干粉吸入剂可控多孔化载体的成型机制及其增效机理研究

Pulmonary drug delivery system has become an important treatment of lung disease. Dry powder inhalations (DPIs), the only dosage form in solid state for pulmonary drug delivery system, have attracted more attention in pharmaceutical researches. 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 porous structure present higher fine particle fraction (FPF) and bioavailability comparing to the carriers without modification, which could be attributed to the hypothesis that the porous structure may improve the aerodynamics properties and regulate the drug-carrier adhesion force, and hence improve the drug deposition efficiency of DPIs. However, the systemic theory on the relationship between the porous structure of carriers and drug deposition efficiency of DPIs was not investigated in previous studies, which was restricted by the absence of controllable modification method to produce porous carriers. In our piorneer previous study, controllable porous mannitol carriers could be constructed with thermal-decomposition pore-forming agent. Moreover, it was found that good correlation existed between the porosities of porous carriers and the FPF values of DPIs both in vitro and in vivo. The purpose of this project is to systematically investigate the formation of the controllable porous structure of carriers with small-molecular alditol, establish the quantitative relationship between the pore size and porosity of porous carriers and FPF value, and clarify the mechanism of the enhanced drug efficacy of DPIs with the porous carriers base on the investigations on the aerodynamic properties of carriers and drug-carrier interaction forces. These studies will provide guidance for research and development of DPIs with high bioavailability.

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给药剂型，是药剂学研究热点。干粉吸入剂大多需要载体辅助药物到达有效部位产生疗效，因此载体是影响制剂有效沉积率的重要因素。载体多孔化可以改善载体空气动力学性质，调节药物-载体黏附力，提高药物的有效沉积率。但载体多孔化对干粉吸入剂药效影响的研究仍缺乏系统理论，其瓶颈是无法定向构建可控的多孔载体。申请人前期研究发现，利用热敏性孔道生成剂的孔洞蚀刻作用可产生可控的多孔载体，突破了载体多孔化技术瓶颈。并发现多孔载体孔隙率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。本课题拟在前期基础上，深入研究多孔化载体的成型机制，建立多孔载体结构与药物肺部有效沉积率之间的定量关系，基于多孔化对载体空气动力学、与药物相互作用等的影响以阐明多孔化载体提高药物有效沉积率的机制，对新型干粉吸入制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给药剂型，是药剂学研究热点。干粉吸入剂大多需要载体辅助药物到达有效部位产生疗效，因此载体是影响药效的重要因素。载体多孔化可以改善载体空气动力学性质，调节药物-载体黏附力，提高药物的肺部药物递送效率。但载体多孔化对干粉吸入剂药效影响的研究仍缺乏系统理论，其瓶颈是无法定向构建可控的多孔载体。本项目进行了干粉吸入剂可控多孔化载体的成型机制及其增效机理研究，利用热敏性孔道生成剂的孔洞蚀刻作用可产生可控的多孔载体，突破了载体多孔化技术瓶颈。并发现多孔载体孔隙率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，探究不同处方工艺参数等对热敏性孔道生成剂的孔洞蚀刻作用的调控机制，具体考察了载体材料、溶剂、致孔剂、雾化压力和出风温度对多孔载体形成的影响，构建多种多孔化载体。考察不同的多孔载体的空气动力学性质，流动能、充气能和透气性等，探讨多孔结构对载体空气动力学行为的影响。建立空气动力学性质与肺部有效沉积率的相关性，阐明多孔化载体提高药物有效沉积率的机制。同时初步探究药物-多孔载体DPIs肺部药物递送机理，研究该过程的体内外相关性，对新型干粉吸入制剂的研发具有重要指导意义。