双氯芬酸钠脂质体凝胶的制备及其药动学和刺激性评价

 目的制备双氯芬酸钠(DS)脂质体凝胶,考察其肌注后家兔体内的血药浓度经-时过程及对肌肉的刺激性。方法醋酸钙梯度法制备DS脂质体,再以泊洛沙姆407为基质制成脂质体凝胶剂;家兔分别肌注DS溶液、DS凝胶、DS脂质体及DS脂质体凝胶后,HPLC检测血药浓度;并以血浆肌酸激酶(CPK)变化和给药部位的组织病理改变对肌肉刺激性进行评价。结果制得DS脂质体粒径为40.2nm,平均包封率为81.2%;与DS溶液剂相比,肌注DS凝胶、DS脂质体及DS脂质体凝胶后t_max推迟,ρ_max降低,MRT,t_1/2延长,AUC增加,其中肌注DS脂质体凝胶后的t_max,MRT,t_1/2和AUC相应延长了11.76,3.86,3.02和1.40倍,而ρ_max仅为溶液组的36.2%,且该制剂能显著降低DS肌注后所致的CPK活性升高和病理性损伤。结论脂质体凝胶制剂是DS肌注给药的优良载体。

Preparation, Pharmacokinetics and Intramuscular Irritation Evaluation of Diclofenac Sodium Liposomal Gel in Rabbits

OBJECTIVE To prepare diclofenac sodium (DS) liposomal gel,and evaluate the pharmacokinetics and irritation of DS liposomal gel in rabbits after intramuscular administration.METHODS The DS liposomes were prepared by calcium acetate gradient method,the poloxamer 407 was added as a support base for the preparation of the DS liposomal gel. Four preparations of DS,such as solution,poloxamer gel,liposome and liposomal gel were intramuscularly given to the rabbits.The drug concentrations in plasma were measured by HPLC method.The intramuscular irritations were evaluated by plasma creatine phosphokinase (CPK) activity and pathological changes.RESULTS The mean diameter and encapsulation efficiency of the DS liposomes were 40.2 nm and 81.2%,respectively. Compared with DS solution,the t_max,MRT,t_1/2 of the other three formulations of DS were prolonged and AUC were enhanced, while ρ_max were decreased dramatically. Especially for DS liposomal gel,t_max,MRT,t_1/2 and AUC were 11.76,3.86,3.02 and 1.40 times as much as those of DS solution respectively,while its ρ_max was only 36.2% as that of DS solution. The raise of CPK activity was markedly inhibited and the pathological damages were lessened significantly for DS liposomal gel.CONCLUSION The liposomal gel may be a promising vehicle for the intramuscular administration of DS.