Improved oral bioavailability and brain transport of Saquinavir upon administration in novel nanoemulsion formulations

Abstract

The aim of this investigation was to develop novel oil-in-water (o/w) nanoemulsions containing Saquinavir (SQV), an anti-HIV protease inhibitor, for enhanced oral bioavailability and brain disposition. SQV was dissolved in different types of edible oils rich in essential polyunsaturated fatty acids (PUFA) to constitute the internal oil phase of the nanoemulsions. The external phase consisted of surfactants Lipoid-80 and deoxycholic acid dissolved in water. The nanoemulsions with an average oil droplet size of 100-200 nm, containing tritiated [(3)H]-SQV, were administered orally and intravenously to male Balb/c mice. The SQV bioavailability as well as distribution in different organ systems was examined. SQV concentrations in the systemic circulation administered in flax-seed oil nanoemulsions were threefold higher as compared to the control aqueous suspension. The oral bioavailability and distribution to the brain, a potential sanctuary site for HIV, were significantly enhanced with SQV delivered in nanoemulsion formulations. In comparing SQV in flax-seed oil nanoemulsion with aqueous suspension, the maximum concentration (C(max)) and the area-under-the-curve (AUC) values were found to be five- and threefold higher in the brain, respectively, suggesting enhanced rate and extent of SQV absorption following oral administration of nanoemulsions. The results of this study show that oil-in-water nanoemulsions made with PUFA-rich oils may be very promising for HIV/AIDS therapy, in particular, for reducing the viral load in important anatomical reservoir sites.

Figure 1

Transmission electron micrographs of the blank (A) and saquinavir-containing (B) nanoemulsions. Both of the nanoemulsions were prepared with flax-seed oil. The scale bar represents a distance of 500 nm.

Figure 2

Plasma and brain saquinavir concentration versus time profiles following oral administration of the drug in aqueous suspension or nanoemulsion formulations to Balb/c mice. The plots represent plasma concentrations versus time following oral administration (A) and brain concentrations versus time following oral administration (B). The Balb/c mice was dosed with 0.50 mL of the control aqueous suspension or nanoemulsion formulations by oral gavage. The administered dose contained 1 μCi radioactivity as tritiated [³H]-saquinavir.

Figure 3

Plasma and brain saquinavir concentration versus time profiles following intravenous administration of the drug in aqueous suspension or nanoemulsion formulations to Balb/c mice. The plots represent plasma concentrations versus time following oral administration (A) and and brain concentrations versus time following intravenous administration (B). The Balb/c mice were dosed with 0.10 mL of the control aqueous suspension or nanoemulsion formulations by the intravenous tail vein injection. Each administered dose contained 1 μCi radioactivity as tritiated [³H]-saquinavir.