Evaluation of Atazanavir and Darunavir Interactions with Lipids for Developing pH-Responsive Anti-HIV Drug Combination Nanoparticles

We evaluated two human immunodeficiency virus (HIV) protease inhibitors, atazanavir (ATV) and darunavir (DRV), for pH-dependent solubility, lipid binding, and drug release from lipid nanoparticles (LNPs). Both ATV and DRV incorporated into LNPs composed of pegylated and non-pegylated phospholipids with nearly 100% efficiency, but only ATV-LNPs formed stable lipid-drug particles and exhibited pH-dependent drug release. DRV-LNPs were unstable and formed mixed micelles at low drug-lipid concentrations, and thus are not suitable for lipid-drug particle development. When ATV-LNPs were prepared with ritonavir (RTV), a metabolic and cellular membrane exporter inhibitor, and tenofovir (TFV), an HIV reverse-transcriptase inhibitor, stable, scalable, and reproducible anti-HIV drug combination LNPs were produced. Drug incorporation efficiencies of 85.5 ± 8.2, 85.1 ± 7.1, and 6.1 ± 0.8% for ATV, RTV, and TFV, respectively, were achieved. Preliminary primate pharmacokinetic studies with these pH-responsive anti-HIV drug combination LNPs administered subcutaneously produced detectable plasma concentrations that lasted for 7 days for all three drugs. These anti-HIV LNPs could be developed as a long-acting targeted antiretroviral therapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2520-2529, 2014