Huang Yongpeng, Tang Hui, Liu Dongxin, Liu Yanli, Meng Xiangyan, Chen Bo, Zou Zhiyun
State Key Laboratory of NBC Protection for Civilian, Beijing 102205, China.
State Key Laboratory of NBC Protection for Civilian, Beijing 102205, China.
J Control Release. 2023 Oct;362:243-256. doi: 10.1016/j.jconrel.2023.08.050. Epub 2023 Sep 1.
In this study, the extra-fine dry powder inhalers (DPIs) with chitosan (CS) as carrier were successfully prepared by ionic gel method combined with spray drying technique for deep pulmonary drug delivery of Cyclosporine A (CsA), using sodium hyaluronate (SHA) and sodium polyglutamate (SPGA) as polyanions. The CsA-loaded DPIs of CS-SHA-CsA and CS-SPGA-CsA were spherical particles with wrinkles on the surface, which were more conducive to improving the aerosol properties. The aerodynamic evaluation of CS-SHA-CsA and CS-SPGA-CsA showed that the fine particle fraction (FPF) reached up to 79.22 ± 2.12% and 81.55 ± 0.43%, while the emitted fraction (EF) reached 77.15 ± 1.46% and 78.29 ± 2.10%. In addition, the mass median aerodynamic diameter (MMAD) was calculated as 1.58 ± 0.04 μm and 1.94 ± 0.02 μm for CS-SHA-CsA and CS-SPGA-CsA, indicating that they were all extra-fine particles (d < 2 μm). These in vitro aerodynamic results showed that CS-SHA-CsA and CS-SPGA-CsA could reach the smaller airways, further improving therapeutic efficiency. The cell viability on A549 cell line results showed that CS-SHA-CsA and CS-SPGA-CsA were safe to deliver CsA to lungs. The in vivo pharmacokinetics consequence proved that inhalation administration of CS-SHA-CsA and CS-SPGA-CsA could significantly improve the bioavailability of CsA in vivo compared with oral administration of Neoral®, effectively reducing the risk of a series of adverse effects caused by systemic overexposure. In addition, the safety and compatibility of DPIs using SHA, SPGA, and CS as carriers for pulmonary drug delivery was verified by in vivo repeated dose inhalation toxicity. From these findings, the extra-fine DPIs with CS as carrier could be a viable delivery option for the deep pulmonary drug delivery of CsA relative to orally administered drug.
在本研究中，以壳聚糖（CS）为载体，采用离子凝胶法结合喷雾干燥技术，成功制备了用于环孢素A（CsA）肺部深部给药的超细微干粉吸入剂（DPI），并使用透明质酸钠（SHA）和聚谷氨酸钠（SPGA）作为聚阴离子。载有CsA的CS-SHA-CsA和CS-SPGA-CsA DPI为表面有褶皱的球形颗粒，更有利于改善气溶胶性能。对CS-SHA-CsA和CS-SPGA-CsA的空气动力学评估表明，细颗粒分数（FPF）分别高达79.22±2.12%和81.55±0.43%，而发出分数（EF）分别达到77.15±1.46%和78.29±2.10%。此外，CS-SHA-CsA和CS-SPGA-CsA的质量中值空气动力学直径（MMAD）经计算分别为1.58±0.04μm和1.94±0.02μm，表明它们均为超细微颗粒（d<2μm）。这些体外空气动力学结果表明，CS-SHA-CsA和CS-SPGA-CsA能够到达较小的气道，进一步提高治疗效果。A549细胞系的细胞活力结果表明，CS-SHA-CsA和CS-SPGA-CsA将CsA递送至肺部是安全的。体内药代动力学结果证明，与口服Neoral®相比，吸入CS-SHA-CsA和CS-SPGA-CsA可显著提高CsA在体内的生物利用度，有效降低全身过度暴露引起的一系列不良反应风险。此外，通过体内重复剂量吸入毒性试验验证了以SHA、SPGA和CS为载体的DPI用于肺部给药的安全性和相容性。从这些研究结果来看，相对于口服给药，以CS为载体的超细微DPI可能是CsA肺部深部给药的一种可行给药选择。
