった。
【0057】
配合例1〜40
以下に、種々の製剤の配合例を次に示す。これらの製剤は常法に従い調製した。尚、配合量は重量%で表した。
【0058】
以下に、軟膏の配合例を示す。
【0059】
【表3】
【0060】
以下に、化粧水の配合例を示す。
【0061】
【表4】
【0062】
【表5】
【0063】
以下に、ローションの配合例を示す。
【0064】
【表6】
【0065】
以下に、クリームの配合例を示す。
【0066】
【表7】
【0067】
【表8】
【0068】
以下に、乳液の配合例を示す。
【0069】
【表9】
【0070】
以下に、美容液の配合例を示す。
【0071】
【表10】
【0072】
以下に、パックの配合例を示す。
【0073】
【表11】
【0074】
以下に、ファンデーションの配合例を示す。
【0075】
【表12】
【0076】
以下に、液体ハンドソープの配合例を示す。
【0077】
【表13】
【0078】
以下に、シャンプーの配合例を示す。
【0079】
【表14】
【0080】
以下に、毛髪用化粧水の配合例を示す。
【0081】
【表15】
【産業上の利用可能性】
【0082】
本発明は、化粧品の分野において効果の高いコラーゲン合成促進剤として利用可能である。従来知られていた、レチノイド、レチノール、レチノイン酸と同等以上のコラーゲン合成促進効果があり、催奇性、副作用もなく、より安全なコラーゲン合成促進剤である。
【Technical field】
[0001]
The present invention relates to a collagen synthesis promoter containing zinc as an active ingredient useful for preventing wrinkles, and a composition containing the same.
[Background]
[0002]
Many substances that prevent or improve skin wrinkles have been found, but there are no safe substances that can be completely prevented or improved, and many studies are still being conducted. Various causes of wrinkle formation have been reported, one of which is dry skin. It is a well-known fact that skin wrinkles appear as the amount of water in the stratum corneum decreases. For this reason, a moisturizing component is used to maintain a high amount of moisture in the skin stratum corneum. NMF (Natural Moi) as a moisturizing ingredient in our own skin stratum corneumsturizing factor) is well known, but the amino acid itself, which is a constituent element, has also been found to retain water in the stratum corneum. In addition, proposals have been made to promote the turnover of skin keratinocytes by using cell activation components such as placenta extract and vitamins to prevent and improve wrinkles.
[0003]
As a cause different from dryness, it is considered that a decrease in the amount of collagen in the dermis is related to wrinkles and sagging associated with aging of the skin. Collagen in the skin is a component of the extracellular matrix of the dermis and plays an important role as a connective tissue. Collagen amount is an important factor constituting the softness and tension of the skin.
[0004]
In order to increase the amount of collagen in the skin tissue, it is important to inhibit collagenase activity induced by UV irradiation, suppress collagen degradation, and promote collagen synthesis. It is known that collagen synthesis is promoted by the action of vitamins, hormones, cytokines and the like.
[0005]
Collagen proteins and collagen composition amino acid compositions are commercially available as products that promote collagen synthesis, but the effect of promoting collagen synthesis is not clear.
[0006]
Retinoids, retinol, and retinoic acid are known to promote collagen synthesis, but teratogenicity and side effects have been reported, and a safer and more effective collagen synthesis promoter is required.
[0007]
Ubiquinone is a compound isolated and discovered from intracellular mitochondria of bovine heart in 1957 and is also called coenzyme Q10, coenzyme Q10, or simply CoQ10. Ubiquinone is produced in the body and is present in many organs. One of its functions is the production of energy in intracellular mitochondria. In the mitochondria, high-energy molecules such as ATP are produced through the electron transport system and the TCA cycle using sugars and lipids. That is, ubiquinone works in the electron transport system and contributes to ATP production. The amount of ubiquinone in the heart is said to be reduced to about half of that at the age of 20 after 40 years of age. In the skin, there are still few detailed data on ubiquinone, but as with other organs, the concentration of ubiquinone is thought to decrease with age.
[0008]
Another function of ubiquinone is an antioxidant effect. Since skin is often exposed to ultraviolet rays and the like, an oxidation reaction in the skin is always caused. In order to prevent this oxidation reaction, it is considered that many ubiquinones are produced and used. In 2004, ubiquinone became available as a cosmetic product, and it has come to be used in many cosmetics. However, in addition to promoting skin turnover by promoting energy production and antioxidative effects, ubiquinone is specific to the skin. There are still many unclear points about the positive effects.
[0009]
On the other hand, regarding zinc, zinc oxide, which is a kind of inorganic zinc salt, has been reported to suppress diaper rash (for example, FEBS Letters, 384, 92-96, 1996). However, this compound is hardly soluble in water and oily components and is difficult to use as a component in cosmetics and skin external preparations.
[0010]
It is known that glycine zinc salt which is a kind of organic zinc salt has a metallothionein induction promoting action (Japanese Patent Laid-Open No. 2005-247729). This is an action of suppressing skin damage caused by UV, such as inhibition of melanin synthesis and inhibition of cytotoxicity, through pathways such as an antioxidant effect and radical scavenging ability. However, the effect of glycine zinc salt on collagen synthesis is not known.
[0011]
Similarly, pyrrolidone carboxylic acid zinc salt and acylamino acid zinc salt, which are also one of organic zinc salts, are known to suppress UV-induced inflammatory factors such as AP-1 and NF-κB (JP 2006-2006 A). No. 022090, International Publication WO2005 / 123062 Pamphlet). However, the action of pyrrolidone carboxylic acid zinc salt and acylamino acid zinc salt on collagen synthesis is not known.
[0012]
In addition, organic zinc salts and inorganic zinc salts are known to be incorporated into cosmetic compositions for astringent, anti-inflammatory, white pigment, UV protection, deodorant and bactericidal agents, but expected to be effective Use in the vicinity of the concentration range where it can be made is difficult to use as a cosmetic because of irritation to the skin. Moreover, in the utilization at low concentration, the above-mentioned effectiveness to the skin is not found, and the present condition is that the blending of zinc salts into cosmetics has not progressed.
DISCLOSURE OF THE INVENTION
[0013]
As a result of intensive studies aimed at improving wrinkles by collagen synthesis rather than moisturizing and improving wrinkles by promoting skin turnover, the present inventors have introduced zinc into human dermal fibroblasts. The present inventors have found that it has an effect of promoting the expression of ascorbic acid transporter, and accordingly, it has been found that an effect of promoting collagen synthesis can be obtained.
[0014]
Ascorbate transporters are membrane proteins that promote the uptake of ascorbate into cells (see Hiroya Tsukaguchi etc (1999) Nature 399, 70-75).,By enhancing the expression of the ascorbic acid transporter, the uptake of ascorbic acid essential for collagen synthesis in dermal fibroblasts is increased, and collagen synthesis is promoted.
[0015]
Furthermore, surprisingly, collagen synthesis is synergistically promoted remarkably by adding pyrrolidonecarboxylic acid zinc salt, which is one of zinc salts, to ubiquinone, which has not been known to promote collagen synthesis. I found out.
[0016]
An object of the present invention is to obtain a collagen synthesis accelerator having an excellent collagen synthesis action and a cosmetic composition containing the same based on the above findings.
[Means for Solving the Problems]
[0017]
That is, the present invention comprises a composition for promoting collagen synthesis characterized by containing zinc as an active ingredient, and a composition for promoting collagen synthesis characterized by comprising ubiquinone and zinc pyrrolidonecarboxylic acid as active ingredients. About.
[0018]
From the viewpoint of skin irritation, introduction efficiency into cells, etc., as a practical zinc introduction method, it is necessary to make zinc a zinc salt and apply it to the skin at a certain concentration. Includes the following inventions.
[0019]
(1) A collagen synthesis promoter containing zinc as an active ingredient.
(2) Zinc is pyrrolidone carboxylic acid zinc salt, gluconic acid zinc salt,Zinc phenol sulfonateThe collagen synthesis promoter according to (1), which is a compound selected from the group consisting of zinc lactate, various amino acid zinc salts, acylamino acid zinc salts, zinc sulfate, zinc chloride and zinc oxide.
(3) The collagen synthesis promoter according to (1), wherein the zinc is pyrrolidone carboxylic acid zinc salt.
(4) Collagen synthesis promoter containing pyrrolidone carboxylic acid zinc salt and ubiquinone as active ingredients.
(5) The collagen synthesis promoter according to (1) to (4), wherein the collagen synthesis is performed through enhanced expression of an ascorbate transporter of human fibroblasts.
(6) A composition for promoting collagen synthesis, characterized by containing zinc as an active ingredient.
(7) Zinc is pyrrolidone carboxylic acid zinc salt, gluconic acid zinc salt,Zinc phenol sulfonateThe composition for promoting collagen synthesis according to (6), which is a compound selected from the group consisting of zinc lactate, various amino acid zinc salts, acylamino acid zinc salts, zinc sulfate, zinc chloride and zinc oxide.
(8) The composition for promoting collagen synthesis according to (6), wherein the zinc is a pyrrolidone carboxylic acid zinc salt.
(9) A composition for promoting collagen synthesis, comprising zinc pyrrolidonecarboxylic acid and ubiquinone as active ingredients.
(10) The composition for promoting collagen synthesis according to (6) to (9) above, wherein zinc is blended so as to be present in the composition at a concentration of 1 μM to 100 mM.
(11) The composition for promoting collagen synthesis according to (6) to (10) above, further comprising an N-acyl acidic amino acid ester or an amino acid derivative.
(12) The composition for promoting collagen synthesis according to the above (6) to (11), which is an ointment, lotion, lotion, cream, milky lotion, serum, pack, foundation, liquid hand soap, shampoo, or hair lotion. object.
(13) A preventive or therapeutic agent for wrinkles, characterized by containing zinc as an active ingredient.
(14) Zinc is pyrrolidone carboxylic acid zinc salt, gluconic acid zinc salt,Zinc phenol sulfonateThe wrinkle preventive or therapeutic agent according to (13), which is a compound selected from the group consisting of zinc lactate, various amino acid zinc salts, acylamino acid zinc salts, zinc sulfate, zinc chloride and zinc oxide.
(15) The wrinkle preventive or therapeutic agent according to (13), wherein the zinc is a pyrrolidone carboxylic acid zinc salt.
(16) A prophylactic or therapeutic agent for wrinkles characterized by comprising pyrrolidonecarboxylic acid zinc salt and ubiquinone as active ingredients.
(17) Use of zinc for promoting collagen synthesis.
(18) pyrrolidone carboxylic acid zinc salt, gluconate zinc salt for promoting collagen synthesis,Zinc phenol sulfonateUse of a zinc salt selected from the group consisting of zinc lactate, various amino acid zinc salts, acylamino acid zinc salts, zinc sulfate, zinc chloride and zinc oxide.
(19) Use of pyrrolidone carboxylic acid zinc salt for promoting collagen synthesis.
(20) A combination of pyrrolidone carboxylic acid zinc salt and ubiquinone for promoting collagen synthesis.
(21) A method for promoting collagen synthesis, comprising applying the composition according to (6) to (12) to the skin.
(22) The collagen synthesis promoter according to (4) above, wherein ubiquinone and pyrrolidonecarboxylic acid zinc salt are contained in a weight ratio of 50: 1 to 0.1: 1.
(23) A composition for promoting collagen synthesis, comprising 0.0001 wt% to 10 wt% ubiquinone and 0.000035 wt% to 3.5 wt% pyrrolidone carboxylic acid zinc salt.
(24) A wrinkle preventive or therapeutic agent comprising 0.0001 wt% to 10 wt% ubiquinone and 0.000035 wt% to 3.5 wt% pyrrolidone carboxylic acid zinc salt.
(25) Promoting collagen synthesis characterized by applying to the skin a composition containing 0.0001 wt% to 10 wt% ubiquinone and 0.000035 wt% to 3.5 wt% pyrrolidone carboxylic acid zinc salt Method.
[Brief description of the drawings]
[0020]
FIG. 1 is a diagram confirming the collagen synthesis promoting effect of zinc salt using human dermal fibroblasts.
FIG. 2 is a diagram confirming the collagen synthesis promoting effect of pyrrolidone carboxylic acid zinc salt using human dermal fibroblasts.
FIG. 3 is a diagram confirming the ascorbic acid transporter mRNA expression enhancing effect by pyrrolidone carboxylic acid zinc salt.
FIG. 4 is a diagram confirming the collagen synthesis promoting effect by pyrrolidone carboxylic acid zinc salt and ubiquinone using human dermal fibroblasts.
FIG. 5 is a diagram in which the effect of promoting collagen synthesis in three-dimensional cultured human skin by the prescription of pyrrolidone carboxylic acid zinc salt is confirmed.
DETAILED DESCRIPTION OF THE INVENTION
BEST MODE FOR CARRYING OUT THE INVENTION
[0021]
Details of the present invention will be described below.
[0022]
Zinc used in the present invention needs to be applied to the skin at a constant concentration in the form of zinc salt as a realistic zinc salt from the viewpoint of skin irritation and cell introduction efficiency. In this case, both an organic zinc salt and an inorganic zinc salt can be used. Organic zinc salts include pyrrolidone carboxylic acid zinc salt, gluconic acid zinc salt,Zinc phenol sulfonateZinc lactate, various amino acid zinc salts, acylamino acid zinc salts, and the like. Inorganic zinc salts include zinc sulfate, zinc chloride, zinc oxide and the like.
[0023]
As amino acid zinc salt, glycine zinc salt, alanine zinc salt, valine zinc salt, leucine zinc salt, isoleucine zinc salt, phenylalanine zinc salt, methionine zinc salt, tryptophan zinc salt, asparagine zinc salt, glutamine zinc salt, serine zinc salt, Examples include various amino acid zinc salts such as threonine zinc salt, cysteine zinc salt, tyrosine zinc salt, zinc aspartate, zinc glutamate, lysine zinc, arginine zinc, or histidine zinc.
[0024]
The acylamino acid zinc salt is a zinc salt of a compound in which an acyl group is bonded to the amino group of the amino acid, and examples of the acylamino acid include compounds having the following structural formula.
[0025]
[Chemical 1]
[0026]
(In the above (I), R1 is an acyl group having 2 to 22 carbon atoms, R2 is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, R3 is an amino acid such as valine, leucine, or isoleucine. , Phenylalanine, methionine, tryptophan, asparagine, glutamine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamic acid, lysine, arginine, histidine, alanine or a hydrogen atom, n represents an integer of 0 or 1 .)
[0027]
In terms of enhancing collagen synthesis promoting effect, pyrrolidone carboxylic acid zinc salt, which has blood flow promoting effect, is expected to collect useful substances such as ascorbic acid in blood vessels at the application site. It is a zinc salt whose expression promoting effect is more remarkably reflected in the collagen synthesis promoting effect.
[0028]
The pyrrolidone carboxylic acid zinc salt (hereinafter also referred to as PCA zinc salt or PCAZn salt) is a zinc salt of 2-pyrrolidone-5-carboxylic acid, and may be various hydrates. The pyrrolidone carboxylic acid zinc salt used in the examples is a dihydrate and has the following structure.
[0029]
[Chemical 2]
[0030]
As the pyrrolidone carboxylic acid zinc salt, any of D-form, L-form and DL-form (mixture of D-form and L-form) may be used. For example, L-PCA zinc salt or DL-PCA zinc salt can be used. These can be used alone or in combination. When a DL form is used, the ratio of the D form and the L form is not particularly limited.
[0031]
The collagen synthesis promoter of the present invention is used by being blended in a composition such as a cosmetic or a skin external preparation. At this time, the blending amount is 1 μM to 100 mM (0.000035 wt% to 3.5 wt% as PCA zinc salt), preferably 1 μM to 10 mM (0.000035 wt% to 0.35 wt% as PCA zinc salt). More preferably, it is important to add a very small amount of about 1 μM to 1 mM (0.000035 wt% to 0.035 wt% as PCA zinc salt). When the blending amount is 3.5% by weight or more, there is a problem that the skin is irritated or a squeaky sensation is produced. Does not occur and is not preferable.
[0032]
When the collagen synthesis promoter of the present invention is blended in a composition such as a cosmetic or a skin external preparation, in addition to these components, a component that is generally used as a cosmetic or a skin external preparation does not inhibit the effects of the present invention. Can be added.
[0033]
The second aspect of the present invention relates to a collagen synthesis accelerator containing ubiquinone and pyrrolidone carboxylic acid zinc salt as active ingredients. As explained so far, pyrrolidone carboxylic acid zinc salt can be used alone as a collagen synthesis promoter, but when used in combination with ubiquinone, it can be used as a collagen synthesis promoter having a surprising synergistic effect. it can. Thereby, the improvement of wrinkles by collagen synthesis can be expected, not the improvement of wrinkles due to the promotion of skin turnover and the antioxidant effect.
[0034]
In the present invention, ubiquinone is a ubiquinone in which the side chain isoprene unit of 2,3-dimethoxy-5-methyl-6-polyprenyl-1,4-benzoquinone is 10, in order to appropriately express the effects of the present invention. The amount of ubiquinone is preferably 0.0001% by weight or more, more preferably 0.01% by weight or more, and still more preferably 0.03% by weight or more. Further, if the blending amount of ubiquinone is increased more than necessary, it may be crystallized or the color of the product may be yellowed, so it is preferably 10% by weight or less, more preferably 1% by weight or less, More preferably, the content is 0.1% by weight or less. In order for the pyrrolidone carboxylic acid zinc salt to express its effect appropriately, the blending ratio of ubiquinone and pyrrolidone carboxylic acid zinc salt is contained in a ratio of 50: 1 to 0.1: 1.RuIt is preferable.
[0035]
Further, as a further aspect of the present invention, a composition comprising the collagen synthesis promoter of the present invention and one or more selected from the group consisting of N-acyl acidic amino acid esters, amino acids and amino acid derivatives, at the same time. Related to things.
[0036]
The N-acyl acidic amino acid ester that can be blended in the composition of the present invention is represented by the following structure:
[0037]
[Chemical 3]
[0038]
(Wherein X and Y may be the same or different, X and Y are ester-forming residues of sterols, linear or branched liquid higher alkyl alcohols or alkenyl alcohols having 8 to 30 carbon atoms, or It is at least one selected from ester-forming residues of solid linear or branched higher alcohols having 12 to 38 carbon atoms, and COR bonded to the nitrogen atom is a linear acyl group having 8 to 22 carbon atoms. N is 1 or 2. a and b are 0 to 10, and b is 0 to 10.)
[0039]
N-acyl acidic diesters are particularly preferred, and suitable examples thereof include, for example, N-lauroyl glutamate di (cholesteryl behenyl octyldodecyl), N-lauroyl glutamate di (cholesteryl octyldodecyl), N-lauroyl glutamate di (phytosteryl 2) -Octyl dodecyl), N-lauroyl glutamate di (octyl dodecyl phytosteryl behenyl), and the like, which are available from Ajinomoto Co., Inc., respectively, "El Deu CL-301", "El Deu CL-202", "El Deu PS -203 "and" El Dew PS-304 ".
[0040]
And in this invention, this N-acyl acidic amino acid ester contributes to the improvement of moisture retention and skin conditioning, and also contributes to the improvement of stability. The blending amount is preferably 0.01% by weight or more, more preferably 0.1% by weight or more, further preferably 0.5% by weight or more, and an N-acyl acidic amino acid. If the blending amount of the ester is increased more than necessary, it may become sticky. Therefore, the amount is preferably 20% by weight or less, more preferably 10% by weight or less, and even more preferably 5% by weight or less.
[0041]
An amino acid or an amino acid derivative is included in the composition to contribute to the improvement of the moisturizing effect. Examples of the amino acid include alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glutamic acid, Glycine, histidine, oxyproline, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, etc., and any of those L, D or DL forms It may also be a salt thereof. Examples of such salts include sodium salt, potassium salt, triethanolamine salt and the like.
[0042]
Examples of amino acid derivatives include those obtained by cyclization, acylation or esterification of the above-mentioned amino acids, such as acetyl glutamic acid, acetyl methionine, acetyl cysteine, N, N-diacetyl-L-cystine dimethyl ester, acyl glutamic acid. Salts, acylglycine salts, acylalanine salts, acylarginine ethyl ester salts, and the like. However, N-acyl acidic amino acid ester is not included.
[0043]
Ingredients commonly used in cosmetics or external preparations for skin include antioxidants, anti-inflammatory agents, UV absorbers, whitening agents, cell activators, moisturizers, metal chelating agents, oily raw materials, surfactants, solvents , Polymer substances, powder substances, pigments, fragrances, transdermal absorption enhancers and steroid hormones.
[0044]
There is no restriction | limiting in particular in the form of the composition containing the said zinc salt, Arbitrary forms, such as solution form, paste form, gel form, solid form, powder form, can be taken. Further, the composition of the present invention comprises oil, lotion, cream, emulsion, gel, shampoo, hair rinse, hair conditioner, enamel, foundation, lipstick, funny, pack, ointment, tablet, injection solution, granule, capsule, perfume, Powder, eau de cologne, toothpaste, soap, aerosol, cleansing foam, etc., skin aging prevention improver, skin inflammation prevention improver, bath preparation, hair nourishing agent, skin beauty solution, sunscreen agent, xeroderma pigmentosum / Nikko urticaria Photosensitivity prevention and improvement agent, photoallergy prevention improvement agent, photoimmune suppression prevention improvement agent or skin roughening prevention and improvement agent such as trauma, scuffing and cracking, disinfectant, antibacterial agent, insecticide, pest control Agent, keratolytic agent, epidermis remover, acne prevention / amelioration agent, prevention of various skin diseases such as keratosis, psoriasis, ichthyosis and psoriasis It can be used to good agent.
[0045]
Furthermore, other commonly used components can be added to the composition as long as the effects of the present invention are not impaired. Other commonly used ingredients in the composition of the present invention include antiseptics, anti-fading agents, buffers, acne agents, anti-dandruff and itching agents, antiperspirant deodorants, burn agents, anti-ticks and lice agents, keratin softening , Agents for xeroderma, antiviral agents, hormones, vitamins, amino acids / peptides, proteins, astringents, refreshing / stimulating agents, animal and plant derived components, antibiotics, antifungal agents, hair restorers, etc. be able to.
【Example】
[0046]
EXAMPLES Hereinafter, although an Example (synthesis example, a test example, and a compounding example) demonstrates this invention further more concretely, this invention is not limited to these Examples. In these examples, the blending amount was expressed in wt%.
[0047]
Test Example 1 Collagen synthesis promoting effect of zinc salt
In order to confirm the collagen synthesis promoting effect of the zinc salt, two types of zinc salt and the same sodium salt were prepared, and the collagen synthesis promoting effect from normal human dermal fibroblasts was evaluated. Normal human dermal fibroblasts in a confluent state are peeled off, seeded in a 96-well plate in D-MEM (containing 10% FBS), and subjected to saturated water vapor at 37 ° C., 5% CO for 24 hours.2And aseptically cultured. After 24 hours, the medium was removed, and each sample was added with D-MEM prepared to a predetermined concentration (50 μM, containing 250 μM sodium ascorbate and 2% FBS). 48 hours under saturated steam at 37 ° C, 5% CO2And aseptically cultured. After 48 hours, the culture supernatant was collected, and the amount of type I procollagen released from human dermal fibroblasts in the liquid was quantitatively evaluated by ELISA.
The results are shown in FIG. As can be seen from the graph, both types of zinc salts increased the amount of collagen synthesized in the medium in 48 hours compared to the control. However, the corresponding sodium salt did not increase the amount of collagen synthesis in the medium.
[0048]
Test Example 2 Effect of PCAZn salt on blood flow
The difference between PCAZn salt and other Zn salt was confirmed from the blood flow promoting effect (blood volume increase). The Zn salt and Na salt of each sample were prepared and applied to a human forearm to visually evaluate the blood flow promoting effect. sample,(1)PCAZn salt,(2)PCANA salt,(3)Zn gluconate,(4)Gluconic acid Na salt,(5)Zn sulfate,(6)Na sulfate2Salt was used. The concentration was 5 wt%, and the pH was adjusted between 5.5 and 6.5. 80 μl of the sample was semi-occluded patched on the forearm, 30 minutes later, the patch was removed, and visual evaluation was performed. Further, visual observation was performed after 30 minutes and after 50 minutes, and a score was assigned according to Table 1. The results are shown in Table 2. The result is the average of the scores obtained.
[0049]
[Table 1]
[0050]
[Table 2]
[0051]
sample(1)as well as(2)Then, a transient blood flow promoting effect was confirmed. However, in the other samples, the blood flow promoting effect was not observed in any evaluation time zone. From this result, it was found that the PCAZn salt induces a temporary blood flow promoting effect when applied to the skin as compared with other Zn salts.
As a result, by collecting useful substances such as ascorbic acid in blood vessels at the application site, the PCAZn salt is expected to enhance the collagen production promoting effect more than other Zn salts.
[0052]
Test Example 3 Effect of zinc pyrrolidonecarboxylate on the synthesis of human dermal fibroblast collagen
Normal human dermal fibroblasts were seeded in 6-well plates with DMEM (Dulbecco's modified Eagle medium, containing 10% FBS). 5% CO2The cells were cultured in a 37 ° C. incubator under saturated steam for 24 hours. After 24 hours, the medium of the 6-well plate was replaced with DMEM (containing 10% FBS and containing 500 μM ascorbic acid) to which a sample (PCA zinc salt or the like) was added at a concentration of 10 μM. Samples were exchanged every day, for a total of 5 sample exchanges (8 days). After changing the last sample, 24 hours later, the medium was removed by suction and the wells were rinsed with PBS. The obtained collagen sheet was enzymatically decomposed and solubilized, and the amount of type I collagen was quantitatively evaluated by ELISA.
As shown in FIG. 2, the amount of type I collagen to which 10 μM of pyrrolidone carboxylic acid zinc salt was added showed an increase of 180% compared to the control (no addition of pyrrolidone carboxylic acid zinc salt).
[0053]
Test Example 4 Ascorbic acid transporter mRNA expression enhancing effect of pyrrolidone carboxylic acid zinc salt
Normal human dermal fibroblasts were seeded in a petri dish with D-MEM (Dulbecco's modified Eagle medium, containing 10% FBS). 5% CO2Then, the cells were cultured in a 37 ° C. incubator under saturated steam for 1 day. A sample (PCA zinc salt or the like) was added to the petri dish at a concentration of 1 μM or 50 μM and cultured in an incubator for 24 hours. After culturing, the medium was removed by suction and rinsed with PBS. The cells were extracted with RNA in the cells according to the protocol of RN easy Mini Kit (manufactured by Qiagen). From the obtained RNA, c-DNA was synthesized according to a conventional method, and a method known in the literature (Christopher P. Corp et c (2005) J. Biol. Chem. 280, 5211-5220), ascorbic acid transporter; SVCT RT-PCR was performed (primer: sense primer; 5'-CTGAGCTCATGGCGATTAC-3 '(SEQ ID NO: 1), antisense; 5'-CATGTCAGGTAGTGCTGTTAGCCCCA-3' (SEQ ID NO: 2)). The obtained DNA was electrophoresed to evaluate the expression level of SVCT RNA depending on the presence or absence of the sample. The evaluation of the band of electrophoresis was performed using a numerical value standardized by G3PDH using a lumino image analyzer (LAS-3000 / manufactured by Fuji Film).
As shown in FIG. 3, the addition of 1 μM and 50 μM pyrrolidone carboxylic acid zinc salt confirms an increase in RNA expression level of ascorbic acid transporter by 150% at 1 μM and 200% by addition of 50 μM compared to the control without addition. It was done. As a result, the ascorbic acid transporter in NHDF was increased, the intracellular ascorbic acid concentration was increased, and the collagen synthesis amount of NHDF was increased accordingly.
[0054]
Test Example 5. Effects of zinc pyrrolidonecarboxylate and ubiquinone on human dermal fibroblast collagen synthesis
Normal human dermal fibroblasts were seeded in 6-well plates with D-MEM (Dulbecco's modified Eagle medium, containing 10% FBS). 5% CO2The cells were cultured in a 37 ° C. incubator under saturated steam for 24 hours. 24 hours later, DMEM (containing 10% FBS, ascorbic acid) to which sample (1) PCA zinc salt (30 μM) + ubiquinone (30 μM), sample (2) PCA zinc salt (30 μM), sample (3) ubiquinone (30 μM) was added 6-well plate medium was changed to 500 μM). Samples were exchanged every day, for a total of 5 sample exchanges (8 days). After changing the last sample, 24 hours later, the medium was removed by suction and the wells were rinsed with PBS. The obtained collagen sheet was enzymatically decomposed and solubilized, and the amount of type I collagen was quantitatively evaluated by ELISA.
As shown in FIG. 4, the pyrrolidone carboxylic acid zinc salt alone showed about 300% collagen matrix formation promoting effect compared to the control (no sample added), and ubiquinone alone showed 250% promoting effect. Furthermore, when the pyrrolidone carboxylic acid zinc salt and ubiquinone were administered in combination, the collagen synthesis promotion increased to about 400%, confirming a stronger collagen synthesis accelerating effect than that of the pyrrolidone carboxylic acid zinc salt alone.
This shows that the combination of ubiquinone and pyrrolidone carboxylic acid zinc salt, which has not been known so far, has an effect of promoting collagen synthesis, and further, pyrrolidone carboxylic acid zinc salt leads to the promotion of collagen synthesis by promoting the energy production promoting effect of ubiquinone, By using both together, we succeeded in synergistically increasing collagen synthesis promotion.
[0055]
Test Example 6. Collagen synthesis promotion effect in three-dimensional cultured human skin by formulation containing pyrrolidone carboxylic acid zinc salt
PCA zinc salt (0.001 wt%), ubiquinone, N, N'-diacetylcystine dimethyl ester (DACDM) using a three-dimensional cultured human skin model that has a stratum corneum, epidermis layer and dermis layer to form a
As shown in FIG. 5, the three-dimensional cultured human skin model coated with cream A containing pyrrolidone carboxylic acid zinc salt has 170 type I collagen in the collagen matrix of the dermis layer compared to control and cream B. Increased by about%.
[0056]
Synthesis Example 1 Synthesis of pyrrolidone carboxylic acid zinc salt
DL-PCA zinc salt was prepared by reacting DL-PCA and zinc oxide in water at 100 ° C. for 2 hours in accordance with the method described in JP-A-3-168240, followed by stirring at room temperature for 5 hours. It was synthesized by separating. L-PCA zinc salt was synthesized by the following method. In an autoclave, an aqueous solution of sodium L-glutamate monohydrate (61.1 g) was heated at 180 ° C. for 2 hours to obtain a 50 wt% pyrrolidonecarboxylic acid sodium salt solution. To 100.0 g (0.33 mol, pH 7.7, optical purity 84%, L / D ratio = 92/8) of 50 wt% pyrrolidone carboxylic acid sodium salt solution, 2.7 g of nitric acid (
[0057]
Formulation Examples 1-40
Below, the compounding example of various preparations is shown below. These preparations were prepared according to a conventional method. In addition, the compounding quantity was represented by weight%.
[0058]
Below, the compounding example of an ointment is shown.
[0059]
[Table 3]
[0060]
Below, the example of a lotion is shown.
[0061]
[Table 4]
[0062]
[Table 5]
[0063]
Below, the formulation example of a lotion is shown.
[0064]
[Table 6]
[0065]
Below, the compounding example of a cream is shown.
[0066]
[Table 7]
[0067]
[Table 8]
[0068]
Below, the compounding example of an emulsion is shown.
[0069]
[Table 9]
[0070]
Below, the formulation example of a cosmetic liquid is shown.
[0071]
[Table 10]
[0072]
Below, the formulation example of a pack is shown.
[0073]
[Table 11]
[0074]
Below, the compounding example of a foundation is shown.
[0075]
[Table 12]
[0076]
Below, the formulation example of a liquid hand soap is shown.
[0077]
[Table 13]
[0078]
Below, the example of a shampoo is shown.
[0079]
[Table 14]
[0080]
Below, the formulation example of the skin lotion for hair is shown.
[0081]
[Table 15]
[Industrial applicability]
[0082]
INDUSTRIAL APPLICABILITY The present invention can be used as a collagen synthesis promoter that is highly effective in the cosmetic field. It has a collagen synthesis promoting effect equivalent to or better than that of conventionally known retinoids, retinol and retinoic acid, and is a safer collagen synthesis promoter without teratogenicity and side effects.
Claims (8)
Priority Applications (1)
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JP2008522615A JP5423002B2 (en) | 2006-06-23 | 2007-06-21 | Collagen synthesis promoter containing zinc as an active ingredient |
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US86650306P | 2006-11-20 | 2006-11-20 | |
US86649906P | 2006-11-20 | 2006-11-20 | |
US60/866,503 | 2006-11-20 | ||
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JP2006329172 | 2006-12-06 | ||
JP2006329172 | 2006-12-06 | ||
US87184506P | 2006-12-26 | 2006-12-26 | |
US60/871,845 | 2006-12-26 | ||
JP2008522615A JP5423002B2 (en) | 2006-06-23 | 2007-06-21 | Collagen synthesis promoter containing zinc as an active ingredient |
PCT/JP2007/062958 WO2007148831A1 (en) | 2006-06-23 | 2007-06-21 | Collagen synthesis promoter containing zinc as the active ingredient |
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US9782336B2 (en) | 2014-09-10 | 2017-10-10 | Ajinomoto Co., Inc. | Moisturizer and cosmetic containing same |
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- 2007-06-21 JP JP2008522638A patent/JP5552741B2/en active Active
- 2007-06-21 TW TW96122284A patent/TW200808365A/en unknown
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JPS58180410A (en) * | 1982-04-16 | 1983-10-21 | Shiseido Co Ltd | Cosmetic |
JPH06211641A (en) * | 1992-10-26 | 1994-08-02 | Jouvance Daniel | Cosmetic product having stable oxidation-reduction potential |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9782336B2 (en) | 2014-09-10 | 2017-10-10 | Ajinomoto Co., Inc. | Moisturizer and cosmetic containing same |
Also Published As
Publication number | Publication date |
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JPWO2007148831A1 (en) | 2009-11-19 |
TW200808365A (en) | 2008-02-16 |
JPWO2007148832A1 (en) | 2009-11-19 |
JP5552741B2 (en) | 2014-07-16 |
TW200808717A (en) | 2008-02-16 |
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