Exploration of lipidic prodrug-loaded oil depot system for intramuscular prolonged delivery of entecavir

Entecavir (EV) is a first-line antiretroviral agent to treat chronic hepatitis B. However, its oral administration is challenging, due to food effect on intestinal absorption. Therefore, in order to afford improved patient's compliance, a novel long-acting injectable oil depot (OD) system of entecavir-3-palmiate (EV-P), a lipidic ester prodrug of EV, was formulated. The OD consisted of oleic acid and benzyl alcohol as oily vehicles, with a suitable viscosity (38.6 centipoise with shear rate of 1 s(-1)). The prodrug was gradually released from the OD under sink conditions, providing delayed liberation than that by the hydrophilic parent compound. Following the intramuscular injection in rats, EV-P OD provided a markedly protracted EV profile compared to oral EV; the EV levels in plasma were expanded over 2 weeks, with elimination half-life of about 7 days. Therefore, we concluded that EV-P OD can be a promising approach for a prolonged delivery of EV.