Remdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for emergency use. To maximize delivery to the lungs, we formulated remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces brittle matrix nanostructured aggregates that are sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients exhibited desirable aerosol performance (up to 93.0% FPF_{< 5 µm}; 0.82 µm mass median aerodynamic diameter). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one month of storage at 25 °C/60% relative humidity. An in vivo pharmacokinetic evaluation showed that TFF remdesivir–leucine was poorly absorbed into systemic circulation while TFF remdesivir-Captisol^® demonstrated increased systemic uptake compared to leucine. Remdesivir was hydrolyzed to the nucleoside analog GS-441524 in the lung, and levels of GS-441524 were greater in the lung with leucine formulation compared to Captisol^®. In conclusion, TFF technology produces high-potency remdesivir dry powder formulations for inhalation that are suitable to treat patients with COVID-19 on an outpatient basis and earlier in the disease course where effective antiviral therapy can reduce related morbidity and mortality.

中文翻译：

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薄膜冷冻法吸入瑞姆昔韦干粉的研制

雷姆昔韦对SARS-CoV-2表现出体外活性，并被批准用于紧急使用。为了最大程度地输送至肺部，我们将瑞姆昔韦制成干粉配制为可使用薄膜冷冻（TFF）吸入。TFF产生的脆性基体纳米结构聚集体在通过被动干粉吸入器雾化后被剪切成可吸入的低密度微粒。体外空气动力学测试表明，载药量和赋形剂类型会影响瑞德昔韦的气雾剂性能。Remdesivir具有最佳赋形剂组合表现出期望的气溶胶性能（高达93.0％FPF _{< 5 μ米}; 质量中值空气动力学直径为0.82 µm）。TFF过程后，雷姆昔韦是无定形的，这有助于药物在模拟肺液中的溶解。TFF瑞地昔韦制剂在25°C / 60％相对湿度下储存一个月后稳定。体内药代动力学评价表明，TFF remdesivir亮氨酸被吸收较差进入体循环而TFF remdesivir -阴离子β-环糊精^®相比表现出亮氨酸增加全身吸收。Remdesivir水解成核苷类似物GS-441524在肺，和GS-441524的水平大于与相比于多阴离子β-环糊精的制剂的亮氨酸肺^®。总而言之，TFF技术生产了高效的瑞德昔韦干粉吸入剂，适合在门诊患者以及较早的疾病过程中治疗COVID-19的患者使用，有效的抗病毒治疗可以降低相关的发病率和死亡率。