Su Catherine, Saha Tushar, Sinha Shubhra, Hird Cody P, Smith Sophie X Y, Quiñones-Mateu Miguel E, Das Shyamal C
School of Pharmacy, University of Otago, Dunedin, New Zealand.
Department of Physiology, University of Otago, Dunedin, New Zealand.
Int J Pharm. 2025 Feb 25;671:125302. doi: 10.1016/j.ijpharm.2025.125302. Epub 2025 Jan 30.
SARS-CoV-2, the virus responsible for the COVID-19 pandemic, predominantly affects the respiratory tract, underscoring the need to develop antiviral agents in an inhalable formulation that can be delivered as prophylactic and/or therapeutic drugs directly to the infection site. Since the beginning of the pandemic, our group has been exploring the possibility of developing combinations of antiviral drugs that can be delivered as inhalable therapy, including combinations of remdesivir and ebselen or remdesivir and disulfiram prepared using a spray-drying technique. In this study, we used a similar spray-drying technique to develop inhalable dry powders combining the controversial drugs ivermectin and niclosamide, which have been reported to exhibit synergistic activity against SARS-CoV-2 in vitro. The combined dry powders were within the size range of 1-5 μm, amorphous in nature and displayed characteristic morphology after spray drying. The emitted dose (ED) of the spray-dried powders ranged from 68 to 83 %, whereas the fine particle fraction (FPF) ranged between 50 and 74 %. All the prepared dry powders remained stable under different humidity conditions (<15 % RH and 53 % RH). Interestingly, the optimized combinational dry powder of ivermectin and niclosamide showed an improved cytotoxic profile (CC value of 45.99 µM) and enhanced anti-SARS-CoV-2 activity in vitro (EC of 2.67 µM) compared to the single dry powders of ivermectin (CC = 20.25 µM and EC = 8.61 µM) and niclosamide (CC = 21.36 µM and EC = 5.28 µM). In summary, we developed a stable and inhalable combinational dry powder containing ivermectin and niclosamide, capable of inhibiting SARS-CoV-2 replication in vitro, demonstrating the potential to prepare dry powders that could be developed and delivered as inhalable antiviral drugs to prevent and/or treat SARS-CoV-2 or similar respiratory viruses.
导致新冠疫情的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主要侵袭呼吸道，这凸显了研发可吸入制剂形式抗病毒药物的必要性，这类药物能够作为预防和/或治疗药物直接递送至感染部位。自疫情开始以来，我们团队一直在探索开发可作为吸入疗法的抗病毒药物组合的可能性，包括使用喷雾干燥技术制备的瑞德西韦与依布硒联用，以及瑞德西韦与双硫仑联用。在本研究中，我们采用类似的喷雾干燥技术，研发了含有有争议药物伊维菌素和氯硝柳胺的可吸入干粉，据报道这两种药物在体外对SARS-CoV-2表现出协同活性。混合后的干粉粒径范围在1至5微米之间，呈无定形，喷雾干燥后呈现出特征性形态。喷雾干燥粉末的喷出剂量（ED）在68%至83%之间，而细颗粒分数（FPF）在50%至74%之间。所有制备的干粉在不同湿度条件下（<15%相对湿度和53%相对湿度）均保持稳定。有趣的是，与伊维菌素（CC = 20.25微摩尔，EC = 8.61微摩尔）和氯硝柳胺（CC = 21.36微摩尔，EC = 5.28微摩尔）的单一干粉相比，优化后的伊维菌素与氯硝柳胺组合干粉显示出改善的细胞毒性特征（CC值为45.99微摩尔）以及增强的体外抗SARS-CoV-2活性（EC为2.67微摩尔）。总之，我们研发出了一种稳定且可吸入的含有伊维菌素和氯硝柳胺的组合干粉，其能够在体外抑制SARS-CoV-2复制，证明了制备可作为吸入性抗病毒药物进行开发和递送以预防和/或治疗SARS-CoV-2或类似呼吸道病毒的干粉的潜力。
