Abstract
Cabazitaxel (CTX) is currently formulated for clinical use in neat liquid surfactant (at a 27:1 mass ratio of Tween-80:CTX). We show here that CTX and Pluronic F127 can be dissolved together in a mixed solvent system comprising water and 1,4-dioxane, two commonly used freeze-drying solvents. This enables the sterile filtration of the mixture, subsequent lyophilization, and aqueous reconstitution of drug-loaded micelles. The micellization properties of the solvent system enabled sterile filtration only at low or high dioxane concentrations. Lyophilizate morphology and reconstituted micelle properties depended on the cosolvent/solvent ratio and the ratio of F127 to CTX, enabling the tuning of the size of reconstituted nanoparticles. A F127-to-CTX mass ratio of 3:1 by the post hydration method using 60% dioxane yielded good batch-to-batch reproducibility and resulted in micelles that were stable for at least 3 h following aqueous reconstitution. Upon intravenous administration to mice, CTX circulation in blood was not dependent on the micelle size and comparable to that of the neat Tween-80 formulation. In vivo antitumor efficacy in mice bearing human MIA Paca-2 tumors was also found comparable to that of the Tween-80 formulation. Taken together, these results demonstrate the utility of a simple CTX formulation methodology to produce a lyophilized drug product with a high drug-to-excipient ratio.
摘要
第二代紫杉醇卡巴他赛(CTX)由于对P-gp糖蛋白的亲和力较低, 具有不易产生耐药性等优点, 被成功地应用于治疗耐药性前列腺癌的 临床治疗中. 由于CTX的疏水性较高, 临床使用的制剂是由液体表面活 性剂Tween-80和乙醇组成的(Tween-80与CTX的质量比为27:1). 而 Tween-80可能在血液中导致溶血问题, 引起过敏反应. 在此工作中, 我 们报道了一种只用少量表面活性剂(pluronic F127与CTX的质量比为 3:1)的冻干CTX的制剂: CTX和Pluronic F127一起溶解在由水和1,4-二 恶烷(两种常用的冷冻干燥溶剂)组成的混合溶剂系统中制成的冻干粉. 胶束状态下的溶剂系统可以经过无菌过滤膜达到除菌效果, 结果表明 在5%和高于60%的1,4-二恶烷浓度下通过过滤才能达到理想的过滤效 果. 冻干CTX制剂和重溶胶束的特性取决于共溶剂/溶剂比和F127与 CTX的比例, 并且能够通过调整比例来调节纳米颗粒的尺寸. 用60%的 1,4-二恶烷溶解质量比为3:1的F127/CTX所得的冻干CTX产物, 重溶后 的胶束在水相中能稳定至少三小时. 在对小鼠进行静脉给药后, 血液中 的CTX浓度不依赖于胶束的粒径大小, 并且血液代谢和纯Tween-80制 剂类似. 小鼠抗肿瘤实验表明小鼠体内MIA Paca-2 肿瘤抑制功效与 Tween-80制剂相似. 综上所述, 此工作报道了一种简单的冻干方法用 于制备紫杉醇药物制剂, 具有制备方法高效和表面活性剂添加量低等 优点.
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Acknowledgements
This work was supported by the National Institutes of Health of the US (DP5OD017898 and R01EB017270), the National Science Foundation of the US (1555220), the National Natural Science Foundation of China (32071384), and the National Key Research and Development Program of China (2021YFC2102300).
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Sun B, Lovell JF and Zhang Y conceived the project and wrote the paper. Sun B and Ghosh S carried out most experiments. Quinn B, Li J, Wang X assisted in animal experiments. Li C assisted in SEM experiments. Shao S and Alexandridis P assisted in manuscript editing. All authors contributed to the general discussion.
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Boyang Sun is an research assistant at the School of Chemical Engineering and Technology, Tianjin University. He obtained his Master degree and Doctorate degree both in chemical engineering from the State University of New York at Buffalo. During his doctoral period, he mainly studied the delivery systems of cabazitaxel including pluronic micelles, liposomes for photodynamic and chemotherapy, and new lyophilized formulations. His current research directions involve metalloimmunotherapy, liposomal formulations for anticancer drugs, and antimicrobial biomaterials.
Yumiao Zhang is a full professor of the School of Chemical Engineering and Technology at Tianjin University. He obtained his dual Bachelor degree from Nankai University and Tianjin University in 2010. And he obtained his PhD degree in chemical engineering from the State University of New York at Buffalo in 2016. His research interest includes molecular imaging, theranostics, immunotherapy and CRSIPR-Cas9 delivery.
Jonathan F Lovell is an empire innovation professor at the Biomedical Engineering Department, University at Buffalo, NY, USA. He received his PhD degree from the University of Toronto. Previously, he completed his MS degree in biochemistry at McMaster University in Hamilton, Ontario and his undergraduate degree at the University of Waterloo in Systems Design Engineering.
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Sun, B., Shao, S., Ghosh, S. et al. Facile preparation of cabazitaxel-loaded nanoparticles directly lyophilized from dioxane. Sci. China Mater. 66, 2513–2522 (2023). https://doi.org/10.1007/s40843-022-2384-3
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DOI: https://doi.org/10.1007/s40843-022-2384-3