Skaggs Pharmaceutical Sciences Center, The University of Arizona College of Pharmacy, 1703 E. Mabel St, Skaggs Pharmaceutical Sciences Center, Tucson, Arizona, 85721-0207, USA.
Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, California, USA.
AAPS J. 2020 Nov 16;23(1):2. doi: 10.1208/s12248-020-00531-3.
Metformin is an activator of the AMPK and Nrf2 pathways which are important in the pathology of several complex pulmonary diseases with unmet medical needs. Organic solution advanced spray drying in the absence of water in closed-mode was used to design and develop respirable dry powders. Following comprehensive characterization, the influence of physicochemical properties was correlated with performance as aerosols using inertial impaction and three different human dry powder inhaler (DPI) devices varying in device properties. In vitro cell assays were conducted to test safety in 2D human pulmonary cell lines and in 3D small airway epithelia comprising primary cells at the air-liquid interface (ALI). In addition, in vitro transepithelial electrical resistance (TEER) was carried out. Metformin remained crystalline following advanced spray drying under these conditions. All SD powders consisted of nanoparticles/microparticles in the solid state. In vitro aerosol dispersion performance showed high aerosolization for all SD metformin powders with all DPI devices tested. High emitted dose for all powders with all three DPI devices was measured. Differences in other aerosol performance parameters and the interplay between the properties of different formulations produced at specific pump rates and the three different DPI devices were correlated with spray drying pump rate and device properties. Safety over a wide metformin dose range was also demonstrated in vitro. Aerosol delivery of metformin nanoparticles/microparticles has the potential to be a new "first-in-class" therapeutic for the treatment of a number of pulmonary diseases including pulmonary vascular diseases such as pulmonary hypertension.
二甲双胍是 AMPK 和 Nrf2 途径的激活剂，这些途径在多种具有未满足医疗需求的复杂肺部疾病的病理学中非常重要。采用有机溶液先进喷雾干燥法（在无水条件下以密闭模式）来设计和开发可吸入干粉。经过全面表征，将理化性质的影响与使用惯性撞击和三种不同的人类干粉吸入器（DPI）装置的气溶胶性能相关联，这些装置在装置特性上有所不同。进行体外细胞测定以在 2D 人肺细胞系和包含在气液界面（ALI）处的原代细胞的 3D 小气道上皮中测试安全性。此外，还进行了体外跨上皮电阻（TEER）测定。二甲双胍在这些条件下经过先进喷雾干燥后仍保持结晶状态。所有 SD 粉末在固态下均由纳米颗粒/微颗粒组成。体外气溶胶分散性能表明，所有 SD 二甲双胍粉末与所有测试的 DPI 装置都具有很高的气溶胶化能力。用所有三种 DPI 装置测量到所有粉末的高发射剂量。不同制剂的不同气溶胶性能参数之间的差异以及在特定泵速和三种不同 DPI 装置下产生的制剂之间的相互作用与喷雾干燥泵速和装置特性有关。在体外也证明了广泛的二甲双胍剂量范围内的安全性。二甲双胍纳米颗粒/微颗粒的气溶胶输送有可能成为治疗多种肺部疾病的新型“首创”疗法，包括肺血管疾病，如肺动脉高压。
