新型可降解聚酯材料地西泮缓释微球的研制

目的　优化制备工艺，用新型的生物可降解材料聚羟基丁酸酯—羟基戊酸酯共聚物（PHBV）与D,L-聚乳酸（PLA）共混物为基材制备以地西泮（diazepam,DZP）为模型药物的缓释微球（MS）。方法　用正交设计优化微球制备工艺，用扫描电镜（SEM）观察微球表面形态。对微球粒径及其分布、体外释药、稳定性及在动物体内药动学进行了测定。结果　微球平均粒径为(20.45±4.50) μm，粒径在15.5～35.2 μm占总数88%以上。载药量为(16.95±0.80)%,包封率为(69.68±1.13)%；体外释药方程为Q=2.7027t+13.50(γ=0.9827),动物体内实验表明，微球的血药浓度-时间曲线下面积AUC是溶液对照组的2.35倍，平均驻留时间MRT是对照组的3.62倍。微球在冰箱4℃与室温（20～25℃）条件下性质稳定。结论　微球制备工艺稳定，与DZP针剂相比，具有明显缓释作用。

STUDY ON PREPARATION OF DIAZEPAM-POLY(HYDROXYBUTYRATE-HYDROXYVALERATE)/POLYLACTIDE MICROSPHERES

AIM　To optimize the preparation of sustained release microspheres (MS) using the biodegradable materials-poly(hydroxybutyrate-hydroxyvalerate)/D,L-polylactide blend as the carriers and diazepam (DZP) as a model drug. METHODS　The orthogonal test design was used to optimize the technology of preparation with good reproducibility. The surface morphology of the microspheres was observed by scanning electron microscope. The mean diameter and the size distribution of MS, drug release in vitro, stability and pharmacokinetics in rabbit were examined. RESULTS　The average particle size was (20.45±4.50) μm with over 88% of the MS being in the range of 15.5～35.2 μm; the drug loading and the incorporation efficiency were 16.95%±0.80% and 69.68%±1.13% respectively; The drug release behavior in vitro could be expressed by the following equation: Q=3.2916t+13.61 (γ=0.9827); Experiments in rabbits indicate that the area under the plasma concentration-time curve (AUC) was 2.35 times higher than that of DZP solution. The mean residence time (MRT) was 3.62 times longer compared with the original drug DZP solution. The microspheres were stable for 3 months at 4℃ and at room temperature. CONCLUSION　The technology of preparation was successful and DZP-PHBV/PLA-MS showed significant sustained release.