吗啡缓控释液体栓的研制及体内外相关性

Preparation and delivery of morphine sustained-release liquid suppository

目的:以泊洛沙姆407和泊洛沙姆188为组合基质,添加生物黏附剂卡波姆和促渗剂氮酮制备温敏型吗啡缓释液体栓,考察体内外相关性。方法:设计新的体外溶出装置,以凝胶温度、凝胶强度、生物黏附力和释放度为指标进行体外筛选;经犬直肠给药测定体内药物释放特性进行体内筛选;用3p97程序计算药代动力学参数。结果:当体外释放结果符合零级模式,R2>0.9且释药时限>10 h,体内药物释放出现血药平台,显示良好的体内外相关性;药代动力学研究结果表明:体内过程为一室模型,t1/2(Ke)=5.65 h,t1/2(Ka)=0.78 h,Cmax=361.8 ng.mL-1,AUC0～∞=4 046.1 ng.h.mL-1,MRT=10.94 h。结论:所制备的吗啡液体栓具有良好的缓控释特征。

Objective： To prepare morphine sustained-release liquid suppositories with poloxamer 407,poloxamer 188,the bioadhesive polymer cabopol and the permeability enhancer azone,and to evaluate its characteristics between in vitro release and in vivo absorption.Methods： The physicochemical properties such as gelation temperature,gel strength,and bioadhesive force were determined.The release of morphine was measured with new scanning instrument made by our lab,and the drug absorption was performed in Beagle dogs.The 3p97 program was used to calculate the pharmacokinetic parameters of morphine.Results： Drug release pattern in vitro was demonstrated to fit zero-order kinetics,and in vivo profile of absorption was to fit one compartment model.The pharmacokinetics pharmerers were： t1/2（Ke）=5.65 h,t1/2（Ka）=0.78 h,Cmax=361.8 ng·mL-1,AUC0~∞=4 046.1 ng·h·mL-1,and MRT=10.94 h.Conclusion： This preparation is characterized to be sustained releasing.