Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery

Yonglu Wang^1,4, Xueming Li^1,2*, Liyao Wang³, Yuanlong Xu¹, Xiaodan Cheng¹, Ping Wei^4
1College of Pharmacy, Nanjing University of Technology, Nanjing; ²State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing University of Technology, Nanjing; ³College of Life Science, Anhui Agricultural University, Hefei; ⁴College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing, People’s Republic of China
^*These authors contributed equally to this work.

Abstract: Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor^® EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01) reduced area under the concentration curve (AUC)_0–∞ (20.343 ± 9.119 µg · h · mL⁻¹ vs 5.196 ± 1.426 µg · h · mL⁻¹), greater clearance (2.050 ± 0.616 L · kg⁻¹ · h⁻¹ vs 0.556 ± 0.190 L · kg⁻¹ · h⁻¹), and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC_0–∞ in liver, lung, and spleen (all P < 0.01), but not in heart or kidney.

Keywords: high-pressure homogenization, tissue distribution, surfactant