可注射5-氟尿嘧啶缓释凝胶体外释放及其大鼠体内药动学研究  

In Vitro Release of Injectable 5-fluorouracil Sustained-release Gel and Its Pharmacokinetic Study on Rats

作　　者：郝堂娜[1] 李镇[2] 乔明曦[3] 范青[1] 黄俊梓[1] 陈大为[3] 

机构地区：[1]大连医科大学附属第二医院药剂科,大连市116027 [2]大连医科大学药学院,大连市116027 [3]沈阳药科大学药学院,沈阳市110016

出　　处：《中国药房》2010年第13期1176-1179,共4页China Pharmacy

摘　　要：目的:制备可注射5-氟尿嘧啶(FU)缓释凝胶,并研究其体外释药及体内药动学特征。方法:以pH/温度双重敏感生物可降解嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1为载体材料,采用物理混合法制备5-FU缓释凝胶。考察载药量和共聚物浓度对其体外释药情况的影响。采用高效液相色谱法分别测定大鼠皮下注射5-FU水溶液(参比制剂)及缓释凝胶(受试制剂)后不同时间点的血药浓度,绘制药-时曲线,计算药动学参数。结果:5-FU在载药量为0.5%,共聚物浓度为15%、20%、25%的缓释凝胶中第9天时平均累积释放百分率为89.66%、87.59%、80.85%;载药量为0.2%、0.5%、1%,共聚物浓度为25%的缓释凝胶中第9天时平均累积释放百分率为75.30%、80.85%、86.90%;参比制剂与受试制剂在大鼠体内tmax分别为0.25、0.50h,Cmax分别为72.7、31.1μg·mL-1,AUC(0～)t分别为44.5、342.4mg·h·mL-1,MRT分别为0.57、27.2h。结论:5-FU缓释凝胶中5-FU体外释放呈现Higuchi动力学特征,表现为以扩散控制型为主的释药模式;释药初期,载药量对释药速率影响较大;释药后期,共聚物浓度对释药速率影响较大。皮下注射给药后,与水溶液相比,缓释凝胶可持续释药3d,具有良好的缓释作用。OBJECTIVE： To prepare injectable 5-fluorouracil （5-FU） sustained-release gel and explore its characteristics of drug release in vitro and pharmacokinetics in rats. METHOD： Injectable 5-FU sustained-release gel was prepared by physical mixing method using PH and temperature sensitive biodegradable block copolymers OSMI-PCLA-PEG-PCLA-OSM1 as drug cartier. The effect of drug-loading rate and concentration of copolymers on in vitro drug release of gel were investigated. HPLC method was applied to plasma concentration of 5-FU at different time points after rats were subcutaneously injected with 5-FU water solution （reference preparation） or 5-FU sustained-release gel （test preparation）. The plasma concentration-time curves of preparations were obtainled and pharmacokinetic parameters were calculated. RESULTS： Average accumulative drug release rates of 5-FU at 9th day in sustained-release gel with 0.5% drug-loading rate and copolymers concentration of 15%, 20%, 25% were 89.66%, 87.59% ,80.85% while those of sustained-release gel with drug-loading rate of 0.2%, 0.5%, 1% and copolymers concentration of 25 % were 75.30 %, 80.85 %, 86.90 %, respectively. Main pharmacokinetic parameters of reference preparation vs. test preparation were as follows： tmax： 0.25 h vs. 0.50 h; Cmax： 72.7 μg·mL^-1 vs. 31.1 μg·mL^-1; AUC（0-t）： 44.5 mg·h·mL^-1 vs. 342.4 mg·h·mL^-1; MRT： 0.57 h vs. 27.2 h. CONCLUSIONS： In vitro drug release of 5-FU is in line with Higuchi dynamics, characterized with diffusion mode. In initial release stage, the drug release rate is effected by drug-loading rate. In the later release stage, the drug release rate is effected by concentration of copolymers. As compared with 5-FU water solution, in vitro drug release of 5-FU lasts 3 days after rats were subcutaneously injected with 5-FU sustained-release gel, which indicates gel represents good sustained-release characteristics.

关 键 词：PH敏感 温度敏感 5-氟尿嘧啶 水凝胶 体外释放 大鼠 药动学 

分 类 号：R969.1[医药卫生—药理学] R979.1[医药卫生—药学]