干粉吸入剂二元载体表面微结构的定向构建及其增效机理的研究

Dry powder inhalations (DPIs), the solid state dosage form for pulmonary drug delivery system, have attracted more attention in pharmaceutical researches due to its compatibility for protein/peptide and water-sensitive drugs. The carriers play a critical role in DPIs since they can help drugs deliver to the action site. An interesting phenomenon showed that the carriers with nano-metered surface present higher fine particle fraction and bioavailability comparing to the carriers without surface modification in the same composition, which could be attributed to the hypothesis that the nano-metered surface roughness may reduce the drug-carrier adhesion force and improve the aerosolization effect. However, the systemic theory on the relationship between the nano-metered topography roughness of DPIs carriers and drug efficacy of DPIs was not investigated in previous studies. The research from our group found that the unique microscale structure surface of the carriers, prepared by using binary alditol system with one-step spray drying based on the different migration rate between two kinds of molecules, significantly increased the fine particle fraction. The purpose of this project is to systematically investigate the formation of the controllable nano-metered topography roughness of carriers with small-molecular alditol, establish the quantitative relationship between nano-metered topography roughness and fine particle fraction, and clarify the mechanism of the enhanced drug efficacy of DPIs with the nano-metered topography roughness carriers. These studies will provide a guidance for research and development of DPIs with high bioavailability.

干粉吸入剂是唯一以固体形式存在的肺部药物传递系统，因其适用于蛋白质多肽类和对水敏感的药物，成为药剂学研究热点。干粉吸入剂大多需要借助载体来辅助药物到达有效部位而获得一定的释药性能，因此载体是影响药物制剂有效沉积率的重要因素。载体表面微结构，尤其是纳米级粗糙结构能降低药物-载体黏附力，改善雾化效果，提高药物的肺部沉积率。但载体表面微结构对干粉吸入剂药效影响的研究缺乏系统理论，其瓶颈问题是无法定向构建可控纳米级粗糙度的载体。本课题组前期研究发现，利用分子量及分子间的迁移速率的差异，能一步制备具有可控纳米级粗糙度的二元载体，可显著提高药物有效沉积率。该课题拟在此基础上，系统地研究可控纳米级粗糙化二元载体的成型机理，建立载体纳米级粗糙度与有效沉积率之间的关系，基于纳米级粗糙度、载体物理性质和药物-载体黏附力来阐明纳米级粗糙提高有效沉积率的机制，对新型干粉吸入剂的研发具有重要指导意义。

肺部药物传递系统已成为治疗肺部疾病的重要手段。干粉吸入剂是唯一以固体形式存在的肺部药物传递系统，因其适用于蛋白质多肽类和对水敏感的药物，成为药剂学研究热点。干粉吸入剂大多需要借助载体来辅助药物到达有效部位而获得一定的释药性能，因此载体是影响药物制剂有效沉积率的重要因素。载体表面微结构，尤其是纳米级粗糙结构能降低药物-载体黏附力，改善雾化效果，提高药物的肺部沉积率。但载体表面微结构对干粉吸入剂药效影响的研究缺乏系统理论，其瓶颈问题是无法定向构建可控纳米级粗糙度的载体。本项目进行了干粉吸入剂表面粗糙载体的成型机制及其增效机理研究，通过改变大分子糖醇和小分子糖醇的比例制备具有可控的不同纳米级表面粗糙度的干粉吸入剂载体。并发现表面粗糙化载体的纳米级表面粗糙度与干粉吸入剂有效沉积率在体内体外试验中均呈现出良好相关性。此外，探究了载体表面修饰材料、溶剂、溶液固含量、雾化压力、出风温度和二元载体质量比对载体的纳米级表面粗糙度的影响，基于纳米级表面粗糙化对载体空气动力学、载体与药物相互作用等的影响以阐明表面粗糙化载体提高药物有效沉积率的机制。同时，探究了药物-纳米级粗糙表面载体用于干粉吸入剂的体内药动学，研究该过程的体内外相关性及长期稳定性，对新型干粉吸入剂的研发具有重要指导意义。