Kashikar Rama, Kotha Arun Kumar, Shrestha Rakshya, Channappanavar Rudragouda, Chougule Mahavir Bhupal
Ingenious Biopharma-Engineered Drugs and Biologics Delivery Laboratory (Ibd2 Lab), Department of Pharmaceutical Sciences, Mercer University, Atlanta, Georgia, 30341, USA.
Department of Pharmaceutical Sciences, Larkin University, Miami, FL, 33169, USA.
AAPS PharmSciTech. 2025 May 16;26(5):139. doi: 10.1208/s12249-025-03099-3.
COVID- 19, caused by the coronavirus SARS-CoV- 2, has arisen as a global health epidemic, claiming the lives of millions of people throughout the world. Combating the pandemic has involved developing and approving vaccines and antiviral products. Camostat Mesylate (Camo) is a TMPRSS2 inhibitor that inhibits virus-cell membrane fusion and, thereby, viral multiplication. Significant limitations of using oral Camo include the limited amount of Camo reaching the site of action, lungs, side effects due to distribution to all tissues, and enzymatic breakdown in the gut. This investigation aims to develop self-administrable and patient-compliant extended-release Camo-loaded pegylated nanoliposomes (Camo-pegNLs) for delivering Camo directly to the lungs, thereby enabling faster onset of action and overcoming limitations of oral Camo delivery. We developed the Camo-pegNLs were composed of 1,2-dipalmitoyl-sn-glycerol- 3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycerol- 3-phosphoethanolamine (DOPE-PEG, MW2000) and cholesterol using the ethanol injection technique and syringe pump. The NLs were characterized for their particle size, polydispersity index (PDI), and zeta potential using Malvern Zetasizer. The assay, unentrapped Camo using Vivaspin 500 ultrafilter (10 kDa) and in-vitro release were determined. The Camo content was analyzed using a validated HPLC method. The aerodynamic properties of Camo-pegNLs were determined using a Westech Andersen Cascade Impactor (ACI) at 28.3L/min and a pneumatic jet nebulizer. The antiviral effect of Camo-pegNLs was assessed in Vero cells expressing TMPRSS2 and infected with SARS-CoV- 2. Camo-pegNLs suspension showed size of 167.50 ± 0.90 nm, zeta potential of 0.48 ± 0.04 mV, and PDI of 0.07 ± 0.01. The quantity of entrapped Camo was found to be 44.86 ± 1.35%w/v, and the drug loading was 27.41 ± 0.04%w/w. The Camo-pegNL- 2 had an extended release of up to 24 h, MMAD of 4.295 ± 0.1 µm, GSD of 1.915 ± 0.064, and FPF of 42.01% ± 6.90. Camo-pegNLs showed a significant antiviral effect on Vero cells compared to no treatment group (p < 0.01). An efficacious nebulized Camo-pegNLs suspension product was successfully developed for direct lung delivery to Camo-pegNLs to treat the SARS-CoV- 2 infection.
由冠状病毒SARS-CoV-2引起的COVID-19已演变成一场全球健康流行病，夺走了全世界数百万人的生命。抗击这一流行病涉及开发和批准疫苗及抗病毒产品。甲磺酸卡莫司他（Camo）是一种TMPRSS2抑制剂，可抑制病毒与细胞膜融合，从而抑制病毒增殖。口服Camo的显著局限性包括到达作用部位（肺部）的Camo量有限、因分布到所有组织而产生的副作用以及在肠道中的酶解。本研究旨在开发可自我给药且患者依从性好的载有Camo的聚乙二醇化纳米脂质体（Camo-pegNLs），以便将Camo直接递送至肺部，从而实现更快起效并克服口服Camo给药的局限性。我们使用乙醇注入技术和注射泵，以1,2-二棕榈酰-sn-甘油-3-磷酸胆碱（DPPC）、1,2-二油酰-sn-甘油-3-磷酸乙醇胺（DOPE-PEG，分子量2000）和胆固醇制备了Camo-pegNLs。使用马尔文Zetasizer对纳米脂质体的粒径、多分散指数（PDI）和zeta电位进行了表征。使用Vivaspin 500超滤器（10 kDa）测定未包封的Camo含量并进行体外释放测定。使用经过验证的高效液相色谱法分析Camo含量。使用Westech Andersen级联撞击器（ACI）在28.3L/min流速下和气动喷射雾化器测定Camo-pegNLs的空气动力学特性。在表达TMPRSS2并感染SARS-CoV-2的Vero细胞中评估Camo-pegNLs的抗病毒效果。Camo-pegNLs悬浮液的粒径为167.50±0.90 nm，zeta电位为0.48±0.04 mV，PDI为0.07±0.01。发现包封的Camo量为44.86±1.35%w/v，载药量为27.41±0.04%w/w。Camo-pegNL-2的释放长达24小时，质量中值空气动力学直径（MMAD）为4.295±0.1 µm，几何标准差（GSD）为1.915±0.064，细粒子分数（FPF）为42.01%±6.90。与未治疗组相比，Camo-pegNLs对Vero细胞显示出显著的抗病毒效果（p＜0.01）。成功开发了一种有效的雾化Camo-pegNLs悬浮液产品，用于将Camo-pegNLs直接递送至肺部以治疗SARS-CoV-2感染。
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