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; 0.82 micron MMAD). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one-month storage at 25C/60%RH. 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 lung, and levels of GS-441524 were greater in lung with the leucine formulation compared to Captisol. In conclusion, TFF technology produces high potency remdesivir dry powder formulations for inhalation 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：

---

薄膜冷冻法吸入瑞姆昔韦干粉的研制

Remdesivir表现出抗SARS-CoV-2的体外活性，并被批准用于紧急用途。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。瑞地昔韦与最佳赋形剂的结合表现出理想的气雾剂性能（FPF高达93.0％； MMAD为0.82微米）。TFF过程后，雷姆昔韦是无定形的，这有利于药物在模拟肺液中的溶解。TFF remdesivir制剂在25°C / 60％RH下储存一个月后稳定。体内药代动力学评估表明，与亮氨酸相比，TFF-瑞地昔韦-亮氨酸被人体吸收较弱，而TFF-瑞地昔韦-Captisol表现出增加的全身吸收。Remdesivir在肺中被水解为核苷类似物GS-441524，与Captisol相比，亮氨酸制剂在肺中GS-441524的水平更高。总之，TFF技术可生产高效的雷姆昔韦干粉吸入剂，适合在门诊患者以及较早的疾病过程中（有效的抗病毒治疗可降低相关的发病率和死亡率）治疗COVID-19的患者。Remdesivir在肺中被水解成核苷类似物GS-441524，与Captisol相比，亮氨酸制剂在肺中GS-441524的水平更高。总之，TFF技术可生产高效的瑞德昔韦干粉吸入剂，适合在门诊患者以及疾病进程中较早的时期使用COVID-19患者进行治疗，在该过程中有效的抗病毒治疗可以降低相关的发病率和死亡率。Remdesivir在肺中被水解为核苷类似物GS-441524，与Captisol相比，亮氨酸制剂在肺中GS-441524的水平更高。总之，TFF技术可生产高效的雷姆昔韦干粉吸入剂，适合在门诊患者以及较早的疾病过程中（有效的抗病毒治疗可降低相关的发病率和死亡率）治疗COVID-19的患者。