Abstract：
Potentially significant drug candidates often face elimination from consideration due to the lack of an effective method for systemic delivery. The poor solubility of these candidates has posed a major obstacle for their development as oral pills or injectables. Niclosamide, a host-directed antiviral, is a good example. In this study, a nanoformulation technology that allows for the non-covalent formulation of niclosamide with cholic acids was developed. This formulation enables efficient systemic delivery through endocytosis and enterohepatic circulation of bile-acid-coated nanoparticles. The oral bioavailability of niclosamide-delivery nanoparticles (NDNs) was significantly enhanced to 38.3%, representing an eight-fold increase compared with pure niclosamide. Consequently, the plasma concentration of niclosamide for the NDN formulation reached 1179.6 ng/mL, which is 11 times higher than the therapeutic plasma level. This substantial increase in plasma level contributed to the complete resolution of clinical symptoms in animals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This nanoformulation not only provides an orally deliverable antiviral drug for SARS-CoV-2 with improved pharmaceutical bioavailability, but also offers a solution to the systemic delivery challenges faced by potentially significant drug candidates.
摘要：
由于缺乏用于全身递送的有效方法,潜在重要的候选药物经常面临从考虑中排除。这些候选物的溶解性差对它们作为口服丸剂或注射剂的发展构成了主要障碍。氯硝柳胺,以宿主为导向的抗病毒药物，将是最好的例子。在这项研究中,我们已经开发了一种纳米制剂技术，该技术允许氯硝柳胺与胆酸的非共价制剂。该制剂能够通过胆汁酸包被的纳米颗粒的内吞作用和肠肝循环进行有效的全身递送。氯硝柳胺纳米粒（NDN）的口服生物利用度显著提高到38.3%，与纯氯硝柳胺相比增加了八倍。因此,NDN制剂中氯硝柳胺的血浆浓度达到1,179.6ng/mL，比治疗血浆水平高11倍。血浆水平的这种实质性增加有助于感染SARS-CoV-2的动物的临床症状的完全缓解。我们的纳米制剂不仅为SARS-CoV-2提供了一种可口服递送的抗病毒药物，具有改善的药物生物利用度，而且还为潜在的重要候选药物所面临的全身递送挑战提供了解决方案。
