Favipiravir-Based Ionic Liquids as Potent Antiviral Drugs for Oral Delivery: Synthesis, Solubility, and Pharmacokinetic Evaluation

Abstract

Coronavirus disease 2019 (COVID-19) has spread across the world, and no specific antiviral drugs have yet been approved to combat this disease. Favipiravir (FAV) is an antiviral drug that is currently in clinical trials for use against COVID-19. However, the delivery of FAV is challenging because of its limited solubility, and its formulation is difficult with common organic solvents and water. To address these issues, four FAV ionic liquids (FAV-ILs) were synthesized as potent antiviral prodrugs and were fully characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FT-IR) spectrometry, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC). The aqueous solubility and in vivo pharmacokinetic properties of the FAV-ILs were also evaluated. The FAV-ILs exhibited improved aqueous solubility by 78 to 125 orders of magnitude when compared with that of free FAV. Upon oral dosing in mice, the absolute bioavailability of the β-alanine ethyl ester FAV formulation was increased 1.9-fold compared with that of the control FAV formulation. The peak blood concentration, elimination half-life, and mean absorption time of FAV were also increased by 1.5-, 2.0-, and 1.5-fold, respectively, compared with the control. Furthermore, the FAV in the FAV-ILs exhibited significantly different biodistribution compared with the control FAV formulation. Interestingly, drug accumulation in the lungs and liver was improved 1.5-fold and 1.3-fold, respectively, compared with the control FAV formulation. These results indicate that the use of ILs exhibits potential as a simple, scalable strategy to improve the solubility and oral absorption of hydrophobic drugs, such as FAV.

Favipiravir and Its Structural Analogs: Antiviral Activity and Synthesis Methods

“…Иной подход к улучшению растворимости фавипиравира использовала группа японских исследователей [74]: они попытались солюбилизировать плохо растворимый фавипиравир с использованием противоионов этиловых эфиров L-пролина (L-Pro-Et + ) и бета-аланина (Beta-Ala-Et + ), холина хлорида, тетраметиламмония гидрохлорида (рис. 14).…”

“…Все солевые формы фавипиравира обладали лучшими фармакокинетическими и фармакодинамическими характеристиками, чем исходный фавипиравир в опытах in vivo [74].…”

“…Another approach to improving the solubility of favipiravir was used by a group of Japanese researchers [ 74 ]. They tried to solubilize poorly soluble favipiravir using counterions of ethyl esters of L-proline (L-Pro-Et+) and beta-alanine (Beta-Ala-Et+), choline chloride, and tetramethylammonium hydrochloride ( Fig.…”

“…In formulations in vivo experiments, all ionic liquid- based formulation of favipiravir had better pharmacokinetic and pharmacodynamic characteristics compared with those of the original favipiravir [ 74 ].…”

Exploring the permeability of covid-19 drugs within the cellular membrane: a molecular dynamics simulation study

“…In this respect, we have performed the MD simulation to investigate the interaction and permeability of the FAV and HCQ drugs with the cellular membrane. While extensive studies have been performed on the FAV and HCQ drugs, 23–28 published works concerning the interactions of FAV and HCQ drugs with and diffusion through phospholipid membrane are still scarce. Consequently, we aim to unravel how these drugs adsorb and penetrate through the cellular membranes.…”