An oral formulation of efavirenz-loaded lactoferrin nanoparticles with improved biodistribution and pharmacokinetic profile.

OBJECTIVES: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, is a drug that is frequently included in highly active antiretroviral therapy for treatment of HIV infection. Decreased bioavailability and increased toxicity limit its use. We report a formulation of efavirenz-loaded lactoferrin nanoparticles (lacto-EFV-nano) for oral delivery which exhibited significantly improved pharmacological properties coupled with reduced toxicity compared with its free form.

METHODS: Lacto-EFV-nano was prepared using the Sol-oil protocol and characterized using various sources of characterization. In vitro and in vivo studies were performed to test the stability, safety, efficacy, biodistribution and pharmacokinetics of lacto-EFV-nano.

RESULTS: The nanoparticles prepared for the present study had an average size of 45-60 nm as revealed by field emission scanning electron microscope measurements. Further, dynamic light scattering data showed a hydrodynamic radius of 103 ± 5.3 nm, a zeta potential of -23 ± 1.2 mV and a polydispersity index of < 0.341. Lacto-EFV-nano was found to be stable as assessed using differential scanning calorimetry and Fourier-transform infrared spectroscopy. Cell viability studies showed that lacto-EFV-nano was at least 2-fold less toxic to peripheral blood mononuclear cells, Jurkat T cell and B16-F10 cell lines than free EFV. Furthermore, lacto-EFV-nano [50% inhibitory concentration (IC50 ) < 1.1 nM] showed > 2-fold enhanced anti-HIV-1 activity compared with free EFV (IC50 = 2.56 nM). Lacto-EFV-nano exhibited improved oral bioavailability and an improved in vivo pharmacokinetic profile, with a > 3-4-fold increase in the area under the plasma concentration-time curve (AUC), a 6-7-fold increase in the area under the first moment curve (AUMC), a > 30% increase in the peak plasma concentration of the drug after oral administration (Cmax ) and a 2-fold increase in the time to reach Cmax (Tmax ) and the time required for the concentration of the drug to reach half of its original value (t1/2 ). Furthermore, lacto-EFV-nano did not show any organ-related toxicity. A significant decrease in the concentrations of various parameters, elevated concentrations of which are markers of reduced safety, were also observed in rats treated with lacto-EFV-nano.

CONCLUSIONS: Compared with free EFV, lacto-EFV-nano is a promising oral nanoformulation with enhanced bioavailability and efficacy of EFV and improved safety.