Muralidharan Priya, Jones Brielle, Allaway Graham, Biswal Shyam S, Mansour Heidi M
Colleges of Pharmacy and Medicine, University of Arizona, 1703 E. Mabel St, Tucson, AZ, 85721, USA.
Cureveda LLC, Halethorpe, MD, USA.
Sci Rep. 2020 Nov 13;10(1):19771. doi: 10.1038/s41598-020-76585-2.
Chalcone derivatives are shown to possess excellent anti-inflammatory and anti-oxidant properties which are of great interest in treating respiratory diseases such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF). This study successfully designed and developed dry powder inhaler (DPI) formulations of TMC (2-trifluoromethyl-2'-methoxychalone), a new synthetic trifluorinated chalcone and Nrf2 agonist, for targeted pulmonary inhalation aerosol drug delivery. An advanced co-spray drying particle engineering technique was used to design and produce microparticulate/nanoparticulate formulations of TMC with a suitable excipient (mannitol) as inhalable particles with tailored particle properties for inhalation. Raw TMC and co-spray dried TMC formulations were comprehensively characterized for the first time using scanning electron microscopy (SEM) with energy dispersive X-ray (EDX) spectroscopy, thermal analysis, X-ray powder diffraction (XRPD), and molecular fingerprinting as dry powders by ATR-FTIR spectroscopy and Raman spectroscopy. Further, biocompatibility and suitability of formulations were tested with in vitro cellular transepithelial electrical resistance (TEER) in air-interface culture (AIC) using a human pulmonary airway cell line. The ability of these TMC formulations to perform as aerosolized dry powders was systematically evaluated by design of experiments (DOEs) using three different FDA-approved human inhaler devices followed by interaction parameter analyses. Multiple spray drying pump rates (25%, 75%, and 100%) successfully produced co-spray dried TMC:mannitol powders. Raw TMC exhibited a first-order phase transition temperature at 58.15 ± 0.38 °C. Furthermore, the results demonstrate that these innovative TMC dry powder particles are suitable for targeted delivery to the airways by inhalation.
查尔酮衍生物具有出色的抗炎和抗氧化特性，这对于治疗诸如急性肺损伤（ALI）、急性呼吸窘迫综合征（ARDS）、慢性阻塞性肺疾病（COPD）和肺纤维化（PF）等呼吸系统疾病具有重要意义。本研究成功设计并开发了一种新型合成三氟查尔酮TMC（2-三氟甲基-2'-甲氧基查尔酮）的干粉吸入剂（DPI）制剂，它也是一种Nrf2激动剂，用于靶向肺部吸入气雾剂药物递送。采用先进的共喷雾干燥颗粒工程技术，以合适的辅料（甘露醇）设计并制备了TMC的微粒/纳米粒制剂，使其成为具有适合吸入的定制颗粒特性的可吸入颗粒。首次使用扫描电子显微镜（SEM）结合能量色散X射线（EDX）光谱、热分析、X射线粉末衍射（XRPD）以及通过衰减全反射傅里叶变换红外光谱（ATR-FTIR）和拉曼光谱对原料药TMC和共喷雾干燥的TMC制剂作为干粉进行了全面表征。此外，使用人肺气道细胞系在气液界面培养（AIC）中通过体外细胞跨上皮电阻（TEER）测试了制剂的生物相容性和适用性。通过实验设计（DOE）使用三种不同的FDA批准的人体吸入器装置，随后进行相互作用参数分析，系统地评估了这些TMC制剂作为雾化干粉的性能。多个喷雾干燥泵速（25%、75%和100%）成功制备了共喷雾干燥的TMC：甘露醇粉末。原料药TMC在58.15±0.38°C表现出一级相变温度。此外，结果表明这些创新的TMC干粉颗粒适合通过吸入靶向递送至气道。
