JP3998085B2 - Hyaluronic acid amount increase accelerator - Google Patents
Hyaluronic acid amount increase accelerator Download PDFInfo
- Publication number
- JP3998085B2 JP3998085B2 JP27136598A JP27136598A JP3998085B2 JP 3998085 B2 JP3998085 B2 JP 3998085B2 JP 27136598 A JP27136598 A JP 27136598A JP 27136598 A JP27136598 A JP 27136598A JP 3998085 B2 JP3998085 B2 JP 3998085B2
- Authority
- JP
- Japan
- Prior art keywords
- hyaluronic acid
- skin
- extract
- acid amount
- amount increase
- 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.)
- Expired - Fee Related
Links
Landscapes
- Cosmetics (AREA)
- Anti-Oxidant Or Stabilizer Compositions (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明はヒアルロン酸量増加促進剤（以下、ヒアルロン酸産生促進剤とも記す）に関する。さらに詳しくは、ヒトにおけるヒアルロン酸産生能を促進させるヒアルロン酸産生促進剤に関する。該ヒアルロン酸産生促進剤は、ヒト皮膚の老化防止（皮膚のハリや弾力保持）、関節炎等の予防・治療、熱傷の初期の治療等に有効に適用され得る。特に、本発明ヒアルロン酸産生促進剤の配合により、皮膚のハリや弾力を保持してシワを防ぎ、うるおいのある若々しい肌の状態を維持することのできる皮膚外用剤が提供される。
【０００２】
【従来の技術】
近年、老化に関する研究が進められている。皮膚老化の原因は、マクロ的にみれば加齢が重要な因子であるが、それに加えて乾燥、酸化、太陽光（紫外線）等による影響も皮膚老化に関わる直接的な因子として挙げられる。皮膚老化の具体的な現象としては、ヒアルロン酸をはじめとするムコ多糖類の減少、コラーゲンの架橋反応、紫外線による細胞の損傷などが知られている。
【０００３】
なかでもヒアルロン酸は、細胞間隙への水分の保持、組織内にジェリー状のマトリックスを形成することに基づく細胞の保持、組織の潤滑性と柔軟性の保持、機械的障害等の外力に対する抵抗、および細菌感染の防止など、多くの機能を有している（"Bio Industry"、vol.8、p.346(1991)）。例えば、皮膚のヒアルロン酸量は加齢とともに減少し、それに伴い、小ジワやかさつき等の皮膚老化が現れるといわれている。そのため、このような老化した皮膚の改善剤として、ヒアルロン酸やコラーゲンを配合した化粧料が数多く提案されている。しかしながらこれら従来の化粧料は、皮膚表面における保湿効果を発揮するだけであり、本質的に老化肌を改善し得るものではない。また、皮膚細胞賦活剤として各種のビタミン類や生薬類を配合した化粧料が提案されているが、これらもやはり老化肌を改善、治療し得るまでには至っていないのが現状である。
【０００４】
さらに、関節液中に含まれるヒアルロン酸は、関節軟骨の表面を覆い、関節機能の円滑な作動に役立っている。正常人関節液中のヒアルロン酸濃度は約２．３ｍｇ／ｍｌであるが、慢性関節リウマチの場合、関節液中のヒアルロン酸濃度は約１．２ｍｇ／ｍｌと低下し、同時に関節液の粘度も著しく低下する（"Arthritis Rheumatism"、vol.10、p.357(1967)）。また、化膿性関節炎や痛風性関節炎などでも慢性関節リウマチの場合と同様、ヒアルロン酸含量の低下が起こることが知られている（「結合組成」（金原出版）、４８１頁、１９８４年）。上記疾患において、潤滑機能の改善、関節軟骨の被覆・保護、疼痛抑制および病的関節液の改善若しくは正常化のために、関節液中のヒアルロン酸量を増加させることが考えられる。例えば、慢性関節リウマチ患者にヒアルロン酸ナトリウムの関節注入療法を行うと上記の改善が認められることが報告されている（「炎症」（日本炎症学会）、１１巻、１６頁、１９９１年）。同様に、外傷性関節炎、骨関節炎や変形性関節炎においても、ヒアルロン酸の関節注入療法により上記の改善効果が報告されている。（「結合組織と疾患」（講談社）、２４６頁、１９８０年）。
【０００５】
しかしながら、上記疾患の治療は長期にわたり、しかも医師の処方を必要とする。従って、日常生活のなかで手軽に治療することができるヒアルロン酸産生促進剤を含有させた皮膚外用剤が望まれていた。
【０００６】
また、熱傷受傷後の治癒過程で、壊死組織の下方から増生してくる肉芽組織の初期から組織全体が肉芽組織に置き換えられるまでの期間では、肉芽中にヒアルロン酸が著しく増加することが知られており（「結合組織と疾患」（講談社）、１５３頁、１９８０年）、熱傷の初期の治療薬としても、ヒアルロン酸産生促進剤が期待されている。
【０００７】
一方、ヒト細胞のヒアルロン酸を産生する薬剤としては、インシュリン様成長因子−１や上皮成長因子（"Biochemica Biophysica Acta"、1014、p.305(1989)）およびインターロイキン−１（「日本産科婦人科学会」雑誌、４１巻、１９４３頁、１９８９年）などのサイトカイン、あるいはフォルボールエステル（"Experimental Cell Research"、vol.148、p.377(1983)）などが知られているが、いずれも化粧品、入浴剤や医薬品等として簡便にかつ安心して使用することができるものではない。
【０００８】
【発明が解決しようとする課題】
本発明は上記事情に鑑みてなされたもので、安全で、かつ簡便に用いることができる、ヒトにおけるヒアルロン酸産生能を促進させるヒアルロン酸産生促進剤を提供することを目的とする。本発明のヒアルロン酸産生促進剤は、ヒト皮膚の老化防止（皮膚のハリや弾力保持）、関節炎等の予防・治療、熱傷の初期の治療等に有効に適用され得る。特に、このヒアルロン酸産生促進剤の配合により、皮膚のハリや弾力を保持してシワを防ぎ、うるおいのある若々しい肌の状態を維持することのできる皮膚外用剤が提供される。
【０００９】
【課題を解決するための手段】
本発明者らは上記課題の解決に向けて広く種々の物質にヒアルロン酸産生促進能を調べた結果、ミカン科に属する植物の花等から得られる抽出物が優れたヒアルロン酸産生促進作用を有することを見出し、これに基づいて本発明を完成するに至った。
【００１０】
すなわち本発明は、ミカン科（Rutaceae）に属する植物の花、葉、茎または木部からの抽出物を有効成分として含有するヒアルロン酸量増加促進剤に関する。
【００１１】
ここで、ミカン科（Rutaceae）に属する植物の花からの抽出物が好ましく用いられる。
【００１２】
また、ミカン科（Rutaceae）の植物の中でも、特にミカン属（Citrus）に属する植物が好ましく用いられる。
【００１３】
さらに本発明は、上記のヒアルロン酸産生促進剤を配合してなる皮膚外用剤に関する。
【００１４】
なお、ミカン科に属する植物抽出物の効果に関しては、ミカン科ミカン属に属する植物の種子の圧搾物および／または抽出物のシワ改善作用（特開平７−１２６１４２号公報）や、ポンカンエッセンスの活性酸素消去能（特開平９−３１５９９３号公報）等が既に知られている。しかしながら、ミカン科植物の抽出物にヒアルロン酸産生促進作用が認められたという報告はこれまでなく、本発明者らによって今回初めて見出されたものである。
【００１５】
【発明の実施の形態】
以下、本発明について詳述する。
【００１６】
本発明に用いられるミカン科（Rutaceae）に属する植物としては、ミカン属（Citrus）、キンカン属（Fortunella）、カラタチ属（Poncirus）、ミヤマシキミ属（Skimmia）、ヘンルーダ属（Ruta）等に属する植物が挙げられるが、中でもミカン属（Citrus）に属する植物が好ましく用いられる。
【００１７】
ミカン属（Citrus）に属する植物としては、例えば、ウンシュウミカン（C. unshiu）、ナツミカン（C. natsudaidai）、オレンジ〔スイートオレンジ〕（C. cinensis）、ダイダイ〔サワーオレンジ、ビターオレンジ〕（C. aurantium）、マンダリンオレンジ（ポンカンを含む）（C. reticulata）、ハッサク（C. hassaku）、イヨカン（C. iyo）、グレープフルーツ（C. paradisi）、スダチ（C. sudachi）、カボス（C. sphaerocarpa）等が挙げられる。中でもウンシュウミカン（C. unshiu）、オレンジ（C. cinensis）、ダイダイ（C. aurantium）が好ましく用いられる。
【００１８】
本発明において、ミカン科に属する植物は、生のままでも乾燥したものでも使用することができるが、使用性、製剤化等の点から乾燥粉末あるいは溶媒抽出物として用いることが好ましい。ミカン科植物の使用部位は、植物体全体を用いることができるが、好ましくは花、葉、茎または木部等が用いられ、中でも花または葉がより好ましく用いられ、特に好ましくは花である。なお、この場合の「花」は、いわゆる花軸と花葉を含む、有性生殖に関与する諸器官を含んだものをいい、花弁、雄ずい、雌ずい、蕚片等を含む。
【００１９】
ミカン科植物の抽出物は、常法により得ることができ、例えばミカン科に属する植物を抽出溶媒とともに浸漬または加熱還流した後、濾過し、濃縮して得ることができる。抽出溶媒としては、通常抽出に用いられる溶媒であれば任意に用いることができ、例えば、水、メタノール、エタノール、プロピレングリコール、１，３−ブチレングリコール、グリセリン等のアルコール類、含水アルコール類、クロロホルム、ジクロルエタン、四塩化炭素、アセトン、酢酸エチル、ヘキサン等の有機溶媒等を、それぞれ単独あるいは組み合わせて用いることができる。上記溶媒で抽出した得た抽出液をそのまま、あるいは濃縮したエキスを吸着法、例えばイオン交換樹脂を用いて不純物を除去したものや、ポーラスポリマー（例えばアンバーライトＸＡＤ−２）のカラムにて吸着させた後、メタノールまたはエタノールで溶出し、濃縮したものも使用することができる。また分配法、例えば水／酢酸エチルで抽出した抽出物等も用いられる。
【００２０】
このようにして得たミカン科に属する植物またはその抽出物は、ヒアルロン酸産生促進作用を有する。このようなミカン科に属する植物またはその抽出物は、好ましくは外用剤に配合して用いられる。
【００２１】
上記ミカン科に属する植物またはその抽出物を皮膚外用剤に配合して用いる場合、外用剤全量中に乾燥重量として０．０００５〜２０．０重量％配合するのが好ましく、より好ましくは０．００１〜１０．０重量％である。０．０００５重量％未満では本発明のヒアルロン酸産生促進効果が十分に発揮され難く、一方、２０．０重量％超では製剤化が難しいので好ましくない。また、１０．０重量％を超えて配合してもさほど大きな効果の向上は認められない。
【００２２】
本発明のヒアルロン酸産生促進剤を皮膚外用剤に用いる場合、上記成分に加えて、さらに必要により、本発明の効果を損なわない範囲内で、通常化粧品や医薬品等の皮膚外用剤に用いられる成分、例えば保湿剤、酸化防止剤、油分、紫外線防御剤、界面活性剤、増粘剤、アルコール類、粉末成分、色材、水性成分、水、各種皮膚栄養剤等を必要に応じて適宜配合することができる。
【００２３】
さらに、エデト酸二ナトリウム、エデト酸三ナトリウム、クエン酸ナトリウム、ポリリン酸ナトリウム、メタリン酸ナトリウム、グルコン酸等の金属イオン封鎖剤、メチルパラベン、エチルパラベン、ブチルパラベン等の防腐剤、カフェイン、タンニン、ベラパミル、トラネキサム酸およびその誘導体、甘草抽出物、グラブリジン、カリンの果実の熱水抽出物、各種生薬、酢酸トコフェロール、グリチルリチン酸およびその誘導体またはその塩等の薬剤、ビタミンＣ、アスコルビン酸リン酸マグネシウム、アスコルビン酸グルコシド、アルブチン、コウジ酸等の美白剤、グルコース、フルクトース、マンノース、ショ糖、トレハロース等の糖類なども適宜配合することができる。
【００２４】
また、本発明の皮膚外用剤は、外皮に適用される化粧料、医薬部外品等、特に好適には化粧料に広く適用することが可能であり、その剤型も、皮膚に適用できるものであればいずれでもよく、溶液系、可溶化系、乳化系、粉末分散系、水−油二層系、水−油−粉末三層系、軟膏、化粧水、ゲル、エアゾール等、任意の剤型が適用される。
【００２５】
また、本発明の皮膚外用剤の使用形態も任意であり、例えば化粧水、乳液、クリーム、パック等のフェーシャル化粧料やファンデーション、口紅、アイシャドウ等のメーキャップ化粧料、芳香化粧料、浴用剤等に用いることができる。
【００２６】
なお、上記の剤型および使用形態に本発明の皮膚外用剤が採り得る形態が限定されるものではない。
【００２７】
また、本発明のヒアルロン酸産生促進剤は、優れたヒアルロン酸産生促進能を有することから、上記のように皮膚外用剤に用いる以外にも、関節炎の予防治療や熱傷の初期治療等としての適用が可能である。
【００２８】
【実施例】
次に、実施例を挙げて本発明をさらに詳細に説明するが、本発明の技術的範囲はこれによってなんら限定されるものでない。なお、配合量はすべて重量％である。
【００２９】
実施例に先立ち、本発明のミカン科植物由来の溶媒抽出物のヒアルロン酸産生促進作用の試験方法について説明する。
【００３０】
１． 試料の調製
オレンジ（C. sinensis）、ウンシュウミカン（C. unshiu）、またはダイダイ（C. aurantium）の花５００ｇを、メタノールに室温で１週間浸漬し、抽出液を得た。この抽出液を濃縮し、ミカン科植物抽出物（以下、「本抽出物」と記す）９０ｇを得た。
【００３１】
本抽出物をジメチルスルホキシド（ＤＭＳＯ）に濃度１０％となるよう溶解して、本抽出物含有溶液（以下、「元溶液」と記す）とした。
【００３２】
この元溶液を希釈して濃度を調整した溶液を、元溶液とともに被験溶液とし、以下の実験を行った。
【００３３】
２． ヒアルロン酸産生促進作用の測定
２４穴シャーレにヒト皮膚由来不死化表皮細胞を１ウエルあたり２万播種し、増殖因子入りＫＧＢ培地（クラボウ（株）製）で４日間培養した。この後、培地を、上記被験溶液を含むＫＧＢ培地２ｍｌに交換し、さらに４日間培養した。なお、被験溶液の濃度は、ＤＭＳＯが培地に対して最終濃度０．１％になるように調整した。また、培地中での本抽出物濃度は１０-5〜１０-2重量％とした。
【００３４】
培養後、培地を採取し、ヒアルロン酸の測定を行った。ヒアルロン酸の測定は、市販のヒアルロン酸測定キット（中外製薬（株）製）を用いて行った。またシャーレ中のＤＮＡ量を測定し、細胞数の指標とした。ＤＮＡ量の測定は「ヘキスト３３２５８」（ヘキスト社製）を用いた蛍光測定法で行った。
【００３５】
なお、本抽出物については、上記実験濃度では細胞毒性は認められなかった。
【００３６】
ヒアルロン酸産生促進作用の評価はヒアルロン酸産生促進率により行った。ヒアルロン酸産生促進率（％）は、本抽出物を添加しない培地で培養したヒト皮膚由来不死化表皮細胞（コントロール）のＤＮＡあたりのヒアルロン酸量を１００とした時の、本抽出物含有培地で培養したヒト皮膚由来不死化表皮細胞のＤＮＡあたりのヒアルロン酸量と定義した。結果を表１に示す。
【００３７】
また、参考例として、既にヒアルロン酸産生促進作用を有することが知られている高麗人参の抽出物（メタノール抽出物）についても上記と同様の試験を行い、１０-3重量％濃度でのヒアルロン酸産生促進率を測定した。結果を表１に併せて示す。
【００３８】
【表１】
表１から明らかなように、ミカン科植物の抽出物は、優れたヒアルロン酸産生促進効果を有することがわかる。
【００４０】
以下に、種々の剤型の本発明によるヒアルロン酸産生促進剤の配合例を挙げる。なお、各実施例で用いたミカン科植物の溶媒抽出物は常法により得た。なおこれら抽出物の配合量は乾燥重量で示す。
【００４１】
（１１）に（５）〜（７）を加え溶解し、加熱して７０℃に保った（水相）。一方、（１）〜（４）、（８）〜（１０）を混合して加熱溶融し、７０℃に保った（油相）。次いで、水相に油相を攪拌しながら徐々に添加し、全部加え終わってからしばらくその温度に保ち反応を起こさせた。その後、ホモミキサーで均一に乳化し、よく攪拌しながら３０℃まで冷却した。
【００４２】
（１３）に（８）を加え溶解し、加熱して７０℃に保った（水相）。一方、（１）〜（７）、（９）〜（１２）を混合して加熱溶融し、７０℃に保った（油相）。次いで、水相に油相を加え予備乳化を行い、ホモミキサーで均一に乳化した後、よく攪拌しながら３０℃まで冷却した。
【００４３】
（１３）に（６）〜（７）を加え、加熱溶解して７０℃に保った（水相）。一方、（１）〜（５）、（８）〜（１２）を混合し加熱溶融し、７０℃に保った（油相）。次いで、水相に油相を攪拌しながら徐々に加え反応を行った。反応終了後、ホモミキサーで均一に乳化した後、よく攪拌しながら３０℃まで冷却した。
【００４４】
少量の（１３）に（８）を溶解した（Ａ相）。残りの（１３）に（６）〜（７）を加え、加熱溶解して７０℃に保った（水相）。一方、（１）〜（５）、（９）〜（１２）を混合し加熱溶融して７０℃に保った（油相）。水相に油相を加え予備乳化を行い、さらにＡ相を加えホモミキサーで均一に乳化し、乳化後よく攪拌しながら３０℃まで冷却した。
【００４５】
（１３）に（８）を加え、加熱して７０℃に保った（水相）。一方、（１）〜（７）、（９）〜（１２）を混合し、加熱溶融して７０℃に保った（油相）。油相を攪拌しながら水相を徐々に加え、ホモミキサーで均一に乳化し、乳化後よく攪拌しながら３０℃まで冷却した。
【００４６】
（１２）に（４）を均一に溶解した（水相）。一方、（１）に（７）と（３）を溶解し、これを水相に添加した。次いでここに、（２）、（８）〜（１１）を加えた後、（５）、（６）で中和させ増粘した。
【００４７】
Ａ相、Ｃ相をそれぞれ均一に溶解し、Ｃ相にＡ相を加えて可溶化した。次いでＢ相を加え充填を行った。
【００４８】
Ａ相、Ｂ相、Ｃ相をそれぞれ均一に溶解し、Ａ相にＢ相を加えて可溶化した。次いでＣ相を加え充填を行った。
【００４９】
（１）〜（７）の粉末成分をブレンダーで十分混合し、これに（８）〜（１１）の油性成分、（１２）、（１３）、（１４）を加え、よく混練した後、容器に充填、成型した。
【００５０】
水相を加熱攪拌後、十分に混合粉砕した粉体部を添加してホモミキサー処理した。さらに加熱混合した油相を加えてホモミキサー処理した後、攪拌しながら香料を添加して室温まで冷却した。
【００５１】
（１３）に（８）を加え溶解し、加熱して７０℃に保った（水相）。一方、（１）〜（７）、（９）〜（１２）を混合して加熱溶解し、７０℃に保った（油相）。次いで、水相に油相を加え予備乳化を行い、ホモミキサーで均一に乳化した後、よく攪拌しながら３０℃まで冷却した。
【００５２】
上記実施例１〜１１の各皮膚外用剤は、いずれもヒアルロン酸産生促進効果に優れるものであり、これを皮膚へ適用することにより、皮膚のハリや弾力を維持してシワを防ぎ、うるおいのある若々しい肌の状態を維持することができる。
【００５３】
【発明の効果】
以上説明したように、本発明のヒアルロン酸産生促進剤は優れたヒアルロン酸産生促進作用を有しており、ヒト皮膚の老化防止（皮膚のハリや弾力保持）、関節炎等の予防・治療、熱傷の初期の治療等に有効に適用され得る。特に、本発明のヒアルロン酸産生促進剤を皮膚外用剤（医薬品、医薬部外品、化粧料を含む）等に配合することにより、細胞外マトリックス成分の一つであるヒアルロン酸の産生を促進し、皮膚のハリや弾力を維持してシワを防ぎ、うるおいのある若々しい肌の状態を維持することのできるという効果を有する。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a hyaluronic acid amount increase accelerator (hereinafter also referred to as hyaluronic acid production accelerator) . More specifically, the present invention relates to a hyaluronic acid production promoter that promotes hyaluronic acid production ability in humans. The hyaluronic acid production promoter can be effectively applied to prevent aging of human skin (skin elasticity and elasticity retention), prevention / treatment of arthritis, etc., initial treatment of burns, and the like. In particular, the formulation for hyaluronic acid production promoter of the present invention provides an external preparation for skin that can maintain skin firmness and elasticity, prevent wrinkles, and maintain a moist and youthful skin state.
[0002]
[Prior art]
In recent years, research on aging has been promoted. As for the cause of skin aging, aging is an important factor when viewed macroscopically, but in addition to that, the effects of drying, oxidation, sunlight (ultraviolet rays) and the like are also directly related to skin aging. As specific phenomena of skin aging, reduction of mucopolysaccharides such as hyaluronic acid, cross-linking reaction of collagen, cell damage due to ultraviolet rays, and the like are known.
[0003]
Among them, hyaluronic acid retains moisture in the cell gap, retains cells based on the formation of a jelly-like matrix in the tissue, retains the lubricity and flexibility of the tissue, and resists external forces such as mechanical failure. And has many functions such as prevention of bacterial infection ("Bio Industry", vol.8, p.346 (1991)). For example, it is said that the amount of hyaluronic acid in the skin decreases with aging, and accompanying this, skin aging such as fine wrinkles and roughness appears. For this reason, many cosmetics containing hyaluronic acid and collagen have been proposed as an ameliorating agent for such aging skin. However, these conventional cosmetics only exhibit a moisturizing effect on the skin surface, and cannot essentially improve aging skin. In addition, cosmetics containing various vitamins and herbal medicines as skin cell activators have been proposed, but these have not yet been able to improve and treat aging skin.
[0004]
Furthermore, the hyaluronic acid contained in the joint fluid covers the surface of the articular cartilage and is useful for smooth operation of the joint function. Hyaluronic acid concentration in normal human joint fluid is about 2.3 mg / ml, but in the case of rheumatoid arthritis, hyaluronic acid concentration in joint fluid is reduced to about 1.2 mg / ml and at the same time the viscosity of joint fluid is Remarkably reduced ("Arthritis Rheumatism", vol. 10, p. 357 (1967)). In addition, it is known that hyaluronic acid content decreases in pyogenic arthritis and gouty arthritis as in the case of rheumatoid arthritis (“binding composition” (Kanehara Publishing), page 481, 1984). In the above diseases, it is conceivable to increase the amount of hyaluronic acid in synovial fluid in order to improve lubrication function, cover / protect articular cartilage, suppress pain, and improve or normalize pathological joint fluid. For example, it has been reported that the above-mentioned improvement is observed when sodium hyaluronate joint injection therapy is performed on patients with rheumatoid arthritis ("Inflammation" (Japan Inflammation Society), 11, 16, 1991). Similarly, in traumatic arthritis, osteoarthritis and osteoarthritis, the above-mentioned improvement effect has been reported by joint injection therapy with hyaluronic acid. ("Connective tissue and disease" (Kodansha), p. 246, 1980).
[0005]
However, treatment of the above diseases is long-lasting and requires a doctor's prescription. Therefore, an external preparation for skin containing a hyaluronic acid production promoter that can be easily treated in daily life has been desired.
[0006]
In the healing process after burn injury, hyaluronic acid is known to increase significantly in the granulation during the period from the beginning of the granulation tissue growing from below the necrotic tissue until the entire tissue is replaced with granulation tissue. (“Connective tissue and diseases” (Kodansha), p. 153, 1980), hyaluronic acid production promoters are also expected as early treatments for burns.
[0007]
On the other hand, drugs that produce hyaluronic acid in human cells include insulin-like growth factor-1, epidermal growth factor ("Biochemica Biophysica Acta", 1014, p.305 (1989)) and interleukin-1 ("Japanese obstetrics women" Cytokines such as "Science Society" magazine, 41, 1943, 1989) or phorbol ester ("Experimental Cell Research", vol.148, p.377 (1983)) are known. It cannot be used simply and safely as a cosmetic, a bath agent or a pharmaceutical.
[0008]
[Problems to be solved by the invention]
This invention is made | formed in view of the said situation, and it aims at providing the hyaluronic acid production promoter which accelerates | stimulates the hyaluronic acid production ability in humans which can be used safely and simply. The hyaluronic acid production promoter of the present invention can be effectively applied to prevention of human skin aging (skin elasticity and elasticity retention), prevention / treatment of arthritis, initial treatment of burns, and the like. In particular, the formulation for hyaluronic acid production promoter provides an external preparation for skin that can maintain the firmness and elasticity of the skin, prevent wrinkles, and maintain a moist and youthful skin state.
[0009]
[Means for Solving the Problems]
As a result of examining the hyaluronic acid production promoting ability of various substances for solving the above-mentioned problems, the present inventors have an excellent hyaluronic acid production promoting action of an extract obtained from flowers of plants belonging to the citrus family. Based on this finding, the present invention has been completed.
[0010]
That is, the present invention relates to a hyaluronic acid amount increase promoter containing, as an active ingredient, an extract from a flower, leaf, stem or xylem of a plant belonging to the Rutaceae family.
[0011]
Here, flowers or these extract of a plant belonging to Rutaceae (Rutaceae) is preferably used.
[0012]
In addition, among the plants of the Rutaceae family, plants belonging to the genus Citrus are particularly preferably used.
[0013]
Furthermore, this invention relates to the skin external preparation formed by mix | blending said hyaluronic acid production promoter.
[0014]
In addition, regarding the effect of the plant extract belonging to the citrus family, the wrinkle-improving action (see JP-A-7-126142) of the seeds of the plant belonging to the citrus genus genus and the extract, and the activity of the ponkan essence Oxygen scavenging ability (Japanese Patent Laid-Open No. 9-315993) is already known. However, there has never been a report that hyaluronic acid production-promoting action has been observed in the extracts of Citrusaceae plants, which has been found for the first time by the present inventors.
[0015]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
[0016]
Examples of the plant belonging to Rutaceae used in the present invention include plants belonging to the genus Citrus, the genus Fortunella, the genus Poncirus, the genus Skimmia, the genus Ruta, and the like. Among them, plants belonging to the genus Citrus are preferably used.
[0017]
Examples of the plants belonging to the genus Citrus include C. unshiu, C. natsudaidai, orange (C. cinensis), Daidai (sour orange, bitter orange) (C. aurantium), Mandarin orange (including Ponkan) (C. reticulata), Hassaku (C. hassaku), Iyokan (C. iyo), Grapefruit (C. paradisi), Sudachi (C. sudachi), Kavos (C. sphaerocarpa) Etc. Of these, C. unshiu, orange (C. cinensis), and die-dye (C. aurantium) are preferably used.
[0018]
In the present invention, a plant belonging to the citrus family can be used as it is, whether it is raw or dried, but it is preferably used as a dry powder or a solvent extract from the viewpoints of usability and formulation. Although the whole plant body can be used for the use site | part of a citrus plant, Preferably a flower, a leaf, a stem, a xylem, etc. are used, Among these, a flower or a leaf is used more preferably, Especially preferably, it is a flower. The “flower” in this case refers to those containing various organs involved in sexual reproduction, including so-called flower axes and flower leaves, and includes petals, stamens, pistils, sepals, and the like.
[0019]
An extract of a citrus family plant can be obtained by a conventional method. For example, a plant belonging to the citrus family can be obtained by immersing or heating and refluxing a plant belonging to the citrus family with an extraction solvent, followed by filtration and concentration. As the extraction solvent, any solvent that is usually used for extraction can be used. For example, water, methanol, ethanol, propylene glycol, 1,3-butylene glycol, glycerin and other alcohols, hydrous alcohols, chloroform , Organic solvents such as dichloroethane, carbon tetrachloride, acetone, ethyl acetate, hexane and the like can be used alone or in combination. The extract obtained by extraction with the above solvent is adsorbed as it is, or the concentrated extract is adsorbed by an adsorption method, for example, by removing impurities using an ion exchange resin, or by a column of a porous polymer (eg Amberlite XAD-2). Thereafter, a product eluted with methanol or ethanol and concentrated can also be used. Further, a partitioning method, for example, an extract extracted with water / ethyl acetate can be used.
[0020]
The plant belonging to the citrus family thus obtained or its extract has a hyaluronic acid production promoting action. Such a plant belonging to the citrus family or an extract thereof is preferably used by being blended with an external preparation.
[0021]
When the plant belonging to the citrus family or the extract thereof is blended and used in the external preparation for skin, it is preferably blended in the total amount of the external preparation by 0.0005 to 20.0% by weight as the dry weight, more preferably 0.001. -10.0 wt%. If it is less than 0.0005% by weight, the hyaluronic acid production promoting effect of the present invention is not sufficiently exhibited. On the other hand, if it exceeds 20.0% by weight, it is difficult to make a preparation. Further, even if it exceeds 10.0% by weight, no significant improvement in effect is observed.
[0022]
In the case where the hyaluronic acid production promoter of the present invention is used for a skin external preparation, in addition to the above components, components that are usually used in skin external preparations such as cosmetics and pharmaceuticals as long as they do not impair the effects of the present invention. , For example, moisturizers, antioxidants, oils, UV protection agents, surfactants, thickeners, alcohols, powder components, color materials, aqueous components, water, various skin nutrients, etc., as appropriate be able to.
[0023]
Furthermore, edetate disodium, edetate trisodium, sodium citrate, sodium polyphosphate, sodium metaphosphate, sequestering agents such as gluconic acid, preservatives such as methylparaben, ethylparaben, butylparaben, caffeine, tannin, Verapamil, tranexamic acid and its derivatives, licorice extract, grabrizine, hot water extract of karin fruit, various herbal medicines, tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, Whitening agents such as ascorbic acid glucoside, arbutin, and kojic acid, and sugars such as glucose, fructose, mannose, sucrose, and trehalose can also be appropriately blended.
[0024]
Further, the external preparation for skin of the present invention can be widely applied to cosmetics, quasi-drugs, etc., particularly preferably cosmetics applied to the outer skin, and the dosage form can also be applied to the skin. Any agent may be used as long as it is a solution, solubilization system, emulsification system, powder dispersion system, water-oil two-layer system, water-oil-powder three-layer system, ointment, lotion, gel, aerosol, etc. The type is applied.
[0025]
The use form of the external preparation for skin of the present invention is also arbitrary, for example, facial cosmetics such as lotion, emulsion, cream and pack, makeup cosmetics such as foundation, lipstick and eye shadow, aromatic cosmetics, bath preparations, etc. Can be used.
[0026]
In addition, the form which the skin external preparation of this invention can take is not limited to said dosage form and usage form.
[0027]
In addition, since the hyaluronic acid production promoter of the present invention has an excellent hyaluronic acid production promoting ability, it can be used as a preventive treatment for arthritis, an initial treatment for burns, etc., in addition to being used as a skin external preparation as described above. Is possible.
[0028]
【Example】
EXAMPLES Next, although an Example is given and this invention is demonstrated further in detail, the technical scope of this invention is not limited at all by this. In addition, all compounding quantities are weight%.
[0029]
Prior to the examples, the test method for the hyaluronic acid production promoting action of the solvent extract derived from the citrus family of the present invention will be described.
[0030]
1. Sample Preparation Orange (C. sinensis), C. unshiu or C. aurantium flowers (500 g) were immersed in methanol at room temperature for 1 week to obtain an extract. The extract was concentrated to obtain 90 g of Citrus plant extract (hereinafter referred to as “the present extract”).
[0031]
This extract was dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10% to obtain a solution containing this extract (hereinafter referred to as “original solution”).
[0032]
A solution whose concentration was adjusted by diluting the original solution was used as a test solution together with the original solution, and the following experiment was performed.
[0033]
2. Measurement of hyaluronic acid production promoting action 20,000 human skin-derived immortalized epidermal cells were seeded per well in a 24-well petri dish and cultured in a growth factor-containing KGB medium (Kurabo Co., Ltd.) for 4 days. Thereafter, the medium was replaced with 2 ml of KGB medium containing the above test solution, and further cultured for 4 days. In addition, the density | concentration of the test solution was adjusted so that DMSO might become final concentration 0.1% with respect to a culture medium. Further, the concentration of the present extract in the medium was 10 −5 to 10 −2 wt%.
[0034]
After the culture, the medium was collected and hyaluronic acid was measured. The hyaluronic acid was measured using a commercially available hyaluronic acid measurement kit (manufactured by Chugai Pharmaceutical Co., Ltd.). Further, the amount of DNA in the petri dish was measured and used as an index of the number of cells. The amount of DNA was measured by a fluorescence measurement method using “Hoechst 33258” (manufactured by Hoechst).
[0035]
The extract was not cytotoxic at the above experimental concentrations.
[0036]
The hyaluronic acid production promoting action was evaluated by the hyaluronic acid production promoting rate. Hyaluronic acid production promotion rate (%) is the medium containing this extract when the amount of hyaluronic acid per DNA of human skin-derived immortalized epidermal cells (control) cultured in a medium not containing this extract is 100. It was defined as the amount of hyaluronic acid per DNA of cultured human skin-derived immortalized epidermal cells. The results are shown in Table 1.
[0037]
As a reference example, a ginseng extract (methanol extract), which is already known to have a hyaluronic acid production promoting action, was tested in the same manner as described above, and hyaluronic acid at a concentration of 10 −3 wt%. The production promotion rate was measured. The results are also shown in Table 1.
[0038]
[Table 1]
As is clear from Table 1, it is understood that the extract of the citrus family plant has an excellent hyaluronic acid production promoting effect.
[0040]
Below, the formulation example of the hyaluronic acid production promoter by this invention of various dosage forms is given. In addition, the solvent extract of the Citrus family plant used in each Example was obtained by the conventional method. In addition, the compounding quantity of these extracts is shown with a dry weight.
[0041]
(5) to (7) were added to (11), dissolved, and heated to maintain at 70 ° C. (aqueous phase). On the other hand, (1) to (4) and (8) to (10) were mixed, heated and melted, and kept at 70 ° C. (oil phase). Subsequently, the oil phase was gradually added to the aqueous phase with stirring, and after the addition was completed, the temperature was maintained for a while to cause a reaction. Thereafter, the mixture was uniformly emulsified with a homomixer and cooled to 30 ° C. with good stirring.
[0042]
(8) was added to (13) and dissolved, and heated to 70 ° C. (water phase). On the other hand, (1) to (7) and (9) to (12) were mixed, heated and melted, and kept at 70 ° C. (oil phase). Subsequently, the oil phase was added to the aqueous phase, preliminarily emulsified, and uniformly emulsified with a homomixer, and then cooled to 30 ° C. with good stirring.
[0043]
(6) to (7) were added to (13), dissolved by heating and kept at 70 ° C. (aqueous phase). On the other hand, (1) to (5) and (8) to (12) were mixed, heated and melted, and kept at 70 ° C. (oil phase). Next, the oil phase was gradually added to the aqueous phase while stirring to carry out the reaction. After completion of the reaction, the mixture was uniformly emulsified with a homomixer and then cooled to 30 ° C. with good stirring.
[0044]
(8) was dissolved in a small amount of (13) (A phase). (6) to (7) were added to the remaining (13), dissolved by heating and kept at 70 ° C. (aqueous phase). On the other hand, (1) to (5) and (9) to (12) were mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase for preliminary emulsification, and the A phase was further added and uniformly emulsified with a homomixer. After emulsification, the mixture was cooled to 30 ° C. with good stirring.
[0045]
(8) was added to (13) and heated to 70 ° C. (aqueous phase). On the other hand, (1) to (7) and (9) to (12) were mixed, melted by heating and kept at 70 ° C. (oil phase). The aqueous phase was gradually added while stirring the oil phase, and the mixture was uniformly emulsified with a homomixer. After emulsification, the mixture was cooled to 30 ° C. with good stirring.
[0046]
(4) was uniformly dissolved in (12) (aqueous phase). On the other hand, (7) and (3) were dissolved in (1) and added to the aqueous phase. Next, (2) and (8) to (11) were added thereto, and then neutralized and thickened with (5) and (6).
[0047]
The A phase and the C phase were uniformly dissolved, and the A phase was added to the C phase and solubilized. Then phase B was added and filled.
[0048]
A phase, B phase, and C phase were uniformly dissolved, and B phase was added to A phase to solubilize. C phase was then added and filled.
[0049]
(1)-(7) powder components are sufficiently mixed with a blender, (8)-(11) oily components, (12), (13), (14) are added to this and kneaded well. Filled and molded.
[0050]
After the aqueous phase was heated and stirred, the powder part sufficiently mixed and ground was added and homomixed. Furthermore, after adding the heat-mixed oil phase and carrying out a homomixer process, the fragrance | flavor was added while stirring and it cooled to room temperature.
[0051]
(8) was added to (13) and dissolved, and heated to 70 ° C. (water phase). On the other hand, (1) to (7) and (9) to (12) were mixed, dissolved by heating, and kept at 70 ° C. (oil phase). Subsequently, the oil phase was added to the aqueous phase, preliminarily emulsified, and uniformly emulsified with a homomixer, and then cooled to 30 ° C. with good stirring.
[0052]
Each of the external preparations for skin of Examples 1 to 11 is excellent in hyaluronic acid production promoting effect, and by applying this to the skin, it maintains the elasticity and elasticity of the skin to prevent wrinkles and moisturizes. A certain youthful skin condition can be maintained.
[0053]
【The invention's effect】
As described above, the hyaluronic acid production promoter of the present invention has an excellent hyaluronic acid production promoting action, preventing human skin aging (retaining skin elasticity and elasticity), preventing and treating arthritis, etc. It can be effectively applied to the initial treatment and the like. In particular, by blending the hyaluronic acid production promoter of the present invention with an external preparation for skin (including pharmaceuticals, quasi-drugs, and cosmetics), the production of hyaluronic acid, which is one of the extracellular matrix components, is promoted. It has the effect of maintaining the firmness and elasticity of the skin to prevent wrinkles and maintaining a moist and youthful skin condition.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27136598A JP3998085B2 (en) | 1998-09-25 | 1998-09-25 | Hyaluronic acid amount increase accelerator |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27136598A JP3998085B2 (en) | 1998-09-25 | 1998-09-25 | Hyaluronic acid amount increase accelerator |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000096050A JP2000096050A (en) | 2000-04-04 |
| JP3998085B2 true JP3998085B2 (en) | 2007-10-24 |
Family
ID=17499067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27136598A Expired - Fee Related JP3998085B2 (en) | 1998-09-25 | 1998-09-25 | Hyaluronic acid amount increase accelerator |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3998085B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009110205A1 (en) | 2008-03-04 | 2009-09-11 | ナガセケムテックス株式会社 | Agent for increasing the quantity of hyaluronic acid |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004083416A (en) * | 2002-08-22 | 2004-03-18 | Takeda Food Products Ltd | Skin care preparation for external use and food and drink product |
| US20040223942A1 (en) * | 2003-03-06 | 2004-11-11 | Kao Corporation | Skin aging-preventing or improving agent |
| JP2008007412A (en) * | 2006-06-27 | 2008-01-17 | Maruzen Pharmaceut Co Ltd | Involucrin production promoter and epidermal keratinization-normalizing agent |
| JP5074163B2 (en) * | 2007-12-04 | 2012-11-14 | 共栄化学工業株式会社 | Cosmetics |
| JP2011037721A (en) * | 2009-08-06 | 2011-02-24 | Pola Chemical Industries Inc | Skin care preparation for external use exhibiting sleep-improving action |
| CN104434622A (en) * | 2014-11-05 | 2015-03-25 | 航天神舟生物科技集团有限公司 | Novel function and application of seville orange flower extract |
| TWI746917B (en) * | 2018-12-22 | 2021-11-21 | 大江生醫股份有限公司 | Use of citrus aurantium flower extract for reducing skin aging and fat content |
-
1998
- 1998-09-25 JP JP27136598A patent/JP3998085B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009110205A1 (en) | 2008-03-04 | 2009-09-11 | ナガセケムテックス株式会社 | Agent for increasing the quantity of hyaluronic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000096050A (en) | 2000-04-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2001163794A (en) | Promoter for production of hyaluronic acid and preparation for external use for skin | |
| JP2007126368A (en) | Antiaging agent, collagenase inhibitor and antioxidant | |
| JP2003201229A (en) | Matrix metalloprotease activity inhibitor and ageing- resistant cosmetic | |
| KR100443588B1 (en) | Cosmetic composition containing paeonia suffruticosa andrews extract and albizzia julibrissin dura extract having anti-ageing effect | |
| JP2006137690A (en) | Skin external preparation and hyaluronic acid production accelerator | |
| KR101142541B1 (en) | Anti-wrinkle cosmetic composition containing oriental herb extract treated by enzyme and its extraction method | |
| JP2004323406A (en) | Humectant, method for using plant extract and external preparation | |
| JP3998085B2 (en) | Hyaluronic acid amount increase accelerator | |
| JP2001158728A (en) | Agent for promoting production of hyaluronic acid and skin preparation for external use | |
| KR101400264B1 (en) | Compositions for enhancing skin barrier comprising mixture extract of Citrus unshiu Markovich and Achyranthes fauriei | |
| JPH1160496A (en) | Medicine for enhancing hyaluronic acid-producing ability | |
| JP2007084448A (en) | Production-accelerating agent of hyaluronic acid and skin lotion | |
| KR20150112103A (en) | Compositions for improving skin conditions comprising plant extracts or fractions thereof | |
| JPH1029924A (en) | Antiaging agent | |
| JP2007045733A (en) | Hyaluronidase inhibitor | |
| CN107693411B (en) | Composition containing extract of sunflower sprout and semen Ciceris Arietini with antiinflammatory effect | |
| JPH1029927A (en) | Antiaging agent | |
| JP2010024211A (en) | Cell proliferation promoting agent | |
| JP4716497B2 (en) | External preparation for skin and hyaluronidase inhibitor | |
| KR101154772B1 (en) | Cosmetic composition containing the zizyphus jujuba fruit extract and walnut extract for moisturizing effect on the skin | |
| KR20120090137A (en) | Cosmetic compositions for promoting lipolysis and removing cellulite | |
| JP2000226311A (en) | Anti-aging agent | |
| KR20110081514A (en) | Anti-aging cosmetic composition containing knotgrass extracts | |
| KR20160122052A (en) | Composition for treating wound containing stellera chamaejasme extract or fraction thereof and method for treating wound in a subject | |
| KR100946584B1 (en) | Cosmetic Composition Comprising Poncirus trifoliata fruit extract and Nymphaea caerulea extract |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20051114 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20051222 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060220 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20070510 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20070709 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20070801 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20070801 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20100817 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110817 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120817 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130817 Year of fee payment: 6 |
|
| LAPS | Cancellation because of no payment of annual fees |