Favipiravir-Based Ionic Liquids as Potent Antiviral Drugs for Oral Delivery: Synthesis, Solubility, and Pharmacokinetic Evaluation
Favipiravir-Based Ionic Liquids as Potent Antiviral Drugs for Oral Delivery: Synthesis, Solubility, and Pharmacokinetic Evaluation
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DOI：
10.1021/acs.molpharmaceut.1c00324
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发表时间：
2021-07-10
影响因子：
4.9
通讯作者：
Goto, Masahiro
中科院分区：
文献类型：
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作者：
Moshikur, Rahman Md;Ali, Md Korban;Goto, Masahiro
2019年冠状病毒病（COVID-19）已经在全球蔓延，目前还没有特定的抗病毒药物被批准用于对抗这种疾病。Favipiravir （FAV）是一种抗病毒药物，目前正在临床试验中用于治疗COVID-19。然而，由于FAV的溶解度有限，其配方难以与普通有机溶剂和水混合，因此FAV的递送具有挑战性。为了解决这些问题，合成了四种FAV离子液体（FAV- ils）作为有效的抗病毒前药，并通过核磁共振（NMR）光谱、傅里叶变换红外（FT-IR）光谱、粉末x射线衍射（PXRD）、热重分析（TGA）、导数热重分析（DTG）和差示扫描量热法（DSC）对其进行了充分的表征。评价了fav - il的水溶性和体内药动学性质。与游离FAV相比，FAV- ils的水溶性提高了78 ~ 125个数量级。经小鼠口服给药后，β -丙氨酸乙酯FAV制剂的绝对生物利用度比对照FAV制剂提高1.9倍。FAV的血药峰浓度、消除半衰期和平均吸收时间也分别比对照提高1.5倍、2.0倍和1.5倍。此外，FAV在FAV- il中的生物分布与对照FAV制剂有显著差异。有趣的是，与对照FAV制剂相比，肺和肝脏的药物蓄积分别提高了1.5倍和1.3倍。这些结果表明，使用il作为一种简单、可扩展的策略，具有改善疏水药物（如FAV）的溶解度和口服吸收的潜力。
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 beta-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.