Characterization and evaluation of an oral microemulsion containing the antitumor diterpenoid compound ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid

Abstract

Yingnian Lu,1,2 Kefeng Wu,2 Li Li,2 Yuhui He,2 Liao Cui,2 Nianci Liang,2 Bozhong Mu11Department of Chemistry, East China University of Science and Technology, Shanghai, 2Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical College, Zhanjiang, People’s Republic of ChinaAbstract: The objective of this study was to develop an oral microemulsion formulation of the antitumor diterpenoid agent, ent-11a-hydroxy-15-oxo-kaur-16-en-19-oic- acid (henceforth referred to as 5F), to enhance its bioavailability and evaluate its hepatotoxicity. Pseudoternary phase diagrams showed that the optimal microemulsion formulation contained 45% water, 10% castor oil as the oil phase, 15% Cremophor EL as the surfactant, and 30% as a cosurfactant mixture of 1,2-propanediol and polyethylene glycol (PEG)-400 (2:1, w/w). The microemulsion preparation was characterized and its droplet diameter was within 50 nm. Release of 5F in vitro from the microemulsion was slightly increased compared with a suspension containing the same amount of active drug. Pharmacokinetic parameters in vivo indicated that bioavailability was markedly improved, with the relative bioavailability being 616.15% higher for the microemulsion than for the suspension. Toxicity tests showed that the microemulsion had no hepatotoxicity in mice. These results suggest the potential for 5F microemulsion to be administered by the oral route.Keywords: antitumor, diterpenoid, microemulsion, pharmacokinetics, toxicity