Harmine-loaded galactosylated pluronic F68-gelucire 44/14 mixed micelles for liver targeting

Abstract

Harmine (HM), a phytoconstituent has wide range of pharmacological activities including antimicrobial, antifungal, antioxidative, and anticancer. HM has shown promising anticancer activity against liver cancer cells. However, poor aqueous solubility, multidrug pump P-gp efflux, extensive in vivo metabolism, and rapid elimination due to glucuronidation/sulfation limit clinical utility of HM. In order to overcome the drawbacks of HM, the current work reports preparation of HM-loaded galactosylated pluronic F-68 (PF68)-Gelucire® 44/14 (GL44) mixed micelles (HM-MM). 32 factorial design was used to investigate the effect of formulation variables on formation HM-loaded mixed micelles. Solvent evaporation method was used for preparation of HM-MM. The optimized HM-MM was evaluated for size, percent drug entrapped (EE), in vitro HM release, oral bioavailability, and biodistribution in rats. HM-MM with an average size 277.5 ± 3.24 nm had an EE of 86.5 ± 1.51% w/w. HM-MM released HM in a controlled manner. Additionally, HM-MM showed significant enhancement in oral bioavailability (around six-folds) of HM when compared to HM alone. Further, HM-MM showed around sevenfold higher amount of HM in the liver when compared to HM alone revealing efficient drug targeting capability. Such significant improvement in oral bioavailability of HM when formulated into mixed micelles could be attributed to solubilization of hydrophobic HM into micellar core along with P-gp inhibition effect of both galactosylated PF68 and GL44. Thus, the present work highlights galactosylated PF68 and GL44 mixed micelles as an efficient carrier system having drug targeting capability and potential to enhance bioavailability of BCS class II drugs.