JP2016540781A - 心筋ikrチャネルの薬剤誘発性阻害のリポソームによる軽減 - Google Patents
心筋ikrチャネルの薬剤誘発性阻害のリポソームによる軽減 Download PDFInfo
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- JP2016540781A JP2016540781A JP2016536919A JP2016536919A JP2016540781A JP 2016540781 A JP2016540781 A JP 2016540781A JP 2016536919 A JP2016536919 A JP 2016536919A JP 2016536919 A JP2016536919 A JP 2016536919A JP 2016540781 A JP2016540781 A JP 2016540781A
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Abstract
Description
心室QT間隔の再分極持続時間を制御するための組成物及び方法が本明細書中で開示される。本発明の方法は、修正されない場合に心筋細胞活動電位における再分極の延長、トルサード・ド・ポアンツ及びQT延長症候群を誘発し得る先天的欠損の修正又は治療薬による機能的介入を、それを必要とする対象に投与することを含む。本発明は、非経口投与(静脈内又は皮下)投与前にQT延長薬をリポソームと結合させるか、あるいは、QT延長の高いリスクを有することを知られている1若しくは2以上の治療薬の前若しくは治療薬と同時、又は毒物注入の直後に空リポソームを投与することのいずれかからなる。本発明の知見は、クルクミン及び他のQT延長剤の有害作用が、リポソームクルクミン及び空リポソームのボルテックスされた混合物を用いることで用量依存的に抑止されることを示す。
クリゾチニブ(Xalkori(登録商標))及びニロチニブ(Tasigna(登録商標))はそれぞれ、非小細胞肺がん及び慢性骨髄性白血病の処置のために承認されたチロシンキナーゼ阻害薬である。両方とも、ヒト及び動物におけるQT延長をもたらすことが示されている。リポソームは、ヒトether−a−go−go関連遺伝子(hERG)によりコード化されたIKr(KV11.1)チャネルに対する薬剤誘発性効果を改善することが示されている。本研究は、リポソームもIKrチャネルに対するクリゾチニブ及びニロチニブの効果を低下させるかどうかを判定するために行った。hERGで安定的にトランスフェクトしたヒト胎児由来腎臓(HEK)293細胞を使用した標準インビトロIKrアッセイにおいて、クリゾチニブ及びニロチニブを試験した。用量反応を判定し、50%阻害濃度(IC50s)を算出した。HEK293細胞をリポソームと混合したクリゾチニブ及びニロチニブで処理した場合、これらの2つの薬剤のIKrチャネル阻害効果に著しい減少がみられた。リポソーム被包性QT延長薬の使用、又はこれらの薬剤をリポソームと混合するだけで、これらの心臓性の傾向が低下することが見出された。
ウサギの心臓の心臓電気生理学的パラメータに対するクリゾチニブ及びリポソーム+クリゾチニブの効果に関するインビボでの評価。本研究の目的は、ウサギ心臓の心臓電気生理学的(PR、QRS、RR、QT及びQTc間隔)パラメータに対するクリゾチニブ及びリポソーム+クリゾチニブのインビボでの効果を定量化することである。
ウサギの心臓の心臓電気生理学的パラメータに対するニロチニブ及びリポソーム+ニロチニブのインビボでの効果に関するインビボでの評価。本研究の目的は、ウサギの心臓からの心臓電気生理学的(PR、QRS、RR、QT及びQTc間隔)パラメータに対するニロチニブ及びリポソーム+ニロチニブのインビボでの効果を定量化することである。
クリゾチニブは、11及び56μMの濃度で、それぞれ、20mVでのIKrテール電流密度の57及び89%の阻害を引き起こしたことが見出された(図18A)。対応のあるステューデントのt検定は、ベースライン時並びに11及び56μMのクリゾチニブの存在下で測定した正規化電流密度の差異が、統計学的に有意な所定の閾値(p≦0.05)に達したことを示した。IC50はクリゾチニブ単独で8.9μMであった(表35)。クリゾチニブをリポソームと9:1の比率で混合した場合、56μMの最高濃度のクリゾチニブのみがベースラインに比し統計的に有意な阻害(59%)に達した。IC50は44μMであった。11μMでのリポソーム+クリゾチニブは、IKrテール電流密度に何ら効果を及ぼさなかった。56μMでのリポソーム+クリゾチニブは、ベースラインに比しIKrテール電流密度に何ら有意な効果を及ぼさなかった。一方、11及び56μMでのクリゾチニブとリポソーム+クリゾチニブとの間の電流密度を比較すると、リポソームと混合した場合、クリゾチニブの効果である有意な阻害がみられた。リポソーム単独は、IKrテール電流密度に何ら効果を及ぼさなかった(図18A)。
クリゾチニブは、11及び56μMの濃度で、QTc間隔の用量依存的な延長を引き起こした(図30A)。クリゾチニブをリポソームと9:1の比率で混合すると、クリゾチニブ誘発性QTc延長の有意な阻害をもたらした。ニロチニブもまた、14及び28μMの濃度で、QTc間隔の用量依存的な延長を引き起こした(図30B)。クリゾチニブの場合と同様、ニロチニブをリポソームと混合すると、ニロチニブ誘発性QTc延長の有意な阻害をもたらした。シサプリド陽性対照は、QTc間隔の予想された延長を示した。
10分間にわたって静脈内注入により1、2及び3mg/kgでクリゾチニブを投与し、その後15分間維持用量を投与したウサギは、QT間隔の用量依存的な延長を示した(図23)。クリゾチニブでの処理5分前、リポソームを注入すると、クリゾチニブ誘発性QTc延長の有意な阻害がもたらされた。10分間にわたって静脈内注入により2、4及び5.5mg/kgでニロチニブを投与し、その後15分間維持用量を投与したウサギは、QT間隔の用量依存的な延長を示した(図28)。クリゾチニブの場合と同様、ニロチニブでの処理5分前、リポソームを注入すると、ニロチニブ誘発性QTc延長の有意な阻害がもたらされた。
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Claims (37)
- ヒト又は動物対象における、1若しくは2以上の心臓チャネル病、又は心パターンにおける異常若しくは変化に起因する状態、或いはそれらの両方を予防するための組成物であって、
ether−a−go−go関連遺伝子(hERG)の活性を阻害することによって、IKrチャネル阻害又はQT延長のうちの少なくとも1つを引き起こす1又は2以上の薬理学的活性剤と、
1又は2以上のリポソームと
を含み、
前記リポソームが、空リポソームであり、かつ前記薬理学的活性剤の投与の前、同時又は後に投与され、
前記空リポソームが、心臓チャネル病又は心パターンにおける異常若しくは変化に起因する状態を低減させるのに有効な量で提供される、前記組成物。 - 心臓チャネル病又は心パターンにおける異常若しくは変化に起因する状態が、心臓における遅延整流性K+電流、多形性心室性頻拍、QTc、LQT2、LQTSの延長、又はトルサード・ド・ポアンツに関与するイオンチャネルの阻害である、請求項1に記載の組成物。
- 心臓関連又は非心臓関連の疾患の処置において使用される1又は2以上の薬剤の投与によって誘発されるIKrチャネル阻害の延長、又はQT延長の処置若しくは予防のために使用される、請求項1に記載の組成物。
- 1又は2以上の活性剤が、クリゾチニブ、ニロチニブ、テルフェナジン、アステミゾール、グリパフロキサシン、テロジレン、ドロペリドール、リドフラジン、レボメタジル、セルチンドイル、又はシサプリドのうちの少なくとも1つから選択される、請求項1に記載の組成物。
- 1又は2以上の活性剤が:アロキシ;アミオダロン;亜ヒ酸;アステミゾール;ベプリジル;クロロキン;クロルフェニラミン;クロルプロマジン(ソラジン);シサプリド;セレクサ;シタロプラム;クラリスロマイシン;エリスロマイシン;クルクミン;ジソピラミド;ドフェチリド;ドンペリドン;ドキソルビシン;ドロネダロン;ドロペリドール;グレパフロキサシン;ハルドール;ハロペリドール;ハロファントリン;イブチリド;レボメタジル;リドフラジン;ロラチジン;ロボスタチン;メソリダゾン;メサドン;メタンスルホンアニリド;モキシフロキサシン;パロナシトロン;ペンタマジン;ピモジド;プレニラミン;プロブコール;プロカインアミド;プロパフェノン;ピリラミン;キニジン;テルフェニジン; セルチンドール;ソタロール;スパルフロキサシン;チオリダジン;又はバンデタニブのうちの少なくとも1つから選択される、請求項1に記載の組成物。
- 経腸、非経口、静脈内、腹腔内又は経口投与に適合される、請求項1に記載の組成物。
- 活性剤及びリポソームが、一緒に結合又はコンジュゲートされてもよい、請求項1に記載の組成物。
- リポソームが、アニオン性、カチオン性、又は中性のリポソームを含む、請求項1に記載の組成物。
- リポソームが、脂質又はリン脂質壁を含み、前記脂質又は前記リン脂質が、ホスファチジルコリン(レシチン)、リゾレシチン、リゾホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルイノシトール、スフィンゴミエリン、ホスファチジルエタノールアミン(セファリン)、カルジオリピン、ホスファチジン酸、セレブロシド、リン酸ジセチル、ホスファチジルコリン、及びジパルミトイルホスファチジルグリセロール、ステアリルアミン、ドデシルアミン、ヘキサデシルアミン、パルミチン酸アセチル、レチノール酸グリセロール、ステアリン酸ヘキサデシル、ミリスチン酸イソプロピル、両性アクリルポリマー、脂肪酸、脂肪酸アミド、コレステロール、コレステロールエステル、ジアシルグリセロール、及びジアシルグリセロールスクシネートからなる群から選択される、請求項1に記載の組成物。
- 薬学的に許容される分散媒、溶媒又は媒体をさらに含み、活性剤、リポソーム、又はそれらの両方が、前記分散媒、前記溶媒又は前記媒体中に溶解、分散又は懸濁している、請求項1に記載の組成物。
- リポソームが、DMPC(1,2−ジミリストイル−sn−グリセロ−3−ホスホコリン)及びDMPG(1,2−ジミリストイル−sn−グリセロ−3−ホスホ−rac−[1−グリセロール])を含む、請求項1に記載の組成物。
- リポソームが、9.7:1の比率のDMPC(1,2−ジミリストイル−sn−グリセロ−3−ホスホコリン)及びDMPG(1,2−ジミリストイル−sn−グリセロ−3−ホスホ−rac−[1−グリセロール])を含む、請求項1に記載の組成物。
- ether−a−go−go−関連遺伝子(hERG)の活性を阻害することによって、IKrチャネル阻害又はQT延長のうちの少なくとも1つを引き起こすヒトにおける治療的活性剤又は薬剤の投与に起因する1又は2以上の有害反応を予防又は処置するための組成物であって、
IKrチャネル阻害又はQT延長のうちの少なくとも1つを引き起こす1又は2以上の薬理学的活性剤と、
1又は2以上のリポソームと
を含み、
前記リポソームが、空リポソームであり、かつ前記治療的活性剤又は薬剤の投与に起因する有害反応を低減させるのに有効な量で前記治療的活性剤又は薬剤の投与の前、同時又は後に投与される、
前記組成物。 - 治療的活性剤又は薬剤が、ヒト又は動物対象における1又は2以上の心臓性又は非心臓性疾患の予防又は処置に使用される、請求項13に記載の組成物。
- 心臓チャネル病又は心パターンにおける異常若しくは変化に起因する状態が、心臓における遅延整流性K+電流、多形性心室性頻拍、QTc、LQT2、LQTSの延長、又はトルサード・ド・ポアンツに関与するイオンチャネルの阻害である、請求項13に記載の組成物。
- 心臓性又は非心臓性疾患の処置に使用される1又は2以上の薬剤の投与によって誘発されるIKrチャネル阻害の延長又はQT延長の処置又は予防のために使用される、請求項13に記載の組成物。
- 1又は2以上の活性剤が、クリゾチニブ、ニロチニブ、テルフェナジン、アステミゾール、グリパフロキサシン、テロジレン、ドロペリドール、リドフラジン、レボメタジル、セルチンドイル、又はシサプリドのうちの少なくとも1つから選択される、請求項13に記載の組成物。
- 経腸、非経口、静脈内、腹腔内又は経口投与に適応する、請求項13に記載の組成物。
- 活性剤及びリポソームが、一緒に結合又はコンジュゲートされてもよい、請求項13に記載の組成物。
- リポソームが、アニオン性、カチオン性、又は中性のリポソームを含む、請求項13に記載の組成物。
- リポソームが、脂質又はリン脂質壁を含み、前記脂質又は前記リン脂質が、ホスファチジルコリン(レシチン)、リゾレシチン、リゾホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルイノシトール、スフィンゴミエリン、ホスファチジルエタノールアミン(セファリン)、カルジオリピン、ホスファチジン酸、セレブロシド、リン酸ジセチル、ホスファチジルコリン、及びジパルミトイルホスファチジルグリセロール、ステアリルアミン、ドデシルアミン、ヘキサデシルアミン、パルミチン酸アセチル、レチノール酸グリセロール、ステアリン酸ヘキサデシル、ミリスチン酸イソプロピル、両性アクリルポリマー、脂肪酸、脂肪酸アミド、コレステロール、コレステロールエステル、ジアシルグリセロール、及びジアシルグリセロールスクシネートからなる群から選択される、請求項13に記載の組成物。
- リポソームが、10nm〜200nmの範囲の直径を有する球状のリポソームである、請求項13に記載の組成物。
- リポソームが、DMPC(1,2−ジミリストイル−sn−グリセロ−3−ホスホコリン)及びDMPG(1,2−ジミリストイル−sn−グリセロ−3−ホスホ−rac−[1−グリセロール])を含む、請求項13に記載の組成物。
- リポソームが、9.7:1の比率のDMPC(1,2−ジミリストイル−sn−グリセロ−3−ホスホコリン)及びDMPG(1,2−ジミリストイル−sn−グリセロ−3−ホスホ−rac−[1−グリセロール])を含む、請求項13に記載の組成物。
- 1又は2以上の活性剤が:アロキシ;アミオダロン;亜ヒ酸;アステミゾール;ベプリジル;クロロキン;クロルフェニラミン;クロルプロマジン(ソラジン);シサプリド;セレクサ;シタロプラム;クラリスロマイシン;エリスロマイシン;クルクミン;ジソピラミド;ドフェチリド;ドンペリドン;ドキソルビシン;ドロネダロン;ドロペリドール;グレパフロキサシン;ハルドール;ハロペリドール;ハロファントリン;イブチリド;レボメタジル;リドフラジン;ロラチジン;ロボスタチン;メソリダゾン;メサドン;メタンスルホンアニリド;モキシフロキサシン;パロナシトロン;ペンタマジン;ピモジド;プレニラミン;プロブコール;プロカインアミド;プロパフェノン;ピリラミン;キニジン;テルフェニジン; セルチンドール;ソタロール;スパルフロキサシン;チオリダジン;又はバンデタニブのうちの少なくとも1つから選択される、請求項13に記載の組成物。
- ヒト又は動物対象における1又は2以上の心臓チャネル病、心パターンにおける異常若しくは変化、又はその両方を予防又は処置する方法であって、
前記1又は2以上の心臓チャネル病、心パターンにおける異常若しくは変化、又はその両方の予防又は処置を必要とするヒト又は動物対象を特定するステップと、
ether−a−go−go関連遺伝子(hERG)の活性を阻害することによって、IKrチャネル阻害又はQT延長のうちの少なくとも1つを引き起こす1又は2以上の薬学的活性剤と、1又は2以上のリポソームと、任意選択の薬学的に許容される分散媒、溶媒又は媒体とを含む治療有効量の組成物を、前記ヒト又は動物対象に投与するステップであって、
前記リポソームが、空リポソームであり、かつ前記薬学的活性剤の投与前、同時、又は投与後に投与され、
前記活性剤、前記リポソーム、又はそれらの両方が、溶解、分散又は懸濁している、ステップと
を含む、前記方法。 - 心臓チャネル病又は心パターンにおける異常若しくは変化に起因する状態が、心臓における遅延整流性K+電流、多形性心室性頻拍、QTc、LQT2、LQTSの延長、又はトルサード・ド・ポアンツに関与するイオンチャネルの阻害である、請求項26に記載の方法。
- 1又は2以上の活性剤が、クリゾチニブ、ニロチニブ、テルフェナジン、アステミゾール、グリパフロキサシン、テロジレン、ドロペリドール、リドフラジン、レボメタジル、セルチンドイル、又はシサプリドのうちの少なくとも1つから選択される、請求項26に記載の方法。
- リポソームが、DMPC(1,2−ジミリストイル−sn−グリセロ−3−ホスホコリン)及びDMPG(1,2−ジミリストイル−sn−グリセロ−3−ホスホ−rac−[1−グリセロール])を含む、請求項26に記載の方法。
- リポソームが、9.7:1の比率のDMPC(1,2−ジミリストイル−sn−グリセロ−3−ホスホコリン)及びDMPG(1,2−ジミリストイル−sn−グリセロ−3−ホスホ−rac−[1−グリセロール])を含む、請求項26に記載の方法。
- 1又は2以上の活性剤が:アロキシ;アミオダロン;亜ヒ酸;アステミゾール;ベプリジル;クロロキン;クロルフェニラミン;クロルプロマジン(ソラジン);シサプリド;セレクサ;シタロプラム;クラリスロマイシン;エリスロマイシン;クルクミン;ジソピラミド;ドフェチリド;ドンペリドン;ドキソルビシン;ドロネダロン;ドロペリドール;グレパフロキサシン;ハルドール;ハロペリドール;ハロファントリン;イブチリド;レボメタジル;リドフラジン;ロラチジン;ロボスタチン;メソリダゾン;メサドン;メタンスルホンアニリド;モキシフロキサシン;パロナシトロン;ペンタマジン;ピモジド;プレニラミン;プロブコール;プロカインアミド;プロパフェノン;ピリラミン;キニジン;テルフェニジン; セルチンドール;ソタロール;スパルフロキサシン;チオリダジン;又はバンデタニブのうちの少なくとも1つから選択される、請求項26に記載の方法。
- ヒト又は動物対象における治療的活性剤、又は薬剤の投与に起因する1又は2以上の有害反応を予防又は処置するための方法であって、
ether−a−go−go関連遺伝子(hERG)の活性を阻害することによって、IKrチャネル阻害又はQT延長のうちの少なくとも1つを引き起こす前記治療的活性剤又は薬剤の投与に起因する前記1又は2以上の有害反応の予防又は処置を必要とするヒト又は動物対象を特定するステップと;
1又は2以上のリポソームを含む治療有効量の組成物を前記ヒト又は動物対象に投与するステップであって、前記リポソームが、空リポソームであり、かつ前記治療的活性剤又は薬剤の投与前、同時、又は投与後に投与されるか、あるいは前記治療的活性剤又は薬剤が充填されている、ステップと;
薬剤誘発性チャネル病に対する前記リポソームと、前記治療的活性剤又は薬剤との組合せの効果を測定するステップであって、前記組成物が、前記治療的活性剤又は薬剤によって誘発される前記チャネル病を低減又は排除する、ステップと
を含む、前記方法。 - ヒト又は動物対象における薬剤誘発性チャネル病を引き起こすクリゾチニブ、ニロチニブ、又は任意の他の活性剤の投与に起因するIKrチャネル阻害、又はQT延長のうちの少なくとも1つを予防又は処置するための方法であって、
薬剤誘発性チャネル病を引き起こすクリゾチニブ、ニロチニブ又は任意の他の活性剤の投与に起因するIKrチャネル阻害又はQT延長のうちの少なくとも1つの予防又は処置を必要とする前記ヒト又は動物対象を特定するステップと;
1又は2以上のリポソームを含む治療有効量の組成物を、前記ヒト又は動物対象に投与するステップであって、
前記リポソームが、空リポソームであり、かつ薬剤誘発性チャネル病を引き起こすクリゾチニブ、ニロチニブ又は任意の他の活性剤の投与前、同時、又は投与後に投与され、
前記組成物が、前記治療的活性剤又は薬剤によって誘発されるチャネル病を低減又は排除する、ステップと
を含む、前記方法。 - 活性剤が、薬剤誘発性IKrチャネル阻害又はQT延長が原因で、以前に臨床試験が不成功であった、請求項33に記載の方法。
- 薬剤誘発性IKrチャネル阻害又はQT延長の副作用が原因で不成功であったか又は限定された臨床使用の履歴のある薬剤を、臨床試験において特定するステップをさらに含む、請求項33に記載の方法。
- 薬理学的活性剤によって引き起こされるチャネル病を低減する候補薬剤を評価する方法であって、
(a)患者の第1のサブセットに候補薬剤、及び患者の第2のサブセットにプラセボを投与するステップであって、組成物が、IKrチャネル阻害又はQT延長のうちの少なくとも1つを引き起こす薬理学的活性剤と、1又は2以上のリポソームとを組み合わせて提供され、前記リポソームが、空リポソームであり、かつ治療的活性剤又は薬剤の投与前、同時、又は投与後に投与される、ステップと;
(b)一組の患者から薬剤誘発性チャネル病に罹患している疑いのある者についてチャネル病を測定するステップと;
(c)前記候補薬剤又は前記プラセボの投与後にステップ(a)を反復するステップと;
(d)前記組成物が、患者の前記第2のサブセットにおいて生じる低減と比較して、統計学的に有意な前記薬剤誘発性チャネル病の低減をもたらすかどうかを判定するステップであって、統計学的に有意な低減が、前記候補薬剤が前記疾患状態を処置するのに有用であることを示す、ステップと
を含む、前記方法。 - 薬剤が、薬剤誘発性IKrチャネル阻害又はQT延長が原因で、以前に臨床試験が不成功であった、請求項36に記載の方法。
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JP2019131581A (ja) | 2019-08-08 |
WO2015095576A1 (en) | 2015-06-25 |
CA2933204C (en) | 2020-04-28 |
EP3082768B1 (en) | 2023-02-22 |
US20200108056A1 (en) | 2020-04-09 |
JP2021138736A (ja) | 2021-09-16 |
JP6895252B2 (ja) | 2021-06-30 |
CA2933204A1 (en) | 2015-06-25 |
ES2940564T3 (es) | 2023-05-09 |
US20150164878A1 (en) | 2015-06-18 |
US10532045B2 (en) | 2020-01-14 |
EP3082768A4 (en) | 2017-06-14 |
EP3082768A1 (en) | 2016-10-26 |
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