Changsan Narumon, Atipairin Apichart, Muenraya Poowadon, Sritharadol Rutthapol, Srichana Teerapol, Balekar Neelam, Sawatdee Somchai
College of Pharmacy, Rangsit University, Pathum Thani 12000, Thailand.
School of Pharmacy, Walailak University, Thasala 80160, Nakhon Si Thammarat, Thailand.
Antibiotics (Basel). 2024 Jul 6;13(7):630. doi: 10.3390/antibiotics13070630.
Inhaled colistin is used to treat pneumonia and respiratory infections through nebulization or dry powder inhalers. Nevertheless, the development of a metered-dose inhaler (MDI) for colistin, which could enhance patient convenience and treatment efficacy, has not yet been developed. Colistin is known for its ability to induce cellular toxicity. Gold nanoparticles (AuNPs) can potentially mitigate colistin toxicity. Therefore, this study aimed to evaluate the antimicrobial effectiveness of colistin conjugated with chitosan-capped gold nanoparticles (Col-CS-AuNPs) and their potential formulation for use with MDIs to deliver the aerosol directly to the deep lung. Fourier-transform infrared spectroscopy, nuclear magnetic resonance, and elemental analysis were used to characterize the synthesized Col-CS-AuNPs. Drug release profiles fitted with the most suitable release kinetic model were evaluated. An MDI formulation containing 100 µg of colistin per puff was prepared. The aerosol properties used to determine the MDI performance included the fine particle fraction, mass median aerodynamic diameter, and geometric standard deviation, which were evaluated using the Andersen Cascade Impactor. The delivered dose uniformity was also determined. The antimicrobial efficacy of the Col-CS-AuNP formulation in the MDI was assessed. The chitosan-capped gold nanoparticles (CS-AuNPs) and Col-CS-AuNPs had particle sizes of 44.34 ± 1.02 and 174.50 ± 4.46 nm, respectively. CS-AuNPs effectively entrapped 76.4% of colistin. Col-CS-AuNPs exhibited an initial burst release of up to 60% colistin within the first 6 h. The release mechanism was accurately described by the Korsmeyer-Peppas model, with an R > 0.95. The aerosol properties of the Col-CS-AuNP formulation in the MDI revealed a high fine particle fraction of 61.08%, mass median aerodynamic diameter of 2.34 µm, and geometric standard deviation of 0.21, with a delivered dose uniformity within 75-125% of the labeled claim. The Col-CS-AuNP MDI formulation completely killed at 5× and 10× minimum inhibitory concentrations after 6 and 12 h of incubation, respectively. The toxicity of CS-AuNP and Col-CS-AuNP MDI formulations in upper and lower respiratory tract cell lines was lower than that of free colistin. The stability of the Col-CS-AuNP MDI formulation was maintained for at least 3 months. The Col-CS-AuNP MDI formulation effectively eradicated bacteria over a 12-h period, showing promise for advancing lung infection treatments.
吸入用黏菌素通过雾化或干粉吸入器用于治疗肺炎和呼吸道感染。然而，用于黏菌素的定量吸入器（MDI）尚未研发出来，而这种吸入器可以提高患者的便利性和治疗效果。黏菌素以其诱导细胞毒性的能力而闻名。金纳米颗粒（AuNPs）有可能减轻黏菌素的毒性。因此，本研究旨在评估壳聚糖包覆金纳米颗粒（Col-CS-AuNPs）与黏菌素结合后的抗菌效果，以及它们用于MDI将气雾剂直接递送至肺深部的潜在制剂。采用傅里叶变换红外光谱、核磁共振和元素分析对合成的Col-CS-AuNPs进行表征。评估符合最合适释放动力学模型的药物释放曲线。制备了每喷含100μg黏菌素的MDI制剂。用于确定MDI性能的气雾剂特性包括细颗粒分数、质量中值空气动力学直径和几何标准偏差，使用安德森级联撞击器进行评估。还测定了递送剂量均匀性。评估了MDI中Col-CS-AuNP制剂的抗菌效果。壳聚糖包覆金纳米颗粒（CS-AuNPs）和Col-CS-AuNPs的粒径分别为44.34±1.02和174.50±4.46nm。CS-AuNPs有效包封了76.4%的黏菌素。Col-CS-AuNPs在最初6小时内表现出高达60%黏菌素的初始突释。释放机制由Korsmeyer-Peppas模型准确描述，R>0.95。MDI中Col-CS-AuNP制剂的气雾剂特性显示细颗粒分数高达61.08%，质量中值空气动力学直径为2.34μm，几何标准偏差为0.21，递送剂量均匀性在标签声明的75-125%范围内。Col-CS-AuNP MDI制剂在孵育6小时和12小时后，分别在5倍和10倍最小抑菌浓度下完全杀灭细菌。CS-AuNP和Col-CS-AuNP MDI制剂在上呼吸道和下呼吸道细胞系中的毒性低于游离黏菌素。Col-CS-AuNP MDI制剂的稳定性至少维持3个月。Col-CS-AuNP MDI制剂在12小时内有效根除细菌，显示出推进肺部感染治疗的前景。
