Facile preparation of cabazitaxel-loaded nanoparticles directly lyophilized from dioxane

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. [Figure not available: see fulltext.].