搭载雷帕霉素纳米晶的透明质酸微针贴片的制备及性质初步探究

Preparation and preliminary investigation of hyaluronic acid microneedle patches loaded with rapamycin nanocrystals

目的可降解载药微针可以持续、安全、无痛地实现局部药物缓释,而微针载药系统用于心血管领域可最大程度发挥药物的局部抗凝,抑制内膜增生,减小药物全身给药带来的毒副作用。为此本文制备了一款搭载雷帕霉素纳米晶的透明质酸(hyaluronic acid,HA)微针贴片,并对该贴片进行初步理化性质评价、体外模拟释药性能评估以及刺入大隐静脉性能的分析评价。方法首先以150万分子量的透明质酸为基材掺杂的雷帕霉素水相纳米晶混悬液(rapamycin nanoparticles,RAP-NPs)形成药物均匀分散的水凝胶;然后通过聚二甲基硅氧烷微针模板(polydimethylsiloxane,PDMS)制备可溶于水的雷帕霉素水相纳米晶混悬液的透明质酸微针贴片(hyaluronic acid-rapamycin-microneedle,HA-RAP-MN);最后对这种载药微针进行初步理化性质评价和体外模拟释药性能分析评价。结果RAP-NPs水相混悬液可与HA水凝胶形成混匀的混合物,使药物能够均匀分散在微针中并持续释放药物,解决了难溶性药物分子无法在HA水凝胶中均匀分散的技术瓶颈。药物模拟释放实验表明雷帕霉素可在8h内释放70%以上,达到缓释效果。免疫荧光结果表明雷帕霉素均匀分布于静脉中膜及内膜。结论可溶于水的雷帕霉素水相纳米晶混悬液的透明质酸微针贴片在局部降低冠状动脉旁路移植术后内膜增生方面具有可预期的应用潜力。

Objective Biodegradable drug loaded microneedles can achieve sustained,safe,and painless local drug release,while microneedle drug delivery systems used in the cardiovascular field can maximize the local anticoagulation of drugs,inhibit endometrial hyperplasia,and reduce the toxic side effects of systemic drug administration.For this purpose,this article prepared a hyaluronic acid microneedle patch loaded with rapamycin nanocrystals,and evaluated its preliminary physicochemical properties,in vitro simulated drug release performance evaluation,and analysis and evaluation of its puncture performance into the great saphenous vein.Methods Firstly,the aqueous rapamycin nanoparticles(RAP⁃NPs)doped with 1.5 million molecular weight hyaluronic acid(HA)as the base material are used to form drug evenly dispersed hydrogels.Then the water⁃soluble hyaluronic acid microneedle patches(HA⁃RAP⁃MN)of rapamycin aqueous nanocrystalline suspensions are prepared by the polydimethylsiloxane(PDMS)template method.Finally,preliminary physicochemical properties and in vitro simulated drug release performance analysis and evaluation are conducted on this drug loaded microneedle.Results RAP NPs aqueous suspension can form a mixed mixture with HA hydrogel,which enables drugs to be evenly dispersed in microneedles and continuously release drugs,and solves the technical bottleneck that insoluble drug molecules cannot be evenly dispersed in HA hydrogel.Drug simulation release experiments show that rapamycin can release more than 70%of drugs within 8 hours,achieving sustained release effect.Immunofluorescence application testing can prove that rapamycin is uniformly distributed in the venous media and intima.Conclusions The hyaluronic acid microneedle patch HA⁃RAP⁃MN,a water⁃soluble rapamycin nanocrystal suspension,has promising potential for local reduction of intimal hyperplasia after coronary artery bypass grafting.