Formulation and pharmacokinetic evaluation of an asulacrine nanocrystalline suspension for intravenous delivery

Asulacrine (ASL) is an inhibitor of topoisomerase II, which has shown potential against breast and lung cancer. It is a poorly water soluble drug. To allow intravenous (i.v.) administration, ASL was formulated as a nanocrystalline suspension by high pressure homogenization. The nanosuspension was lyophilized to obtain the dry ASL nanoparticles (average size, 133 ± 20 nm), which enhanced both the physical and chemical stability of the ASL nanoparticles. ASL dissolution and saturation solubility were enhanced by the nanosuspension. Differential scanning calorimetry and X-ray diffraction analysis showed that the crystallinity of the ASL was preserved during the high pressure homogenization process. The pharmacokinetics and tissue distribution of ASL administered either as a nanosuspension or as a solution were compared after i.v. administration to mice. In plasma, ASL nanosuspension exhibited a significantly (P < 0.01) reduced Cmax (12.2 ± 1.3 μg ml−1vs 18.3 ± 1.0 μg ml−1) and AUC0–∞ (18.7 ± 0.5 μg ml−1 h vs 46.4 ± 2.6 μg ml−1 h), and a significantly (P < 0.01) greater volume of distribution (15.5 ± 0.6 l kg−1vs 2.5 ± 0.1 l kg−1), clearance (1.6 ± 0.04 l h−1 kg−1vs 0.6 ± 0.04 l h−1 kg−1) and elimination half-life (6.1 ± 0.1 h vs 2.7 ± 0.2 h) compared to the ASL solution. In contrast, the ASL nanosuspension resulted in a significantly greater AUC0–∞ in liver, lung and kidney (all P < 0.01), but not in heart.