Microsuspension of fatty acid esters of entecavir for parenteral sustained delivery

Abstract

Entecavir (EV), an anti-viral agent for hepatitis B infection, should be administered under fasted state, as intestinal absorption of this hydrophilic compound is markedly decreased under post-prandial conditions. Herein, in order to improve therapeutic adherence, a parenteral sustained delivery system was constructed, by synthesizing water-insoluble ester prodrugs of the nucleotide analogous with fatty acids. EV-3-palmitate (named EVP), exhibited the lowest solubility in phosphate buffered saline (pH 7.4, 1.1 mu g/ml), with extended release profile compared with EV, EV-3-myristate, and EV-3-stearate, was selected as a candidate to formulate drug suspension. The crystalline suspension was fabricated using anti-solvent crystallization technique, with a mean particle size of 7.7 mu m. After subcutaneous (SC) injection in beagle dogs (0.43 mg/kg as EV), the plasma concentrations of EV were markedly protracted with lowered maximum plasma concentration (C-max, 4.7 ng/ml), extended time required to reach C-max (T-max, 9.0 days), and lengthened elimination half-life (T-1/2,T- 129.3 h) compared with those after oral administration (0.0154 mg/kg, C-max, 15.4 ng/ml; T-max, 0.01 days; T-1/2, 4.1 h). The systemic exposure of the lipidic prodrug was below 0.1% compared with that of EV following SC injection, denoting that EV-P was rapidly converted into the parent compound in blood. Therefore, SC delivery of EV-P microsuspension can be an alternative to oral EV therapy, offering prolonged pharmacokinetic profile after single injection.