经皮递释蛋白多肽类药物的可溶微针制备和优化基础理论体系的构建

Proteins and peptides play an increasingly important role in drug research and development with the advancement of biotechnology. However, the structural instability of these drugs limits their administration to the sole injection route, which is desperately insufficient to meet the needs of proteins and peptides development and clinical applications. Previous studies have shown that the dissolving microneedle array (DMNA) which combining the efficient delivery of injection and the safety and patient compliance of transdermal delivery system could solve the problem and efficiently transdermal delivery biomacromolecule drugs. Proteins and peptides were released by inserting and dissolving the microneedles made from water soluble materials and drugs into epidermis. The drug release mechanism of dissolving microneedles indicated that mechanical property of microneedles, drug distribution inside microneedle array and stability of proteins and peptides in microneedles were the key problems for dissolving microneedles to successfully penetrate the skin and quantitatively deliver effective proteins and peptides. Most related researches focused on excavation the advantages of dissolving microneedles in transdermal delivering various kinds of drugs but ignored the in-depth base study on influence factors and control mechanism of the key problems above, which restricted the development and application of dissolving microneedles. In this project, on the base of the microneedle fabrication technology which was originally developed in our laboratory, the drug-excipients interaction mechanism which effecting drug stability and microneedle strength will be researched, and the migration process of proteins and peptides during dissolving microneedle array preparation will be traced to explore the drug distribution mechanism with the help of timing track detection methods (TTDM) which build in our previous research. A fabrication optimization theoretical system will be built by the outcomes of these studies which can provide a scientific support and a practical guiding for development of dissolving microneedle array loading proteins and peptides.

蛋白多肽类药物是新药研发极有前景的方向，然而单一的释药途径严重制约了其发展和应用。研究表明，可溶微针结合了注射与经皮给药的优势，可以突破该瓶颈，高效递释大分子药物。可溶微针将水溶性辅料与药物制成的微针插入皮内，通过针体的溶解释放药物。微针的机械性能、药物在微针中的定位分布以及微针中蛋白多肽药物的稳定性是实现可溶微针成功穿透皮肤、定量递释有效药物的关键。目前研究集中于发掘可溶微针在各类药物递释中的优势，对上述关键问题的理论基础缺乏深入研究，阻碍了蛋白多肽药物可溶微针的研究和应用。本项目拟以自主研发的可溶微针制备系统为基础，通过剖析药物与辅料的结构变化及相互作用研究微针机械性能的影响机制和可溶微针提高蛋白多肽药物稳定性的机理，采用自建的微针内药物迁移追踪方法研究蛋白多肽类药物在可溶微针中的分布机制及调控规律，构建蛋白多肽药物可溶微针制备与优化的基础理论体系，为该递释系统的开发提供科学依据。

蛋白多肽类药物是新药研发极有前景的方向，然而单一的释药途径严重制约了其发展和应用。研究表明，可溶微针结合了注射与经皮给药的优势，可以突破该瓶颈，高效递释大分子药物。可溶微针将水溶性辅料与药物制成的微针插入皮内，通过针体的溶解释放药物。微针的机械性能、药物在微针中的定位分布以及微针中蛋白多肽药物的稳定性是实现可溶微针成功穿透皮肤、定量递释有效药物的关键。目前研究集中于发掘可溶微针在各类药物递释中的优势，对上述关键问题的理论基础缺乏深入研究，阻碍了蛋白多肽药物可溶微针的研究和应用。本项目以自主研发的可溶微针制备系统为基础，通过剖析药物与辅料的相互作用研究微针机械性能的影响机制和可溶微针提高蛋白多肽药物稳定性的机理，构建蛋白多肽药物可溶微针制备与优化的基础理论体系。研究结果表明，右旋糖酐作为优选的微针辅料，制备的可溶微针尺寸与主模的复合度高，具有适中的吸湿性，极佳的机械强度和离体猪皮穿透能力；微针针形对于针尖载药量和药物溶出没有显著影响，但是会通过影响微针机械性能从而影响微针最终的经皮释药效率；鲑鱼降钙素（sCT）可溶微针机械性能符合要求，制备成可溶微针有利于sCT的稳定，高温和高湿是影响 sCT稳定性的主要原因，海藻糖有助于提高sCT的稳定性；可溶微针贴片能显著提高sCT 经皮传递的效率，相对生物利用度由普通贴片的10%提高至60%；微针给药后，皮肤刺激性极小，微针可穿透皮肤角质层，但未对皮肤造成其他损伤或炎性反应，制备所用辅料均未产生溶血作用，微针溶液对 NIH/3T3 细胞无明显细胞毒性，生物相容性较好。本研究构建了生物技术药物可溶微针经皮释药系统，该系统兼具注射给药的高效和经皮给药的顺应性，同时避开口服给药的胃肠道环境和肝脏首过效应，极有研究和应用前景，有望解决生物大分子药物给药途径单一这一瓶颈问题。本项目的研究为这一给药系统的深入发展奠定了基础。