去羟肌苷脂质前药药质体稳定性研究.docVIP

去羟肌苷脂质前药药质体的稳定性研究 摘要：目的 制备，考察其稳定性。。药剂学稳定性Abstract: Objective The pharmacosomes of cholesteryl-adipoyl didanosine (CAD) were prepared and investigated on physical and chemical stability. Methods The pharmacosomes were prepared from the previously synthesized lipophilic prodrug of didanosine (CAD) using the THF injection method. The morphology and particle size of pharmacosomes were explored using TEM and laser particle analyzer. The effects of heat, centrifugation and storage on the physical stability were investigated. The degradation of prodrugs in buffer solutions, carboxylester enzyme solutions, rat plasma and liver homogenates was also investigated. Results The pharmacosomes were spherical vesicles with the size of 122 nm and showed the good physical stability. The degradation of prodrugs was different in various environments. The half-life (t1/2) of CAD in rat liver homogenates was 23 h and the parent drug was produced though not completely. Conclusion CAD pharmacosomes can transform to ddI in a sustained state in biological conditions, and function as a promising delivery system for anti-HIV ddI. Key words：pharmaceutics；stability；；harmacosome）概念由Vaizoglu等[1,2,3]首先提出，是指将药物与甘油酯、磷脂等脂质共价结合成两亲性脂质前药，后者在水中自组装形成高度分散的有序聚集体，如囊泡等。它属于一种自组装药物传递系统（self-assembled drug delivery systems，SADDS）[4]。与脂质体相比，药质体的成膜材料本身就是携带活性药物的前药分子，不存在被动包封的问题，载药量高，稳定性好[4]。金义光等[5,6,7]合成了阿昔洛韦的单硬脂酸甘油酯前药，并制得其药质体，稳定性好，家兔静注后对网状内皮系统有明显的靶向性[7]。 去羟肌苷（didanosine，ddI）是合成的嘌呤核苷类似物，治疗HIV感染的逆转录酶抑制剂，其毒副作用小于齐多夫定（AZT），是一种有效且具有较好耐受性的抗HIV药物。但由于ddI的强亲水性，其不易顺利跨越脂溶性的细胞膜进入细胞内部抑制病毒的复制，口服生物利用度仅为20％～40％，血浆消除半衰期为1~2 h [8]，严重影响其药效的发挥。有报道用前药的方法提高ddI脂溶性，改善其细胞膜亲和性[9]，提高药效。艾萍[10]合成了去羟肌苷的两亲性前药胆固醇基琥珀酰去羟肌苷（CSD）并制备了药质体，研究发现CSD药质体具有有显著的肝靶向性和缓释作用，但在大鼠肝中其降解半衰期（t1/2）长达10d，释放原药速率非常少，难以获得足够的抗病毒效果。为得到在体内能较好代谢的ddI前药，作者进一步合成了胆固醇基己二酰去羟肌苷（cholesteryl-adipoyl didanosine，CAD）并初步制备了药质体（Fig.1）[11]。本文注重考察CAD药质体在体内外环境中的稳定性，为其的体内行为提供依据。 Fig. 1 Structure of the didanosine prodrug CAD 图1 去羟肌苷前药CAD的结构式 1 材料与方法 1.1 仪器与试剂 紫外可见分光光度仪（UV-2501PC，日本岛津），透射电子显微