Design and development of innovative microparticulate/nanoparticulate inhalable dry powders of a novel synthetic trifluorinated chalcone derivative and Nrf2 agonist.
Design and development of innovative microparticulate/nanoparticulate inhalable dry powders of a novel synthetic trifluorinated chalcone derivative and Nrf2 agonist.
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DOI：
10.1038/s41598-020-76585-2
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发表时间：
2020-11-13
影响因子：
4.6
通讯作者：
Mansour HM
中科院分区：
文献类型：
--
作者：
Muralidharan P;Jones B;Allaway G;Biswal SS;Mansour HM
查尔酮衍生物具有优异的抗炎和抗氧化特性，对于治疗急性肺损伤（ALI）、急性呼吸窘迫综合征（ARDS）、慢性阻塞性肺病（COPD）和肺纤维化（PF）等呼吸系统疾病具有重要意义。本研究成功设计和开发了TMC（2-三氟甲基-2'-甲氧基查酮）的干粉吸入器（DPI）配方，TMC是一种新型合成三氟化查尔酮和Nrf2激动剂，用于靶向肺部吸入气雾剂药物输送。采用先进的共喷雾干燥颗粒工程技术来设计和生产 TMC 的微粒/纳米颗粒制剂与合适的赋形剂（甘露醇）作为可吸入颗粒，具有适合吸入的定制颗粒特性。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 ATR-FTIR 光谱和拉曼光谱对干粉进行分子指纹分析，对原始 TMC 和共喷雾干燥 TMC 制剂进行了全面表征。此外，使用人肺气道细胞系在空气界面培养（AIC）中通过体外细胞跨上皮电阻（TEER）测试制剂的生物相容性和适用性。使用 FDA 批准的三种不同的人体吸入器设备，通过实验设计 (DOE) 系统评估这些 TMC 制剂作为雾化干粉的性能，然后进行相互作用参数分析。多个喷雾干燥泵速率（25%、75% 和 100%）成功生产了共喷雾干燥的 TMC:甘露醇粉末。原始 TMC 的一级相变温度为 58.15±0.38 °C。此外，结果表明这些创新的 TMC 干粉颗粒适合通过吸入定向输送到气道。
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.
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影响因子：
3.6
作者：
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通讯作者：
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