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+/-20nm), 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 C(max) (12.2+/-1.3microg ml(-1)vs 18.3+/-1.0microg ml(-1)) and AUC(0-infinity) (18.7+/-0.5microg ml(-1)h vs 46.4+/-2.6microg ml(-1)h), and a significantly (P<0.01) greater volume of distribution (15.5+/-0.6lkg(-1)vs 2.5+/-0.1lkg(-1)), clearance (1.6+/-0.04lh(-1)kg(-1)vs 0.6+/-0.04lh(-1)kg(-1)) and elimination half-life (6.1+/-0.1h vs 2.7+/-0.2h) 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.
School of Pharmacy, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Srinivas
S
Ganta
James W
JW
Paxton
Bruce C
BC
Baguley
Sanjay
S
Garg
D000677:Amsacrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D004339:Drug Compounding; D004355:Drug Stability; D004356:Drug Storage; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D012995:Solubility; D013499:Surface Properties; D013535:Suspensions; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D013535:Suspensions; D000677:Amsacrine; C042315:asulacrine