Formulation of insulin-loaded N-trimethyl chitosan microparticles with improved efficacy for inhalation by supercritical fluid assisted atomization
Formulation of insulin-loaded N-trimethyl chitosan microparticles with improved efficacy for inhalation by supercritical fluid assisted atomization
复制标题
通过超临界流体辅助雾化改善吸入功效的负载胰岛素的N-三甲基壳聚糖微粒的制剂
DOI：
10.1016/j.ijpharm.2016.03.053
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发表时间：
2016
影响因子：
5.8
通讯作者：
Shan-Jing Yao
中科院分区：
文献类型：
--
作者：
Yu-Bin Shen;Zhe Du;Chuan Tang;Yi-Xin Guan;Shan-Jing Yao
采用超临界流体辅助流体空化混合器（SAA HCM）制备了高分子粘膜粘附吸收促进剂--N-三甲基壳聚糖（TMC），并利用SAA HCM对TMC进行了超微粉碎。所制备的球形TMC微粒具有良好的结构和热稳定性，是一种潜在的蛋白质载体。然后，在不使用任何有机溶剂的情况下，使用SAA-HCM从水溶液中共沉淀具有高负载效率的负载胰岛素的TMC微粒。聚合物/蛋白质的比例是影响颗粒形态的一个因素，在本工作中可以得到非聚结的无定形复合微粒，主要分布在1 μm到5 μm之间。采用下一代撞击式采样器（NGI）对空气动力学特性进行了评价，结果表明，空气动力学质量中值直径（MMAD）在1-5 μm的可吸入范围内，细颗粒物含量（FPF）达到60%以上。经HPLC、圆二色谱和荧光光谱分析证实了包封胰岛素的结构完整性，体内研究表明TMC可提高胰岛素经肺给药制剂在SD大鼠体内的吸收和生物利用度。这些结果表明，TMC微粒可以有效地制备作为一个有前途的药物载体，和SAA-HCM是一个有前途的技术，制备可吸入的聚合物/蛋白质复合物干粉。
Supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) was proposed as a green technique to fabricate insulin-loaded dry powders for inhalation administration.N-trimethyl chitosan (TMC), a polymeric mucoadhesive absorption enhancer, was synthesized and successfully micronized from aqueous solution using SAA-HCM. The prepared well-defined spherical TMC microparticles with preserved structure and thermal stability were potential carriers for delivery of proteins. Then, insulin-loaded TMC microparticles with high loading efficiency were coprecipitated from aqueous solutions using SAA-HCM without use of any organic solvents. The polymer/protein ratio revealed to be a factor influencing the particle morphology, and non-coalescing composite microparticles in amorphous state mainly ranging from 1 μm to 5 μm could be obtained in this work. Aerodynamic properties were assessed by next generation impactor (NGI) and the mass median aerodynamic diameter (MMAD) lied inside the inhalable range of 1–5 μm, while fine particle fraction (FPF) reached above 60%. The structural integrity of encapsulated insulin was confirmed by HPLC, circular dichroism and fluorescence spectroscopy.In vivostudy demonstrated that TMC could enhance the absorption and bioavailability of the pulmonarily administered insulin formulation for SD rats. These results suggest that TMC microparticles could be efficiently prepared as a promising vehicle for drug delivery, and SAA-HCM is a promising technique to prepare inhalable polymer/protein composite dry powders.