基于纳米晶体的肺部吸入缓释复合微粒的设计及其释放度和黏液穿透性的研究

Mucociliary clearance represents a major obstacle for the delivery of inhaled drug.A drug deposited as particulate material has to be rapidly dissolved and available for absorption,otherwise it may be subject to clearance by muciciliary or cough clearance. Improvement in the dissolution of drug and/or mucus penentration and adhesion capability of delivery system are promising strategies to overcome the mucus barrier. In current project, nano-crystal based hyaluronic acid micro-composite particles will de desined with the purpose of slowing or evading the clearance mechanism by combining the advantage of both nanocrystal and biocompatible hyaluronic acid to obtain sustained release charactersitcs, prolonged lung resitence time and higher local drug concentration. On the other hand, although the release profiles of dry powder controlled release (CR) formulations have previously been studied, there is no standard pharmacopoeia methodology to date for the evaluation of in vitro release rates for CR respiratory drugs. This could be attributed to the lack of predictability and correlation between available in vitro models and the in vivo state for pulmonary drugs. In addition, the respiratory system displays great complexity with regards to accessibility, anatomy, dose delivery and consistency; hence, developing a physiological relevant model remains a challenge.The second task of this project is to set up a novel bio-relevant model which is able to differentiate formulation types, control the batch-to-batch consistency and give an estimate of release behavior in vivo A modified Franz diffusion cell model is proposed, in which a thin layer of artificial mucus is added onto the top of diffusion membrane to mimic the real physiological microenvironment. The in vitro release of budesonide from hyaluronic acid micro-composite particles and the mucus penetration will be evaluated in the established model. According to the obtained in vitro release data, the settings of critical parameters in this model, like the viscosity, the composition, and the depth of the mucus lay will be optimized until in- vitro in-vivo correlation is established. In addition, the relationship of drug release rate from HA microspheres with the rheology properties of artificial mucus and the physic-chemical properties of drug will be investigated systematically to elucidate the possible mechanism of drug release. The achievement of this project will promote the progress in the field of formulation design, process optimization and quality control for controlled release inhalable dry powder.

肺上皮细胞表面的黏液层是难溶性药物微粒发挥药效的主要屏障。提高药物溶解速度、增强对黏液穿透能力或粘附能力是克服该屏障的有效策略。本研究以布地奈德为模型药，构建了基于纳米晶体的透明质酸复合微粒用于肺部吸入，旨在联合纳米晶体能提高药物溶解速度以及透明质酸的生物粘附性及控制药物释放的能力，获得较长的肺部滞留时间和缓释特征。另外，由于复杂的肺部组织结构，目前仍然缺乏肺部缓释制剂释放性能的标准评价方法，这严重阻碍了肺部缓释制剂的发展。本研究将黏液层引入到Franz扩散池中，构建一个模拟体内环境的新模型，用于透明质酸复合微粒体外释放性能以及黏液穿透能力的评价，探讨与体内数据的相关性，并依据相关程度对黏液层的组成、厚度、黏度等关键因素进行优化，阐明黏液层流变学特性、药物理化性质与药物释放速度之间的关系，揭示透明质酸复合微粒在肺部特殊微环境下的释放机制。研究成果将为肺部缓释制剂的设计和体外评价提供新思路。

肺上皮细胞表面的黏液清除和透过上皮细胞吸收入血是造成肺吸制剂在肺局部滞留时间短、药物浓度低、药物治疗效率低的重要原因。提高药物溶解速度、增强对黏液层粘附能力是克服该屏障的有效策略。本研究分别以水溶性的硫酸沙丁胺醇（SAS）和难溶性的布地奈德（BUD）为模型药，构建了基于内源性生物粘附材料透明质酸的生物粘附缓释多功能微球干粉制剂，用于肺部吸入。 结果显示，喷雾干燥技术是适宜制备透明质酸肺吸微球的技术，制备得到的微球不需递送载体即可获得较高的肺部沉积效率，且能有效延长SAS在肺部的滞留时间，减少其吸收入血的比例，有利于提高其治疗效率。另外，由于复杂的肺部组织结构，目前仍然缺乏肺部缓释制剂释放性能的标准评价方法，这严重阻碍了肺部缓释制剂的发展。本研究以SAS和BUD的缓释微球制剂为研究对象，将黏液层引入到Franz 扩散池中，构建一个模拟体内环境的新模型，用于透明质酸复合微粒体外释放性能的评价，探讨与体内数据的相关性，并依据相关程度对黏液层的组成、厚度、黏度等关键因素进行优化，阐明黏液层流变学特性、药物理化性质与药物释放速度之间的关系，揭示透明质酸复合微粒在肺部特殊微环境下的释放机制。研究成果将为肺部缓释制剂的设计和体外评价提供新思路。