超声触发胺碘酮缓释微针贴片的构建及用于心房颤动治疗的研究

Construction of ultrasound-triggered amiodarone sustained-release microneedle patch and its application in the treatment of atrial fibrillation

目的制备超声触发胺碘酮缓释微针贴片,并进一步探讨胺碘酮缓释微针在心房颤动(房颤)治疗中的应用效果。方法制备超声触发胺碘酮缓释微针贴片,用高效液相色谱法(HPLC)测定载药量,通过光学显微镜、扫描电镜及皮肤穿刺实验等方法检测微针形态学、稳定性、皮肤穿刺性能,用Franz扩散池法测定微针体外渗透性,药效学实验观察微针对大鼠房颤模型治疗情况。结果本研究制备的微针队列排布完好、排列完整,背衬无气泡,针形锐利、完整无断裂,形态良好,针尖平均载药量为(4.67±0.51)μg,且微针穿刺性能良好,针尖硬度合格、溶解能力良好;体外透皮渗透结果显示,两组溶液前0~6 h释放较为缓慢,8~24 h明显提高,24~36 h急剧升高,在72 h累计释放量最高,且8~72 h胺碘酮混悬液累积释放曲线明显高于胺碘酮脂质体溶液。药效学结果显示,超声触发胺碘酮缓释微针贴片可延缓大鼠房颤诱发时间[(7.52±1.26)s比(5.75±1.14)s],缩短房颤持续时间[(4.21±0.89)s比(6.32±1.02)s],改善大鼠心功能[左心房内径为(3.52±0.50)s比(4.11±0.35)s、舒张期室间隔厚度为(2.24±0.18)s比(2.58±0.3)、收缩期室间隔厚度为(3.11±0.32)s比(3.59±0.50)];组织药物含量结果,模型大鼠心房中胺碘酮含量明显增加,血浆、肺、肝脏、肾脏、脾脏中胺碘酮含量明显降低。结论制备的超声触发胺碘酮缓释微针贴片性能良好,可促进胺碘酮透皮递送,具有良好的缓释性能,具有良好的临床应用前景。

Objective To prepare an ultrasound-triggered amiodarone sustained-release microneedle patch and further investigate the application effect of amiodarone sustained-release microneedles in the treatment of atrial fibrillation(AF).Methods Ultrasound-triggered amiodarone sustained-release microneedle patches were prepared,and the drug loading was determined by high-performance liquid chromatography(HPLC);microneedle morphology,stability and skin puncture performance were examined by light microscopy,scanning electron microscopy and skin puncture experiments;microneedle in vitro permeability was measured by the Franz diffusion cell method;and microneedle treatment in a rat model of atrial fibrillation was observed by a pharmacodynamic experiment.Results The microneedle array prepared in this study was well-arranged and complete,with no bubbles on the backing,sharp and complete needle shape without breakage,good morphology,and an average drug loading of(4.67±0.51)μg at the needle tip.The microneedle had good puncture performance,with acceptable needle tip hardness and good dissolution ability.The results of in vitro transdermal penetration showed that the release of the two solutions was relatively slow in the first 0-6 hours,significantly increased in the 8-24 hours,and sharply increased in the 24-36 hours.The cumulative release amount was the highest at 72 hours,and the cumulative release curve of amiodarone suspension was significantly higher than that of amiodarone liposome solution in the 8-72 hours.The pharmacodynamic results showed that ultrasound-triggered amiodarone sustained-release microneedle patch could delay the induction time of atrial fibrillation in rats[(7.52±1.26)s vs.(5.75±1.14)s],shorten the duration of atrial fibrillation[(4.21±0.89)s vs.(6.32±1.02)s],improve the cardiac function of rats[left atrial diameter was(3.52±0.50)s vs.(4.11±0.35)s,diastolic interventricular septal thickness was(2.24±0.18)s vs.(2.58±0.3),systolic interventricular septal thickness was(3.11±0.32)s vs.(3.59±0.50)].The results of tissue drug content showed that the content of amiodarone increased significantly in the atria of model rats,while the content of amiodarone decreased significantly in the plasma,lung,liver,kidney and spleen.Conclusion The prepared ultrasound-triggered amiodarone sustained-release microneedle patch has good performance,which promotes the transdermal delivery of amiodarone,owns good sustained-release performance,and has good clinical application prospects.