JP2017508806A - 出血性疾患の治療における止血を改善するためのヒトプロトロンビン及び活性化第x因子の組成物 - Google Patents
出血性疾患の治療における止血を改善するためのヒトプロトロンビン及び活性化第x因子の組成物 Download PDFInfo
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Abstract
Description
本出願は、参照によりその全内容を本明細書に組み入れる、2014年3月14日に出願された米国仮特許出願第61/953,496号の利益を主張する。
本明細書に開示されているのは、出血性疾患の治療における止血及び抗凝固活性の逆転(reversal)を改善するための組成物及び方法である。
較正自動トロンボグラフィー(CAT)アッセイを使用して、ヒト血漿中の物質の凝固促進効果及び抗凝固効果をモニタリングした。トロンボグラムは凝固血漿中のトロンビンの濃度を記載するものであり、従ってCATは止血システムの一般的な生理学的機能試験である。このアッセイは、組織因子(TF)による凝固開始後のトロンビンによる蛍光発生基質Z-G-G-R-AMCの経時的分解によって発生する蛍光の測定に基づく。アッセイは、Thermo Scientific社から入手できる96-ウェルプレートの蛍光光度計、ThrombographTMで実施し、内部フィルター効果、血漿色のドナーによる変動、基質の欠乏及び装置の違いを補正するために必要なトロンビン較正器を使用する。
この概念実証試験の目的は、FVIII阻害したウサギにおけるネイルクリップ出血モデルで併用投与又は単独投与された3つのFII/FXa投与量の有効性を評価することであった(図3A)。最も高いFII量を有する投与量は4.4 mg/kgのFII+275 ng/kgのFXaであり、これを「FEIBA(登録商標)比率」及びFII及びFXaの双方について100%であると定義する。2つ目の投与量1.1 mg/kg FII+551 ng/kg FXaは、FIIが25%まで減少し、FXaが200%まで増加していた。3つ目の投与量0.44 mg/kg FII+826 ng/kg FXaは、FIIが10%まで減少し、FXaが300%まで増加していた。緩衝液のみの対照群と比較した処置後の血液損失の減少によって、各処置について有効性を決定した。FEIBA(登録商標)(75 U/kg)を陽性対照とした。
FEIBA(登録商標)、FII若しくはFXaの単独または組合せ、あるいは緩衝液の投与後のFVIII阻害されたウサギの血液サンプルを、トロンボエラストグラフィー(TEG)によってex vivoで分析した。測定は、TEG hemostasis analyzer 5000(Haemonetics Corp, USA)を使用して37℃で実施した。FVIII-インヒビター血漿の投与前及び投与45分後、試験物質又は対照物質の投与直後、及び2回目の出血観察期間の最後(試験物質投与のおよそ40分後)に血液をサンプリングした。血液は、0.1 mLのクエン酸ナトリウム及び21μLのCTI(Haematologic Technologies, 3 mg/mL)を充填した2-mLのシリンジ(20ゲージ針)を使用して中央耳動脈(central ear artery)に穿刺することによってサンプリングした。2回目の出血観察期間の最後に心穿刺を行って動物から放血させた。1 mLのクエン酸加全血(血液:クエン酸=10:1)を採った。各血液サンプル(320μL)を20μLのTF(最終濃度0.04 pM)と混合し、予め温めたTEGキュベット中の20μLの0.2 M CaCl2溶液で37℃で再石灰化した。速やかに測定を開始し、各血液サンプルについて並行して二重に測定した。TEG測定は、全ての関連する測定が得られた後に停止するか、又は凝血塊が形成しない場合には2時間後に中止した。凝固時間(R-時間)、凝血塊形成速度(K-時間)、凝血塊強化速度(角度)及び凝血塊の最大硬度(MA)のTEGパラメーターを記録した。
Claims (13)
- プロトロンビン(FII)及び活性化第X因子(FXa)を含有し、FXaのFIIに対するモル比が1:20,000未満である、出血性疾患の治療のための組成物。
- FII及びFXaが血漿由来であるか、又は組換え体である、請求項1記載の組成物。
- FIIの濃度が約0.44mg/kgであり、FXaの濃度が約826ng/kgである、請求項1又は2記載の組成物。
- FIIの濃度が約0.2mg/kg〜約1mg/kgであり、FXaの濃度が約560ng/kg〜約1100ng/kgである、請求項1又は2記載の組成物。
- FIIの濃度が約4.4mg/kgであり、FXaの濃度が約275ng/kgである、請求項1又は2記載の組成物。
- FIIの濃度が約1.2mg/kg〜約5mg/kgであり、FXaの濃度が約200ng/kg〜約540ng/kgである、請求項1又は2記載の組成物。
- 出血性疾患がA型血友病、B型血友病、フォン・ヴィレブラント病、インヒビターを有する先天性A型血友病又はFVIIIに対する阻害性自己抗体を有する後天性A型血友病、インヒビターを有する先天性B型血友病又はFIXに対する阻害性自己抗体を有する後天性B型血友病、外傷による失血、FVII欠乏症、FV欠乏症、FX欠乏症、FXI欠乏症、FXIII欠乏症、フィブリノゲン欠乏症、プロトロンビン欠乏症、希釈性(dilutional)凝固障害、血小板減少症、高リスクの手術による失血、脳出血、フォン・ヴィレブラント因子に対するインヒビターを有するフォン・ヴィレブラント病、又はこれらの組合せである、請求項1〜6のいずれか1項記載の組成物。
- 非経口注入、皮下注射、筋肉内注射、又は静脈内注射を介して投与される、請求項1〜7のいずれか1項記載の組成物。
- 組成物が医薬組成物である、請求項1〜8のいずれか1項記載の組成物。
- 少なくとも1種の賦形剤を更に含有する、請求項1〜9のいずれか1項記載の組成物。
- 賦形剤が、水、NaCl又は等張性のための他の塩、5%デキストロース水溶液、pH2-8の緩衝溶液、トレハロース、マンニトール、ソルビトール、リン酸塩緩衝剤、酢酸塩緩衝剤、塩又はアミノ酸等の等張化剤、及び界面活性剤ポリオキシエチレン-ソルビタンモノオレエート(TWEEN 80)からなる群より選択される、請求項10記載の組成物。
- ヒトプロトロンビン(FII)及び活性化第X因子(FXa)を含有する抗凝固活性の逆転を補助するための組成物であって、FXaのFIIに対するモル比が1:20,000未満である、上記組成物。
- プロトロンビン(FII)及び活性化第X因子(FXa)を含有する組成物を投与することを含む出血性疾患の治療方法であって、FXaのFIIに対するモル比が1:20,000未満である、上記方法。
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US201461953496P | 2014-03-14 | 2014-03-14 | |
US61/953,496 | 2014-03-14 | ||
PCT/US2015/020361 WO2015138847A1 (en) | 2014-03-14 | 2015-03-13 | Compositions of human prothrombin and activated factor x for improving hemostasis in the treatment of bleeding disorders |
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Title |
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HIMMELSPACH M.ET AL.: "A fully recombinant partial prothrombin complex effectively bypasses fVIII in vitro and in vivo.", THROMB HAEMOST., vol. 88(6), JPN6018042453, December 2002 (2002-12-01), pages 1003 - 11, XP055441352 * |
VARADI K.ET AL.: "New insights into the role of hemostatic components(FEIBA(R)).", JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. Vol. 7, No. S2, JPN6018042454, July 2009 (2009-07-01), pages pp.1137-1138,Abstract Number: PP-TH-611 * |
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