JP4716655B2 - 抗炎症剤としてのモノ−およびジアシルグリセロールのグリコシドの使用 - Google Patents
抗炎症剤としてのモノ−およびジアシルグリセロールのグリコシドの使用 Download PDFInfo
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- JP4716655B2 JP4716655B2 JP2003545294A JP2003545294A JP4716655B2 JP 4716655 B2 JP4716655 B2 JP 4716655B2 JP 2003545294 A JP2003545294 A JP 2003545294A JP 2003545294 A JP2003545294 A JP 2003545294A JP 4716655 B2 JP4716655 B2 JP 4716655B2
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- Prior art keywords
- inflammatory
- compound
- octadeca
- hydrogen
- active ingredient
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Description
本発明は、炎症病態の治療、たとえば、白血球の走化性(化学遊走)(chemotaxis)および活性酸素発生応答(oxidative burst response)を軽減・緩和することによって、炎症を治療するためのモノ−またはジアシルグリセロールのグリコシド、たとえば、3−β−D−ガラクトピラノシルオキシ−2−(オクタデカ−9Z,12Z,15Z−トリエノイルオキシ)プロパニル オクタデカ−9Z,12Z,15Z−トリエノエート(バラの実の成分(rose-hips)(ロサ・カニナ・エルの果実(the fruits of Rosa canina L.))の使用に関する。
バラの果実・実(rose-hips)の水抽出物が抗炎症作用があることは、以前から報告されてきた(Winther, Rein, and Kharazmi, Inflammopharmacology, Vol.7,pp63−68(1999))。バラの実の抽出物はイン・ビトロにおいて、人の末梢血液の好中球のケモタキシス(chemotaxis)および化学発光を阻害すること、およびイン・ビボにおいて、ある炎症のパラメーターを減少させることも知られている(Kharazmi and Winther, Inflammopharmacology, Vol.7,pp377−386(1999))。
出願人が、バラの実の濃縮物について継続して研究してきた中で、出願人は驚くべきことにバラの実の特定の成分が、抗炎症剤として高い活性を有していることを見い出した。経口で摂取されるバラの実は、関節炎に伴う痛みのような炎症の痛みを効率的に軽減・緩和するので、特定化された抗炎症剤を製剤化することは、炎症性の病気に伴う症状の治療に有益であると考えられる。単離された物質は、下記に示されるように3−β−D−ガラクトピラノシルオキシ−2−(オクタデカ−9Z,12Z,15Z−トリエノイルオキシ)プロパニル オクタデカ−9Z,12Z,15Z−トリエノエート(1,2−ジ−O−α−リノレノイル−3−O−β−D−ガラクトピラノシル−グリセロール)(3-β−D−galactopyranosyloxy-2-(octadeca-9Z,12Z,15Z−trienoyloxy)propanyl octadeca-9Z,12Z,15Z-trienoate(1,2-di−O−α−linolenoyl-3-O−β−D−galactopyranosyl-glycerol))であるガラクト脂質として確認された。驚くべきことに、この化合物は、白血球の多形核白血球のケモタキシスおよび化学発光(chemiluminescence)を強く阻害することが見出された。
図1は、ロサ・カニナエル(Rosa canina L.)のバラの実から抗炎症剤を単離するために独自に使用される分別のプロセスの最初のステップを説明している。
用語“モノ−またはジエステル化されたグリセロールのグリコシド(glycoside of a mono-or diesterified glycerol)”、“モノ−またはジアシルグリセロールのグリコシド(glycosides of mono-or diacylglycerol)”および類似の用語はここで種々の式で説明されているように植物から単離することができるようなモノまたはジアシルグリセロール(およびエーテル)のグリコシドの部類を意味することを意図しているが、エイコサペンタエン酸のエステルではない。“グリコシド”部分(part)は、典型的には、ペントース、ヘキソースまたはヘプトースであり、特にガラクトースおよびグルコース、たとえば、ガラクトースのようなヘキソースであるが、二つまたはそれ以上の糖部分を組み合わせて有している、特にたとえば6−O−(α−D−ガラクトピラノシル)−β−D−ガラクトピラノースであるジガラクトシドおよびジグルコシドのような二つまたはそれ以上の糖部分を組み合わせて含んでいるジ−およびオリゴサッカライド(オリゴ糖)であることもできる。
式(III)
上記に述べたごとく、抗炎症剤は、純粋の化合物としてか、または濃縮されるかもしくは標準(規格)化された植物抽出物の成分としてか、または標準(規格)化された乾燥植物材料の成分として、直接的に使用されうる。
前記天然医薬産物は、哺乳動物の炎症病態の治療、軽減・緩和、予防のために意図されており、前記方法は:
(a)式(I)の化合物を包含する一回分の仕込み量(a batch)の植物抽出物または植物材料を提供し;
(b)前記仕込み量(batch)中の式(I)の化合物の濃度を決定し;
(c)あらかじめ決定された量の活性成分をそれぞれ含有する単位投与形態の形で、天然医薬産物を調製(preparing)することから成り;
前記あらかじめ決定された活性成分の量は、前記仕込み量(バッチ)によって提供され、前記バッチ(仕込み)量は、前記バッチの中の活性成分の濃度によって、割り算され(除され)たあらかじめ決定された量として決定される。式(I)の化合物は、好ましくは、3−β−D−ガラクトピラノシルオキシ−2−(オクタデカ−9Z,12Z,15Z−トリエノイルオキシ)プロパニル オクタデカ−9Z,12Z,15Z−トリエノエートである。この態様は、実施例4で更に説明されている。
ドッグ・ローズの果実(dog rose fruits)中の活性化合物は、活性に基づく分別法で決定された。具体的には、1000mgの乾燥粉砕された果実を、連続的にヘキサン、ジクロロメタン、メタノール、水で抽出し、抽出物は蒸発させる(脱水する)。その結果生じた残渣をイン・ビトロでヒトの末梢血液の好中球のケモタキシスを阻害するか否か試験した。この結果から、活性成分が、ジクロロメタンに存在していることが決定された(図1)。この抽出物は、シリカゲルクロマトグラフィーによって、一つのグループ(集団)に分離した。この際、グラジエント溶離剤としては、ジクロロメタンおよびメタノール(最初はジクロロメタンのみでおこない、最後は、メタノールのみ)を用いた。個々のフラクションによって、イン・ビトロにおけるヒトの末梢血液の好中球のケモタキシスを阻害するか否かを試験した。これらの結果から、このアッセイでの活性は主として、全部ではないとしても一つの化合物に限定された。この化合物を分取HPLC(preparative HPLC)で精製し、構造が、1H−、13C−、NOESY−、COSY−、およびHECTOR−NMR(核磁気共鳴分析法)実験で、3−β−D−ガラクトピラノシルオキシ−2−(オクタデカ−9Z,12Z,15Z−トリエノイルオキシ)プロパニル オクタデカ−9Z,12Z,15Z−トリエノエート(GOPO)であることを同定した。化学構造式は、更にメタノールでの塩基性加水分解(basic hydrolysis in methanol(metanolysis))(メタノール分解)および酸性加水分解(acidic hydrolysis)で確認された。塩基性分解により、リノレンメチルエステル(methyl linolenate)であることが判明し、メチルエステルのみであることが、GC−MSによって示され、一方、酸性加水分解により、分析HPLC分析(analytical HPLC analysis)によって示されたように、D−ガラクトースおよびグリセロールの存在が示された。
決定された。多重度の略号:s=シングレット(singlet), d=ダブレット(doublet),t=トリプレット(triplet),q=クアルテット(quartet) 同一欄(column)のa,b,c:これらの帰属は、変更がありうる(These assignment may be interchanged)
乾燥粉砕(粉末)されたドッグ・バラ(dog rose)(Rosa canina L.)果実をHyben Vital Interanational ApS(Tulleboelle, Denmark)から入手した。
HPLC−グレードのヘキサン、メタノール(CH3OH)、アセトニトリル(CH3CN)、ジクロロメタン(CH2Cl2)およびテトラヒドロフラン(THF)は、Merck(Darmstadt, Germany)から得られた。シリカゲル60(Silica gel 60)(0.063−0.200mm)および分析用(Analytical) (0.1mm)シリカゲル60F254プレート(TLC plates)もまたメルク社(Merck)から得られた。分析用TLCプレートは、メタノール中の10%硫酸を用いて展開され、ついで加熱した。
ドッグ・バラの粉末(1000g)を24時間、ヘキサン中(2L)に浸し、ついで、ろ過し、粉末は、ヘキサンで洗浄した(2×500mL)。集められたヘキサン溶液を減圧下で蒸発乾燥(evaporated to dryness)した。粉末は、ジクロロメタン(2L)中に24時間浸し、ろ過し、ついで残渣の粉末をジクロロメタンで洗浄した(2×500mL)。集められたジクロロメタン溶液を減圧下で蒸発乾燥した。粉末は、メタノール(2L)中に24時間浸し、ろ過し、ついで粉末をメタノールで洗浄した(2×500mL)。集められたメタノール溶液を減圧下で蒸発乾燥した。最後に、粉末を水(2L)中に24時間浸し、ろ過し、ついで粉末を水で洗浄した(2×500mL)、集められた水溶液を減圧下で蒸発乾燥した(図1)。
ジクロロメタン溶液の蒸発させた残渣を、100mLのジクロロメタンに溶解し、ついでその溶液は、ヘキサン中のシリカゲルカラム(500×40mm i.d.)におかれた。カラムはジクロロメタン中のメタノールで段階的なグラジエント(1L)(0,1,2,5,10,20および100%メタノール)で溶出をおこなった。それぞれのフラクション(100mL)は、分析用TLCで分析をおこなったが、適切な場合は、減圧下で蒸発乾燥した。
分取HPLCのために、Merck L−6200 インテリジェントポンプ(intelligent pump)およびMerck L−4200 UV−VIS 検出器(detector)が使用された。分離は、35℃で、カラムと同じ材料で包装されているガードカートリッジ(guard cartridge)(50×20mm i.d.)を取り付けたDevelosil ODS−HG−5(RP−18,粒子径(particle size)5μm;250×20mm i.d.,Nomura Chemical,Co., Japan)カラムで行われたが、使用したグラジエントは次のとおりである:150mL 25%アセトニトリル(CH3CN(aq)); 150mL 50%アセトニトリル(CH3CN(aq));150mL 60%アセトニトリル(CH3CN(aq)); 150mL 70%アセトニトリル(CH3CN(aq));150mL 80%アセトニトリル(CH3CN(aq));150mL 90%アセトニトリル(CH3CN(aq)および300mL 100%アセトニトリル(CH3CN)。化合物は230nmで検出された。流速:5mL min−1、注入量:5mL。
分析HPLCは、フォトダイオードアレー検出器を取り付けたSUMMIT/Dionex HPLC システムで実施された(波長範囲(wavelength range) 195−700nm)。単離された化合物の純度は、35℃で、逆相分析HPLC(reversed phase analytical HPLC)によって、LiChrospher 100 RP−18(粒子サイズ 5μm;244×4mm i.d., Merck)カラムで、次のグラジエントを用いて決定された:0−10min(100% 溶媒B);10−25min(100−50% 溶媒B、0−50%溶媒A);25−55min(50−0% 溶媒B、50−100%溶媒A);55−64min(100%溶媒A);64−74min(100−80% 溶媒A、0−20%溶媒C);74−85min(80% 溶媒A、20%溶媒C);85−95min(80−100% 溶媒A、20−0%溶媒C);95−105min(100−0% 溶媒A、0−100%溶媒B);および105−110min(100% 溶媒B)。グラジエントのすべての変化は、直線勾配である。溶媒A:100%アセトニトリル(100%CH3CN)、溶媒B:20%アセトニトリル(20%CH3CN)(aq)、溶媒C:100%テトラヒドロフラン(THF)。化合物は、203nmで検出された。データコレクションタイム:0−75分。流速:1mL min-1、注入量:20μL。GOPOの保持時間(retention time):約54分(図2)。
ジメチルスルホキサイド(DMSO)で調整された20mg/mlのGOPOを上記に述べられた方法で得、最小必須培地(minimal essential medium)(MEM)で細胞機能アッセイに使用するために、最終的には、100μg/ml、50μg/ml、10μg/ml、1μg/ml、および0.1μg/mlまで希釈した。
多形核白血球(PMNs)は、クエン酸を含むガラス管の中の健常人の末梢血液から単離された。細胞は、デキストラン密度勾配(dextran density gradient)およびヒト単核分離(lymphoprep separation)により、分離された。PMNsの純度は、98%より高く、細胞の生存能力はトリパンブルーダイエックスクルーション試験(trypan blue dye exclusion)によって決定されるように、98%以上であった。
ケモタキシスアッセイが、Jensen, P. and Kharazmi, A., Computer−assisted image analysis assay of human nuetrophil chemotaxis in vitro. J. Immunol. Methods, 144, 43−48.1991に述べられているように、改変されたボイエンチャンバーテクニーク(Boyden chamber technique)を用いておこなわれた。純粋化されたPMNsは、異なる希釈度の抽出されたガラクト脂質で、30分間、37℃でプレインキュベイションされた(The purified PMNs were pre-incubated with different dilutions of the extracted galactolipid for 30min at 37℃)。プレインキュベーションのあと、生物学的に活性のある化学誘引因子(chemoattractant)C5aを含んでいる、細胞の走化性(遊走)因子であるザイモサンによって活性化される血清(ZAS)のほうへ細胞が走行するケモタキシスが測定された。遊走した細胞は、コンピューターによってアシストされたイメージ分析システムによってカウントされた。
活性化されたPMNs(多形核白血球)を用い、酸素ラジカル発生を測定するために化学発光アッセイが使用された。方法は、Kharazmi,A., Hoily, N., Doring, G., and Valerius, N.H.Pseudomonas aeruginosa exoproteases inhibit human neutrophil chemiluminescence.Infect.Immun.44,587,1984.に記載されているように実施された。PMNsを、異なる濃度の抽出されたガラクト脂質でプレインキュベートし、次いで、オプソニンを作用させたザイモサンで刺激を与えた(PMNs were pre-incubated with different concentrations of the extracted galactolipid and then stimulated with opsonized zymosan.)。活性化された細胞の酸化(活性水素)発生応答が、ルミノメーター(1250−LKB Wallace)によって測定された。
ケモタキシス
表3は、GOPO(100μg/mlおよび50μg/ml希釈)のヒトの末梢血液多形核白血球のケモタキシスに対する結果を示す。結果は、走化(遊走)した細胞の数および阻害(抑制)パーセントで示す。
表3および4に示されているように、単離された化合物(GOPO)は、C5aを包含する生物学的に活性な走行(遊走)性の化学誘引因子、ザイモサンを活性化する血清の方向へ、ヒトの末梢血液の白血球が走行(遊走)することをかなり低い濃度で阻害(抑制)した。
セクション`分析HPLC条件´で述べられた分析HPLC法は、欧州委員会(European Commission(Volume 3A Guidelines; Medicinal products for human use;Quality and biotechnology 1998 Edition))からのICH−ガイドラインによる特異性(specificity)、併行精度(Repeatability)、室内再現精度(intermediate precision)、真度(accuracy)、直線性(linearity)、範囲および頑健性(range and robustness)に関して、バリデイションされており、ドッグ・ローズ製品として商業的に手に入る製品のGOPOを定量化するために使用されてきた。表7は、GOPOの市販されている10個のドッグ・ローズ製品の分析の結果が示されている。
デンマーク医薬品局(Danish Medicidines Agency(Laegeniddelstyrelsen)によって発行されているガイドラインによると、天然医薬産物は、製造される植物性または動物性の物質に特有である特定の量のある化合物を包含するように標準化されなければならない。薬剤の臨床効果を説明する義務があると認められる化合物の場合は、活性化合物として定義され、標準化をおこなうために使用されなければならない。もし、どんな活性化合物も知られていなければ、生産者は、標準化するためのマーカー化合物として、別の特徴的な化合物を選択することができる。本発明はGOPOが、関節炎ための痛みを軽減することができるローズ・ヒップ(バラの果実)製剤の活性化合物であるので、天然医薬産物として登録されているいかなるローズ・ヒップ製剤品をも標準化するために使用されなければならない。植物起源の製品(herbal product)などの標準化された製剤を登録するための同様な規制が他の国でも存在する。
Claims (5)
- 有効成分が3−β−D−ガラクトピラノシルオキシ−2−(オクタデカ−9Z,12Z,15Z−トリエノイルオキシ)プロパニル オクタデカ−9Z,12Z,15Z−トリエノエートである、請求項1または2に記載の標準化物。
- 有効成分を含む単位投与形態に調製されており、当該有効成分の量はその粗製物の量によって提供され、当該粗製物の量は有効成分の量を当該粗製物中の有効成分の濃度により割算して決定される、請求項1〜3のいずれかに記載の標準化物。
- 天然医薬品である、請求項1〜4のいずれかに記載の標準化物。
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JPWO2008108001A1 (ja) * | 2007-03-02 | 2010-06-10 | 株式会社東洋新薬 | ガラクト脂質 |
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DK177605B1 (en) | 2010-03-16 | 2013-11-18 | Hyben Vital Licens Aps | Compositions of rose hips enriched with seeds of rose hips and their use as anti-inflammatory natural medicine for alleviating/reducing symptoms associated with inflammation and joint diseases such as arthritis and/or osteo-arthritis |
EP2389816A1 (en) | 2010-05-25 | 2011-11-30 | Nestec S.A. | Synergistic antioxidant composition |
DK2585088T3 (da) * | 2010-06-25 | 2014-08-25 | Horphag Res Ip Pre Ltd | Sammensætning til forbedring af seksuel sundhed |
TWI558403B (zh) * | 2013-06-04 | 2016-11-21 | 中央研究院 | 富含半乳糖脂之植物萃取物及其用途 |
JP6339426B2 (ja) * | 2014-06-30 | 2018-06-06 | 株式会社ファンケル | グリセロ糖脂質を含有する組成物の製造方法及びグリセロ糖脂質含有組成物 |
JP2019518798A (ja) * | 2016-06-27 | 2019-07-04 | オハイオ・ステイト・イノベーション・ファウンデーション | リポヌクレオチドに基づくardsの治療 |
CN106983763B (zh) * | 2017-04-25 | 2021-04-20 | 中国海洋大学 | 单半乳糖基二酰基甘油酯及其制备方法与用途 |
CN110201026B (zh) * | 2019-07-15 | 2021-09-24 | 青岛农业大学 | 一种非抗生素型结肠炎修复制剂 |
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2002
- 2002-11-21 EP EP02803339.7A patent/EP1453844B1/en not_active Expired - Lifetime
- 2002-11-21 DK DK02803339.7T patent/DK1453844T3/da active
- 2002-11-21 US US10/300,831 patent/US7084122B2/en not_active Expired - Lifetime
- 2002-11-21 WO PCT/DK2002/000783 patent/WO2003043613A2/en active Application Filing
- 2002-11-21 PL PL370888A patent/PL213644B1/pl not_active IP Right Cessation
- 2002-11-21 AU AU2002366210A patent/AU2002366210A1/en not_active Abandoned
- 2002-11-21 PL PL393941A patent/PL393941A1/pl not_active Application Discontinuation
- 2002-11-21 CN CNB028258169A patent/CN100469784C/zh not_active Expired - Lifetime
- 2002-11-21 JP JP2003545294A patent/JP4716655B2/ja not_active Expired - Lifetime
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JPH06336437A (ja) * | 1993-03-30 | 1994-12-06 | Takeda Shokuhin Kogyo Kk | 発癌プロモーション抑制組成物 |
JPH07149786A (ja) * | 1993-11-26 | 1995-06-13 | Sagami Chem Res Center | グリセロ糖脂質及び発癌プロモーター阻害剤 |
WO1999053934A1 (en) * | 1998-04-17 | 1999-10-28 | HANSEN, Otto, Torbjørn | Rose-hip formulations as anti-inflammatory natural medicine for alleviating/reducing symptoms associated with inflammation and arthritis |
Also Published As
Publication number | Publication date |
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JP2005513023A (ja) | 2005-05-12 |
CN100469784C (zh) | 2009-03-18 |
PL213644B1 (pl) | 2013-04-30 |
EP1453844B1 (en) | 2013-11-20 |
US7084122B2 (en) | 2006-08-01 |
US20050049205A1 (en) | 2005-03-03 |
PL370888A1 (en) | 2005-05-30 |
US20030139350A1 (en) | 2003-07-24 |
CN1606563A (zh) | 2005-04-13 |
AU2002366210A1 (en) | 2003-06-10 |
NO334587B1 (no) | 2014-04-14 |
AU2002366210A8 (en) | 2003-06-10 |
WO2003043613A2 (en) | 2003-05-30 |
EP1453844A2 (en) | 2004-09-08 |
WO2003043613A3 (en) | 2004-03-25 |
DK1453844T3 (da) | 2014-02-10 |
PL393941A1 (pl) | 2011-06-20 |
JP2010215660A (ja) | 2010-09-30 |
NO20042112L (no) | 2004-07-09 |
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