国产外周动脉洗脱支架药膜制备及体外药代动力学研究

目的评价国产雷帕霉素-聚丙交酯乙交酯（PLGA）外周动脉洗脱支架药膜性能及其药物释放特点。方法采用自制PLGA与雷帕霉素制成雷帕霉素-PLGA药膜,并用该药膜涂层12枚国产镍钛合金外周血管支架。用OLYMPUS体式显微镜观察支架表面药物涂层的宏观形貌,NanoscopeⅢa原子力显微镜观察和分析涂层表面的三维形貌和表面粗糙度。并对洗脱支架进行血液相容性,体外降解行为及体外药代动力学研究,数据进行了标准曲线测定,释放曲线拟合测定,并进行LPMS／PLGA涂层多支架释放曲线测定等统计学分析。结果12枚支架药膜表面光整,层厚均一,未见皲裂、脱落、翘起现象。雷帕霉素-PLGA洗脱支架的OLYMPUS体式宏观形貌,涂层支架无缠绕、粘连,且涂层表面均匀、光滑。Nano ScopeⅢa原子力显微镜示金属支架表面略粗糙,存在机械划痕微坑。但PLGA载药涂层将基体的微坑覆盖后,表面平滑PLGA涂层表面黏附的血小板有个别变形伸出伪足,血小板部分激活,没有产生聚集;含雷帕霉素涂层表面黏附的血小板数量明显减少,没有变形和聚集,血小板处于未激活状态。在体内环境模拟系统中,PLGA在2周之内降解约20％,在2至6周降解速度逐渐加快直至完全降解。雷帕霉素-PLGA洗脱支架体外药代动力学实验结果显示,药物洗脱支架药物释放可持续50d。在0、1、3、5、7、9d取样测定释放量,释放曲线符合Higuchi方程：Mt/M∞（％）=3．1722＊t1／2（h）-5．682（r=0．9944,n=5）。实测曲线与拟合曲线拟合很好,r=0．9944。在30d时仍存在较为稳定的药物释放。24h突释量11．02％;9d累积释放量41．23％;30d累积释放量79．44％。结论国产雷帕霉素-PLGA外周动脉洗脱支架药膜涂层均匀光滑,可有效控制药物释放,具有进一步临床应用价值。

Pharmacodynamics of China-made rapamycin-polylactide-co-glycolide peripheral arterial eluting stent membrane: in vitro experiment

OBJECTIVE: To evaluate the property and drug releasing pattern of the China-made rapamycin-polylactide coglycotide (PLGA) peripheral arterial eluting stent membrane. METHODS: Rapamycin was put into PLGA so as to made rapamycin-PLGA complex. Twelve nickel-titanium self-expanding stents were dipped into the complex to make drug-eluting stents. Somatotype microscope was used to observe the macro-form of the surface of the eluting membrane, and atom force microscope was used to analyzing the three-dimensional appearance and surface roughness of the membrane. The stents were put into fluid with platelets to observe the form of platelets blood compatibility by scanning electron microscopy. The extra degradation of the coating layer, by putting the stents into a simulation system of internal environment. High efficacy liquid chromatography was used to study the pharmacokinetics of the stents. Standard curve and simulative curve, and drug release curve of multiple stents were drawn and analyzed. RESULTS: The membranes of all 12 stents had smooth surfaces and regular thickness and no membrane falling-off was observed. The platelets on the surfaces of the stents were inactivated and the number of the platelets adhering to the surfaces of the stents were reduced obviously in comparison with the blank control. PLGA degraded by 20% within 2 weeks and then the degradation speed accelerated until complete degradation occurred within 6 weeks, and the drug releasing lasted more than 50 days. The percentage of accumulative drug release was 11.02% in 24 hours, 41.23% in 9 days, and 79.44% in 30 days. CONCLUSION: Smooth and even, and capable of controlling the drug release, rapamycin-PLGA peripheral arterial eluting stent membrane coating has the potential clinical value in preventing in-stent stenosis.