Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 367, Issue 1-2, Pages 179-186Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2008.09.022
Keywords
Asulacrine; Nanosuspension; High; pressure homogenization; Dissolution; Pharmacokinetics; Tissue distribution
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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.
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