JP6813355B2 - 新規な安定製剤 - Google Patents
新規な安定製剤 Download PDFInfo
- Publication number
- JP6813355B2 JP6813355B2 JP2016525504A JP2016525504A JP6813355B2 JP 6813355 B2 JP6813355 B2 JP 6813355B2 JP 2016525504 A JP2016525504 A JP 2016525504A JP 2016525504 A JP2016525504 A JP 2016525504A JP 6813355 B2 JP6813355 B2 JP 6813355B2
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- Prior art keywords
- spdb
- immune complex
- glycine
- histidine
- sucrose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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Description
本実施例は、MF−T−SPDB−DM4を含む各種液体組成物を製造した方法を示すものである。次に、下記実施例に記載の方法に従って、これらの組成物を分析した。
本実施例は、外観ならびに動的光散乱(DLS)によって評価される凝集に対する、そしてMF−T−SPDB−DM4についての示差走査熱量測定(DSC)で測定される免疫複合体安定性に対する、いくつかの緩衝系の効果を示すものである。
(1)100mMリン酸カリウムpH7.5
(2)10mML−ヒスチジン、130mMグリシンpH7.3
(3)20mMクエン酸ナトリウム、10%トレハロースpH6.6
(4)10mML−ヒスチジン、130mMグリシンpH5.5
(5)0.9%NaCl
中、約5.0mg/mLで製剤化した。
本実施例は、下記の3実験で外観、動的光散乱(DLS)およびサイズ排除クロマトグラフィー(SEC)によって評価した凝集に対するいくつかの緩衝剤系の効果を示すものである。
b.20℃での24時間にわたる振盪ストレス試験
c.20℃での24時間にわたるストッパー接触のある反転振盪ストレス試験。
(1)100mMリン酸カリウムpH7.5
(2)10mML−ヒスチジン、130mMグリシンpH7.3
(3)20mMクエン酸ナトリウム、10%トレハロースpH6.6
(4)10mML−ヒスチジン、130mMグリシンpH5.5
(5)0.9%NaCl
中、約5.0mg/mLで製剤化した。
本実施例は、外観検査およびDLSによって評価されるタンパク質凝集に対するポリソルベート80の効果を示すものである。
0.0%から0.1%ポリソルベート80を含む10mML−ヒスチジン、130mMグリシンpH5.5中、約5.0mg/mLで製剤化した。
本実施例は、14日間の期間にわたる好ましい液体製剤の安定性を示すものである。さらに、外観検査、DLSおよびサイズ排除クロマトグラフィー(SEC)によって評価されるタンパク質凝集に関して、2種類のショ糖濃度を調べた。
(1)10%ショ糖、0.01%ポリソルベート80、10mML−ヒスチジン、130mMグリシンpH5.5
(2)5%ショ糖、0.01%ポリソルベート80、10mML−ヒスチジン、130mMグリシンpH5.5
中、約5.0mg/mLで製剤化した。
本実施例は、凍結乾燥の堅牢性および凍結乾燥への液体組成物の好適性を示すものである。さらに、凍結乾燥サンプルの再生後に得られた結果は、その組成物によってさらに、凍結乾燥製剤が可能であることを明瞭に示している。
本実施例は、14日の期間にわたる、いくつかの好ましい液体製剤中の免疫複合体MF−T−SPDB−DM4の化学的安定性を示すものである。二つの異なるショ糖濃度を用いた。
(1)10%ショ糖、0.01%ポリソルベート80、10mML−ヒスチジン、130mMグリシンpH5.5
(2)5%ショ糖、0.01%ポリソルベート80、10mML−ヒスチジン、130mMグリシンpH5.5
中、約5.0mg/mLで製剤化した。
本実施例は、好ましい凍結乾燥組成物中での免疫複合体MF−T−SPDB−DM4の長期安定性を示すものである。
タンパク質濃度の測定およびマイタンシノイド/抗体比(DM4/Ab比)の測定
Nanodrop 2000(Thermo Scientific)を用いる2波長(280nmおよび252nm)での吸収測定を介して、タンパク質濃度およびマイタンシノイド/抗体比(DM4/Ab比)を測定した。各溶液を、独立の3サンプルについて2回測定した。
外観に関して、粒子または濁度について暗色背景を用いて、MF−T−SPDB−DM4を含む試験溶液を調べた。緩衝液交換またはストレス試験後の透明溶液は、二量体および/またはオリゴマー形成がわずかしか存在しないか存在しないことの徴候であり、溶液の視認される濁度は二量体およびオリゴマーの高い含有量と相関する。
動的光散乱は、レーザーによって発生する散乱光を分析する方法である。可溶化もしくは懸濁プローブによって散乱する光を用いて、流体力学半径(dH[nm])を計算することができる。流体力学半径の増加が、免疫複合体凝集の指標である。Horiba LB550(Retsch Technology)を用いて、DLSによる流体力学半径を測定した。25nmより大きい測定dHが臨界であることがわかった。16nmから25nmのdH値が、良好な挙動の免疫複合体を示した。
融点の測定を介して、タンパク質安定性を測定することができる。示差走査熱量測定(DSC)により、いくつかの溶液におけるMF−T−SPDB−DM4の融点(Tm)を測定した。サンプルを20℃から105℃まで加熱し、VP−DSC熱量計(GE Healthcare)を用いて融点(Tm)を測定した。
MF−T−SPDB−DM4のような免疫複合体は、製造、充填または輸送時に行われる機械的撹拌に対して非常に敏感である。一定強度の運動があると、免疫複合体は凝集および変性を開始する。振盪ストレス試験中、制御された条件下の凝集および変性についてMF−T−SPDB−DM4を含む液体組成物を分析した。
モノマーおよび二量体含有量ならびに低分子量断片(LMW)および高分子量(HMW)含有量の測定のため、HPLCシステムを用いてサイズ排除クロマトグラフィー(SEC)を行った。MF−T−SPDB−DM4を、蛍光検出器を用いて検出し、面積パーセント法を用いて定量した。タンパク質用の標準的なHPLC SECカラム、例えばTosoh Biosep TSKゲルG3000 SWXL 5μm、300mm(長さ)×7.8mm(内径)を用いた。
視認できない粒子の検出およびカウンティングのために、HIACおよびMFI法を用いた。MFI(微小流動画像処理)測定のため、供給者の説明書に従って、Micro−Flow Imaging(商標名)DPA 4200システム(Brightwell Technologies Inc.)を用いた。供給者の説明書に従って、HRLD−150 13−150μmセンサーと組み合わせてHIAC9703+液体粒子カウンター(HACH Lange)を用いて、HIAC測定を行った。
HPLC法を用いて、遊離マイタンシノイドを測定した。Supelcosil LC−HISEP、50mm×4.6mm、5μm(Sigma−Aldrich)または同等のカラムを、Zorbax Eclipse XDB−C18、50mm×2.1mm、3.5μm(Agilent)または同等のカラムと組み合わせて用いた。それらのカラムは、Agilent HPLCシステムとともに用いた。遊離マイタンシノイドをHISEPクロマトグラフィーによってタンパク質から分離し、その後逆相高速クロマトグラフィー(RP−HPLC)によって定量した。カラムは35℃で用いた。溶媒として、移動相A(0.1%TFAの水溶液)および移動相B(0.08%TFAのアセトニトリル中溶液)を用いた。マイタンシノイド(DM4)および他の全ての成分の含有量を、ルチン水和物較正曲線の線形回帰分析を用いるEmpower計算ルーチンによってμg/mLで計算する。ルチン水和物およびDM4の各種相関係数を補正するためには、DM4および他の全ての成分の結果に係数1.05497を乗じなければならない。
WO2010/124797に詳細に記載の細胞による効力アッセイを用いて、免疫複合体MF−T−SPDB−DM4の生理活性を調べた。すなわち、メソテリントランスフェクトHT29−細胞を96ウェルプレートに接種し、4時間かけてのMF−T−SPDB−DM4の連続希釈をしながらインキュベートを行った。免疫複合体を用いたこのインキュベーション後に、細胞を培地で注意深く洗浄し、さらに68から96時間インキュベートした。その後、標準法(例えば、WST−1細胞増殖試薬、Roche)を用いて細胞増殖を定量した。標準値と比較した活性比を評価および報告する。
Claims (4)
- a.5mg/mLのMF−T−SPDB−DM4、
b.10mMのL−ヒスチジン、
c.130mMのグリシン、
d.5%のショ糖、および
e.0.01%のポリソルベート80
を含み、
pH5.5の緩衝水溶液である、免疫複合体製剤。 - 請求項1に記載の液体免疫複合体製剤の凍結乾燥によって得られる凍結乾燥組成物。
- 再生されて5mg/mLのMF−T−SPDB−DM4を含むようになり、免疫複合体MF−T−SPDB−DM4 1mg当たりL−ヒスチジン0.31mg、グリシン1.95mg、ショ糖9.99mg、およびポリソルベート80 0.02mgを含み、水で再生したらpHが約5.5である、請求項2に記載の凍結乾燥組成物。
- 治療的適用で使用される請求項1から3のいずれか1項に記載の免疫複合体製剤。
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