十六酸拉米夫定酯固体脂质纳米粒的制备

Preparation of lamivudyl palmitate solid lipid nanoparticles

目的 :为了提高拉米夫定 (lamivudine ,LA)的疗效 ,降低其毒副作用 ,制备十六酸拉米夫定酯固体脂质纳米粒(LAP SLN) .方法 :在二环己基碳二亚胺和 4 二甲氨基吡啶存在时 ,LA与十六酸反应 ,制备十六酸拉米夫定酯 (lamivudylpalmitate,LAP) ,并测定其核磁共振氢谱 .RP HPLC测定其在正辛醇和磷酸盐缓冲液中的分配系数及不同 pH缓冲液和组织匀浆中的稳定性 .采用薄膜分散法制备LAP SLN ;透射电镜研究其形态、粒径及粒径分布 ;RP HPLC测定载药量、包封率 .结果 :LAP在弱酸性溶液中较稳定 ,在弱碱性溶液中水解较快 ;在血清和组织匀浆中易水解 ,在肝匀浆中水解最快 ;LAP分配系数为 5 2 .2 .LAP SLN粒径为 (2 81± 98)nm ,载药量为 9.6 % ,包封率为 97.7% .结论 :LA转化成LAP后亲脂性增加 ;LAP SLN包封率较高 。

AIM: To improve the therapeutic efficacy and to reduce the side effects of lamivudine (LA) by preparing lamivudyl palmitate solid lipid nanoparticles (LAP SLN). METHODS: LA was esterified with palmitic acid in the presence of dicyclohexylcarbodiimide and 4 dimethylaminopyridine. The structure of expected compound, lamivudyl palmitate (LAP), was identified by proton nuclear magnetic resonance. The stability of LAP in mouse serum and tissue homogenates and octanol buffer partition coefficient of LAP were investigated by reversed phase high performance liquid chromatography (RP HPLC). LAP was used to prepare LAP SLN by dry membrane technique. Transmission electron microscopy was employed to study the shape and particle diameter distribution of LAP SLN. Drug loading and entrapment efficiency were also determined by RP HPLC. RESULTS: LAP was more stable in weak acid solution than in base solution and hydrolyzed fast in serum and tissue homogenates, especially in liver homogenate. Partition coefficient of LAP was 52.2 and the diameter distribution of LAP SLN was (281±98) nm. Drug loading was 9.6% and entrapment efficiency was 97.7%. CONCLUSION: The lipophilicity of LA is dramatically increased after the esterification with palmitic acid. LAP SLN has a high entrapment efficiency and an even distribution in size, indicating that it is a possible liver targeted preparation.