JP2004331566A - Skin collagen production enhancer - Google Patents
Skin collagen production enhancer Download PDFInfo
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- JP2004331566A JP2004331566A JP2003129510A JP2003129510A JP2004331566A JP 2004331566 A JP2004331566 A JP 2004331566A JP 2003129510 A JP2003129510 A JP 2003129510A JP 2003129510 A JP2003129510 A JP 2003129510A JP 2004331566 A JP2004331566 A JP 2004331566A
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- angiogenin
- collagen production
- skin
- skin collagen
- promoting
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、皮膚の荒れ、シワ、弾性低下等を防止するのに有用な皮膚コラーゲン産生促進剤、皮膚コラーゲン産生促進用飲食品及び皮膚コラーゲン産生促進用化粧料に関する。さらに詳しくは、本発明は、 アンジオジェニン及び／またはアンジオジェニンをタンパク質分解酵素で分解して得られるアンジオジェニン分解物を有効成分とする皮膚コラーゲン産生促進剤に関する。
【０００２】
【従来の技術】
近年、皮膚のメカニズムに関する研究が進められ、皮膚の乾燥感や肌荒れの原因としてマクロ的には、加齢による新陳代謝の減衰によるもののほかに、太陽光（紫外線）、乾燥、酸化等の作用が複雑に関与していることが確認されてきた。これらの因子による作用によって、真皮の最も主要なマトリックス成分であるコラーゲン繊維が顕著に減少していることが明らかとなってきた。コラーゲン繊維によって保たれていた皮膚のハリや弾力性といった張力保持機構が紫外線等の作用によって、破壊されると、皮膚はシワやたるみを増した状態になる。また、コラーゲンはその分子中に水分を保持することができ、それにより、皮膚をしっとりとした状態に保つことにも役立っているから、外的因子により、コラーゲンが破壊されると肌は、乾燥し、荒れた状態になる。
以上のことから、真皮層の主要な成分の一つであるコラーゲンの生合成を促進させることにより、皮膚のシワやたるみを防止でき、しかも安全性の点でも問題のない皮膚コラーゲン産生促進剤が望まれていた。
【０００３】
アンジオジェニンは血管形成因子の一つである。ヒトのアンジオジェニンは分子量１４，４００のタンパク質であることが知られており、全アミノ酸配列も決定されている。アンジオジェニンは血液や乳中にも存在しており、ボンドらはウシアンジオジェニンを牛の血液から分離し（非特許文献１参照。）、またスピックらは牛乳中のアンジオジェニンを単離し、このアミノ酸配列を決定している（非特許文献２参照。）。アンジオジェニンの牛乳からの製造については、牛乳を陽イオン交換クロマトグラフィーに吸着後、弱有機酸のアルカリ金属塩水溶液で溶出し、この溶出液を再度陽イオン交換クロマトグラフィーとゲル濾過クロマトグラフィーにより回収する方法が開示されている（特許文献１参照。）。
アンジオジェニンの生理的活性で最も重要なものは上記した血管形成活性である。この作用により、アンジオジェニンは外傷、潰瘍、臓器移植、循環機能不全等の疾患への使用が示唆されている。このような作用以外はあまり知られていないが、アンジオジェニンを養毛、育毛剤に使用する例が開示されている（特許文献２参照。）。また、アンジオジェニンがメラノーマ細胞であるＢ−１６細胞のメラニン産生を特異的に抑制することを見出したことから、アンジオジェニンを有効成分とする美白剤が開示されている（特許文献３参照。）。しかし、アンジオジェニン及びその分解物が皮膚コラーゲン産生促進作用を持ち、皮膚コラーゲン産生促進剤として有用であることについては知られていない。
【０００４】
【先行技術文献】
【特許文献１】
特開平２−２９６０００号公報
【特許文献２】
特開平４−２１０６１８号公報
【特許文献３】
特許第２５７２９３１号公報
【非特許文献１】
ボンドら（Ｂｏｎｄ ｅｔ ａｌ．）「バイオケミストリー（Ｂｉｏｃｈｅｍｉｓｔｒｙ）」、１９８８年、２７巻、６２８２−６２８７ページ
【非特許文献２】
ジー・スピックら（Ｇ．Ｓｐｉｋ ｅｔ ａｌ．）「バイオケミストリー（Ｂｉｏｃｈｅｍｉｓｔｒｙ）」、１９８９年、２８巻、６１１０−６１１３ページ
【０００５】
【発明が解決しようとする課題】
本発明は、皮膚の乾燥感や肌荒れ、しわやタルミを防止でき、しかも安全性の点でも問題のない、皮膚コラーゲンの生合成を促進する物質を有効成分とする皮膚コラーゲン産生促進剤を提供することを課題とする。また、本発明は、そのような物質を配合した皮膚コラーゲン産生促進用飲食品及び皮膚コラーゲン産生促進用化粧料を提供することを課題とする。
【０００６】
【課題を解決するための手段】
本発明者らは、これらの課題を解決するために、広く食品素材に含まれている皮膚コラーゲン産生促進作用を示す物質について、鋭意、探索を進めていたところ、アンジオジェニンあるいはそのアンジオジェニンをペプシンやパンクレアチン等のタンパク質分解酵素で分解して得られるアンジオジェニン分解物が、皮膚のコラーゲン量を増加させることができる、すなわち、コラーゲン産生促進作用があることを見出した。そして、このアンジオジェニンやアンジオジェニン分解物を皮膚コラーゲン産生促進剤、皮膚コラーゲン産生促進用飲食品及び皮膚コラーゲン産生促進用化粧料の有効成分として利用できることを見出し、本発明を完成するに至った。
【０００７】
したがって、本発明は、この皮膚コラーゲン産生促進活性を有するアンジオジェニンあるいはアンジオジェニンをタンパク質分解酵素で分解して得られるアンジオジェニン分解物を有効成分とする皮膚コラーゲン産生促進剤に関する。また、本発明は、これらのアンジオジェニン及び／またはアンジオジェニン分解物を配合した皮膚コラーゲン産生促進用飲食品や皮膚コラーゲン産生促進用化粧料に関する。
【０００８】
本発明で皮膚コラーゲン産生促進剤とは、経口投与あるいは塗布等により、皮膚コラーゲン産生促進効果を発揮するものを言うものとする。また、本発明では、この皮膚コラーゲン産生促進剤のうち、粉末剤、顆粒剤、錠剤、カプセル剤、ドリンク剤等に製剤化してそのまま、あるいは製剤化した後、栄養剤や飲食品等に配合して経口投与するものを皮膚コラーゲン産生促進用飲食品と言うものとする。また、本発明では、皮膚コラーゲン産生促進剤のうち、軟膏、ゲル、クリーム、スプレー剤、貼付剤、ローション等に製剤化して肌に塗布するものを皮膚コラーゲン産生促進用化粧料と言うものとする。また、本発明では、医薬品であるが、製剤化してそのまま経口投与するものを便宜上、前記皮膚コラーゲン産生促進用飲食品の中に含め、医薬品であるが、製剤化して肌に塗布するものを便宜上、前記皮膚コラーゲン産生促進用化粧料の中に含めるものとする。
【０００９】
【発明の実施の形態】
本発明の皮膚コラーゲン産生促進剤の特徴は、アンジオジェニン及び／またはアンジオジェニンをタンパク質分解酵素で分解して得られるアンジオジェニン分解物を有効成分とすることにある。
【００１０】
本発明の原料のアンジオジェニンはどのような由来のものであっても使用可能である。たとえば、ヒト及びウシ由来のアンジオジェニンはすでにその遺伝子配列が明らかになっており、遺伝子組換えによる生産が可能であるが、本発明では、遺伝子工学的手法により生産されたアンジオジェニンも使用し得る。また、アンジオジェニンはウシ初乳中に比較的大量に含有されており、乳から回収したものであっても良い。さらにアンジオジェニンは細胞培養の培養液から回収することも可能であり、このような細胞由来のものであっても使用可能である。
【００１１】
本発明においては、哺乳動物の乳より調製したアンジオジェニンを使用し、皮膚コラーゲン産生促進剤を調製する方法を実施例に開示するが、乳由来のアンジオジェニンに限定されるものではない。給源とする乳としては、ウシ、水牛、ヒト、ブタ、ヒツジ、ヤギ、ウマ等の分娩後１〜７日以内、特に好ましくは分娩後１〜５日以内の初乳がアンジオジェニン含量が高いため適しているが、通常の泌乳期の乳であっても本発明の原料として使用可能である。それを製造するには、公知の方法、例えば上記［特許文献１］であげた陽イオン交換クロマトグラフィーとゲル濾過クロマトグラフィーを組み合わせてアンジオジェニンを精製する方法等を工業的に有利に利用することができる。
【００１２】
アンジオジェニン分解物は、上記のアンジオジェニンをトリプシン、パンクレアチン、キモトリプシン、ペプシン、パパイン、カリクレイン、カテプシン、サーモライシン、Ｖ８プロテアーゼ等のタンパク質分解酵素で分子量が１０，０００以下となるように限定分解したペプチド混合物である。分子量の下限は５００以上が好ましい。
【００１３】
本発明の皮膚コラーゲン産生促進剤は、経口投与あるいは塗布することにより、皮膚コラーゲン産生促進効果を発揮する。
本発明の皮膚コラーゲン産生促進剤を経口投与するに際しては、有効成分であるアンジオジェニンあるいはアンジオジェニン分解物をそのままの状態で用いることもできるが、常法に従い、粉末剤、顆粒剤、錠剤、カプセル剤、ドリンク剤等に製剤化して用いることもできる。本発明において、粉末剤、顆粒剤、錠剤、カプセル剤等の経口剤は、例えば、澱粉、乳糖、白糖、マンニット、カルボキシメチルセルロース、コーンスターチ、無機塩類等の賦形剤を用いて常法によって製剤化される。この種の製剤には、前記賦形剤の他に、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、着色料、香料等を適宜使用することが出来る。より具体的には、結合剤としては、例えば、澱粉、デキストリン、アラビアガム末、ゼラチン、ヒドロキシプロピルスターチ、カルボキシメチルセルロースナトリウム、メチルセルロース、結晶性セルロース、エチルセルロース、ポリビニルピロリドンが挙げられる。また、崩壊剤としては、例えば、澱粉、ヒドロキシプロピルスターチ、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、架橋カルボキシメチルセルロースナトリウム、結晶性セルロース等が挙げられる。界面活性剤としては、大豆レシチン、蔗糖脂肪酸エステル等が、滑沢剤としては、タルク、ロウ、蔗糖脂肪酸エステル、水素添加植物油等が、流動性促進剤としては無水ケイ酸、乾燥水酸化アルミニウム、ケイ酸マグネシウム等が挙げられる。
【００１４】
さらには、これらのアンジオジェニンやアンジオジェニン分解物をそのままあるいは製剤化した後、これを栄養剤や飲食品等に配合することも可能である。また、ビタミンＣ等の従来からコラーゲン産生に有効な作用を持つと考えられている成分とともにアンジオジェニンやアンジオジェニン分解物を配合すれば、一層の皮膚コラーゲン産生促進作用が期待できる。なお、アンジオジェニンあるいはアンジオジェニン分解物は、比較的熱に対して安定であるので、アンジオジェニンあるいはアンジオジェニン分解物を含む原料を通常行われるような条件で加熱殺菌することも可能である。
【００１５】
本発明の皮膚コラーゲン産生促進剤を塗布するに際しては、その使用目的に応じて、通常用いられる公知の成分に配合することによって、液剤、固形剤、半固形剤等の各種剤形に調製することが可能で、好ましい組成物として軟膏、ゲル、クリーム、スプレー剤、貼付剤、ローション、粉末等が挙げられる。例えば、本発明の皮膚コラーゲン産生促進剤をワセリン等の炭化水素、ステアリルアルコール、ミリスチン酸イソプロピル等の高級脂肪酸低級アルキルエステル、ラノリン等の動物性油脂、グリセリン等の多価アルコール、グリセリン脂肪酸エステル、モノステアリン酸、ポリエチレングリコール等の界面活性剤、無機塩、ロウ、樹脂、水及び、要すればパラオキシ安息香酸メチル、パラオキシ安息香酸ブチル等の保存料に混合することによって、皮膚コラーゲン産生促進用化粧料や医薬品を製造することができる。
【００１６】
本発明の皮膚コラーゲン産生促進剤の経口投与による有効量は、その製剤形態、投与方法、使用目的、及びこれを適用される患者の年齢、体重、病状により適宜規定され一定でないが、ラットを用いた動物実験の結果によると、皮膚コラーゲン産生促進作用を示すためには、アンジオジェニン及び／またはアンジオジェニン分解物をラット体重１ｋｇ当たり２０ｍｇ以上摂取する必要があることが判った。したがって、外挿法によると、通常、成人一人当たり一日２０ｍｇ以上のアンジオジェニン及び／またはアンジオジェニン分解物を摂取すれば効果が期待できるので、この必要量を確保できるよう飲食品に配合するか、あるいは、医薬として投与すれば良い。なお、投与は必要に応じて一日数回に分けて行うことも可能である。
【００１７】
本発明の皮膚コラーゲン産生促進剤の塗布による有効量は、剤形により異なるが、適用する組成物全量を基準として、好ましくは、０．００１〜２重量％となるように、アンジオジェニン及び／またはアンジオジェニン分解物を配合すれば良い。ただし、入浴剤のように使用時に希釈されるものは、さらに配合量を増やすことができる。
【００１８】
次に、実施例及び試験例を示して本発明を詳細に説明するが、これらは単に本発明の実施態様を例示するのみであり、本発明はこれらによって何ら限定されるものではない。
【００１９】
【実施例１】
陽イオン交換樹脂であるスルホン化キトパール（富士紡績社製）４００ｇを充填したカラム（直径５ｃｍ×高さ３０ｃｍ）を脱イオン水で十分に洗浄した後、このカラムに未殺菌脱脂乳４０ ｌ （ｐＨ ６．７）を流速２５ｍｌ／ｍｉｎで通液した。通液後、カラムを脱イオン水で十分洗浄し、２．０Ｍ塩化ナトリウムを含む ０．０２Ｍ炭酸緩衝液（ｐＨ ７．０）で溶出した。そしてアンジオジェニンを含有する溶出画分をＳ−Ｓｅｐｈａｒｏｓｅ ＦＦカラム（アマシャムバイオサイエンス社製）に吸着させ、脱イオン水で十分洗浄し、１０ｍＭリン酸緩衝液（ｐＨ７．０）で平衡化した後、０〜２．０Ｍ塩化ナトリウムのリニアグラジエントで吸着した画分を溶出し、アンジオジェニンを含む画分を回収した。そしてその画分をＨｉＬｏａｄ １６／６０ Ｓｕｐｅｒｄｅｘ ７５ ｐｇ（アマシャムバイオサイエンス社製）を用いたゲル濾過クロマトグラフィーで処理し、アンジオジェニンを多く含む画分１．８ｇを得た。なお、このようにして得られたアンジオジェニンを多く含む画分中のアンジオジェニン含量は１０％であり、そのまま皮膚コラーゲン産生促進剤として使用可能である。
【００２０】
【実施例２】
陽イオン交換樹脂であるスルホン化キトパール （富士紡績社製） ３，０００ｇを充填したカラムを脱イオン水で十分に洗浄した後、このカラムに未殺菌脱脂乳１００ ｌ （ｐＨ ６．７）を通液した。次に、このカラムを脱イオン水で十分洗浄した後、０．１〜２．０Ｍ塩化ナトリウムの直線濃度勾配で溶出した。そして、アンジオジェニンを含有する溶出画分を Ｓ−Ｓｅｐｈａｒｏｓｅ陽イオン交換クロマトグラフィー（アマシャムバイオサイエンス社製）で分画し、得られたアンジオジェニン含有画分を９０℃で１０分間加熱処理し、遠心分離することにより沈澱を除去した。さらに、このアンジオジェニン含有画分をＭｏｎｏ Ｓ陽イオン交換クロマトグラフィー、Ｓｕｐｅｒｏｓｅ１２ゲル濾過クロマトグラフィー、ヒドロキシアパタイトクロマトグラフィー及びＣ４逆相クロマトグラフィーで順次処理し、アンジオジェニン５５ｍｇを得た。なお、このようにして得られたアンジオジェニンの純度は９９％であり、そのまま皮膚コラーゲン産生促進剤として使用可能である。
【００２１】
【実施例３】
実施例２で得られたアンジオジェニン５ｍｇを水１０ｍｌに溶解し、最終濃度０．０１重量％となるようパンクレアチン（シグマ社製）を１％加え、３７℃で５時間酵素処理した。そして、９０℃で５分間加熱処理して酵素を失活させた後、凍結乾燥してアンジオジェニン分解物 ４．０ｍｇを得た。このようにして得られたアンジオジェニン分解物の分子量は１０，０００以下であり、そのまま皮膚コラーゲン産生促進剤として使用可能である。
【００２２】
【実施例４】
実施例２で得られたアンジオジェニン５ｍｇを水１０ｍｌに溶解し、最終濃度０．０１重量％となるようトリプシン（シグマ社製）を加え、３７℃で５時間酵素処理した。そして、９０℃で５分間加熱処理して酵素を失活させた後、凍結乾燥してアンジオジェニン分解物 ４．２ｍｇを得た。このようにして得られたアンジオジェニン分解物の分子量は１０，０００以下であり、そのまま皮膚コラーゲン産生促進剤として使用可能である。
【００２３】
【試験例１】
実施例２で得られたアンジオジェニン及び実施例３で得られたアンジオジェニン分解物について、ラットを用いた動物実験によりコラーゲン産生促進作用を調べた。７週齢のＷｉｓｔａｒ系雄ラットを、生理食塩水投与群（Ａ群）、実施例２で得られたアンジオジェニンをラット体重１ｋｇ当たり２０ｍｇ投与する群（Ｂ群）、実施例２で得られたアンジオジェニンをラット体重１ｋｇ当たり２００ｍｇ投与する群（Ｃ群）、実施例３で得られたアンジオジェニン分解物をラット体重１ｋｇ当たり２０ｍｇ投与する群（Ｄ群）、実施例３で得られたアンジオジェニン分解物をラット体重１ｋｇ当たり２００ｍｇ投与する群（Ｅ群）の５試験群（ｎ＝６）に分け、それぞれを毎日１回ゾンデで投与して１０週間飼育した。
皮膚のコラーゲン量については、ラットの真皮をＮｉｍｎｉらの方法（Ａｒｃｈ． Ｂｉｏｃｈｅｍ． Ｂｉｏｐｈｙｓ．， ２９２頁， １９６７年 参照）に準じて処理した後、可溶性画分に含まれるヒドロキシプロリン量を測定した。ヒドロキシプロリンはコラーゲンのみに含まれる特殊なアミノ酸で、コラーゲンを構成する全アミノ酸の約１０％を占めることからコラーゲン量の推定ができる（浅野隆司ら，Ｂｉｏ Ｉｎｄｕｓｔｏｒｙ，１２頁， ２００１年 参照）。その結果を表１に示す。
【００２４】
【表１】
また、※は対照群であるＡ群と比較して有意差があることを示す（ｐ＜０．０５）。
【００２５】
これによると、１０週間後の可溶性画分中、ヒドロキシプロリン量は、Ａ群に比べ、Ｂ群、Ｃ群、Ｄ群及びＥ群で有意に高い値を示した。
このことから、アンジオジェニン及びアンジオジェニン分解物には皮膚コラーゲン産生促進作用があることが明らかとなり、皮膚コラーゲン産生促進剤として有用であることが示された。
また、この皮膚コラーゲン産生促進作用はアンジオジェニンまたはアンジオジェニン分解物をラット体重１ｋｇ当たり最低２０ｍｇ投与した場合に認められることが明らかとなった。
【００２６】
【実施例５】
表２に示す配合の皮膚コラーゲン産生促進用飲料を常法により製造した。製造した飲料の風味は良好で、常温１年間保存によっても風味が劣化することはなく、沈殿等の問題もなかった。
【００２７】
【表２】
【実施例６】
表３に示す配合のドウを常法により作製し、成形した後、焙焼して皮膚コラーゲン産生促進用ビスケットを製造した。
【００２９】
【表３】
【実施例７】
表４に示す配合の皮膚コラーゲン産生促進剤を常法により製造した。
【００３１】
【表４】
【試験例２】
実施例２で得られたアンジオジェニン及び実施例３で得られたアンジオジェニン分解物について、正常ヒト線維芽細胞株〔白人女性の皮膚より採取されたＣＣＤ４５ＳＫ（ＡＴＣＣＲＬ １５０６）〕を用いた実験により皮膚コラーゲン産生促進作用を調べた。１０容量％ウシ胎児血清（以下ＦＢＳと略記）含有変法イーグル培地（ＭＥＭ、１０‐１０１、大日本製薬社製）を用いて、正常ヒト線維芽細胞株を４×１０４個／ウエル／０．４ｍｌとなるように２４ウエルプレートに播種して、５％炭酸ガス、飽和水蒸気下、３７℃で２４時間培養した後、０．６容量％ＦＢＳ含有ＭＥＭ培地に置換した。そして、実施例２で得られたアンジオジェニン及び実施例３で得られたアンジオジェニン分解物を、各ウエルに０．１容量％となるように添加（ｎ＝６）して、２４時間培養した後、β−アミノプロピオニトリルを５０μｇ／ｍｌ、トリチウム−Ｌ−プロリンを１μＣｉ／ｍｌとなるように添加して、さらに２４時間培養して培養液を得た。このようにして得られた培養液より、Ｗｅｂｓｔｅｒらの方法（Ａｎａｌｙｔｉｃａｌ Ｂｉｏｃｈｅｍｉｓｔｒｙ，２２０頁，１９７９年 参照）に従いコラーゲン画分を分画し、コラーゲン画分に取り込まれた放射能を測定した。なお、対照として、アンジオジェニン及びアンジオジェニン分解物を添加しないで同様の試験を行った。その結果を表５に示す。
【００３３】
【表５】
また、※は対照群と比較して有意差があることを示す（ｐ＜０．０５）。
【００３４】
これによると、アンジオジェニン及びアンジオジェニン分解物を添加した群は、アンジオジェニン及びアンジオジェニン分解物を添加していない群（対照）に比べていずれも２倍以上のコラーゲン産生促進能を示した。
このことから、アンジオジェニン及びアンジオジェニン分解物には、皮膚線維芽細胞に働きかけ、コラーゲン産生を促進する作用があることが明らかとなり、皮膚コラーゲン産生促進剤として有用であることが示された。
【００３５】
【実施例８】
表６に示す配合の化粧水を常法により製造した。
【００３６】
【表６】
【実施例９】
表７に示す配合のクリームを常法により製造した。
【００３８】
【表７】
【試験例３】
実施例８で得られた化粧水及び実施例９で得られたクリームを用いて、実使用テストを行った。比較品としては、アンジオジェニンを除いた以外は実施例８及び９と同じ配合のものを用いた。
顔面のたるみや小ジワが認められる乾燥肌を有する成人女子２０人を、それぞれ１０人ずつ無作為に２群（Ａ、Ｂ群）に、また、手に肌荒れが認められる女子２０人を、それぞれ１０人ずつ無作為に２群（Ｃ、Ｄ群）に分け、Ａ群の顔面には本発明品の化粧水を、Ｂ群の顔面には比較品の化粧水を、Ｃ群の手指には本発明品のクリームを、Ｄ群の手指には比較品のクリームを、それぞれ１日２回通常の使用状態と同様に１０日間塗布してもらった。その結果、本発明品の化粧水は、比較品の化粧水に比べて、乾燥感の改善、肌荒れ等の改善が顕著であり、皮膚コラーゲン産生促進効果に優れていることが実証された。また、本発明品のクリームについても、比較品のクリームに比べて、乾燥感の改善、肌荒れに顕著な改善がみられ、肌荒れ等の自然増悪抑制効果を有することが明らかとなった。
【００４０】
【発明の効果】
本発明により、アンジオジェニン及び／またはアンジオジェニン分解物を有効成分とする皮膚コラーゲン産生促進剤、皮膚コラーゲン産生促進用飲食品及び皮膚コラーゲン産生促進用化粧料が提供される。
本発明の皮膚コラーゲン産生促進剤、皮膚コラーゲン産生促進用飲食品及び皮膚コラーゲン産生促進用化粧料は、皮膚のコラーゲン産生を促進させる作用を有し、皮膚のシワやたるみ、乾燥感や肌荒れの予防や治療に有用である。[0001]
TECHNICAL FIELD OF THE INVENTION
TECHNICAL FIELD The present invention relates to a skin collagen production promoter, a food and drink for promoting skin collagen production, and a cosmetic for promoting skin collagen production, which are useful for preventing skin roughness, wrinkles, and decreased elasticity. More specifically, the present invention relates to a skin collagen production promoter containing angiogenin and / or angiogenin hydrolyzate obtained by decomposing angiogenin with a protease, as an active ingredient.
[0002]
[Prior art]
In recent years, studies on the mechanism of the skin have been promoted, and as a cause of dry skin and rough skin, macroscopically, the effects of sunlight (ultraviolet rays), drying and oxidation are complicated in addition to the decrease in metabolism due to aging. Has been confirmed to be involved in The effects of these factors have revealed that collagen fibers, the most major matrix component of the dermis, have been significantly reduced. When the tension holding mechanism such as firmness and elasticity of the skin held by the collagen fibers is destroyed by the action of ultraviolet rays or the like, the skin becomes wrinkled or sagged. Collagen can also retain moisture in its molecules, which helps to keep the skin moist, so if external factors destroy the collagen, the skin will dry out Then, it becomes rough.
From the above, by promoting the biosynthesis of collagen, one of the main components of the dermis layer, a skin collagen production promoter that can prevent skin wrinkles and sagging and has no problem in terms of safety. Was desired.
[0003]
Angiogenin is one of the angiogenic factors. It is known that human angiogenin is a protein having a molecular weight of 14,400, and the entire amino acid sequence has been determined. Angiogenin is also present in blood and milk, Bond et al. Separated ursian diogenin from bovine blood (see Non-Patent Document 1), and Spick et al. Isolated angiogenin in cow's milk. The amino acid sequence has been determined (see Non-Patent Document 2). For the production of angiogenin from milk, the milk is adsorbed to cation exchange chromatography, then eluted with an aqueous solution of an alkali metal salt of a weak organic acid, and the eluate is collected again by cation exchange chromatography and gel filtration chromatography. (See Patent Document 1).
The most important physiological activity of angiogenin is the angiogenic activity described above. Due to this effect, angiogenin has been suggested for use in diseases such as trauma, ulcers, organ transplantation, and circulatory dysfunction. Although little known other than such action, there is disclosed an example of using angiogenin as a hair growth and hair growth agent (see Patent Document 2). In addition, since angiogenin was found to specifically suppress melanin production of B-16 cells, which are melanoma cells, a whitening agent containing angiogenin as an active ingredient has been disclosed (see Patent Document 3). . However, it has not been known that angiogenin and its decomposition product have a skin collagen production promoting action and are useful as a skin collagen production promoting agent.
[0004]
[Prior art documents]
[Patent Document 1]
JP-A-2-296000 [Patent Document 2]
JP-A-4-210618 [Patent Document 3]
Japanese Patent No. 2572931 [Non-Patent Document 1]
Bond et al., "Biochemistry", 1988, vol. 27, p. 6282-6287 [Non-Patent Document 2].
G. Spik et al., "Biochemistry", 1989, 28, 6110-6113.
[Problems to be solved by the invention]
The present invention provides a skin collagen production promoter comprising, as an active ingredient, a substance that promotes the biosynthesis of skin collagen, which can prevent dry feeling, rough skin, wrinkles and tarmi of the skin and has no problem in terms of safety. That is the task. Another object of the present invention is to provide a food and drink for promoting skin collagen production and a cosmetic for promoting skin collagen production, which contain such a substance.
[0006]
[Means for Solving the Problems]
In order to solve these problems, the present inventors have been keenly searching for a substance that has a skin collagen production promoting effect widely contained in food materials, and found that angiogenin or its angiogenin was pepsin. Angiogenin hydrolyzate obtained by decomposition with proteolytic enzymes such as pancreatin and pancreatin can increase the amount of collagen in the skin, that is, has an action of promoting collagen production. Then, they have found that this angiogenin or angiogenin hydrolyzate can be used as an active ingredient of a skin collagen production promoter, a food / beverage product for promoting skin collagen production, and a cosmetic composition for promoting skin collagen production, and have completed the present invention.
[0007]
Therefore, the present invention relates to a skin collagen production promoter comprising as an active ingredient angiogenin having the skin collagen production promoting activity or an angiogenin degradation product obtained by decomposing angiogenin with a protease. The present invention also relates to a food and drink for promoting skin collagen production and a cosmetic for promoting skin collagen production, which contain these angiogenin and / or angiogenin hydrolyzate.
[0008]
In the present invention, the skin collagen production promoter refers to a substance that exhibits a skin collagen production promotion effect by oral administration or application. Further, in the present invention, of this skin collagen production promoter, it is formulated into powders, granules, tablets, capsules, drinks, etc., and as it is, or after being formulated, it is added to nutrients, foods and drinks, etc. What is orally administered is referred to as a food and drink for promoting skin collagen production. In the present invention, among the skin collagen production promoters, those formulated into ointments, gels, creams, sprays, patches, lotions and the like and applied to the skin are referred to as skin collagen production promotion cosmetics. . Further, in the present invention, for convenience, pharmaceuticals, which are formulated and administered orally as they are, are included in the food and drink for promoting skin collagen production, and pharmaceuticals, which are formulated and applied to the skin for convenience. And the cosmetic for promoting the production of skin collagen.
[0009]
BEST MODE FOR CARRYING OUT THE INVENTION
The skin collagen production promoter of the present invention is characterized in that angiogenin and / or angiogenin hydrolyzate obtained by decomposing angiogenin with a protease is used as an active ingredient.
[0010]
The angiogenin used as the raw material of the present invention can be of any origin. For example, human and bovine-derived angiogenin has already been clarified in its gene sequence and can be produced by genetic recombination. In the present invention, angiogenin produced by genetic engineering techniques can also be used. . Further, angiogenin is contained in bovine colostrum in a relatively large amount, and may be recovered from milk. Further, angiogenin can be recovered from the culture solution of cell culture, and even if it is derived from such cells, it can be used.
[0011]
In the present invention, a method for preparing a skin collagen production promoter using angiogenin prepared from milk of a mammal is disclosed in Examples, but the present invention is not limited to angiogenin derived from milk. As milk as a source, cows, buffaloes, humans, pigs, sheep, goats, horses, etc. within 1 to 7 days after parturition, particularly preferably colostrum within 1 to 5 days after parturition has a high angiogenin content Although suitable, even normal lactating milk can be used as a raw material in the present invention. In order to produce it, a known method, for example, a method of purifying angiogenin by combining cation exchange chromatography and gel filtration chromatography described in the above-mentioned [Patent Document 1] is advantageously used industrially. Can be.
[0012]
The angiogenin hydrolyzate is a peptide obtained by subjecting the above-described angiogenin to a limited digestion with a protease such as trypsin, pancreatin, chymotrypsin, pepsin, papain, kallikrein, cathepsin, thermolysin, or V8 protease to have a molecular weight of 10,000 or less. It is a mixture. The lower limit of the molecular weight is preferably 500 or more.
[0013]
The skin collagen production promoter of the present invention exerts a skin collagen production promoting effect by oral administration or application.
When orally administering the skin collagen production promoter of the present invention, the active ingredient angiogenin or angiogenin hydrolyzate can be used as it is, but according to a conventional method, powders, granules, tablets, capsules It can also be formulated into a preparation, a drink and the like and used. In the present invention, oral preparations such as powders, granules, tablets, capsules and the like are prepared in a usual manner using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts. Be converted to In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a colorant, a flavor, and the like can be appropriately used in addition to the above-mentioned excipients. More specifically, examples of the binder include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, sodium carboxymethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, and polyvinylpyrrolidone. Examples of the disintegrant include starch, hydroxypropyl starch, carboxymethylcellulose, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, and crystalline cellulose. As a surfactant, soybean lecithin, sucrose fatty acid ester, etc., as a lubricant, talc, wax, sucrose fatty acid ester, hydrogenated vegetable oil, etc., as a fluidity promoter, silicic anhydride, dried aluminum hydroxide, And magnesium silicate.
[0014]
Furthermore, these angiogenin and angiogenin hydrolyzate can be used as they are or after being formulated, and then added to nutritional supplements, foods and drinks, and the like. Further, when angiogenin or an angiogenin hydrolyzate is blended with a component which is conventionally considered to have an effective effect on collagen production, such as vitamin C, a further action of promoting skin collagen production can be expected. Since angiogenin or angiogenin hydrolyzate is relatively stable to heat, a raw material containing angiogenin or angiogenin hydrolyzate can be heat-sterilized under the usual conditions.
[0015]
When applying the skin collagen production promoter of the present invention, depending on the purpose of use, it may be prepared into various dosage forms such as liquid preparation, solid preparation, semi-solid preparation, etc. by blending it with commonly used known components. Preferred compositions include ointments, gels, creams, sprays, patches, lotions, powders and the like. For example, the skin collagen production promoter of the present invention may be a hydrocarbon such as petrolatum, stearyl alcohol, lower alkyl esters of higher fatty acids such as isopropyl myristate, animal fats and oils such as lanolin, polyhydric alcohols such as glycerin, glycerin fatty acid esters, Cosmetic for promoting skin collagen production by mixing with surfactants such as stearic acid and polyethylene glycol, inorganic salts, waxes, resins, water and, if necessary, preservatives such as methyl paraoxybenzoate and butyl paraoxybenzoate. And can manufacture pharmaceuticals.
[0016]
Although the effective amount of the skin collagen production promoter of the present invention by oral administration is appropriately defined depending on the formulation form, administration method, purpose of use, and the age, weight, and medical condition of the patient to which the agent is applied, it is not constant. According to the results of animal experiments, it was necessary to ingest at least 20 mg of angiogenin and / or angiogenin hydrolyzate per 1 kg of rat body weight in order to exhibit a skin collagen production promoting effect. Therefore, according to the extrapolation method, it is usually expected to take 20 mg or more of angiogenin and / or angiogenin hydrolyzate per adult per day. Therefore, the effect can be expected. Alternatively, it may be administered as a medicine. The administration can be carried out several times a day, if necessary.
[0017]
The effective amount of the skin collagen production promoter of the present invention by application varies depending on the dosage form, but is preferably from 0.001 to 2% by weight, based on the total amount of the composition to be applied, such that angiogenin and / or What is necessary is just to mix angiogenin decomposition product. However, the amount of a substance that is diluted at the time of use, such as a bathing agent, can be further increased.
[0018]
Next, the present invention will be described in detail with reference to Examples and Test Examples, which merely exemplify embodiments of the present invention, and the present invention is not limited thereto.
[0019]
Embodiment 1
A column (diameter 5 cm × height 30 cm) packed with 400 g of a cation exchange resin sulfonated chitopearl (manufactured by Fuji Boseki Co., Ltd.) was sufficiently washed with deionized water, and then 40 l of unsterilized skim milk (pH 6.7) was passed at a flow rate of 25 ml / min. After the passage, the column was sufficiently washed with deionized water, and eluted with a 0.02 M carbonate buffer (pH 7.0) containing 2.0 M sodium chloride. Then, the eluted fraction containing angiogenin was adsorbed to an S-Sepharose FF column (manufactured by Amersham Bioscience), washed sufficiently with deionized water, and equilibrated with 10 mM phosphate buffer (pH 7.0). The adsorbed fraction was eluted with a linear gradient of 0 to 2.0 M sodium chloride, and the fraction containing angiogenin was collected. Then, the fraction was subjected to gel filtration chromatography using HiLoad 16/60 Superdex 75 pg (manufactured by Amersham Bioscience) to obtain 1.8 g of a fraction rich in angiogenin. The angiogenin content in the fraction containing much angiogenin thus obtained is 10% and can be used as it is as a skin collagen production promoter.
[0020]
Embodiment 2
After sufficiently washing a column filled with 3,000 g of a cation exchange resin sulfonated chitopearl (manufactured by Fuji Boseki) with deionized water, 100 l of unsterilized skim milk (pH 6.7) was passed through the column. Liquid. Next, the column was sufficiently washed with deionized water, and then eluted with a linear concentration gradient of 0.1 to 2.0 M sodium chloride. Then, the eluted fraction containing angiogenin was fractionated by S-Sepharose cation exchange chromatography (manufactured by Amersham Bioscience), and the obtained angiogenin-containing fraction was heated at 90 ° C. for 10 minutes and centrifuged. The precipitate was removed by separation. Further, this angiogenin-containing fraction was sequentially treated by Mono S cation exchange chromatography, Superose 12 gel filtration chromatography, hydroxyapatite chromatography and C4 reverse phase chromatography to obtain 55 mg of angiogenin. The purity of the angiogenin thus obtained is 99%, and can be used as it is as a skin collagen production promoter.
[0021]
Embodiment 3
5 mg of angiogenin obtained in Example 2 was dissolved in 10 ml of water, and 1% of pancreatin (manufactured by Sigma) was added to a final concentration of 0.01% by weight, followed by enzyme treatment at 37 ° C. for 5 hours. Then, the enzyme was inactivated by heat treatment at 90 ° C. for 5 minutes, and then freeze-dried to obtain 4.0 mg of angiogenin hydrolyzate. The molecular weight of the angiogenin hydrolyzate thus obtained is 10,000 or less and can be used as it is as a skin collagen production promoter.
[0022]
Embodiment 4
5 mg of angiogenin obtained in Example 2 was dissolved in 10 ml of water, and trypsin (manufactured by Sigma) was added to a final concentration of 0.01% by weight, followed by enzyme treatment at 37 ° C. for 5 hours. Then, the enzyme was inactivated by heat treatment at 90 ° C. for 5 minutes, and then freeze-dried to obtain 4.2 mg of angiogenin hydrolyzate. The molecular weight of the angiogenin hydrolyzate thus obtained is 10,000 or less and can be used as it is as a skin collagen production promoter.
[0023]
[Test Example 1]
The angiogenin obtained in Example 2 and the angiogenin hydrolyzate obtained in Example 3 were examined for the effect of promoting collagen production by animal experiments using rats. Seven-week-old Wistar male rats were obtained in a saline-administered group (Group A), a group administered with 20 mg of the angiogenin obtained in Example 2 per kg of rat weight (Group B), and Example 2. A group that administers 200 mg / kg of rat body weight of angiogenin (Group C), a group that administers 20 mg / kg of rat angiogenin degradation product obtained in Example 3 (Group D), and the angiogenin obtained in Example 3 The hydrolyzate was divided into 5 test groups (n = 6), each of which was administered with 200 mg / kg of rat body weight (Group E), and each was administered once daily with a sonde and bred for 10 weeks.
The amount of collagen in the skin was determined by treating rat dermis according to the method of Nimni et al. (See Arch. Biochem. Biophys., P. 292, 1967), and then measuring the amount of hydroxyproline contained in the soluble fraction. Hydroxyproline is a special amino acid contained only in collagen, and the amount of collagen can be estimated because it accounts for about 10% of the total amino acids constituting collagen (see Takashi Asano et al., Bio Industry, page 12, 2001). Table 1 shows the results.
[0024]
[Table 1]
In addition, * indicates that there is a significant difference compared to the control group A (p <0.05).
[0025]
According to this, the amount of hydroxyproline in the soluble fraction after 10 weeks showed significantly higher values in the B, C, D and E groups than in the A group.
From this, it was clarified that angiogenin and angiogenin-decomposed product had a skin collagen production promoting action, and were shown to be useful as a skin collagen production promoting agent.
In addition, it was revealed that this skin collagen production promoting effect was observed when at least 20 mg of angiogenin or angiogenin hydrolyzate was administered per 1 kg of rat body weight.
[0026]
Embodiment 5
A beverage for promoting skin collagen production having the composition shown in Table 2 was produced by a conventional method. The flavor of the produced beverage was good, and the flavor did not deteriorate even after storage at room temperature for one year, and there was no problem such as precipitation.
[0027]
[Table 2]
Embodiment 6
A dough having the composition shown in Table 3 was prepared by a conventional method, molded, and then roasted to produce a skin collagen production promoting biscuit.
[0029]
[Table 3]
Embodiment 7
A skin collagen production promoter having the formulation shown in Table 4 was produced by a conventional method.
[0031]
[Table 4]
[Test Example 2]
The angiogenin obtained in Example 2 and the angiogenin degradation product obtained in Example 3 were subjected to an experiment using a normal human fibroblast cell line [CCD45SK (ATCCRL1506) collected from the skin of a white female]. The effect of promoting collagen production was examined. Using a modified Eagle's medium (MEM, 10-101, manufactured by Dainippon Pharma Co., Ltd.) containing 10% by volume of fetal bovine serum (hereinafter abbreviated as FBS), 4 × 10 4 normal human fibroblast cell lines / well / 0 The cells were inoculated in a 24-well plate so as to have a volume of 0.4 ml, cultured at 37 ° C. for 24 hours under 5% carbon dioxide gas and saturated steam, and then replaced with a MEM medium containing 0.6% by volume of FBS. Then, the angiogenin obtained in Example 2 and the angiogenin degradation product obtained in Example 3 were added to each well so as to be 0.1% by volume (n = 6) and cultured for 24 hours. Thereafter, β-aminopropionitrile was added at 50 μg / ml and tritium-L-proline at 1 μCi / ml, and the mixture was further cultured for 24 hours to obtain a culture solution. From the culture solution thus obtained, a collagen fraction was fractionated according to the method of Webster et al. (See Analytical Biochemistry, page 220, 1979), and the radioactivity incorporated in the collagen fraction was measured. As a control, a similar test was performed without adding angiogenin and angiogenin degradation product. Table 5 shows the results.
[0033]
[Table 5]
* Indicates that there is a significant difference compared to the control group (p <0.05).
[0034]
According to this, the group to which angiogenin and angiogenin hydrolyzate were added showed a collagen production promoting ability twice or more as compared to the group to which angiogenin and angiogenin hydrolyzate were not added (control).
From this, it was clarified that angiogenin and angiogenin hydrolyzate act on skin fibroblasts to promote collagen production, and were shown to be useful as a skin collagen production promoter.
[0035]
Embodiment 8
A lotion having the composition shown in Table 6 was produced by a conventional method.
[0036]
[Table 6]
Embodiment 9
A cream having the composition shown in Table 7 was produced by a conventional method.
[0038]
[Table 7]
[Test Example 3]
An actual use test was performed using the lotion obtained in Example 8 and the cream obtained in Example 9. As a comparative product, the same formulation as in Examples 8 and 9 was used except that angiogenin was omitted.
Twenty adult women with dry skin with sagging face and fine wrinkles are observed in two groups (A and B groups) at random, and 20 women with rough skin on their hands. Ten groups were randomly divided into two groups (groups C and D), the lotion of the present invention was applied to the face of group A, the comparative lotion was applied to the face of group B, and the hands of group C were applied to the fingers. The cream of the present invention and the cream of the comparative product were applied to the fingers of the group D twice a day for 10 days in the same manner as in a normal use state. As a result, it was demonstrated that the lotion of the product of the present invention had remarkable improvements in dry feeling, rough skin, etc. as compared with the lotion of the comparative product, and had an excellent skin collagen production promoting effect. In addition, the cream of the present invention also showed a significant improvement in dry feeling and rough skin as compared with the cream of the comparative product, and it was clarified that it had an effect of suppressing natural deterioration such as rough skin.
[0040]
【The invention's effect】
According to the present invention, there are provided a skin collagen production promoter, a food and drink for promoting skin collagen production, and a cosmetic for promoting skin collagen production, which contain angiogenin and / or angiogenin hydrolyzate as an active ingredient.
The skin collagen production promoter, skin collagen production promotion food / beverage product and skin collagen production promotion cosmetic of the present invention have an action of promoting skin collagen production, and prevent skin wrinkles and sagging, dryness and rough skin. And is useful for treatment.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003129510A JP4698935B2 (en) | 2003-05-07 | 2003-05-07 | Skin collagen production promoter |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003129510A JP4698935B2 (en) | 2003-05-07 | 2003-05-07 | Skin collagen production promoter |
Publications (2)
| Publication Number | Publication Date |
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| JP2004331566A true JP2004331566A (en) | 2004-11-25 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2008024703A (en) * | 2006-06-23 | 2008-02-07 | Rohto Pharmaceut Co Ltd | Composition having collagen production-promoting ability and/or fibroblast proliferation-promoting ability |
| WO2008055310A1 (en) * | 2006-11-10 | 2008-05-15 | Murray Goulburn Co-Operative Co. Limited | Process for the preparation of angiogenin |
| JP2011519960A (en) * | 2008-05-14 | 2011-07-14 | アグリカルチャー ヴィクトリア サービス ピーティーワイ エルティーディー | Orally administrable dosage form containing angiogenin and use thereof |
| JP2011519961A (en) * | 2008-05-14 | 2011-07-14 | アグリカルチャー ヴィクトリア サービス ピーティーワイ エルティーディー | Use of angiogenin or angiogenin agonists to treat diseases and disorders |
| JP2013079216A (en) * | 2011-10-04 | 2013-05-02 | Snow Brand Milk Products Co Ltd | Sense-improving agent |
| WO2013164995A1 (en) * | 2012-05-02 | 2013-11-07 | 雪印メグミルク株式会社 | Hyaluronic acid production promoter |
| AU2008320272B2 (en) * | 2007-11-01 | 2014-01-23 | Megmilk Snow Brand Co., Ltd. | Food material for inhibiting bone resorption |
| ITRM20130199A1 (en) * | 2013-04-03 | 2014-10-04 | Irbm Science Park S P A | PEPTIDES FOR DERMATOLOGICAL AND / OR COSMETIC USE |
| US9067972B2 (en) | 2008-12-15 | 2015-06-30 | Calpis Co., Ltd. | Skin aging-inhibiting peptide |
| US9247766B2 (en) | 2008-05-14 | 2016-02-02 | Murray Goulburn Co-Operative Co., Limited | Angiogenin-enriched milk fractions |
| US9839676B2 (en) | 2012-05-10 | 2017-12-12 | Murray Goulburn Co-Operative Co., Limited | Methods of treating cancer using angiogenin or an angiogenin agonist |
| WO2021029684A1 (en) * | 2019-08-14 | 2021-02-18 | 주식회사 에스알바이오텍 | Peptide-complexed microneedle and cosmetic composition comprising same |
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| JP2002501906A (en) * | 1998-01-28 | 2002-01-22 | リンク・テクノロジー，インコーポレイテッド | Composition for preventing or treating fibrosis and sclerosis |
| JP2002537939A (en) * | 1999-03-09 | 2002-11-12 | サーメイジ インコーポレイテッド | Apparatus and method for treating tissue |
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| JPH107585A (en) * | 1996-06-20 | 1998-01-13 | Snow Brand Milk Prod Co Ltd | Osteogenesis promoting and bone resorption preventing agent |
| JP2002501906A (en) * | 1998-01-28 | 2002-01-22 | リンク・テクノロジー，インコーポレイテッド | Composition for preventing or treating fibrosis and sclerosis |
| JP2002537939A (en) * | 1999-03-09 | 2002-11-12 | サーメイジ インコーポレイテッド | Apparatus and method for treating tissue |
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| JP2008024703A (en) * | 2006-06-23 | 2008-02-07 | Rohto Pharmaceut Co Ltd | Composition having collagen production-promoting ability and/or fibroblast proliferation-promoting ability |
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| WO2008055310A1 (en) * | 2006-11-10 | 2008-05-15 | Murray Goulburn Co-Operative Co. Limited | Process for the preparation of angiogenin |
| JP2010508827A (en) * | 2006-11-10 | 2010-03-25 | マリー ゴールバーン シーオー−オペレイティブ シーオー．リミテッド | Method for preparing angiogenin |
| CN101626693B (en) * | 2006-11-10 | 2014-05-14 | 墨累古尔本合作有限公司 | Process for preparation of angiogenin |
| AU2007317200B8 (en) * | 2006-11-10 | 2012-02-02 | Agriculture Victoria Services Pty Ltd. | Process for the preparation of angiogenin |
| AU2007317200A8 (en) * | 2006-11-10 | 2012-02-02 | Agriculture Victoria Services Pty Ltd. | Process for the preparation of angiogenin |
| AU2008320272B2 (en) * | 2007-11-01 | 2014-01-23 | Megmilk Snow Brand Co., Ltd. | Food material for inhibiting bone resorption |
| JP2011519960A (en) * | 2008-05-14 | 2011-07-14 | アグリカルチャー ヴィクトリア サービス ピーティーワイ エルティーディー | Orally administrable dosage form containing angiogenin and use thereof |
| US9789168B2 (en) | 2008-05-14 | 2017-10-17 | Agriculture Victoria Services Pty Ltd | Use of angiogenin or angiogenin agonists for treating diseases and disorders |
| US9247766B2 (en) | 2008-05-14 | 2016-02-02 | Murray Goulburn Co-Operative Co., Limited | Angiogenin-enriched milk fractions |
| US10456453B2 (en) | 2008-05-14 | 2019-10-29 | Agriculture Victoria Services Pty Ltd | Use of angiogenin or angiogenin agonists for treating diseases and disorders |
| JP2011519961A (en) * | 2008-05-14 | 2011-07-14 | アグリカルチャー ヴィクトリア サービス ピーティーワイ エルティーディー | Use of angiogenin or angiogenin agonists to treat diseases and disorders |
| US9067972B2 (en) | 2008-12-15 | 2015-06-30 | Calpis Co., Ltd. | Skin aging-inhibiting peptide |
| US10016481B2 (en) | 2011-10-04 | 2018-07-10 | Megmilk Snow Brand Co., Ltd. | Sensation-improving agent |
| JP2013079216A (en) * | 2011-10-04 | 2013-05-02 | Snow Brand Milk Products Co Ltd | Sense-improving agent |
| JP2013234131A (en) * | 2012-05-02 | 2013-11-21 | Snow Brand Milk Products Co Ltd | Hyaluronic acid production promotor |
| WO2013164995A1 (en) * | 2012-05-02 | 2013-11-07 | 雪印メグミルク株式会社 | Hyaluronic acid production promoter |
| US9839676B2 (en) | 2012-05-10 | 2017-12-12 | Murray Goulburn Co-Operative Co., Limited | Methods of treating cancer using angiogenin or an angiogenin agonist |
| WO2014161863A1 (en) | 2013-04-03 | 2014-10-09 | Irbm Science Park S.P.A. | Dermatological and/or cosmetic peptides for use in skin treatment |
| ITRM20130199A1 (en) * | 2013-04-03 | 2014-10-04 | Irbm Science Park S P A | PEPTIDES FOR DERMATOLOGICAL AND / OR COSMETIC USE |
| WO2021029684A1 (en) * | 2019-08-14 | 2021-02-18 | 주식회사 에스알바이오텍 | Peptide-complexed microneedle and cosmetic composition comprising same |
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