JP5715952B2 - ボスウェリア・セラータエキスを含む相乗作用性抗炎症組成物 - Google Patents
ボスウェリア・セラータエキスを含む相乗作用性抗炎症組成物 Download PDFInfo
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- JP5715952B2 JP5715952B2 JP2011526635A JP2011526635A JP5715952B2 JP 5715952 B2 JP5715952 B2 JP 5715952B2 JP 2011526635 A JP2011526635 A JP 2011526635A JP 2011526635 A JP2011526635 A JP 2011526635A JP 5715952 B2 JP5715952 B2 JP 5715952B2
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Description
ボスウェリア樹脂およびエキスは、以前から、炎症性疾患の処置に使用されている。ボスウェリア酸は、ボスウェリア・セラータに起因する有益な効果を担う活性化合物として同定された。副化合物である3−O−アセチル−11−ケト−β−ボスウェリア酸(AKBA)は、全ボスウェリア酸のうちで最も強力な5−リポキシゲナーゼインヒビターとして同定された[Sailer ERら,British J Pharmacology.1996、117(4):615−8]。そのため、AKBA含量が富化されたエキスまたは画分は、天然エキスと比べて、より充分な有効性を示すと推定された。本発明者らは、そのPCT特許出願番号PCT/IN05/000074(2005年3月7日付)およびPCT特許公開公報WO03074063A1および付与されたインド特許第205269号において、滴定解析法によるとほぼ85%の全ボスウェリア酸とHPLC解析法によるとほぼ3%のAKBA(BE3%)を含む市販のボスウェリア・セラータエキスから、AKBAを30〜100%に選択的に富化したボスウェリア・セラータエキスの作製方法を示した。前記の富化ボスウェリアエキスは、通常のボスウェリア・セラータエキス中に一般的に存在している有意な量のトリテルペン成分(AKBAを除く)は含まないが、通常のボスウェリアエキス中の微量成分(3%まで)であるAKBAが該富化エキスの主成分であることを特徴とする特異な組成物である。通常のボスウェリアエキス中に存在している成分は、1)β−ボスウェリア酸、2)3−O−アセチル−β−ボスウェリア酸、3)11−ケト−β−ボスウェリア酸、4)3−O−アセチル−11−ケト−β−ボスウェリア酸、5)9−エン−β−ボスウェリア酸、6)3α−ヒドロキシウルサ−9,11−ジエン−24−酸、7)2α,3α−ヒドロキシウルサ−12−エン−24−酸である。本発明の組成物に使用する特異なAKBA富化ボスウェリア・セラータエキスの主成分は、1)3−O−アセチル−β−ボスウェリア酸、2)3−O−アセチル−9(11)−デヒドロ−β−ボスウェリア酸、3)3−O−アセチル−11−ケト−β−アミリン、4)3−O−アセチル−11−ケト−α−ボスウェリア酸である。
ボスウェリア・セラータ樹脂は、酸性化合物、非酸性化合物および糖類を含有する。商業規模での生産の実施の際には、通常のボスウェリア・セラータエキス(全ボスウェリア酸85%、BE3%)、主にトリテルペン酸(ボスウェリア酸など)を含有する酸性画分を、樹脂の残余成分から分離する。また、糖類および他の高分子物質も、全ボスウェリア酸の富化の際に水相中に分離する。残りの水不混和性非酸性低極性化合物を、ボスウェリア油状物画分/エキスとして分離する。このような非酸性または中性の低極性化合物は、市販のボスウェリアエキスおよびAKBA富化ボスウェリアエキスのどちらにおいても、存在しないか、または非常に低い濃度で存在するかのいずれかである。このような非酸性成分の存在は、AKBAの富化の増大とともに、さらに少なくなる。
本発明者らは、いくつかの細胞系インビトロ抗炎症性試験を、広範なボスウェリアエキスおよびAKBAを選択的に富化したボスウェリア・セラータエキスにおいて実施した。このような試験により、予期せず、3−O−アセチル−11−ケト−β−ボスウェリア酸(AKBA)を30%に選択的に富化したボスウェリア・セラータエキス[BE30%]は、THP−1ヒト−単球−マクロファージ細胞において、インビトロで5−LOXとFLAPのLPS誘導型発現を強力に下方調節すること示された(図3)。
(a)ボスウェリア・セラータのゴム樹脂を水不混和性有機溶媒で抽出し、この抽出物を注意深く濾過して不溶解樹脂物質を除去し、次いで、該有機溶媒抽出物を水酸化カリウム水溶液などのアルカリ水溶液で、続いて水とブラインで繰り返し洗浄し、次いで、最後に有機層を真空下、高温でエバポレートして有機溶媒を除去した後、揮発性化合物を油状残渣から高温高真空下で除去し、ボスウェリア・セラータの非酸性樹脂エキス(BNRE)を得る工程、
(b)ボスウェリア・セラータゴム樹脂の酸性エキスを選択的に富化し、AKBAを10〜100%に選択的に富化したボスウェリア・セラータエキス(BE)を得る工程、
(c)ボスウェリア・セラータの非酸性樹脂エキス(BNRE)とAKBA富化ボスウェリア・セラータエキスを所望の比率(1種類または複数種)で合わせ、本発明の組成物(1種類または複数種)を得る工程、
(d)任意選択で、該組成物を、生物学的または薬学的に許容され得る賦形剤、希釈剤および添加剤から選択される1種類以上の成分と混合する工程
を含む該組成物の作製方法を提供する。
a)BNREの主要化合物をマーカーとして同定し、該化合物を>98%純度で単離した後、スペクトルデータを用いて充分にキャラクタライズする工程、
b)既知量の各マーカー化合物を個々に、PDA検出器を有するHPLCシステムに載置されたPhenomenex Luna Phenyl−Hexyl分析用カラム(4.6×250mm,5μ)にインジェクトし、各マーカーの保持時間とピーク面積を、210nmおよび248nmでのUV検出を用いて測定する工程、ここで、該カラムは30℃に維持され、0.1%v/vのオルトリン酸を含む水およびアセトニトリルをそれぞれ27%および73%で含む二成分溶媒混合物で、1.5mL/分の流速にて溶出する;次いで、
c)既知量のBNRE試料を同様の条件下で分析し、混合物中のマーカーを、該試料のピークの保持時間と標準のものとの比較に基づいて、任意選択で該試料を各マーカーと同時にインジェクトすることによって同定し、次いで、該試料中の各マーカーのパーセントを、そのピーク面積を既知濃度の標準に対応するピーク面積と比較することにより推定する工程、次いで、
d)全マーカーの総量に対するパーセントで示すことによりBNREの組成を得、次いで、前記組成を他のBNRE試料との比較に使用する工程、該マーカーとしては、限定されないが、ネフテノール、セラトール、ジテルペンX、ルペオール、オレアナ−12−エン−3β−オール、オレアナ−12−エン−3α−オール、ラノスタ−8,24−ジエン−3α−オール、ウルサ−12−エン−3α−オールおよびギオールが挙げられる、
を含む、ボスウェリア・セラータの非酸性樹脂エキス(BNRE)の同定方法を提供する。
ボスウェリア・セラータゴム樹脂(100g)を、600mLのメチルイソブチルケトン(MIBK)溶媒中に分散させ、室温で60分間攪拌した。不溶性のゴム状物質を濾過によって分離した。MIBK溶液を2%KOH溶液(3×200mL)で繰り返し抽出し、酸性化合物を除去した。次いで、MIBK層を、水(400mL)とブライン(200mL)で連続的に洗浄した。MIBK層を減圧下、60〜70℃でエバポレートし、揮発性成分を油状残渣から、真空下、75〜85℃で除去し、ボスウェリア・セラータの非酸性樹脂エキス、すなわちBNREを粘性油状物(12g)として得た。
カラム:Phenoraenex Luna Phenyl−Hexyl,(4.6×250mm)5μ
波長:248 & 210nm
流速:1.50mL/分
インジェクション容量:20μl
温度:30℃
系:勾配
移動相:ポンプA:0.1%v/vのオルトリン酸を含む水
ポンプB:アセトニトリル
約10.0mgの研究所内参照試料を50ml容の容量フラスコ内に精秤し、メタノールで溶解させ、規定の容積にする。
約250.0mgの試料を50ml容の容量フラスコに精秤し、メタノールで溶解させ、規定の容積にする。
標準および試料溶液を、ともに0.45μ膜フィルターに通して濾過し、インジェクションする。
=(試料のピーク面積×標準の濃度×標準の純度)/(標準のピーク面積×試料の濃度)=%
滴定法によって全ボスウェリア酸85%に標準化し、3%の3−O−アセチル−11−ケト−β−ボスウェリア酸(AKBA)を含む市販のボスウェリア・セラータエキスを、10〜100%までのAKBAの選択的富化プロセスに使用した。この混合物は、HPLC分析法により、45〜50%の範囲の全β−ボスウェリア酸[3−O−アセチル−11−ケト−β−ボスウェリア酸、β−ボスウェリア酸、3−O−アセチル−β−ボスウェリア酸、11−ケト−β−ボスウェリア酸、3−O−アセチル−11−ケト−β−ボスウェリア酸]を含む。この混合物を、35〜45%のAKBAを含むように、PCT出願番号PCT/IN02/00034(2002年3月5日出願)およびPCT/IN05/000074(2005年3月7日出願)に記載の手順の一方を用いて選択的に富化した。富化プロセスにクロマトグラフィー工程もしくは晶出または両方を追加することにより、AKBAをさらに45〜100%に富化した。35〜100%の範囲のAKBAを有する富化エキスを賦形剤で、好ましくは白色デキストリンで希釈することにより、10〜35%の3−O−アセチル−11−ケト−β−ボスウェリア酸(AKBA)を含む富化エキスを調製した。AKBAを30%に富化したボスウェリア・セラータエキス(BE30%)を、本発明において使用する。
5−リポキシゲナーゼ酵素阻害活性を、Scheweらの方法(Adv Enzymol,Vol 58,191−272,1986)にReddannaら(Methods of Enzymology,Vol 187,268−277,1990)による改良を加えて使用し、測定した。アッセイ混合物は、80μMのリノール酸と充分量のイモ5−リポキシゲナーゼ(50mMのリン酸バッファー(pH6.3)中)を含むものとした。混合酵素バッファーをリノール酸に添加することにより反応を開始し、酵素活性を、234nmにおける吸光度の増大としてモニタリングした。反応を120秒間モニタリングし、試験物質BE30%、BNREおよび組成物−2の阻害可能性を、種々の濃度の試験物質を2分間インキュベートした後、リノール酸を添加することにより測定した。アッセイはすべて、3回行なった。阻害パーセントは、試験物質で得られた曲線の傾きを、対照のものと比較することにより計算した。BE30%、BNREおよび組成物−1の阻害パーセントを表4にまとめ、図4に示す。
MMP−3を、TNFα誘導型SW982ヒト滑膜細胞において評価した。簡単には、SW982細胞を、2mMのグルタミン、100U/mLのペニシリン、100mg/mLのストレプトマイシンおよび10%のウシ胎仔血清(Hyclone,Logan,UT)を有するDMEM中で培養した。ウェル1つあたり5000個の細胞を、96ウェル細胞培養プレート(Corning,USA)に、実験の1日前に播種した。培養培地を、1%のウシ胎仔血清を含有する新鮮DMEMと交換した。AKBAが30%のボスウェリアエキス(BE30%)、ボスウェリア・セラータの非酸性樹脂エキス(BNRE)および組成物−2を、培地中で5〜100ng/mlの範囲で連続希釈し、細胞とともに5%CO2で37℃にて2時間プレインキュベートし、次いで、10ng/mlのヒト組換えTNFα(R&D System,Minneapolis,MN)で24時間刺激した。培養上清みを回収し、ELISA開発キット(R&D System,Minneapolis,MN,USA)によるMMP−3生成の測定に使用した。無細胞培養上清み中のMMP−3濃度は、既知濃度のMMP−3で作成した標準曲線に光学濃度を補間することにより定量的に推定した。濃度に対して阻害パーセントプロットすることにより作成したプロットから、MMP−3の50%阻害の阻害濃度(IC50)を計算した。BE30%、BNREおよび組成物−2では、それぞれ、58.75、119.32および46.78μg/mLのIC50値が示された。これらの阻害の比較を図5に示す。
3−O−アセチル−11−ケト−β−ボスウェリア酸が30%まで選択的に富化したボスウェリア・セラータエキス(5−Loxin)とボスウェリア・セラータの非酸性樹脂エキス(BNRE)をそれぞれ1:1および2:1の比率で含む組成物−1および組成物−2の抗炎症有効性を、Sprague Dawleyラットの完全フロインドアジュバント誘導関節炎モデルでのインビボ試験によって評価した。いずれかの性のラットを無作為に選択し、各群に5匹の動物を含む5つの群に分けた。処置群ラットには、AKBAを30%まで選択的に富化したボスウェリアエキス(BE30%)またはボスウェリア・セラータの非酸性樹脂エキス(BNRE)、またはBE30%とBNREをそれぞれ1:1および2:1で含む組成物−1もしくは組成物−2を14日間、100mg/kg体重で補給した。陽性対照群には、プレドニゾロンを10mg/kg体重で補給した。供給物はすべて、投与用に10mLの1%CMCで希釈した。対照群の動物には、同じ容量の1%CMCを与えた。第14日目、完全フロインドアジュバント(FCA)を、各動物の左後足の足底下領域に皮下注射した。実験終了時、動物を致死させ、肝臓組織試料を切り取り、アリコートに分けて−80℃で保存した。血液試料を各動物から一定間隔で採取し、足体積をプレチスモグラフィ装置によって、FCA注射の日とFCA接種の13日後に測定した。FCA注射の日と誘導後13日目での浮腫の体積の差を炎症応答とみなす。BE3.0%、BNRE、組成物−1、組成物−2およびプレドニゾロンでのインビボ抗炎症応答を、CMC補給対照と比較したときの足浮腫の抑制パーセントを計算することにより推定した。
Claims (15)
- 炎症、炎症性腸疾患、関節リウマチ、若年性関節リウマチ、乾癬性関節炎、変形性関節症、難治性関節リウマチ、慢性の非リウマチ性関節炎、炎症に関連する骨粗鬆症/骨吸収、アテローム性動脈硬化、脈管炎、潰瘍性大腸炎、乾癬、成人性呼吸窮迫症候群、皮膚疾患における遅延型過敏症、喘息、UV照射によるコラーゲン分解、皮膚のしわ発生および皮膚の老化のコントロール、予防および治療のための、3−O−アセチル−11−ケト−β−ボスウェリア酸(AKBA)を選択的に富化したボスウェリア・セラータエキスと、ボスウェリア・セラータの非酸性樹脂エキス(BNRE)の治療上有効な組合せを含む、AKBAを選択的に富化したボスウェリア・セラータエキスとボスウェリア・セラータの非酸性樹脂エキス(BNRE)が相乗的に作用する、栄養補助用または医薬用またはダイエタリーサプリメント組成物。
- 選択的に富化したボスウェリア・セラータエキス中のAKBAの濃度が、重量基準で10%〜100%の範囲にある、請求項1に記載の栄養補助用または医薬用またはダイエタリーサプリメント組成物。
- 選択的に富化したボスウェリア・セラータエキス中のAKBAの濃度が、25%〜95%の範囲にある、請求項1に記載の栄養補助用または医薬用またはダイエタリーサプリメント組成物。
- 選択的に富化したボスウェリア・セラータエキス中のAKBAの濃度が、25%〜45%の範囲にある、請求項1に記載の栄養補助用または医薬用またはダイエタリーサプリメント組成物。
- ボスウェリア・セラータの非酸性樹脂エキス(BNRE)が、酸性化合物を選択的に除去した後に得られる低極性中性ボスウェリア・セラータゴム樹脂エキスである、請求項1に記載の栄養補助用または医薬用またはダイエタリーサプリメント組成物。
- 作製方法が、
(a)ボスウェリア・セラータのゴム樹脂を水不混和性有機溶媒で抽出し、この抽出物を注意深く濾過して不溶解樹脂物質を除去し、次いで、該有機溶媒抽出物を水酸化カリウム水溶液などのアルカリ水溶液で繰り返し洗浄した後、有機層を水とブラインで洗浄し、次いで、最後に有機層を真空下、高温でエバポレートして有機溶媒を除去した後、揮発性化合物を油状残渣から高温高真空下で除去し、ボスウェリア・セラータの非酸性樹脂エキス(BNRE)を得ること、
(b)ボスウェリア・セラータゴム樹脂の酸性エキスを、10〜100%のAKBAを含むボスウェリア・セラータエキス(BE)に選択的に富化すること、
(c)ボスウェリア・セラータの非酸性樹脂エキス(BNRE)とAKBA富化ボスウェリア・セラータエキス(BE)を所望の比率で合わせ、請求項1に記載の組成物を得ること、
(d)該組成物を、賦形剤、希釈剤および添加剤から選択される1種類以上の成分と混合すること
を含む、請求項1に記載の栄養補助用または医薬用またはダイエタリーサプリメント組成物。 - 3−O−アセチル−11−ケト−β−ボスウェリア酸(AKBA)を選択的に富化したボスウェリア・セラータエキスを重量基準で10%〜90%、およびボスウェリア・セラータの非酸性樹脂エキス(BNRE)を重量基準で90%〜10%含む、請求項1に記載の組成物。
- 3−O−アセチル−11−ケト−β−ボスウェリア酸(AKBA)を選択的に富化したボスウェリア・セラータエキスを重量基準で30%〜70%、およびボスウェリア・セラータの非酸性樹脂エキス(BNRE)を重量基準で70%〜30%含む、請求項1に記載の組成物。
- 1種類以上の栄養補強的または薬学的または栄養学的に許容され得る賦形剤または希釈剤または添加剤を含むものであり得る、請求項1に記載の組成物。
- 栄養補強的または薬学的または栄養学的に許容され得る賦形剤または希釈剤または添加剤として、蒸留水、生理食塩水、グルコース水溶液、アルコール(例えば、エタノール)、プロピレングリコールおよびポリエチレングリコール;ならびに種々の動物油および植物油などの油性担体、白軟パラフィン、パラフィン、ワックス、グルコース、フルクトース、スクロース、マルトース、黄色デキストリン、白色デキストリン、エアロゾル、微晶質セルロース、ステアリン酸カルシウム、ステアリン酸マグネシウム、ソルビトール、ステビオサイド、コーンシロップ、ラクトース、クエン酸、酒石酸、リンゴ酸、コハク酸、乳酸、L−アスコルビン酸、dl−α−トコフェロール、グリセリン、プロピレングリコール、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、スクロース脂肪酸エステル、ソルビタン脂肪酸エステル、プロピレングリコール脂肪酸エステル、アカシア、カラギーナン、カゼイン、ゼラチン、ペクチン、寒天、ビタミンB群、ニコチンアミド、パントテン酸カルシウム、アミノ酸、カルシウム塩、色素、フレーバーおよび保存料が挙げられる、請求項9に記載の組成物。
- さらに、1種類以上の既知の薬理学的に許容され得る酸化防止剤、アダプトゲン、抗炎症剤、抗糖尿病剤、抗肥満剤または抗アテローム性動脈硬化剤と混合したものであり得る、請求項1又は9に記載の組成物。
- 組成物は、炎症性障害の治療を必要とする被検体に、経口、局所的もしくは非経口または吸入によって投与され、投与形態は、輸液、注射液、錠剤、カプセル剤、クリーム剤、ゲル剤、顆粒剤、軟膏、注腸剤、医薬パックまたは栄養補助食品である、請求項1、9又は11に記載の組成物。
- 錠剤、カプセル剤、軟カプセル剤、硬カプセル剤、丸剤、顆粒剤、粉剤、乳剤、懸濁剤、シロップ剤、ペレット剤を含む経口薬剤;ならびに注射液、滴剤、坐剤を含む非経口薬剤;ならびに貼付剤、経表面クリーム剤およびゲル剤を含む経皮薬剤、ならびに食品成分または飲料として配合され得る、請求項1、9又は11に記載の栄養補助用または医薬用またはダイエタリーサプリメント組成物。
- i.ボスウェリア・セラータの非酸性樹脂エキス(BNRE)の主要化合物をマーカーとして同定し、該化合物を98%より高い純度で単離した後、スペクトルデータを用いて充分にキャラクタライズし、
ii.既知量の各マーカー化合物を個々に、PDA検出器を有するHPLCシステムに載置されたPhenomenex Luna Phenyl−Hexyl分析用カラム(4.6×250mm,5μ)に注入し、ここで、該カラムは30℃に維持され、0.1%v/vのオルトリン酸を含む水並びにアセトニトリルをそれぞれ27%および73%で含むバイナリー溶媒混合物で、1.5mL/分の流速にて溶出させ、各マーカーの保持時間とピーク面積を、210nmおよび248nmでのUV検出を用いて測定し、;次いで、
iii.既知量のBNRE試料を同様の条件下で分析し、混合物中のマーカーを、該試料のピークの保持時間と標準のものとの比較に基づいて、該試料を各マーカーと同時にインジェクトすることによって同定し、次いで、該試料中の各マーカーのパーセントを、そのピーク面積を既知濃度の標準に対応するピーク面積と比較することにより推定し、次いで、
iv.全マーカーの総量に対するパーセントで示すことによりBNREの組成を得、該マーカーとしては、ネフテノール、セラトール、ジテルペンX、ルペオール、オレアナ−12−エン−3β−オール、オレアナ−12−エン−3α−オール、ラノスタ−8,24−ジエン−3α−オール、ウルサ−12−エン−3α−オールおよびギオールが挙げられ、次いで、前記組成を他のBNRE試料との比較に使用する、
工程を含む、請求項1に記載の組成物の作製のために使用されるボスウェリア・セラータの非酸性樹脂エキス(BNRE)の同定方法。 - 炎症マーカーの改善のために使用される前記組成物が、5−リポキシゲナーゼ(5−LOX)、5−リポキシゲナーゼ活性化タンパク質(FLAP)、マクロファージ/脂肪細胞脂肪酸結合タンパク質(aP2)、IFN−γ、IL−4、ICAM、VCAM、MMP、TNFαおよびIL−1βを含んでいる、請求項1、9又は11に記載の組成物。
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US20190175678A1 (en) | 2019-06-13 |
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BRPI0913499B1 (pt) | 2020-03-17 |
US9101599B2 (en) | 2015-08-11 |
US10206964B2 (en) | 2019-02-19 |
US20150290270A1 (en) | 2015-10-15 |
BRPI0913499A2 (pt) | 2016-06-07 |
AU2009290366A1 (en) | 2010-03-18 |
WO2010029578A3 (en) | 2010-07-15 |
JP2012502901A (ja) | 2012-02-02 |
EA025110B1 (ru) | 2016-11-30 |
KR20110056410A (ko) | 2011-05-27 |
EA201170466A1 (ru) | 2011-12-30 |
CN102170892A (zh) | 2011-08-31 |
US20110159120A1 (en) | 2011-06-30 |
WO2010029578A2 (en) | 2010-03-18 |
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