JPWO2003057700A1 - Composition containing pigmentation inhibitor, its use and production method - Google Patents

Composition containing pigmentation inhibitor, its use and production method Download PDF

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JPWO2003057700A1
JPWO2003057700A1 JP2003558015A JP2003558015A JPWO2003057700A1 JP WO2003057700 A1 JPWO2003057700 A1 JP WO2003057700A1 JP 2003558015 A JP2003558015 A JP 2003558015A JP 2003558015 A JP2003558015 A JP 2003558015A JP WO2003057700 A1 JPWO2003057700 A1 JP WO2003057700A1
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篤文 岩永
篤文 岩永
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Sansho Pharmaceutical Co Ltd
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    • A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
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    • A61K8/00—Cosmetics or similar toiletry preparations
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    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
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    • A61K8/355—Quinones
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
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    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
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    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
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    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
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    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
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    • A61K8/676—Ascorbic acid, i.e. vitamin C
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract

特定のクエルセチン誘導体からなる色素沈着抑制物質とその用途ならびに製造方法を提供する。式（１）ないし（４）（省略）で表される１種または２種以上の色素沈着抑制物質を配合した色素沈着抑制組成物、ならびに式（５）および（６）（省略）で表わされる新規化合物およびそれを配合した色素沈着抑制組成物。この色素沈着抑制組成物は、化粧料組成物、飲食物組成物、医薬品組成物、および品質改良剤組成物としての用途に有用である。この色素沈着抑制組成物には、さらに、アスコルビン酸、リクイリチン、ハイドロキノン、エラグ酸、コウジ酸及びこれらの誘導体、ルシノール、胎盤抽出液及びカミツレエキスから選ばれる１種または２種以上を配合することにより、色素沈着抑制効果が相乗的に優れた組成物とすることができる。Provided are a pigmentation-inhibiting substance comprising a specific quercetin derivative, its use and production method. A pigmentation-suppressing composition comprising one or more pigmentation-inhibiting substances represented by formulas (1) to (4) (omitted), and formulas (5) and (6) (omitted) A novel compound and a pigmentation-suppressing composition containing the same. This pigmentation-suppressing composition is useful for use as a cosmetic composition, a food and drink composition, a pharmaceutical composition, and a quality improver composition. By adding one or more selected from ascorbic acid, liquiritin, hydroquinone, ellagic acid, kojic acid and their derivatives, lucinol, placental extract and chamomile extract to this pigmentation-suppressing composition Thus, a composition having a synergistically excellent pigmentation inhibitory effect can be obtained.

Description

［技術分野］
本発明は、色素沈着抑制物質とその用途ならびに製造方法に関するもので、さらに詳しくは、クセルセチン誘導体からなる色素沈着抑制物質とその用途ならびに製造方法に関するものである。
［従来の技術］
ヒト皮膚上に現れるシミやソバカス、炎症後の色素沈着等はメラニン色素の異常発現に起因する。このメラニン色素生成を抑制する化合物や抽出物として、過酸化水素や過ホウ酸亜鉛等の過酸化物やビタミンＣ、胎盤抽出エキスなどが挙げられるが、いずれも安定性、安全性、美白効果のすべての点を満たすものは得られていない。
メラニン色素の沈着を抑制し、優れた素材として利用されている微生物培養生産物であるコウジ酸は，特開平２−２００６２２号公報等で開示されているが、物性的に光曝露により着色する傾向がありその着色機構は複雑であるため、その問題解決のためには様々な製剤設計上の工夫が講じられてきた。
また、他には例えば、甘草抽出成分であるリクイリチンのメラニン生成抑制剤が特開平１−６３５０６号公報に開示されているが、同素材は水系溶媒への溶解性が悪く、有用性を発現するため十分に外用剤基剤に溶かし込むことができないというコウジ酸とは別異の製剤設計上の欠点を有している。
［発明の技術的課題］
本発明の目的は、前述した問題点を解決し、安定性に優れ、各種外用剤基剤への配合が可能で、かつ、容易に製造可能な色素沈着を改善する効果を有する色素沈着抑制物質ならびに各種の用途組成物ならびにその製造方法を提供することにある。
［発明の開示］
本発明者は長年にわたってヒトの皮膚に現れるシミなどの色素沈着を予防または除去するための美白化粧料について研究を行ってきた。その中で、メラノサイトで形成されるメラニン顆粒の貯留が最も大きな色素沈着の要因であることの確証を得、このメラニンの生成を抑制する物質を探索してきた。その結果、タマネギ（Ａｌｌｉｕｍ ｃｅｐａ）を光存在下に乾燥させた鱗片を水または／および低級アルコールで抽出した物質が特に優れた色素生成抑制作用を有することを見出し、既に特許出願した（特願２００１−２９８５３４号）。
本発明者らはさらに上記先願発明の有効成分について追試する過程で、抽出物の活性本体に関する知見を得ることができ、光に安定で製剤設計の容易な色素沈着抑制物質とその用途組成物ならびにその製造方法を完成させた。
すなわち、本発明によれば、下記式（１）ないし（４）で表される１種または２種以上の色素沈着抑制物質を配合することを特徴とする色素沈着抑制組成物が提供される。
＜式１＞

Figure 2003057700
＜式２＞
Figure 2003057700
＜式３＞
Figure 2003057700
＜式４＞
Figure 2003057700
また、本発明によれば、組成物が化粧料組成物である上記色素沈着抑制組成物が提供される。
また、本発明によれば、組成物が飲食物組成物である上記色素沈着抑制組成物が提供される。
また、本発明によれば、組成物が医薬品組成物である上記色素沈着抑制組成物が提供される。
また、本発明によれば、組成物が品質改良剤組成物である上記色素沈着抑制組成物が提供される。
また、本発明によれば、下記式（５）で表される新規化合物が提供される。
＜式５＞
Figure 2003057700
（式中、Ｒは、ＣＨ３，Ｃ２Ｈ５，ＣＯＣＨ３である。）
また、本発明によれば、下記式（６）で表される新規化合物が提供される。
＜式６＞
Figure 2003057700
（式中、Ｒは、６単糖類、５単糖類、アミノ糖類、二糖類、三糖類である。）
また、本発明によれば、上記式（５）および／または（６）で表わされる化合物からなる群より選ばれた１種または２種以上の化合物を配合することを特徴とする化粧料組成物が提供される。
また、本発明によれば、上記式（５）および／または（６）で表わされる化合物からなる群より選ばれた１種または２種以上の化合物を配合することを特徴とする飲食物組成物が提供される。
また、本発明によれば、上記式（５）および／または（６）で表わされる化合物からなる群より選ばれた１種または２種以上の化合物を配合することを特徴とする医薬品組成物が提供される。
また、本発明によれば、上記式（５）および／または（６）で表わされる化合物からなる群より選ばれた１種または２種以上の化合物を配合することを特徴とする品質改良剤組成物が提供される。
また、本発明によれば、上記式（５）および／または（６）で表わされる化合物からなる群より選ばれた１種または２種以上の化合物を配合することを特徴とする請求項１ないし５のいずれか１項記載の組成物が提供される。
また、本発明によれば、アスコルビン酸、リクイリチン、ハイドロキノン、エラグ酸、コウジ酸及びこれらの誘導体、ルシノール、胎盤抽出液及びカミツレエキスから選ばれる１種または２種以上をさらに配合することを特徴とする請求項１ないし５または請求項８ないし１２のいずれか１項記載の組成物が提供される。
また、本発明によれば、下記式（１）ないし（４）の化合物群から選ばれる色素沈着抑制物質を原料として、アルコール水による抽出法、合成手段による水酸基の修飾、あるいは酵素法により下記式（５）の新規化合物を製造する方法が提供される。
＜式１＞
Figure 2003057700
＜式２＞
Figure 2003057700
＜式３＞
Figure 2003057700
＜式４＞
Figure 2003057700
＜式５＞
Figure 2003057700
「発明を実施するための最良の形態」
本発明の色素沈着抑制物質は、大別すると２つのカテゴリーに分類される。
すなわち、第１のカテゴリーは、特願２００１−２９８５３４号に記載されているように、食用の黄色または白タマネギに由来する原料抽出物から単離精製された特定の化合物であって、第２のカテゴリーは、当該第１カテゴリーで得られた特定の化合物を原料として特定の置換基を導入した新規化合物群である。
以下、発明の詳細をこの２つのカテゴリーに分けて説明する。
第１カテゴリーで規定される化合物は、上述の化学構造式（１）ないし（４）で既に示した４種類の化合物で、シス、トランス縮合の幾何異性体と鏡像（光学）異性体の関係を有するものである。すなわち、式（１）と式（２）ならびに式（３）と式（４）で表わされる化合物とはそれぞれ鏡像異性体の関係にあり、式（１）と式（３）ならびに式（２）と式（４）で表わされる化合物とはそれぞれ幾何異性体の関係にある。なお、式（１）ないし（４）で表わされる化合物については、さらにそれぞれ１種類の構造異性体が存在することから、第１カテゴリーで規定される化合物はこれら異性体を含め合計８種類である。
これらの化合物の製造方法は、特願２００１−２９８５３４号に記載の方法に従って得られた抽出物を精製する方法が収率が良いが、これに限定されるものではない。特願２００１−２９８５３４号で得られた抽出物を例に好適な製法の一例を述べると以下のとおりである。
すなわち、タマネギ鱗茎を包む皮を含む皮を外側から３層まで剥離し、この鱗片を原料に水およびエタノールを加えて、抽出し、吸着カラムクロマトグラフィー等の分離操作によって単離することができる。なお、単離前の抽出液には二量体のほかに三量体、四量体等の多量体を含むことが確認されている。
第２カテゴリーで規定される新規化合物としては、上記式（５）および（６）で示したように、メチル基、エチル基及びアセチル基を化学合成的に導入したもの、酵素法により糖を結合させたものが挙げられる。
前者の化学合成法の好適な条件としては、アルカリ条件下で、硫酸ジメチル試薬等を用いて芳香族水酸基にメチル基、エチル基等のアルキル基を導入する方法、無水酢酸等と反応させてアセチル基を導入する方法が挙げられる。
また、後者の糖類誘導体としては、グルコース、ガラクトース、マンノースなどの公知の単糖類、スクロース、ルチノースなどの公知の二糖類、グルコサミン、ガラクトサミンなど公知のアミノ糖類が結合した配糖体があげられる。
これらの製法については、合成法のみならず酵素法も量産化に適している。その好適な条件としては、植物カルス培養系にグルコース等の糖を添加し、植物が有する合成酵素を利用する方法や、グルコーストランスフェラーゼなどの公知の変換酵素を抽出して糖を結合させる方法があげられる。
第１カテゴリーおよび第２カテゴリーで規定する化合物について、その用途の例を挙げれば、化粧料組成物の場合は医薬部外品の概念を含むものであるが、紫外線等による日焼け防止、種々の作用機序によって発生するシミ・ソバカス防止等の美白を目的とするものが挙げられ、医薬組成物の場合には、老人性黒子、炎症後色素沈着等の公知の種々の色素沈着症、皮膚弾力線維症、抗菌・酸化防止力を応用した治療を目的とするものが挙げられる。また、食品分野、品質改良組成物の場合には、金属キレート形成能、タイロシネース活性阻害作用、抗酸化作用を応用して、エビ・カニ等の甲殻類の褐変防止、菜食・根菜類の鮮度保持、めん類の斑点防止、退色防止、油脂類や各種飲食物の酸化防止など種々の用途適応性が挙げられる。
なお、上記本発明の第１および第２カテゴリーにおける各化合物を、各種組成物に使用する場合には、単離精製されたもののほか、これらの有効成分を含む抽出液としての使用を包含するものであり、さらに他の類似の有効成分、例えば、アスコルビン酸、ハイドロキノン及びこれらの公知誘導体や胎盤抽出液、カミツレエキス及びフェノール性化合物との併用により、それぞれの目的において相乗的な効果を得ることができる。
フェノール性化合物の例としては、カテキン、エピカテキン、カテキンガレート、エピカテキンガレート、リクイリチン、クエルセチン及びエラグ酸等のフラボノイド類、コウジ酸、イソコウジ酸等のコウジ酸関連物質及びコウジ酸誘導体、レゾルシン及びレゾルシン誘導体であるアルキルレゾルシン、アルコキシレゾルシン、ルシノール等が挙げられる。
コウジ酸（５−オキシ−２−オキシメチル−γ−ピロン）としては、５−オキシ−２−オキシメチル−γ−ピロンの純品、コウジ酸生産能を有する公知の菌株を培養して得られるコウジ酸を主成分とする発酵液の濃縮物及び該発酵液からコウジ酸を抽出して結晶化したものなどが使用される。
本発明の色素沈着抑制物質をクリーム、乳液、パック、エッセンス、軟膏、入浴剤、頭髪化粧料等の請求項に記載した各種の組成物に使用する場合には、その用途によって多少異なるが、概ね製剤全体に対して通常０．００５重量％ないし５重量％、好ましくは０．０１重量％ないし０．５重量％、さらに好ましくは０．０５重量％ないし０．２重量％の範囲で配合される。
また、これらの各組成物を製する場合に通常用いられる種々の公知の有効成分、例えば塩化カルプロニウム、セファランチン、ビタミンＥ、ビタミンＥニコチネート、ニコチン酸、ニコチン酸アミド、ニコチン酸ベンジル、ショウキョウチンキ、トウガラシチンキ等の末梢血管拡張剤、カンフル、メントール、ハッカ油等の清涼剤、ヒノキチオール、塩化ベンザルコニウム、ウンデシレン酸等の抗菌剤、副腎皮質ホルモン、ε−アミノカプロン酸、塩化リゾチーム、グリチルリチン、アラントイン等の消炎剤、甘草フラボノイド、紫根エキス、乳酸菌培養抽出物等の動物・植物・微生物由来の各種機能性を有する抽出物等を適宜添加して使用することができる。
さらに、本発明の色素沈着抑制物質には先の公知の有効成分に加え、油脂類等の基剤成分のほか、必要に応じて公知の保湿剤、増粘剤、防腐剤、酸化防止剤、キレート剤、ｐＨ調整剤等の種々の添加剤を適宜選択し、剤型の特性や用途に応じて至適条件下で配合することができる。
保湿剤としては、例えば、アミノ酸、乳酸ナトリウム、ピロリドンカルボン酸ナトリウム等のＮＭＦ成分、ヒアルロン酸、コラーゲン、エラスチン、コンドロイチン硫酸、デルマタン硫酸、フィブロネクチン、セラミド類、ヘパリン類似様物質、キトサン等の水溶性高分子物質等を例示することができる。
増粘剤としては、アルギン酸ナトリウム、キサンタンガム、ケイ酸アルミニウム、マルメロ種子抽出物、トラガントゴム、デンプン等の天然高分子物質、メチルセルロース、ヒドロキシエチルセルロース、カルボキシメチルセルロース、可溶性デンプン、カチオン化セルロース等の半合成高分子物質、カルボキシビニルポリマー、ポリビニルアルコール等の合成高分子物質等を例示することができる。
防腐剤としては、安息香酸塩、サリチル酸塩、デヒドロ酢酸塩、パラオキシ安息香酸エステル、２，４，４’−トリクロロ−２’−ヒドロキシジフェニルエーテル、３，４，４’−トリクロロカルバニド、塩化ベンザルコニウム、ヒノキチオール、レゾルシン等を例示することができる。
酸化防止剤としては、例えば、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、没食子酸プロピル、アスコルビン酸等を例示することができる。さらにキレート剤としては、エチレンジアミン四酢酸塩、ピロリン酸塩、ヘキサメタリン酸塩、酒石酸、グルコン酸等を例示することができ、ｐＨ調整剤としては、乳酸、クエン酸等を例示することができる。
「実施例」
以下に、実施例に基づいて本発明を説明する。
最初に本発明の色素沈着抑制物質の製造例を示す。
製造例１）
水で洗浄したタマネギ外皮１０ｋｇを一晩５０％エタノール１００Ｌ中に浸漬し、ろ過布を用いて外皮を除いて、ろ液９７Ｌを得た。この液をＨＰ２０（三菱化学製）樹脂を充填したカラム（φ１０ｃｍ×８０ｃｍ）に充填し、５０％エタノールで洗浄した後、９５％エタノールで溶出させ、溶出液を減圧乾燥することにより、式（１）ないし（４）の化合物の混合物［混合比；（１）：（２）：（３）：（４）＝２：２：１：１（ｗ／ｗ）］２１１ｇを得た。
製造例２）
製造例１で得られた式（１）ないし（４）の化合物のうち、（１）および（２）の等量混合物をＬＨ２０カラムクロマトグラフィーにより精製した乾燥物１０ｇを０．２Ｎ ＮａＯＨ３００ｍＬに溶解し、硫酸ジメチル１０ｇを加え、７０℃で１時間加温し、放置冷却後、酢酸エチルを３００ｍＬ加え、強く振り混ぜ、酢酸エチル層を分離した。減圧濃縮後、残渣に６０％エタノールを加え、ＨＰ２０カラムクロマトグラフィーにより、式（１）および（２）のメチル誘導体の等量混合物［式（５）のＲがすべてメチル基］６．７ｇを得た。
異性体混合物の物性
分子量：７００
元素分析値：Ｃ３７Ｈ３２Ｏ１４
フォリンデニス法によるポリフェノールの確認：陰性
ＴＬＣ；Ｒｆ値＝０．７７（展開溶媒；酢酸エチル：ブタノール：水＝１４：５：１）
製造例３）
クエルセチン−３，４’−ジグルコシド３０ｇを６０％エタノール１５００ｍＬに溶かし、透明ガラス瓶に入れ、人工太陽光を２４０万Ｌｕｘ・ｈｒ照射後減圧下にエタノールを留去した。遠心分離により不溶物を除去後、エタノール７００ｍＬ及び活性炭０．５ｇを加え、３０分攪拌後、ろ過し、ろ液を減圧留去し、乾燥後、式６で示されるグルコース配糖体２．５ｇを得た。
分子量：１１３８
元素分析値：Ｃ４８Ｈ５０Ｏ３２
フォリンデニス法によるポリフェノールの確認：陽性
ＴＬＣ；Ｒｆ値＝０．４９（展開溶媒；酢酸エチル：ブタノール：水＝１４：５：１）
製造例４）
製造例１で得られた式（１）ないし（４）の化合物の混合物をＬＨ２０カラムクロマトグラフィー、引き続きＯＤＳ系シリカゲルカラムを充填した分取ＨＰＬＣにより精製し乾燥した化合物（１）１．５ｇを０．１Ｍリン酸緩衝液１００ｍＬに溶解し、変換酵素としてＵＤＰ−グルコシルトランスフェラーゼ及び基質としてグルコース−６−リン酸を添加し、インキュベート後、ＬＨ２０カラムクロマトグラフィーに附した。水５００ｍＬで洗浄後、５０％エタノールで式（１）ないし（４）のフェノール性水酸基にグルコースが結合していると推定される式（１）のグルコース配糖体［式（５）のＲがすべてグルコシル基］０．２ｇを得た。
フォリンデニス法によるポリフェノールの確認；弱陽性
ＩＲ；１７００ｃｍ−１付近に吸収あり
製造例５）
水で洗浄したタマネギ外皮５００ｇを３日間５０％アセトン５０Ｌに浸漬し、ろ過布を用いて外皮を除き、ろ液４５Ｌを得た。この液を減圧濃縮し凍結乾燥後、６０ｇの抽出物を得、０．６Ｌのアセトンに溶解し、可溶部を濃縮してセファデックスＬＨ２０（ファルマシア製）樹脂を充填したカラム（φ２．６ｃｍ×８５ｃｍ）に充填し、エタノール・ヘキサンで溶出させ、溶出液を減圧乾燥することによりクエルセチン三量体０．８ｇを得た。
クエルセチン三量体の物性
分子量：９０２（ＦＡＢ−ＭＳｍ／ｚ；９０３「Ｍ＋Ｈ」＋）
ＴＬＣ；Ｒｆ値＝０．７３（展開溶媒；ブタノール：酢酸：水＝４：１：５（上層））
ＩＲ；特性吸収 ３３６５、１６４１、１５０４、１０８８、８２０ｃｍ−１
次に、上記製造例で得られた化合物を用いてその用途の有用性について検証する。
試験例１）
マウスメラノーマＢ１６細胞における色素生成抑制作用
ａ）試験方法
１０％牛胎児血清を含むイーグルＭＥＭ培地１０ｍｌを培養シャーレに入れ、本発明品（製造例１ないし製造例４で得られた乾燥物）をそれぞれ２５、５０、１００μｇ／ｍＬになるように添加した。また、試料無添加のものをコントロールとした。以上のように調製した培地に、Ｂ１６細胞を０．５×１０５個ずつ播種し、３７℃、５％ＣＯ２気相下で５日間培養し、その間、１回の培地交換を行った。培養後、培養シャーレから細胞を剥離し、遠心分離（約７００Ｇ）して細胞ペレットを作製した。この細胞ペレットのメラニン色素生成度を肉眼的に観察し、以下の判断基準にしたがって判定した。また、培養後の細胞数を測定し細胞生存率を算出した。
また、他の美白成分との併用によるＢ１６細胞におけるメラニン色素生成度を調べた。
［メラニン色素生成度の判定基準］
−：黒色（コントロールと同程度）
＋：黒色（コントロールより淡い）
２＋：灰色〜黒色
３＋：灰色
４＋：白色〜灰色
５＋：白色
ｂ）試験結果
試験の結果を表１および表２に示した。
【表１】
Figure 2003057700
【表２】
Figure 2003057700
表１から明らかなように、本発明品すべてにおいて色素生成抑制作用を示した。また、表２から明らかなように、他の美白有効成分との併用により相乗的に色素生成抑制作用を高めることができた。
以上の結果は、本発明品が色素沈着改善効果、他の美白有効成分との併用効果を有していることを裏付けるものである。
試験例２）
紫外線照射モルモットを用いた色素沈着抑制効果
ａ）試験方法
黄褐色モルモット（ブラウンタケイ）の背部皮膚を用い、該モルモットの背部毛をバリカンにて刈毛し、さらに電気カミソリで剃毛した。このモルモットの背部の４カ所（サンプル塗布部位：２カ所、基剤塗布部位：２カ所）を正方形（２×２ｃｍ）の穴の開いたアルミ箔で覆い、ＵＶＢ（東芝ＳＥランプ３本、１４０ｍＪ／ｃｍ２）で１日１回９０秒、３日ごとに４回照射した。照射開始日から表３に示したサンプルを基剤（水：エタノール：プロピレングリコール＝５：４：１（ｖ／ｖ））に配合し、１日３回連続して塗布した。塗布を開始してから２０日後に塗布部位の色素沈着抑制度の判定を行った。色素沈着抑制度の判定基準を以下に示す。
［判定基準］
３：色素沈着をほとんど認めない。
２：わずかな色素沈着を認める。
１：中程度の色素沈着を認める。
０：基剤塗布部位と変わらない。
−１：基剤塗布部位よりも強い色素沈着を認める。
ｂ）試験結果
結果を表３に示した。表の結果から本発明品はいずれも強い色素沈着抑制作用を示すことがわかる。
【表３】
Figure 2003057700
試験例３）
臨床試験
ａ）試験方法
処方例１のクリーム剤（製造例１の発明品配合）を用いて顔面における肝斑に対する臨床試験を実施した。皮膚科受診患者の総数は４５名であった。
ｂ）試験結果
試験結果を表４に示した。表の結果から明らかなように、本発明の化合物を配合したクリーム剤には肝斑に対する色素沈着抑制効果が認められた。
【表４】
Figure 2003057700
判定基準
全治：色素沈着がまったく認められない。
略治：ほとんど色素沈着が消失している。
著効：明らかに色素沈着抑制効果を認める。
有効：中程度の色素沈着抑制効果を認める。
やや有効：わずかに色素沈着効果を認める。
無効：色素沈着抑制効果が認められない。
悪化：色素沈着の増悪が観察される。
［処方例］
以下に本発明における美白剤の処方例を示す。処方例中、「適量」とは、処方全体で１００％重量になる割合を示す。
処方例１ クリーム
Figure 2003057700
処方例２ クリーム
Figure 2003057700
処方例３ クリーム
Figure 2003057700
処方例４ パック
Figure 2003057700
処方例５ 乳液
Figure 2003057700
処方例６ 軟膏剤
Figure 2003057700
処方例７ 化粧水
Figure 2003057700
処方例８ 化粧水
Figure 2003057700
処方例９ 錠菓
Figure 2003057700
処方例１０ キャンディー
Figure 2003057700
処方例１１ ドリンク
Figure 2003057700
「発明の効果」
本発明によれば、光に安定で製剤設計の容易な色素沈着抑制物質とこれを有効成分とする各種の用途組成物ならびにそのその製造方法が提供され、当該組成物は、化粧品、医薬品、飲食物及び品質改質剤としての剤型はもとより、アスコルビン酸、リクイリチン、ハイドロキノン、エラグ酸、コウジ酸及びこれらの誘導体、ルシノール、胎盤抽出液及びカミツレエキスから選ばれる１種または２種以上との組み合わせによって種々の機能特性に優れた組成物を提供することができる。[Technical field]
The present invention relates to a pigmentation-inhibiting substance, its use and production method, and more particularly, to a pigmentation-inhibiting substance comprising a quercetin derivative, its use and production method.
[Conventional technology]
Spots and freckles appearing on human skin, pigmentation after inflammation, etc. are caused by abnormal expression of melanin pigment. Examples of compounds and extracts that suppress this melanin pigment formation include peroxides such as hydrogen peroxide and zinc perborate, vitamin C, and placental extract, all of which have stability, safety, and whitening effects. No one that satisfies all the points has been obtained.
Kojic acid, which is a microorganism culture product that suppresses the deposition of melanin pigment and is used as an excellent material, is disclosed in Japanese Patent Application Laid-Open No. 2-200622, etc., but has a physical tendency to be colored by exposure to light. Since the coloring mechanism is complicated, various device design measures have been taken to solve the problem.
In addition, for example, a melanin production inhibitor of liquiritin, which is a licorice extract component, is disclosed in Japanese Patent Laid-Open No. 1-63506, but the material has poor solubility in an aqueous solvent and exhibits usefulness. Therefore, it has a drawback in formulation design different from kojic acid, which cannot be sufficiently dissolved in the external preparation base.
[Technical Problem of the Invention]
The object of the present invention is to solve the above-mentioned problems, have excellent stability, can be blended into various external preparation bases, and has an effect of improving pigmentation that can be easily produced, and has an effect of improving pigmentation It is another object of the present invention to provide various use compositions and methods for producing the same.
[Disclosure of the Invention]
The present inventor has conducted research on whitening cosmetics for preventing or removing pigmentation such as stains appearing on human skin for many years. Among them, we have confirmed that the accumulation of melanin granules formed in melanocytes is the largest cause of pigmentation, and have searched for substances that suppress the production of melanin. As a result, it was found that a substance obtained by extracting scales obtained by drying onion (Allium cepa) in the presence of light with water or / and a lower alcohol has a particularly excellent pigment formation inhibitory action, and has already filed a patent application (Japanese Patent Application 2001 -298534).
In the process of further studying the active ingredient of the above-mentioned prior application, the present inventors can obtain knowledge about the active substance of the extract, a pigmentation inhibitor that is stable to light and easy to design a formulation, and a composition for its use And the manufacturing method thereof was completed.
That is, according to the present invention, there is provided a pigmentation-suppressing composition comprising one or more pigmentation-inhibiting substances represented by the following formulas (1) to (4).
<Formula 1>
Figure 2003057700
<Formula 2>
Figure 2003057700
<Formula 3>
Figure 2003057700
<Formula 4>
Figure 2003057700
Moreover, according to this invention, the said pigmentation suppression composition whose composition is a cosmetics composition is provided.
Moreover, according to this invention, the said pigmentation suppression composition whose composition is a food-drinks composition is provided.
Moreover, according to this invention, the said pigmentation suppression composition whose composition is a pharmaceutical composition is provided.
Moreover, according to this invention, the said pigmentation suppression composition whose composition is a quality improvement agent composition is provided.
Moreover, according to this invention, the novel compound represented by following formula (5) is provided.
<Formula 5>
Figure 2003057700
(In the formula, R is CH 3 , C 2 H 5 , COCH 3. )
Moreover, according to this invention, the novel compound represented by following formula (6) is provided.
<Formula 6>
Figure 2003057700
(In the formula, R is 6 monosaccharide, 5 monosaccharide, aminosaccharide, disaccharide, or trisaccharide.)
Further, according to the present invention, a cosmetic composition comprising one or more compounds selected from the group consisting of compounds represented by the above formulas (5) and / or (6). Is provided.
Moreover, according to this invention, the food / beverage composition characterized by mix | blending 1 type, or 2 or more types of compounds chosen from the group which consists of a compound represented by said Formula (5) and / or (6). Is provided.
In addition, according to the present invention, there is provided a pharmaceutical composition characterized in that one or more compounds selected from the group consisting of compounds represented by the above formulas (5) and / or (6) are blended. Provided.
Moreover, according to the present invention, a quality improver composition comprising one or more compounds selected from the group consisting of compounds represented by the above formulas (5) and / or (6) Things are provided.
Further, according to the present invention, one or more compounds selected from the group consisting of compounds represented by the above formulas (5) and / or (6) are blended. 6. A composition according to any one of 5 is provided.
Moreover, according to the present invention, one or more selected from ascorbic acid, liquiritin, hydroquinone, ellagic acid, kojic acid and derivatives thereof, lucinol, placenta extract and chamomile extract are further blended. A composition according to any one of claims 1 to 5 or claims 8 to 12 is provided.
Further, according to the present invention, a pigmentation inhibitor selected from the compound groups represented by the following formulas (1) to (4) is used as a raw material, and the following formula is obtained by extraction with alcohol water, modification of hydroxyl groups by synthesis means, or enzymatic method. A method for producing the novel compound of (5) is provided.
<Formula 1>
Figure 2003057700
<Formula 2>
Figure 2003057700
<Formula 3>
Figure 2003057700
<Formula 4>
Figure 2003057700
<Formula 5>
Figure 2003057700
“Best Mode for Carrying Out the Invention”
The pigmentation inhibitor of the present invention is roughly classified into two categories.
That is, the first category is a specific compound isolated and purified from a raw material extract derived from edible yellow or white onion, as described in Japanese Patent Application No. 2001-298534, The category is a novel compound group in which a specific substituent is introduced using the specific compound obtained in the first category as a raw material.
Hereinafter, the details of the invention will be described by dividing into these two categories.
The compounds defined in the first category are the four compounds already shown in the above chemical structural formulas (1) to (4), and the relationship between the geometric isomers of cis and trans condensation and the mirror image (optical) isomers. I have it. That is, the compounds represented by the formulas (1) and (2) and the formulas (3) and (4) are enantiomers, respectively, and the formulas (1), (3), and (2) And the compound represented by the formula (4) are in a geometric isomer relationship. In addition, about the compound represented by Formula (1) thru | or (4), since each one type of structural isomer exists, the compound prescribed | regulated by a 1st category is a total of eight types including these isomers. .
As a method for producing these compounds, a method for purifying an extract obtained according to the method described in Japanese Patent Application No. 2001-298534 has a good yield, but is not limited thereto. An example of a production method suitable for the extract obtained in Japanese Patent Application No. 2001-298534 is as follows.
That is, the skin containing the skin that wraps the onion bulb can be peeled up to three layers from the outside, and this scale can be extracted by adding water and ethanol to the raw material, and can be isolated by a separation operation such as adsorption column chromatography. In addition, it has been confirmed that the extract before isolation contains multimers such as trimers and tetramers in addition to dimers.
As shown in the above formulas (5) and (6), new compounds defined in the second category are those in which a methyl group, an ethyl group and an acetyl group are chemically synthesized, and sugars are bound by an enzymatic method. Can be mentioned.
Suitable conditions for the former chemical synthesis method include a method of introducing an alkyl group such as a methyl group or an ethyl group into an aromatic hydroxyl group using a dimethyl sulfate reagent or the like under alkaline conditions, a reaction with acetic anhydride or the like to react with acetyl The method of introduce | transducing group is mentioned.
Examples of the latter saccharide derivatives include known monosaccharides such as glucose, galactose and mannose, known disaccharides such as sucrose and rutinose, and glycosides bound with known aminosaccharides such as glucosamine and galactosamine.
Regarding these production methods, not only synthetic methods but also enzyme methods are suitable for mass production. Suitable conditions include adding a sugar such as glucose to the plant callus culture system and utilizing a synthetic enzyme possessed by the plant, or extracting a known converting enzyme such as glucose transferase and binding the sugar. It is done.
Examples of uses of the compounds defined in the first category and the second category include the concept of quasi-drugs in the case of cosmetic compositions, but they prevent sunburn caused by ultraviolet rays and the like, and various action mechanisms. In the case of a pharmaceutical composition, various known pigmentation diseases such as senile mole, post-inflammation pigmentation, skin elasticity fibrosis, Examples are those intended for treatment using antibacterial and antioxidant power. In addition, in the case of the food field and quality-improving compositions, the metal chelate-forming ability, tyrosinase activity inhibitory action, and antioxidant action are applied to prevent browning of shrimp and crabs and other shellfish and to maintain the freshness of vegetarian and root vegetables. And various application adaptability such as prevention of spots of noodles, prevention of fading, and oxidation prevention of fats and oils and various foods and drinks.
In addition, when each compound in the first and second categories of the present invention described above is used in various compositions, in addition to those isolated and purified, those including use as an extract containing these active ingredients are included. Furthermore, in combination with other similar active ingredients such as ascorbic acid, hydroquinone and known derivatives thereof, placenta extract, chamomile extract and phenolic compounds, a synergistic effect can be obtained for each purpose. it can.
Examples of phenolic compounds include catechins, epicatechins, catechin gallates, epicatechin gallates, flavonoids such as liquiritin, quercetin and ellagic acid, kojic acid-related substances such as kojic acid and isokojic acid, and kojic acid derivatives, resorcin and resorcin Derivatives such as alkylresorcin, alkoxyresorcin, and lucinol are listed.
Kojic acid (5-oxy-2-oxymethyl-γ-pyrone) is obtained by culturing a pure product of 5-oxy-2-oxymethyl-γ-pyrone, a known strain capable of producing kojic acid. A concentrate of a fermentation broth containing kojic acid as a main component and one obtained by extracting and crystallizing kojic acid from the fermentation broth are used.
When the pigmentation inhibitor of the present invention is used in various compositions described in claims such as creams, emulsions, packs, essences, ointments, bathing agents, hair cosmetics, etc. It is usually blended in the range of 0.005% to 5% by weight, preferably 0.01% to 0.5% by weight, more preferably 0.05% to 0.2% by weight, based on the whole preparation. .
In addition, various known active ingredients usually used in producing each of these compositions, such as carpronium chloride, cephalanthin, vitamin E, vitamin E nicotinate, nicotinic acid, nicotinic acid amide, benzyl nicotinate, ginger tincture, Peripheral vasodilators such as red pepper tincture, softeners such as camphor, menthol, mint oil, antibacterial agents such as hinokitiol, benzalkonium chloride, undecylenic acid, corticosteroids, ε-aminocaproic acid, lysozyme chloride, glycyrrhizin, allantoin, etc. Anti-inflammatory agents, licorice flavonoids, purple root extract, extracts of various functions derived from animals, plants and microorganisms such as lactic acid bacteria culture extract can be added as appropriate.
Furthermore, in addition to the above-mentioned known active ingredients, the pigmentation-inhibiting substance of the present invention, in addition to base ingredients such as fats and oils, as necessary, known moisturizers, thickeners, preservatives, antioxidants, Various additives such as a chelating agent and a pH adjusting agent can be appropriately selected and blended under optimum conditions according to the characteristics and use of the dosage form.
Examples of moisturizers include NMF components such as amino acids, sodium lactate, sodium pyrrolidone carboxylate, hyaluronic acid, collagen, elastin, chondroitin sulfate, dermatan sulfate, fibronectin, ceramides, heparin-like substances, chitosan, and the like. Examples thereof include molecular substances.
Thickeners include natural alginate such as sodium alginate, xanthan gum, aluminum silicate, quince seed extract, tragacanth gum, starch, semi-synthetic polymers such as methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, soluble starch, and cationized cellulose. Examples include materials, synthetic polymer materials such as carboxyvinyl polymer and polyvinyl alcohol.
Examples of preservatives include benzoate, salicylate, dehydroacetate, paraoxybenzoate, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorocarbanide, benzalkco chloride Examples thereof include nium, hinokitiol, and resorcin.
Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, ascorbic acid and the like. Furthermore, examples of the chelating agent include ethylenediaminetetraacetate, pyrophosphate, hexametaphosphate, tartaric acid, and gluconic acid, and examples of the pH adjuster include lactic acid and citric acid.
"Example"
Hereinafter, the present invention will be described based on examples.
First, production examples of the pigmentation inhibitor of the present invention are shown.
Production Example 1)
10 kg of onion skin washed with water was immersed in 100 L of 50% ethanol overnight, and the skin was removed using a filter cloth to obtain 97 L of filtrate. This liquid is packed in a column (φ10 cm × 80 cm) packed with HP20 (Mitsubishi Chemical) resin, washed with 50% ethanol, eluted with 95% ethanol, and the eluate is dried under reduced pressure to obtain the formula (1 ) To (4) mixture [mixing ratio; (1) :( 2) :( 3) :( 4) = 2: 2: 1: 1 (w / w)] 211 g was obtained.
Production Example 2)
Among the compounds of formulas (1) to (4) obtained in Production Example 1, 10 g of a dried product obtained by purifying an equal mixture of (1) and (2) by LH20 column chromatography was dissolved in 300 mL of 0.2N NaOH. Then, 10 g of dimethyl sulfate was added, heated at 70 ° C. for 1 hour, allowed to cool, then 300 mL of ethyl acetate was added, and the mixture was shaken vigorously, and the ethyl acetate layer was separated. After concentration under reduced pressure, 60% ethanol was added to the residue, and HP20 column chromatography gave 6.7 g of an equal mixture of methyl derivatives of formulas (1) and (2) [all R in formula (5) are methyl groups]. It was.
Physical property molecular weight of isomer mixture: 700
Elemental analysis value: C 37 H 32 O 14
Confirmation of polyphenol by Forindennis method: negative TLC; Rf value = 0.77 (developing solvent; ethyl acetate: butanol: water = 14: 5: 1)
Production Example 3)
30 g of quercetin-3,4'-diglucoside was dissolved in 1500 mL of 60% ethanol, placed in a transparent glass bottle, and ethanol was distilled off under reduced pressure after irradiation of artificial sunlight with 2,400,000 Lux · hr. After removing insoluble matter by centrifugation, 700 mL of ethanol and 0.5 g of activated carbon were added, stirred for 30 minutes, filtered, the filtrate was distilled off under reduced pressure, dried, and then 2.5 g of glucose glycoside represented by Formula 6 Got.
Molecular weight: 1138
Elemental analysis value: C 48 H 50 O 32
Confirmation of polyphenol by the Folindenis method: positive TLC; Rf value = 0.49 (developing solvent; ethyl acetate: butanol: water = 14: 5: 1)
Production Example 4)
A mixture of the compounds of the formulas (1) to (4) obtained in Production Example 1 was purified by LH20 column chromatography, followed by preparative HPLC packed with an ODS silica gel column, and 1.5 g of the dried compound (1) was added to 0 g. The sample was dissolved in 100 mL of 1M phosphate buffer, UDP-glucosyltransferase as a converting enzyme and glucose-6-phosphate as a substrate were added, and incubated, and then subjected to LH20 column chromatography. After washing with 500 mL of water, the glucose glycoside of formula (1), which is presumed that glucose is bound to the phenolic hydroxyl group of formulas (1) to (4) with 50% ethanol [R in formula (5) is All obtained glucosyl group] 0.2g.
Confirmation of polyphenol by Folindenis method; weak positive IR; absorption in the vicinity of 1700 cm −1 Production Example 5)
500 g of onion skin washed with water was immersed in 50 L of 50% acetone for 3 days, and the skin was removed using a filter cloth to obtain 45 L of filtrate. This solution was concentrated under reduced pressure and lyophilized to obtain 60 g of extract, dissolved in 0.6 L of acetone, the soluble portion was concentrated, and a column (φ2.6 cm × packed with Sephadex LH20 (Pharmacia) resin was packed. 85 cm) and elution with ethanol / hexane, and the eluate was dried under reduced pressure to obtain 0.8 g of quercetin trimer.
Physical property molecular weight of quercetin trimer: 902 (FAB-MS m / z ; 903 “M + H” + )
TLC; Rf value = 0.73 (developing solvent; butanol: acetic acid: water = 4: 1: 5 (upper layer))
IR; characteristic absorption 3365, 1641, 1504, 1088, 820 cm −1
Next, the usefulness of the use is verified using the compounds obtained in the above production examples.
Test example 1)
Pigment production inhibitory action in mouse melanoma B16 cells a) Test method 10 ml of Eagle's MEM medium containing 10% fetal bovine serum is placed in a culture dish, and the products of the present invention (the dried products obtained in Production Examples 1 to 4) are used. It added so that it might become 25, 50, 100 microgram / mL. Moreover, the sample-free addition was used as a control. The medium prepared as described above was seeded with 0.5 × 10 5 B16 cells at a time and cultured at 37 ° C. in a 5% CO 2 gas phase for 5 days, during which the medium was changed once. After the culture, the cells were detached from the culture dish and centrifuged (about 700 G) to prepare a cell pellet. The degree of melanin pigment formation of this cell pellet was observed visually and determined according to the following criteria. Moreover, the cell number after culture | cultivation was measured and the cell viability was computed.
Moreover, the melanin pigment production | generation degree in B16 cell by combined use with another whitening component was investigated.
[Judgment criteria for melanin pigment formation]
-: Black (same as control)
+: Black (lighter than control)
2+: Gray to black 3+: Gray 4+: White to gray 5+: White b) Test results Tables 1 and 2 show the test results.
[Table 1]
Figure 2003057700
[Table 2]
Figure 2003057700
As is clear from Table 1, all the products of the present invention exhibited a pigment formation inhibitory action. Further, as apparent from Table 2, the pigment formation inhibitory action could be synergistically enhanced by the combined use with other whitening active ingredients.
The above results confirm that the product of the present invention has a pigmentation improving effect and a combined effect with other whitening active ingredients.
Test example 2)
Pigmentation Inhibition Effect Using Ultraviolet Irradiated Guinea Pig a) Test Method Using the back skin of a tan guinea pig (Brown Takei), the back hair of the guinea pig was shaved with a clipper and further shaved with an electric razor. Four places on the back of this guinea pig (sample application site: 2 sites, base application site: 2 sites) are covered with aluminum foil with square (2 × 2 cm) holes and UVB (3 Toshiba SE lamps, 140 mJ / cm 2 ) for 90 seconds once a day and 4 times every 3 days. The samples shown in Table 3 were blended with the base (water: ethanol: propylene glycol = 5: 4: 1 (v / v)) from the irradiation start date, and applied continuously three times a day. The degree of suppression of pigmentation at the application site was determined 20 days after the start of application. The criteria for determining the degree of pigmentation inhibition are shown below.
[Criteria]
3: Little pigmentation is observed.
2: Slight pigmentation is observed.
1: Moderate pigmentation is observed.
0: Same as base application site.
-1: Pigmentation stronger than the base application site is observed.
b) Test results are shown in Table 3. From the results in the table, it can be seen that all of the products of the present invention have a strong pigmentation inhibitory action.
[Table 3]
Figure 2003057700
Test Example 3)
Clinical Test a) Test Method A clinical test for melasma on the face was performed using the cream of Formulation Example 1 (invention product of Production Example 1). The total number of dermatologists was 45.
b) Test results The test results are shown in Table 4. As is clear from the results of the table, the cream containing the compound of the present invention was found to have a pigmentation inhibitory effect on melasma.
[Table 4]
Figure 2003057700
Criteria for complete judgment: No pigmentation is observed.
Oji: The pigmentation has almost disappeared.
Remarkable: Apparently pigmentation inhibitory effect.
Effective: A moderate pigmentation inhibitory effect is observed.
Slightly effective: Slight pigmentation effect is observed.
Invalid: No pigmentation inhibitory effect is observed.
Exacerbation: Exacerbation of pigmentation is observed.
[Prescription example]
Examples of whitening agents in the present invention are shown below. In the formulation examples, “appropriate amount” indicates a ratio of 100% weight in the entire formulation.
Formulation Example 1 Cream
Figure 2003057700
Formulation Example 2 Cream
Figure 2003057700
Formulation Example 3 Cream
Figure 2003057700
Formulation Example 4 Pack
Figure 2003057700
Formulation Example 5 Latex
Figure 2003057700
Formulation Example 6 Ointment
Figure 2003057700
Formulation Example 7 Lotion
Figure 2003057700
Formulation Example 8 Lotion
Figure 2003057700
Formulation Example 9 Tablets
Figure 2003057700
Formulation Example 10 Candy
Figure 2003057700
Formulation Example 11 Drink
Figure 2003057700
"The invention's effect"
According to the present invention, there are provided a pigmentation-inhibiting substance that is stable to light and easy to design a formulation, various use compositions containing the same, and methods for producing the same, and the composition comprises cosmetics, pharmaceuticals, food and drink Combination with one or more selected from ascorbic acid, liquiritin, hydroquinone, ellagic acid, kojic acid and derivatives thereof, lucinol, placental extract and chamomile extract Can provide a composition excellent in various functional properties.

Claims (14)

下記式（１）ないし（４）で表される１種または２種以上の色素沈着抑制物質を配合することを特徴とする色素沈着抑制組成物。
＜式１＞
Figure 2003057700
＜式２＞
Figure 2003057700
＜式３＞
Figure 2003057700
＜式４＞
Figure 2003057700
A pigmentation-inhibiting composition comprising one or more pigmentation-inhibiting substances represented by the following formulas (1) to (4):
<Formula 1>
Figure 2003057700
<Formula 2>
Figure 2003057700
<Formula 3>
Figure 2003057700
<Formula 4>
Figure 2003057700
 組成物が化粧料組成物である請求項１記載の色素沈着抑制組成物。The pigmentation-suppressing composition according to claim 1, wherein the composition is a cosmetic composition. 組成物が飲食物組成物である請求項１記載の色素沈着抑制組成物。The pigmentation-suppressing composition according to claim 1, wherein the composition is a food or drink composition. 組成物が医薬品組成物である請求項１記載の色素沈着抑制組成物。The pigmentation-suppressing composition according to claim 1, wherein the composition is a pharmaceutical composition. 組成物が品質改良剤組成物である請求項１記載の色素沈着抑制組成物。The pigmentation-suppressing composition according to claim 1, wherein the composition is a quality improver composition. 下記式（５）で表される新規化合物。
＜式５＞
Figure 2003057700
（式中、Ｒは、ＣＨ３，Ｃ２Ｈ５，ＣＯＣＨ３である。）A novel compound represented by the following formula (5).
<Formula 5>
Figure 2003057700
(In the formula, R is CH 3 , C 2 H 5 , COCH 3. ) 下記式（６）で表される新規化合物。
＜式６＞
Figure 2003057700
（式中、Ｒは、６単糖類、５単糖類、アミノ糖類、二糖類、三糖類である。）A novel compound represented by the following formula (6).
<Formula 6>
Figure 2003057700
(In the formula, R is 6 monosaccharide, 5 monosaccharide, aminosaccharide, disaccharide, or trisaccharide.) 請求項６および／または請求項７に記載された化合物からなる群より選ばれた１種または２種以上の化合物を配合することを特徴とする化粧料組成物。A cosmetic composition comprising one or more compounds selected from the group consisting of the compounds according to claim 6 and / or 7. 請求項６および／または請求項７に記載された化合物からなる群より選ばれた１種または２種以上の化合物を配合することを特徴とする飲食物組成物。A food or beverage composition comprising one or more compounds selected from the group consisting of the compounds according to claim 6 and / or 7. 請求項６および／または請求項７に記載された化合物からなる群より選ばれた１種または２種以上の化合物を配合することを特徴とする医薬品組成物。A pharmaceutical composition comprising one or more compounds selected from the group consisting of the compounds according to claim 6 and / or 7. 請求項６および／または請求項７に記載された化合物からなる群より選ばれた１種または２種以上の化合物を配合することを特徴とする品質改良剤組成物。A quality improver composition comprising one or more compounds selected from the group consisting of the compounds according to claim 6 and / or 7. 請求項６および／または請求項７に記載された化合物からなる群より選ばれた１種または２種以上の化合物をさらに配合することを特徴とする請求項１ないし５のいずれか１項記載の組成物。The compound according to any one of claims 1 to 5, further comprising one or more compounds selected from the group consisting of the compounds according to claim 6 and / or claim 7. Composition. アスコルビン酸、リクイリチン、ハイドロキノン、エラグ酸、コウジ酸及びこれらの誘導体、ルシノール、胎盤抽出液及びカミツレエキスから選ばれる１種または２種以上をさらに配合することを特徴とする請求項１ないし５または請求項８ないし１２のいずれか１項記載の組成物。6. The method according to claim 1, further comprising one or more selected from ascorbic acid, liquiritin, hydroquinone, ellagic acid, kojic acid and derivatives thereof, lucinol, placental extract and chamomile extract. Item 13. The composition according to any one of Items 8 to 12. 下記式（１）ないし（４）の化合物群から選ばれる色素沈着抑制物質を原料として、アルコール水による抽出法、合成手段による水酸基の修飾、あるいは酵素法により下記式（５）の新規化合物を製造する方法。
＜式１＞
Figure 2003057700
＜式２＞
Figure 2003057700
＜式３＞
Figure 2003057700
＜式４＞
Figure 2003057700
＜式５＞
Figure 2003057700
Production of a novel compound of the following formula (5) by using an extraction method with alcohol water, modification of a hydroxyl group by synthetic means, or an enzymatic method using a pigmentation-inhibiting substance selected from the group of compounds of the following formulas (1) to (4) how to.
<Formula 1>
Figure 2003057700
<Formula 2>
Figure 2003057700
<Formula 3>
Figure 2003057700
<Formula 4>
Figure 2003057700
<Formula 5>
Figure 2003057700
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