JP2023012465A - 凍結乾燥ポリペプチドの再構成時間を低減するための方法及び製剤 - Google Patents
凍結乾燥ポリペプチドの再構成時間を低減するための方法及び製剤 Download PDFInfo
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Abstract
Description
本出願は、2016年12月22日出願の米国仮出願第62/438,232号(参照によりその全体が本明細書に組み込まれる)の利益を主張する。
本明細書の「抗体」という用語は、最も広義に使用され、それらが所望の抗原結合活性を呈する限り、モノクローナル抗体、ポリクローナル抗体、多重特異性抗体(例えば、二重特異性抗体)、及び抗体断片を含むがこれらに限定されない、様々な抗体構造を包含する。
本明細書に記載される抗体の薬学的製剤は、所望の程度の純度を有するかかる抗体を、1つ以上の任意の薬学的に許容される担体と混合することによって(Remington′s Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))、凍結乾燥製剤または水溶液の形態で調製される。薬学的に許容される担体は一般に、レシピエントに対し、用いられる投薬量及び濃度で無毒であり、緩衝液(リン酸、クエン酸、及び他の有機酸など)、アスコルビン酸及びメチオニンを含む酸化防止剤、保存剤(オクタデシルジメチルベンジル塩化アンモニウム、塩化ヘキサメトニウム、塩化ベンザルコニウム、塩化ベンゼトニウム、フェノール、ブチル、もしくはベンジルアルコール、アルキルパラベン(メチルもしくはプロピルパラベンなど)、カテコール、レゾルシノール、シクロヘキサノール、3-ペンタノール、及びm-クレゾールなど)、低分子量(約10残基未満)ポリペプチド、タンパク質(血清アルブミン、ゼラチン、もしくは免疫グロブリンなど)、親水性ポリマー(ポリビニルピロリドンなど)、アミノ酸(グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、もしくはリジンなど)、単糖類、二糖類、及び他の炭水化物(グルコース、マンノース、もしくはデキストリンを含む)、キレート剤(EDTAなど)、糖類(スクロース、マンニトール、トレハロース、もしくはソルビトールなど)、塩形成対イオン(ナトリウムなど)、金属錯体(例えば、Zn-タンパク質錯体)、及び/または非イオン性界面活性剤(ポリエチレングリコール(PEG)など)を含むが、これらに限定されない。本明細書における例示的な薬学的に許容される担体は、可溶性の中性活性ヒアルロニダーゼ糖タンパク質(sHASEGP)、例えば、rHuPH20(HYLENEX(登録商標)、Baxter International,Inc.)などのヒト可溶性PH-20ヒアルロニダーゼ糖タンパク質などの介在性薬物分散剤をさらに含む。rHuPH20を含む、ある特定の例示的なsHASEGP及び使用方法は、米国特許公開第2005/0260186号及び同第2006/0104968号に記載されている。一態様では、sHASEGPは、コンドロイチナーゼなどの1つ以上の追加のグリコサミノグリカナーゼと組み合わせられる。
本発明に従って製剤化され得る抗体を産生するための例示的な技法が本明細書に提供される。一実施形態では、抗体が結合する抗原は、生物学的に重要なタンパク質であり、疾患または障害に罹患している哺乳動物への抗体の投与により、その哺乳動物に治療的利益がもたらされ得る。しかしながら、非ポリペプチド抗原(腫瘍関連糖脂質抗原など、米国特許第5,091,178号を参照されたい)を対象とする抗体もまた企図される。
精製されたモノクローナル抗体(mAb)溶液(mAb1及びmAb2)を、168mMのスクロース、20mMのHis-HCl、0.03%のPS20を含有する緩衝液中で70mg/mLまで希釈した。TBAを、25℃のその融点より上に温めた後、mAb試料を以下のように添加した。最大5%の最終TBA濃度の場合、TBAを70mg/mLのmAb溶液に直接添加した。10%または20%(体積/体積)の最終TBA濃度を有する試料の場合、より高い初期濃度のmAb1(90mg/mL)及びmAb2(100mg/mL)を使用し、適量のTBAの添加に続いて、168mMのスクロース及び0.03% PS20を含有する20mMのHis緩衝液を使用して70mg/mLのタンパク質まで希釈して、最終mAb溶液中10%のTBAまたは20%のTBA(v/v)濃度を得た。
TBAとの組み合わせで、部分真空下に対する完全真空下での凍結乾燥mAb1の再構成時間に対する効果を、以下のように調べた。この研究の場合、70mg/mLで60mLの充填量のmAb1を含有する、100ccバイアルを使用した。TBAをmAb1溶液に添加して、最終濃度を5% TBAまたは10% TBAのいずれかにした。凍結乾燥に続いて、バイアルを100mTorr(真空)または200Torr(部分真空対照)のいずれかに埋め戻した。
TBAとの組み合わせで撹拌器の助けを借りて、または助けなしに再構成を行ったときの、凍結乾燥mAb1の再構成時間に対する効果を、以下のように調べた。この研究の場合、70mg/mLで60mLの充填量のmAb1を含有する、100ccバイアルを使用した。TBAをmAb1溶液に添加して、最終濃度を5% TBAまたは10% TBAのいずれかにした。
TBAとの組み合わせで撹拌器の助けを借りて、真空下(100mTorr)で再構成を行ったときの、凍結乾燥mAb1の再構成時間に対する効果を、以下のように調べた。この研究の場合、70mg/mLで60mLの充填量のmAb1を含有する、100ccバイアルを使用した。TBAをmAb1溶液に添加して、最終濃度を5% TBAまたは10% TBAのいずれかにした。真空及び撹拌器条件は、実施例3で上に記載した通りであった。
液体中のmAb1安定性に対するTBAの効果を調べるための安定性研究を行った。サイズ排除クロマトグラフィー(SEC)によって、及びイオン交換クロマトグラフィー(IEC)によって、mAb1安定性を測定した。mAb1(70mg/mL)を、0% TBA、1% TBA、5% TBA、10% TBA、または20% TBAを含有する50ccバイアル(25mL充填)に添加した。次いで、バイアルを2~8℃または30℃で7日間維持し、その間、SEC及びIEC分析によって、各条件について0日目、3日目、及び7日目に抗体の安定性を決定した。
凍結乾燥に続く乾燥mAbの水分レベルに対する、凍結乾燥前のmAb1またはmAb2へのTBA添加の効果を調べた。mAb1及びmAb2(いずれも70mg/mL)を、上記のように6ccバイアルに添加した。TBAをmAb溶液に添加して、最終濃度を0%、5%、または10% TBAにした。次いで、試料を上に記載したように凍結乾燥した。凍結乾燥に続いて、凍結乾燥試料(すなわち、固体試料)の含水量を、Mettler Toledo DL31容積測定カール・フィッシャー滴定装置(Columbus,OH)を使用して決定した。
表3
凍結乾燥抗体ケーク構造の特定の表面積に対する様々な濃度のTBAの効果を調べた。mAb1及びmAb2を6ccバイアルに70mg/mLで0%、5%、または10% TBAとともに添加し、上記のように凍結乾燥した。特定の表面積の測定は、Quantachrome Quadrasorb Evo自動化表面積及び孔径分析器(Boynton Beach,FL)を用いて行った。相対湿度<3%で、グローブボックス内で試料を粉砕し、タールバルブに装填した。およそ100mgの試料サイズを使用した。強真空で少なくとも3時間にわたって40℃で残留水分の脱着を行った。次いで、Kryptonを吸着物として使用し、0.05~0.24の相対圧力P/Poで、マルチポイントBrunauer-Emmett-Teller(BET)分析を行った。
表4
表5
後次に凍結乾燥された抗体組成物中の抗体の安定性に対する凍結乾燥前の液体抗体/TBA混合物中のTBAの効果を調べる安定性研究を行った。サイズ排除クロマトグラフィー(SEC)によって安定性を測定した。
Claims (22)
- 凍結乾燥抗体組成物の再構成時間の低減方法であって、(a)少なくとも約360:1の糖:抗体のモル比で前記抗体及び糖を含む液体組成物を調製することと、(b)tert-ブチルアルコール(TBA)を前記液体組成物に添加して液体抗体/TBA混合物を形成することであって、前記液体抗体/TBA混合物中の前記TBAの量が、約5体積%~6体積%である、形成することと、(c)前記液体抗体/TBA混合物を冷凍することと、(d)前記液体抗体/TBA混合物を凍結乾燥して凍結乾燥抗体組成物を形成することと、(e)前記凍結乾燥抗体組成物を希釈液で再構成することであって、TBAの存在下で凍結乾燥された前記抗体を再構成するための時間が、TBAの不在下で凍結乾燥された同量の同じ抗体を再構成するための時間よりも少ない、再構成することと、を含む、前記方法。
- 前記液体抗体/TBA混合物中の前記TBAの量が、約5体積%である、請求項1に記載の方法。
- 糖:抗体の前記モル比が、約360:1~約500:1である、請求項1に記載の方法。
- TBAが、前記液体抗体/TBA混合物を冷凍する直前に、前記抗体を含む前記液体組成物に添加される、請求項1に記載の方法。
- 前記抗体が、完全長抗体である、請求項1に記載の方法。
- 前記抗体を含む前記液体組成物中の前記抗体の濃度が、約10mg/mL~約250mg/mL、約25mg/mL~約250mg/mL、約50mg/mL~約250mg/mL、約100mg/mL~約250mg/mL、約150mg/mmL~約250mg/mL、約25mg/mL~約100mg/mL、約50mg/mL~約100mg/mL、約25mg/mL~約125mg/mL、または約50mg/mL~約125mg/mLである、請求項1に記載の方法。
- 前記抗体を含む前記液体組成物中の前記抗体の量が、約150mg~11グラムである、請求項1に記載の方法。
- 前記糖が、スクロースまたはトレハロースである、請求項1に記載の方法。
- 前記液体抗体/TBA混合物が、ガラスバイアル中で凍結乾燥される、請求項1に記載の方法。
- 前記ガラスバイアルが、6ccバイアル、10ccバイアル、15ccバイアル、20ccバイアル、25ccバイアル、50ccバイアル、または100ccバイアルである、請求項9に記載の方法。
- 前記ガラスバイアルが、2.5mL、25mL、50mL、または100mLの充填量を有する、請求項9に記載の方法。
- TBAの存在下で凍結乾燥された前記凍結乾燥抗体組成物を再構成するための時間が、TBAの不在下で凍結乾燥された同量の同じ抗体組成物を再構成するための時間と比較して、約40~95%低減される、請求項1に記載の方法。
- TBAの存在下で凍結乾燥された前記凍結乾燥抗体組成物を再構成するための時間が、TBAの不在下で凍結乾燥された同量の同じ抗体組成物を再構成するための時間と比較して、約50%、約60%、約70%、約80%、約90%、または約95%低減される、請求項1に記載の方法。
- TBAの存在下で凍結乾燥された前記凍結乾燥抗体組成物を再構成するための時間が、TBAの不在下で凍結乾燥された同量の同じ抗体組成物を再構成するための時間と比較して、約50~60%、約60~70%、約70~80%、約80~90%、または約90~95%低減される、請求項1に記載の方法。
- 前記凍結乾燥抗体組成物の再構成は、前記凍結乾燥抗体組成物が真空下にある条件下で行われる、請求項1に記載の方法。
- 前記真空が、100Torr未満、50Torr未満、または100mTorr~50Torrである、請求項15に記載の方法。
- 前記真空が、100mTorrである、請求項15に記載の方法。
- 前記凍結乾燥抗体組成物の再構成が、攪拌器を使用して行われる、請求項1に記載の方法。
- 前記製剤が、前記抗体、糖、希釈液、及びTBAを含み、前記液体製剤中の前記TBAの量が、約5体積%~6体積%であり、前記液体製剤中の前記糖の量が、少なくとも約360:1の糖:抗体のモル比であり、TBAの存在下で凍結乾燥された前記抗体を再構成するための時間が、TBAの不在下で凍結乾燥された同量の同じ抗体を再構成するための時間よりも少ない、凍結乾燥に好適な液体抗体製剤。
- 前記液体組成物中の前記TBAの量が、約5体積%である、請求項19に記載の液体抗体製剤。
- 前記凍結乾燥抗体組成物が、少なくとも約360:1の糖:抗体のモル比で前記抗体及び糖を含む液体組成物を調製することと、tert-ブチルアルコール(TBA)を前記液体組成物に添加して液体抗体/TBA混合物を形成することであって、前記液体製剤中の前記TBAの量が、約5体積%~6体積%である、形成することと、前記液体抗体/TBA混合物を冷凍することと、前記液体抗体/TBA混合物を凍結乾燥して凍結乾燥抗体組成物を形成することであって、希釈液での前記凍結乾燥抗体組成物の再構成時に、TBAの存在下で凍結乾燥された前記抗体を再構成するための時間が、TBAの不在下で凍結乾燥された同量の同じ抗体を再構成するための時間よりも少ない、凍結乾燥することと、を含む、凍結乾燥抗体組成物。
- 前記液体組成物中の前記TBAの量が、約5体積%である、請求項21に記載の凍結乾燥抗体製剤。
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