JP2018519303A - 抗体デュオカルマイシン薬物複合体を含む組成物 - Google Patents
抗体デュオカルマイシン薬物複合体を含む組成物 Download PDFInfo
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- JP2018519303A JP2018519303A JP2017567296A JP2017567296A JP2018519303A JP 2018519303 A JP2018519303 A JP 2018519303A JP 2017567296 A JP2017567296 A JP 2017567296A JP 2017567296 A JP2017567296 A JP 2017567296A JP 2018519303 A JP2018519303 A JP 2018519303A
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Abstract
Description
SYD985の凍結乾燥前溶液の調製
ADC SYD985(すなわち、トラスツズマブvc−seco−DUBA)を、Mol.Cancer Ther.、13(11)2014年11月、2618〜2629中のDOKTER,Wらの補充書において公開されている、方法および手順にしたがって、調製し、精製した。精製後、SYD985溶液を、30kDaカットオフのポリエーテルスルホン膜を有する単回使用タンジェンシャルフローカセット(tangential flow cassette)(Sius(商標))を使用して、界面活性剤なしで、表1に示されている水溶液を使用して、濃縮し、透析濾過した。透析濾過後、界面活性剤を加え、溶液を、SYD985 10mg/mlまで希釈した。次に、最終溶液を、−70℃ですぐに凍結させ、貯蔵した。SYD985濃度を、UV−VISを使用して測定し、mg/mlで表す。モル量を、SYD985(平均DAR2.7)について、151.8kDaの分子量を使用して計算した。
凍結溶液I〜VIを、室温(RT)で解凍し、沈殿物がない場合、0.22μmフィルターで濾過し、バイアルに満たした。バイアルを、小規模凍結乾燥装置に入れた。凍結乾燥は、−35℃まで棚温度を低下させ、続いて、−10℃の棚温度、0.075mbarで一次乾燥させ、40℃の棚温度で二次乾燥させることによって、実施された。マンニトールを含有する組成物Iにおいて、−20℃の棚温度で4時間のアニーリング工程を、凍結工程と一次工程の間に導入した。トレハロース80mg/ml超を有する組成物VIにおいて、−12℃で5時間のアニーリング工程を、−40℃までの凍結後に導入し、一次乾燥を、0.075mbarおよび凍結乾燥物の崩壊を避けるのに必要とされる−21℃で、実施した。−5℃での中間乾燥工程を、一次乾燥と二次乾燥の間に導入して、溶解を防止した。二次乾燥工程を、20℃で実施した。
以下の方法は、本発明による凍結乾燥組成物を得るための一般的手順である。
組成物Vの凍結溶液を、室温で解凍し、沈殿物がない場合、0.22μmフィルターで濾過し、バイアルに満たした。バイアルを、Epsilon2〜6D(MartinChrist)R&D凍結乾燥装置に入れた。凍結乾燥は、0.2〜1℃/分の速さで−40℃まで棚温度を低下させ、続いて、50時間、−10℃の棚温度、0.075mbarで一次乾燥させることによって、実施された。一次乾燥後、棚温度を、3℃/時の速さで40℃まで上昇させ、その温度で10時間保持した。全工程所要時間は、約92時間であった。
凍結乾燥ケーキの外観/品質
多様な製剤の凍結乾燥ケーキの外観を、表4、第3列にまとめる。表1の製剤I、III、IVおよびVは、凍結乾燥後、良好な外観を有した。凍結乾燥保護剤の量がADCのモル量の1,400倍より少ないとき、かなりの量のマンニトールの存在下(製剤I)以外では、最終の凍結乾燥生成物について不満足な結果がもたらされた。溶液IIの凍結乾燥は、劣った品質の凍結乾燥ケーキをもたらした(図1B参照)。外観検査で、亀裂および崩壊が見られた。SYD985のない類似の溶液、プラセボが、凍結乾燥物として許容可能なケーキ外観を有した(図1A参照)ので、劣ったケーキ品質は、予期されなかった。1,605モル過剰のトレハロースを有する、表1の溶液III、IV、およびVの溶液の凍結乾燥は、所望の品質のケーキをもたらす(溶液IIIのケーキを、図1Cに示す)。
多様な凍結乾燥方法についての持続時間を、表2にまとめる。
a)溶液中の安定性
凍結溶液を、RTで解凍し、沈殿物がない場合、0.22μmフィルターで濾過し、バイアルに満たした。顕微鏡でなければ見えない粒子状物質分析を、PAMAS CVSSパーティクルカウンター(HCB−LD−25/25センサー、Partikelmess−und Analyse Systeme GmbH)を使用して、光遮蔽技術(LO)よって、測定した。手順を、Ph.Eur.<2.9.19>、粒子汚染;顕微鏡でなければ見えない粒子。にしたがって、実施する。試料体積300μlを、計測する(実行前(prerun)体積:0.8mL、すすぎ体積:5mL、注入およびすすぎ速度:10mL/分)。少なくとも3回連続してLO測定を、試料毎に、実施した。結果を、PMAソフトウエアを使用して分析する。
凍結乾燥試料を、注射用の水を使用して再構成した。全ての測定された凍結乾燥組成物は、簡単に再構成可能であった。
a)溶液中の安定性
表3は、表1の凍結乾燥前溶液についての安定性結果の概要を提示している。凍結乾燥後の外観が、許容可能でなかったので、溶液IIの安定性は、測定されなかった。測定された5つの溶液は全て、溶液Iを除いて、同等の安定性を示した。トレハロース約800のモル過剰を有する表1の溶液Iは、溶液中の安定性の低下をもたらした(表3参照)。RTで1カ月後、タンパク質様沈殿物を、観察した。溶液Iについて、コロイド安定性の低下も、同様に、室温(RT)で1カ月後、LOおよびDLS測定によって、観察された。溶液Iは、LOによって観察された通り、t=1カ月で、大量の粒子>10μmを有する一方で、その他の溶液で観察された、このサイズの粒子は少量だった。か月保持された溶液について、DLSで測定されたZ平均も、その他の溶液と比較して、溶液I中で、同じく、有意に上昇している。
図2および3は、表1の溶液Iが、凍結乾燥される場合、凍結乾燥ケーキ中の単量体%が、減少することを示す一方で、HMW%は、40℃で時間とともに上昇し、安定性の低下を示す。図2および3は、製剤VおよびVIについて、製剤Iと比べて、単量体%の低下ならびにHMW%の上昇が、時間とともに有意により低下することを示す。t=1カ月において、再構成溶液IIIおよびIV中の単量体の量は、溶液I中の単量体の量より多い。t=1カ月において、HMWの量は、溶液I、IIIおよびIVについて類似している。
Claims (15)
- 式(I)
- 前記凍結乾燥保護剤が、非還元サッカライドである、請求項1に記載の組成物。
- 前記凍結乾燥保護剤が、スクロース、トレハロース、またはそれらの混合物である、請求項1または2に記載の組成物。
- 前記抗体薬物複合体が、水で再構成された場合、1〜30mg/mlの濃度で存在する、請求項1〜3の何れか一項に記載の組成物。
- 前記緩衝剤が、ヒスチジン、クエン酸塩またはコハク酸塩である、請求項1〜4の何れか一項に記載の組成物。
- 前記緩衝剤が、水で再構成された場合、2.5〜25mMの濃度で存在する、請求項1〜5の何れか一項に記載の組成物。
- 前記界面活性剤が、アルキルグリコシド、ポロキサマー、またはポリソルベートである、請求項1〜6の何れか一項に記載の組成物。
- 水で再構成された場合、水溶液が、pH5.3〜6.0を有する、請求項1〜7の何れか一項に記載の組成物。
- 前記モノクローナル抗体が、抗HER2抗体である、請求項1〜8の何れか一項に記載の組成物。
- 凍結乾燥保護剤対抗体薬物複合体のモル比が、1,400〜3,200対1である、式(I)の抗体薬物複合体、緩衝剤、凍結乾燥保護剤、および界面活性剤から本質的になる、請求項1〜9の何れか一項に記載の組成物。
- 凍結乾燥保護剤対抗体薬物複合体のモル比が、1,400〜2,000対1または1,400〜1,800対1である、請求項1〜10の何れか一項に記載の組成物。
- トレハロース対抗体薬物複合体のモル比が、約1,605対1であり、水で再構成された場合、前記ADCが、約10mg/mlの量で存在し、ヒスチジンの濃度が、約5mMであり、ポリソルベート20の量が、約0.01%(m/v)であり、pHが、約5.7である、式(II)
- トレハロース対抗体薬物複合体のモル比が、約1,605対1であり、水で再構成された場合、前記ADCが、約10mg/mlの量で存在し、ヒスチジンの濃度が、約5mMであり、ポリソルベート20の量が、約0.01%(m/v)であり、pHが、約5.7である、式(II)の抗体薬物複合体、ヒスチジン、トレハロース、およびポリソルベート20から本質的になる、請求項12に記載の組成物。
- a)請求項1〜13の何れか一項に記載の組成物の凍結乾燥前水溶液を凍結させる工程、b)大気圧より低い圧力、組成物の崩壊温度より低い製品温度で、一次乾燥する工程、およびc)大気圧より低い圧力、0℃より高く組成物のガラス転移温度より低い製品温度で、二次乾燥する工程を含む、請求項1〜13の何れか一項に記載の組成物の調製のための方法。
- 前記凍結させる工程a)が、アニーリング工程を含み、前記アニーリング工程を、−25℃から−10℃の範囲内の棚温度で、0.5から6時間実施する、請求項14に記載の方法。
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MX368396B (es) | 2014-01-10 | 2019-10-01 | Synthon Biopharmaceuticals Bv | Conjugados de anticuerpo-farmaco (adc) de duocarmicina que muestran actividad antitumoral in vivo mejorada. |
US11077204B2 (en) | 2015-07-10 | 2021-08-03 | Byondis B.V. | Compositions comprising antibody-duocarmycin drug conjugates |
CN110944667A (zh) * | 2017-08-23 | 2020-03-31 | 第一三共株式会社 | 抗体-药物缀合物制剂及其冻干 |
CN110960490A (zh) * | 2018-09-28 | 2020-04-07 | 江苏恒瑞医药股份有限公司 | 一种抗egfr抗体偶联药物组合物及其用途 |
LT3876997T (lt) * | 2018-11-09 | 2022-11-10 | Byondis B.V. | Filtruojamos, duokarmiciną sudėtyje turinčio antikūno-vaisto konjugato kompozicijos ir susiję būdai |
AU2020239621B2 (en) * | 2019-03-26 | 2023-09-21 | Remegen Co., Ltd. | Pharmaceutical formulations of Her2 antibody-drug conjugate |
WO2020233534A1 (zh) * | 2019-05-17 | 2020-11-26 | 百奥泰生物制药股份有限公司 | 抗体-药物偶联物制剂、制备方法及应用 |
WO2021136274A1 (zh) * | 2019-12-30 | 2021-07-08 | 百奥泰生物制药股份有限公司 | 含抗Trop2抗体-药物偶联物的制剂及其制备方法和应用 |
WO2021156289A1 (en) * | 2020-02-06 | 2021-08-12 | Byondis B.V. | Combination containing a duocarmycin derivative-comprising antibody-drug conjugate and thiosulfate |
WO2023143154A1 (zh) * | 2022-01-28 | 2023-08-03 | 四川科伦博泰生物医药股份有限公司 | 一种药物组合物及其制备方法和应用 |
WO2023185907A1 (en) * | 2022-03-29 | 2023-10-05 | Genequantum Healthcare (Suzhou) Co., Ltd. | A freeze-drying process for an ADC |
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ZA201707475B (en) | 2021-04-28 |
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