一种用二氧六环制备紫杉醇冻干制剂的简易方法

Facile preparation of cabazitaxel-loaded nanoparticles directly lyophilized from dioxane

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.

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.