Design of poly(jasmine lactone) micelles for enhanced delivery of remdesivir as a substitute for β-cyclodextrin...

Remdesivir (REM), a nucleoside analogue that has been approved for SARS-CoV-2 treatment, is poorly soluble in water and is currently administered intravenously formulated with sulfobutylether-β-cyclodextrin (SBECD) to facilitate solubilization. The major drawback associated with SBECD in the clinical setting is its high excipient load in the formulation leading to potential risk of renal accumulation, especially in patients with pre-existing impaired renal function and need of specialized staff trained in IV administration. The objective of this study was to investigate acid-functionalized poly(jasmine lactone) (PJL) based copolymers as potential alternatives to β-cyclodextrin based formulations for subcutaneous delivery of REM. PJL was selected because of its hydrophobic backbone and tunable functional group, making it more suited for hydrophobic interaction with REM. REM loaded PJL micelles were prepared utilizing nanoprecipitation technique and characterized for drug content, particle size, stability, in vitro release of REM, antiviral efficacy against human coronavirus HCoV-229E, pharmacokinetic profile and biodistribution in CD-1 mice. The thus prepared REM micelles exhibited a uniform nanoparticulate size with high loading efficiency of 96%, significant physicochemical stability at 4 °C up to 12 months and sustained REM release at pH 6.8 (≈ 100% in 24 h). The micelles demonstrated ≈ 100% inhibition against human coronavirus HCoV-229E, equivalent to the marketed formulation Jubi-R™ used for benchmarking. In vivo studies indicate increased systemic exposure and peak concentration of 217 ng/mL compared to 134 ng/mL after subcutaneous administration compared to marketed IV administration of micelles. The in vivo results also indicated an accumulation of the REM metabolite (GS-441524) in the lungs, demonstrating more targeted tissue distribution and production of active metabolites in vivo. Overall, these results provide evidence that PJL mediated micellar delivery of REM resulted in successful solubilization and delivery through a less invasive means of administration representing a promising biocompatible platform for delivering antiviral drug with improved systemic exposure.