盐酸哌唑嗪缓释贴片的释药行为及其生物相容性评价

Sustained release and biocompatibility of prazosin hydrochloride

背景:盐酸哌唑嗪半衰期短,首剂效应明显,国内仅有普通片上市。目的:研制以聚乙烯醇和明胶为骨架材料的盐酸哌唑嗪缓释贴片,并考察其释药行为和生物相容性。设计、时间及地点:随机设计,动物对照实验,于2007-01/08在重庆医科大学药学院实验室进行。材料:采用水性分散体法,以聚乙烯醇、明胶为骨架材料制备盐酸哌唑嗪亲水性凝胶骨架缓释贴片。方法:①随机选用新西兰大白兔6只,取腹部皮肤进行体外透皮实验,以氮酮、丙二醇、骨架材料配比、载药量为影响因素,稳态透皮速率、时滞为指标,采用正交设计筛选最佳处方。②验证最佳处方,考察贴片物理特性、黏性及透皮行为,并采用差示扫描量热法对其进行差热分析。③随机选用新西兰大白兔12只,通过皮肤刺激性实验,考察贴片的生物相容性。主要观察指标:①贴片最佳处方筛选及验证。②贴片的物理特性评价。③贴片的差热分析。④皮肤刺激性反应。结果:①正交实验筛选的最佳处方为氮酮2%,丙二醇15%,骨架材料配比为5∶4,载药量1.0%。②按最佳处方制备的贴片外观、黏性良好;其稳态透皮速率、时滞和综合评分分别为(8.92±0.58)μg/(cm2?h),(3.38±1.17)h,81.58±8.42,其体外72h内释药行为符合Higuchi方程模式(r=0.9957),并趋近于零级释药模式(r=0.9873),经皮渗透曲线重现性良好(P>0.05);差热分析表明,盐酸哌唑嗪在骨架材料中以分子或无定形存在。③贴片生物相容性良好,对兔皮肤无刺激性。结论:制备的亲水性凝胶骨架盐酸哌唑嗪缓释贴片生物相容性良好,具有持续平稳释药的特性。

BACKGROUND： Prazosin hydrochloride （PRH） has short half-time and strong first-dose response, but only general tablet was sold in China. OBJECTIVE： To discover PRH sustained-release patch based on polyvinyl alcohol and gelatin, and to evaluate the release behavior and biocompatibility. DESIGN, TIME AND SETTING： A randomized design and animal controlled study was performed at Laboratory of Pharmacy College, Chongqing Medical University between January and August 2007. MATERIALS： PRH sustained-release patch was prepared based on polyvinyl alcohol and gelatin using aqueous dispersion method. METHODS： （1） Six New 7ealand rabbits were randomly collected and their abdomen skins were selected for transdermal test in vitro. The formulation was optimized with azone, propylene glycol, the ratio of gel-matrix material and dosage content of the patch as influencing factors, stable percutaneous rate and time lag as index. （2） The optimized formulation was validated. Physical characteristic, viscosity and transdermal behavior of the patch was studied and differential scanning calorimeter was used for thermoanalysis. （3） Twelve New Zealand rabbits were randomly selected to study biocompatibility with skin irritation test. MAIN OUTCOME MEASURES： （1） Screening and verification of optimized formulation; （2） physical characteristic; differential thermal analysis; （3） response of skin irritation. RESULTS： （1） The optimized formulation obtained by erthogonal design was composed of azone （2%）, propylene glycol （15%）, the ratio of gel-matrix material （5：4）, and dosage content （1.0%）. （2） The patch prepared using the optimized formulation had good appearance and viscosity, and the stable percutaneous rate, time lag and synthetic score were （8.92±0.58） μg/（cm2.h）, （3.38±1.17） hours and 81.58±8.42, respectively. The in vitro release behavior within 72 hours was expressed with Higuchi model （t=-0.995 7） and nearly Zero-order equation model （r=0.987 3）. The reproducibility of transdermal penetration curve was good （P 〉 0.05）. The result of thermoanalysis indicated that PRH was dispersed in the gel-matrix material in the molecular or amorphous state. （3） The biocompatibility of the patch was good and no irritation on the rabbit skin was observed. CONCLUTION： The hydrophilic gel-matrix PRH patch exhibits a combination of steady and sustained drug release and good biocompatibility.