Rilpivirine Ionic Liquid Nanoemulsion Augments the Oral Bioavailability of Rilpivirine and Its Delivery to the HIV Sanctuary Sites

Abstract

Rilpivirine (RPV) is a potent antiretroviral drug used for the long-term management of HIV infection. The high crystallinity and very low aqueous solubility of RPV are responsible for the highly variable pharmacokinetics of RPV seen in HIV-infected patients. While fatty meals can increase the absorption of RPV, the low lipid solubility of RPV precludes the development of oral lipid-based formulations such as self-nanoemulsifying systems (SNES). To improve the oral delivery of RPV, we evaluated the potential of six biocompatible bulky anions to transform RPV into amphiphilic RPV ionic liquids with high lipid solubility and only sodium docusate successfully yielded an amphiphilic RPV ionic liquid (IL), RPV docusate (RPV-Doc). Spectroscopic, chromatographic, and thermal characterization techniques confirmed the formation of RPV-Doc as an IL. RPV-Doc showed remarkably higher (∼100-200-fold) solubility in lipids compared to pure RPV. RPV-Doc was incorporated into two SNES formulations that, depending upon the composition of the SNES formulation, yielded a <100 or <250 nm nanoemulsion irrespective of the pH of the dilution medium. Oral pharmacokinetics and biodistribution studies in mice showed that both SNES formulations containing RPV-Doc yielded rapid and significantly higher oral bioavailability (∼6-fold higher C_max and AUC) of RPV compared to the RPV suspension. Furthermore, compared to the RPV suspension, both SNES formulations containing RPV-Doc resulted in significantly higher and sustained RPV levels in the HIV sanctuary sites such as mesenteric lymph nodes and the brain. Taken together, our innovative approach can be used to improve the oral bioavailability and tissue penetration of RPV, which can eventually result in a reduction in the pharmacokinetic variability and therapeutic dose of RPV leading to optimal drug utilization.

Keywords: Capryol 90; HIV reservoirs; Labrafac MC60; Transcutol; nanoemulsion.