基于粉体的核壳型可溶微针构建及其经皮给药性能研究

Dissolvable microneedle patches can be used for safe, efficient, and painless delivery of hydrophilic drugs like proteins, peptides and antibodies across the skin. However, due to their small capacity and processing technological limitations, the amount of drugs loaded on a microneedle is limited, which could not meet the requirement of clinical applications. Here, we propose to develop a dissolvable powder-encapsulated microneedle. Our hypothesis is that combining dissolvable hollow microneedle arrays with drugs in powder condition loaded in the cavities can maximize drug loading amount and enhances drug stability. Moreover, reduced use of excipients makes microneedle more compatible. In this study, the effect of filling processing, shell stress as well as bulk density on the loading capacity and strength of microneedle will be systematically evaluated. The transdermal tests will be conducted on healthy mice and pigs to investigate the fundamental properties and functionality induced by microneedle application. The long-term goal of this proposal is the establishment of transdermal delivery of powder drugs, which will provide novel strategy and theoretical basis for future design of transdermal drug delivery system.

可溶微针可以安全，高效，无痛地将亲水性药物尤其是蛋白多肽类药物经皮递释。但是，受微针尺寸和制剂工艺等因素的影响，可溶微针的载药量十分有限，无法达到药物治疗剂量，限制了可溶微针技术在临床治疗中的应用。因此，本项目在先前疫苗微针制剂的研究基础上，提出核壳型可溶微针构建，采用可溶空心微针装载药物粉末的方式最大限度提高载药量和药物稳定性；同时，降低微针可溶辅料的使用可增加微针系统的适用性。本项目将系统地考察填充工艺，外壳应力，药物堆密度等对载药能力，微针强度的影响；通过体外透皮实验评价不同规格微针的经皮给药性能；通过动物实验考察微针的治疗效果。最终，以可溶微针的方式，建立药物粉末经皮给药体系，为高效透皮给药剂型的设计提供新思路和理论依据。

可溶性微针可直接在皮肤表面形成药物释放通道，显著提高透皮给药效率，近年来在经皮免疫，蛋白和多肽给药，皮肤美容，局部麻醉，皮试诊断等领域均有应用。本项目建立了一种基于粉体的核壳型可溶微针，利用透明质酸可溶性有机高分子材料将生物大分子药物以粉体形式装载于可溶微针内部，并将药物快速透皮释放，达到高剂量透皮给药的目的。目前，我们成功建立基于软光刻技术的不同尺寸微针模板加工方法和基于透明质酸的核壳型可溶微针制备工艺；建立装载不同尺寸粉体药物的核壳型可溶微针，并验证其力学性能，评价经皮给药效率。结果表明，基于粉体的核壳型可溶微针尺寸为100-1000µm，满足本项目药物装载和经皮给药需要；项目采用两步法制备PDMS负性微针模板和透明质酸核壳型可溶微针，结果表明分子量在70,000-100,000的透明质酸具有最佳成膜硬度。采用离心灌注法成功制备装载不同分子量模型药物的可溶微针，可在20分钟内完成透皮给药。这种基于粉体的核壳型可溶微针设计的重要意义在于可将单微针药物含量提高10-15倍左右，并且该载药工艺无需根据药物分子量，亲疏水等物理化学性质而改变微针制造工艺，具有大工业生产可操作性，利于相关微针加工设备设计和透皮微针技术的应用推广。