Optimized self-nanoemulsifying drug delivery system of atazanavir with enhanced oral bioavailability: in vitro/in vivo characterization

Background: Atazanavir (ATV) is a HIV protease inhibitor. Due to its intense lipophilicity, the oral delivery of ATV encounters several problems such as poor aqueous solubility, pH-dependent dissolution and rapid first-pass metabolism in liver by CYP3A5, which result in low and erratic bioavailability.

Objective: The current study aimed to develop self-nanoemulsifying drug delivery systems (SNEDDS) using long-chain triglycerides of ATV in an attempt to circumvent such obstacles.

Methods: Equilibrium solubility studies indicated the choice of Maisine 35-1 as lipid, and of Transcutol P and Span 20 as surfactants, for formulating the SNEDDS. Ternary phase diagrams were constructed to select the areas of nanoemulsions, and the amounts of lipid (X₁) and surfactant (X₂) as the critical factor variables. The SNEDDS were optimized (OPT) using 3² central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in situ single-pass intestinal perfusion studies of OPT formulation were investigated in Wistar rats.

Results: OPT formulation indicated marked improvement in drug release profile vis-à-vis pure drug. Cloud point determination and accelerated stability studies ascertained the stability of OPT formulation. Augmentation in the values of K_a (1.96-fold) and AUC (2.57-fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT formulation compared to pure drug. Successful establishment of in vitro/in vivo correlation Level A substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions.

Conclusion: The studies, therefore, indicate the successful formulation development of SNEDDS with distinctly improved bioavailability of ATV.