Enhanced Oral Bioavailability of The Hydrophobic Chemopreventive Agent (Sr13668) in Beagle Dogs

Aryamitra A.      Banerjee; Hao      Shen; Mathew      Hautman; Jaseem      Anwer; Seungpyo      Hong; Izet M.      Kapetanovic; Ying      Liu; Alexander V.      Lyubimov

Abstract

Potency and activity of SR13668 in cancer prevention have been proven in several in vitro and in vivo cancer models. However, the compound is highly hydrophobic and its limited oral bioavailability has hindered its clinical translation. In this study, we encapsulated SR13668 into polymeric nanoparticles to increase compound aqueous solubility and therefore bioavailability. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (100-200nm) encapsulating SR13668 with narrow size distribution and high drug loading were generated by a continuous and scalable process of flash nanoprecipitation integrated with spray dry. A single gavage dose of SR13668-PLGA nanoparticles at 2.8 mg/kg was administered in eight beagle dogs. Drug levels in animal whole blood and plasma were measured over 24 hours. Enhanced bioavailability of SR13668 using nanoparticles compared with formulations of Labrasol® and neat drug in 0.5% methylcellulose is reported. This is the first attempt to study pharmacokinetics of SR13668 in large animals with orally administrated nanoparticle suspension.

Keywords: Polymeric nanoparticles, Bioavailability, Chemoprevention, Nanoprecipitation, Oral drug delivery, Pharmacokinetics, Size distribution, Surface charges.