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.

Automated summary

The study demonstrates the development of a simple formulation methodology for Cabazitaxel (CTX) to produce a lyophilized drug product with a high drug-to-excipient ratio. The drug and excipient can be dissolved together in a mixed solvent system, allowing for sterile filtration, lyophilization, and reconstitution. The size of the reconstituted nanoparticles can be adjusted by tuning the solvent ratio and the ratio of excipient to drug.