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

Asulacrine (ASL) is an inhibitor of topoisomerase 11, 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 narrosuspension exhibited a significantly (P < 0.01) reduced C-max (12.2 +/- 1.3 mu g ml(-1) vs 18.3 +/- 1.0 mu g ml(-1)) and AUC(0-infinity) (18.7 +/- 0.5 mu g ml(-1) h vs 46.4 2.6 mu g ml(-1) h), and a significantly (P< 0.01) greater volume of distribution (15.5 +/- 0.61 kg(-1) vs 2.5 +/- 0.1 l kg(-1)), clearance (1.6 +/- 0.041 h(-1) kg(-1) vs 0.6 +/- 0.041 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 AUC(0-infinity) in liver, lung and kidney (all P < 0.01), but not in heart. (C) 2008 Elsevier B.V. All rights reserved.