JP2018504440A - 腫瘍の治療および予防のためのメベンダゾール多形 - Google Patents
腫瘍の治療および予防のためのメベンダゾール多形 Download PDFInfo
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Abstract
Description
(材料および方法)
化学薬品および薬物
Janssen Pharmaceuticals(パンテルミン(登録商標))およびMedley PharmaceuticalsのMBZ錠剤(500mg)は、2013年にブラジルの地元薬局から購入し、-20℃の冷凍庫に保存した。Teva Pharmaceuticals USAのMBZ錠剤(100mg)は、2011年にジョンズ・ホプキンス病院の外来薬局で購入し、室温(RT)で保存した。Tevaは、米国市場におけるMBZの製造を2011年10月以来中止している。Aurochem Laboratories LTD。(ムンバイ、インド)は、通常混合多形を有する現在の有効活性成分(API)を含有するS2015と、特定の公開されているAPIを有するS2017(多形C)のMBZ錠剤(500mg)を製造した。Aurochemは、親切にも、MBZ多形A、B、Cを本発明者らに供給した。エラクリダール(ELD;GF120918;N-(4-(2-(1,2,3,4-テトラヒドロ-6,7-ジメトキシ-2-イソキノリニル)エチル)フェニル)-9,10-ジヒドロ-5-メトキシ-9-オキソ-4-アクリジンカルボキサミド))はSigma(セントルイス、ミズーリ、アメリカ)から購入した。チアベンダゾール(TBZ)、フルベンダゾール(FLZ)、オキシフェンダゾール(OXZ)およびフェンベンダゾール(FBZ)は、Sigma(セントルイス、ミズーリ、アメリカ)から購入した。
この研究用の細胞系は、前述の通り得た:マウス神経膠腫細胞株GL261およびヒト髄芽腫異種移植片D425Med(D425)(3,14)。GL261およびD425細胞を、10%ウシ胎仔血清と抗生物質とを補充したDMEM培地において、37℃、5% CO2を含む加湿空気中で維持した。ホタルルシフェラーゼを発現するGL261-luc細胞は前述されている(3)。
Direct Detect(商標)赤外線(IR)分光計を使用した(Millipore、ビルリカ、マサチューセッツ、アメリカ)。製造者の指示に従って、MBZ粉末または粉末に粉砕された錠剤を最初に水と混合し、カードに塗布し、空気乾燥させた。前述のように(9)、-C=Oおよび-NHのスペクトルを分析し、比較した。
全ての動物試験は、ジョンズ・ホプキンス大学の動物管理・使用委員会(ACUC)によって承認された。マウス脳の前頭葉におけるGL261-lucおよび小脳におけるD425細胞の頭蓋内移植は、前述の手順(3,4)に従った。腫瘍移植の5日後、マウスに50mg/kgのMBZまたは他のベンズイミダゾールを週5日強制経口投与した。MBZおよび他のベンズイミダゾールは、パウダー(粉末)をPBSおよびゴマ油(1:1、v:v)(Sigma)と混合するか、または錠剤を粉砕して粉末にし、前述のPBS/ゴマ油混合物に再懸濁することによって調製した。エラクリダールを、前述と同様に(15)、PBS中0.5%ヒドロキシプロピルメチルセルロースおよび0.5% Tween80中の10mg/ml懸濁液として調製した。
5〜6週齢のメスC57BL6マウスを、NCIから購入した。動物実験は、承認されたIACUCプロトコールの下で実施され、地方および国のガイドラインを順守した。全てのMBZ多形および錠剤を、強制経口投与によって50mg/kgの用量で投与した。エラクリダールを、MBZ-C投与の2時間前に50mg/kgの強制経口投与によって投与した。最初に、滅菌した0.9%NaCl溶液中に、ケタミン塩酸塩(75mg/kg)(100mg/ml;ケタミンHCl;Abbot Laboratories、シカゴ、イリノイ、アメリカ)およびキシラジン(7.5mg/kg)(100mg/ml;Xyla-ject(登録商標);Phoenix Pharmaceutical、セントジョーセフ、ミズーリ、アメリカ)を含有する保存溶液60μlを腹腔内注射し、マウス(3匹/時点)を麻酔した。次いで、血液試料を、左心室に穿刺し、吸引することにより採取した。血液試料を5mM EDTAと混合し、10000gで5分間遠心分離し、さらなる分析用の血漿を得た。
MBZと2つの代謝産物、2-アミノ-5-ベンゾイル-ベンゾイミダゾール(MBZ-NH2、CAS 52329-60-9)およびracジヒドロメベンダゾール(MBZ-OH、CAS 60254-95-7)を、血漿、脳および脳腫瘍組織において定量した。組織ホモジネートを、血漿中に200mg/mlの濃度で抽出前に調製した。メベンダゾールおよび代謝産物を、0.5μg/mlの内部標準A620223.69を含有する0.1mlのメタノールで、50μlの血漿または組織ホモジネートから抽出した。遠心分離後、上清(60μl)を水(40μl)と混合し、次いで自動試料バイアルに移した。分離は、室温でAtlantis dC18(2.1×100mm、3μm)カラムで、0.1%ギ酸を含むメタノール/水移動相(60:40、v:v)により、0.25ml/分のアイソクラティックフローを5分間使用して達成した。ポジティブモードで動作するエレクトロスプレーイオン化を使用して、AB Sciex triple quadrapole(商標)5500質量分析検出器(Applied Biosystems、フォスターシティ、カリフォルニア、アメリカ)を用いて分析物を観測した。MBZ、MBZ-NH2、MBZ-OH、およびA620223.69の[MH+]イオンが、それぞれm/z 296.0、238.0、298.0、および287.2で第1四重極(Q1)を通過し、衝突セル(Q2)に入るように、分光器をプログラムした。MBZ(m/z 263.9)、MBZ-NH2(m/z 105.1)、MBZ-OH(m/z 266.0)、およびA620223.69(m/z 124.1)の娘イオンを、第3四重極(Q3)に通して観測した。MBZおよび代謝産物の較正曲線は、1:100(v:v)までの希釈度で、5〜500ng/ml(MBZ)および1〜500ng/ml(代謝産物)の範囲にわたる1/x加重関数を有する二次方程式を使用することにより、分析の面積比ピークを内部標準に用いて計算した。1つ以上の濃度が定量限界未満であった場合、薬物動態計算には定量限界の1/2の値を割り当てた。2つの連続する時点が定量限界未満であった場合、最後の時点は分析から除外した。
動物生存データは、GraphPad Prism 5.0により分析した。p値は、Mantel-Cox検定によって決定した。0.05未満のp値は、統計的に有意であると認められた。
多形Cは、マウスの脳腫瘍の治療に最も有効であった
本発明者らは、市販されているいくつかの錠剤(Janssen、MedleyおよびTeva)と、2つの受注生産の錠剤(Aurochem S2015は、典型的には多形が混在する現在のAPIを使用し、S2017は純粋なMBZ-Cとして指定された)との多形含有量を、それらのIRプロファイルを個々のMBZ多形と比較することによって調べた(図1のAおよびB)。-C=Oおよび-NH結合のIRピークに基づいて、本発明者らは、JanssenおよびMedley錠剤は主にMBZ-CならびにAurochem S2017で作られていると判断した。室温で2年間貯蔵されたAurochem S2015およびTeva錠剤は、主にMBZ-Aのプロファイルを示した。対照として、多形A、BおよびCをDMSOに溶解し、GL261神経膠腫細胞と個別にインキュベートしたが、これは同等の細胞毒性を示した(データは示さず)。
MBZは有意なレベルで脳に達した
50mg/kgの経口投与後、MBZ-Cは16,039h*ng/mlの血漿AUC0-24hを達成した(図2のAおよび図6のA)。それに比べて、MBZ-Bは26,474h*ng/mlの血漿AUC0-24hに達したが、MBZ-A血漿AUC0-24hはわずか3,052h*ng/mlに達しただけであり、3つ全ての多形の中で断然最も低かった(MBZ-B>-C>-Aで、AUC0-24hについてP<0.05;図6のA)。徹底的な灌流後の脳組織の測定は、血漿MBZレベルと密接に関連しているMBZ-Cの有意な存在を経時的に明らかにし、脳/血漿(B/P)比は平均して0.75であり、それは8時間の間比較的安定していた(図2のB〜C)。強制経口投与の6時間後の多形を比較すると、MBZ-Cおよび-Bは、MBZ-Bのより高いレベルおよび血漿中のAUC0-24hにもかかわらず、同様の脳レベルを達成し(図2のDおよび図6のA)、MBZ-BよりもMBZ-Cの平均B/P比がやや良好になったことを、本発明者らは発見した(Cについて0.80対Bについて0.64、およびAについて0.29、p=0.055)(図2のE)。これは、MBZ-Bと-Cとが、GL261モデル(平均生存率:MBZ-Bの45日間対MBZ-Cの48.5日)において同様の生存利益を示した図1のCの有効性データとよく一致する。しかし、MBZ-Bがより大きな毒性を示し、6匹の処置動物のうち1匹のマウスの早期死亡をもたらしたことは注目に値する(図2のD)。GL261脳腫瘍および対側脳組織の分析は、脳腫瘍および正常脳組織におけるMBZ-Cの等分布を示した(図2のD)。
MBZ代謝産物の薬物動態
本発明者らは、MBZ多形の主要代謝産物であるMBZ-NH2およびMBZ-OHの血漿レベルを測定した(MBZ-B>C>Aで、MBZ-NH2のAUC0-24hについてP<0.05;MBZ-BおよびC>Aで、MBZ-OHのAUC0-24hについてP<0.05;図6のA)。血漿および脳におけるMBZ-Cの代謝産物のレベルは、通常、MBZ-Cの濃度と同じパターンに従った(図3のAおよびB)。MBZ-NH2は、血漿中のMBZ-OHよりも高いレベルを示し(図3のA)、AUC0-24hは、5,781h*ng/mlのMBZ-OH(図6のA)と比較して、10,516h*ng/mlであった。特に、逆のパターンでは、MBZ-NH2は、CmaxおよびAUC0-24hに関して、脳のMBZ-OHよりもずっと低いレベルで測定された(図3のBおよび図6のA)。興味深いことに、GL261神経膠腫において、MBZ-NH2は、対側脳より有意に高いレベルに達した(図3のC)。MBZ代謝産物の抗腫瘍作用を解明するために、本発明者らは、GL261細胞におけるMBZ、MBZ-OHおよびMBZ-NH2のIC50を比較し、MBZ-NH2がin vitroで細胞毒性が最も低いMBZの誘導体であると判定した(図3のD)。
MBZとエラクリダールの併用
腫瘍および周囲脳組織において十分な治療濃度を達成することは、ほぼ全ての脳がん治療が直面する重要な課題である。経口投与から4時間後、本発明者らは、MBZ-C脳濃度が2,016ng/g(7.1μMに相当)に達することを見出し(図6のA)、それは培養神経膠腫および髄芽細胞腫細胞(0.11〜1μM)のIC50よりもはるかに高く、in vitroで4.3μMのVEGFR2キナーゼを用いたMBZ阻害IC50よりも高かった(3、4)。比較的高い脳濃度は、脳腫瘍モデルにおけるMBZの有効性を説明するのに役立つかもしれない。次に、本発明者らは、MBZの脳分布のさらなる増加が、治療効果を高める可能性があるため望ましいと推論した。純粋な機械的障害の他に、BBBは、P-糖タンパク質(P-gp)などの、薬剤侵入を制限するための能動的排出機構を採用する。エラクリダール(ELD)は、P-gpならびに乳がん耐性タンパク質(BCRP)を阻害する強力な第3世代阻害剤であり、エラクリダールの同時投与はいくつかの薬物の脳内浸透を増加させた(15、19)。本発明者らはまず、GL261マウス神経膠腫細胞におけるエラクリダールの細胞毒性を調べ、IC50を5.8μMと決定した(図4のA)。エラクリダールを0.25μMのMBZと併用すると、in vitroで細胞毒性がわずかに増加した(図4のB)。MBZ-Cの2時間前の50mg/kgのエラクリダールの経口投与は、AUC0-8hに関してMBZの脳濃度を有意に変化はさせず、一方で2.5、4および8時間のB/P比の平均は、0.75から1.03にわずかに上昇したが、これは、統計学的に有意ではなかった(図6のBおよび図4のC)。興味深いことに、これは、エラクリダールとMBZ-Cとの併用で処置した場合、B/P比が脳内で0.12から0.30に上昇するとともに、MBZ-NH2の有意な増加を伴う(図6のB)。
エラクリダールとの併用により、MBZの治療が改善された
エラクリダールとMBZの併用療法は、GL261同系神経膠腫およびD425異種移植髄芽腫モデルにおける生存利益を増加させた(図5A〜図5D)。これは、50mg/kgの標準MBZ(MBZ-C)投与計画に、7日または14日の50mg/kgエラクリダール処置を加えることによって達成された。具体的には、GL261において、併用療法は、治療期間の長さに依存して、平均生存期間を92.5および110.5日に改善し、これは、MBZ単独の53日ならびに29.5日(対照)および34日(エラクリダール単独)から急激な増加である(図5B)。同様に、同所性D425髄芽腫異種移植モデルでは、エラクリダールとMBZとの併用により、平均生存期間が77日に増加した(図5D)。これは、53日間の生存期間のMBZ単独での治療、およびこの特定の動物モデルにおいて9日間のわずかな生存利益を示したエラクリダール単独での治療からの有意な改善である。
引用された各参考文献の開示は、明示的に本明細書に組み込まれる。
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Claims (59)
- メベンダゾールを含む医薬製剤であって、該製剤中のメベンダゾールの少なくとも90%が多形Cであり、該製剤が顆粒化されている医薬製剤。
- 前記顆粒化された製剤が被覆されている、請求項1に記載の医薬製剤。
- 前記メベンダゾールの少なくとも95%が多形Cである、請求項1に記載の医薬製剤。
- 前記メベンダゾールの少なくとも98%が多形Cである、請求項1に記載の医薬製剤。
- 前記メベンダゾールの少なくとも99%が多形Cである、請求項1に記載の医薬製剤。
- P-糖タンパク質の阻害剤をさらに含む、請求項1に記載の医薬製剤。
- 前記P-糖タンパク質の阻害剤がエラクリダールである、請求項6に記載の医薬製剤。
- 非ステロイド性抗炎症薬(NSAID)をさらに含む、請求項1に記載の医薬製剤。
- 前記NSAIDがスリンダクである、請求項8に記載の医薬製剤。
- 多形CのメベンダゾールとP-糖タンパク質の阻害剤とを含む、医薬製剤。
- 前記製剤が顆粒化されている、請求項10に記載の医薬製剤。
- 前記製剤が被覆されている、請求項11に記載の医薬製剤。
- 前記P-糖タンパク質の阻害剤がエラクリダールである、請求項10に記載の医薬製剤。
- メベンダゾールとNSAIDとを含む医薬製剤。
- 前記製剤が顆粒化されている、請求項14に記載の医薬製剤。
- 前記製剤が被覆されている、請求項15に記載の医薬製剤。
- 前記NSAIDがスリンダクである、請求項14に記載の医薬製剤。
- 前記メベンダゾールが多形Cを含む、請求項14に記載の医薬製剤。
- 請求項1、10および14のいずれか一項に記載の医薬製剤を投与する方法であって、
食品の摂取前に、前記製剤を前記食品に加えること
を含む方法。 - 前記食品が脂質を含む、請求項19に記載の方法。
- 前記医薬製剤の組成物がP-糖タンパク質阻害剤を含み、該P-糖タンパク質阻害剤がエラクリダールである、請求項19に記載の方法。
- 前記組成物がNSAIDを含み、該NSAIDがスリンダクである、請求項19に記載の方法。
- 前記食品ががん患者によって摂取される、請求項19に記載の方法。
- 前記食品が、脳腫瘍を有するがん患者によって摂取される、請求項19に記載の方法。
- 前記食品が、乳がん、結腸直腸がん、および肺腫瘍のうちの1つを有するがん患者によって摂取される、請求項19に記載の方法。
- 前記食品が、多剤耐性ポンプを有する腫瘍を有するがん患者によって摂取される、請求項19に記載の方法。
- 前記食品が、結腸直腸がんを発症するリスクの高い個体によって摂取される、請求項19に記載の方法。
- 前記個体が家族性腺腫様ポリポーシスを有する、請求項27に記載の方法。
- 前記個体が非遺伝性ポリポーシス大腸菌を有する、請求項27に記載の方法。
- メベンダゾールを含む医薬製剤の抗がん効力をモニタリングする方法であって、
医薬製剤をアッセイし、多形Cの量および多形Aの量を測定すること
を含む方法。 - 前記アッセイの工程が赤外分光法を含む、請求項30に記載の方法。
- 前記アッセイの工程が複数回実施される、請求項30に記載の方法。
- ヒトの腫瘍を治療するまたは発生させるリスクを低下させる方法であって、
請求項1、10および14のいずれか一項に記載の医薬製剤を、ヒトに投与するか、またはヒトによる経口摂取として投薬すること
を含む方法。 - 前記腫瘍が脳腫瘍である、請求項33に記載の方法。
- 前記脳腫瘍が髄芽腫である、請求項34に記載の方法。
- 前記脳腫瘍が神経膠腫である、請求項34に記載の方法。
- 前記腫瘍が、乳房腫瘍、結腸直腸腫瘍および肺腫瘍からなる群より選択される、請求項33に記載の方法。
- 前記腫瘍が多剤耐性ポンプを有する、請求項33に記載の方法。
- 腫瘍を治療するまたは腫瘍のリスクを低下させるためのキットであって、
メベンダゾールと、
P-糖タンパク質の阻害剤または非ステロイド性抗炎症薬と、
を含むキット。 - 前記メベンダゾールが多形Cを含む、請求項39に記載のキット。
- 前記多形Cが、前記メベンダゾールの少なくとも90%を構成する、請求項39に記載のキット。
- P-糖タンパク質の阻害剤を含む、請求項39に記載のキット。
- NSAIDを含む、請求項39に記載のキット。
- 前記P-糖タンパク質の阻害剤がエラクリダールである、請求項42に記載のキット。
- 前記NSAIDがスリンダクである、請求項43に記載のキット。
- ヒトの腫瘍を治療するか、またはそのリスクを低下させる方法であって、
ヒトに経口摂取として、
メベンダゾールの多形Cと、
P-糖タンパク質の阻害剤または非ステロイド性抗炎症薬と、
を投与または投薬することを含む方法。 - P-糖タンパク質の阻害剤が投与または投薬される、請求項46に記載の方法。
- 前記P-糖タンパク質の阻害剤がエラクリダールである、請求項47に記載の方法。
- 前記多形Cが、投与される前記メベンダゾールの少なくとも90%を構成する、請求項46に記載の方法。
- 脳腫瘍が治療される、請求項46に記載の方法。
- 前記脳腫瘍が髄芽腫である、請求項50に記載の方法。
- 前記脳腫瘍が神経膠腫である、請求項50に記載の方法。
- 腫瘍が治療され、前記腫瘍が、乳房腫瘍、結腸直腸腫瘍および肺腫瘍からなる群より選択される、請求項46に記載の方法。
- 前記腫瘍が多剤耐性ポンプを有する、請求項53に記載の方法。
- NSAIDが投与または投薬される、請求項46に記載の方法。
- 前記NSAIDがスリンダクである、請求項55に記載の方法。
- 前記ヒトが、がんを発症する高いリスクを有する、請求項46に記載の方法。
- 前記ヒトが、結腸直腸がんを発症する高いリスクを有する、請求項46に記載の方法。
- ヒトの腫瘍のリスクを低下させる方法であって、
ヒトに経口摂取として、
メベンダゾールと、
非ステロイド性抗炎症薬と、
を投与または投薬することを含む方法。
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US20180021310A1 (en) | 2018-01-25 |
US20210369679A1 (en) | 2021-12-02 |
IL253854B (en) | 2021-03-25 |
EP3253384A2 (en) | 2017-12-13 |
ES2907468T3 (es) | 2022-04-25 |
CN107635547A (zh) | 2018-01-26 |
WO2016127168A3 (en) | 2016-10-06 |
JP6796586B2 (ja) | 2020-12-09 |
US20240115552A1 (en) | 2024-04-11 |
EP3253384A4 (en) | 2018-08-22 |
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