Acosta Maria F, Encinas-Basurto David, Abrahamson Michael D, Eedara Basanth Babu, Hayes Don, Fineman Jeffrey R, Black Stephen M, Mansour Heidi M
The University of Arizona College of Pharmacy, Skaggs Pharmaceutical Sciences Center, Tucson, Arizona 85721, United States.
Universidad de Sonora, Department of Physics, Nanotechnology Program, Hermosillo, Sonora 83000, México.
ACS Bio Med Chem Au. 2024 Oct 28;4(6):300-318. doi: 10.1021/acsbiomedchemau.4c00063. eCollection 2024 Dec 18.
This study introduces novel cospray-dried (Co-SD) formulations of simvastatin, a Nrf2 activator ROCK inhibitor, with l-carnitine as molecular mixtures in various molar ratios for targeted pulmonary inhalation aerosol delivery in pulmonary hypertension, optimized for excipient-free dry powder inhalers (DPIs). The two components were spray-dried at various molar ratios by using different starting feed solution concentrations and process parameters. In addition to comprehensive physicochemical characterization, in vitro aerosol dispersion performance as DPIs using two FDA-approved DPI devices with different shear stress properties, in vitro viability as a function of dose on 2D human pulmonary cellular monolayers and on 3D small airway epithelia human primary cultures at the air-liquid interface (ALI), and in vitro transepithelial electrical resistance (TEER) at the ALI were conducted. Solid-state physicochemical characterization confirmed homogeneous molecular mixtures and the crystalline nature of the Co-SD formulations. In vitro aerosolization dispersion performance demonstrated that all Co-SD dual combination molecular mixtures aerosolized successfully with both human FDA-approved DPI devices, had ∼100% emitted dose, and good fine particle fraction values. The in vitro viability and TEER assays demonstrated that all formulations were safe to the human pulmonary cell as 2D and 3D cultures as a function of dose.
本研究介绍了辛伐他汀（一种Nrf2激活剂ROCK抑制剂）与左旋肉碱以不同摩尔比作为分子混合物的新型共喷雾干燥（Co-SD）制剂，用于肺动脉高压的靶向肺部吸入气雾剂递送，并针对无赋形剂干粉吸入器（DPI）进行了优化。通过使用不同的起始进料溶液浓度和工艺参数，将这两种成分以不同摩尔比进行喷雾干燥。除了全面的物理化学表征外，还使用两种具有不同剪切应力特性的FDA批准的DPI装置对作为DPI的体外气溶胶分散性能、在二维人肺细胞单层和三维小气道上皮人原代培养物在气液界面（ALI）上作为剂量函数的体外活力以及在ALI处的体外跨上皮电阻（TEER）进行了研究。固态物理化学表征证实了Co-SD制剂为均匀的分子混合物且具有结晶性质。体外雾化分散性能表明，所有Co-SD二元组合分子混合物均能与两种FDA批准的人用DPI装置成功雾化，发射剂量约为100%，且细颗粒分数值良好。体外活力和TEER测定表明，所有制剂作为二维和三维培养物，作为剂量函数，对人肺细胞都是安全的。
