胰岛素聚酯微粒的制备及大鼠体内药效学研究

STUDY ON PREPARATION AND PHARMACODYNAMICS OF INSULIN-LOADED POLYESTER MICROPARTICLES

目的 探讨利用一种新型聚酯材料—ε 己内酯 D ,L 丙交酯嵌段共聚物 (PCLA)制备微粒型药物载体的可能性。方法 通过双乳化溶剂蒸发技术制备ε 己内酯 D ,L 丙交酯嵌段共聚物微粒 (PCLA MP) ,用扫描电镜观察其形态 ,粒径分析仪 (particleanalyser)测定粒径 ;以胰岛素 (INS)为模型药物 ,制备胰岛素聚酯微粒 (INS PCLA MP) ;建立了测定INS包封率的HPLC方法 ;INS抗体捕捉实验考察PCLA MP载药机理 ;以pH 7 4的磷酸盐缓冲液为介质 ,探讨INS PCLA MP体外释药特性 ;建立了药物致大鼠糖尿病模型 ,通过葡萄糖氧化酶法 (GOD PAP)测定血糖值来评价INS PCLA MP经皮下给药后的降血糖作用 ;以INS SOL为对照 ,计算药理相对生物利用度。结果 制备的微粒大小均匀 ,表面光滑圆整 ,平均粒径 1 9μm ;INS的包封率为 76 46 % ;抗体捕捉实验证实 ,被包封的INS中只有小部分 (18 2 5 % )分布在MP的表面 ;INS PCLA MP的体外释放曲线包括突释相及随后的缓慢释放相 ;药效学研究表明 ,12u·kg-1的INS PCLA MP经糖尿病大鼠皮下给药后具有明显的降血糖作用 ,药理相对生物利用度为132 95 %。结论 PCLA嵌段共聚物作为药物输送系统的载体材料有着良好的前景 ,PCLA

AIM To investigate the possibility of using poly (ε caprolactone block D,L lactide) (PLCA) as a kind of materials to prepare the microparticles drug carrier. METHODS PCLA MP (microparticle, MP) was prepared by double emulsification solvent evaporation method. Its morphology was examined by scanning electron microscope. Its size diameter was examined by particle analyser. Insulin (INS), as a model drug, was then encapsulated into PCLA MP (INS PCLA MP). HPLC method was established for determining INS in INS PCLA MP. An “antibody capture” procedure was devised for investigating encapsulation mechanism. The in vitro release behaviour of INS PCLA MP was determined in phosphatic buffer solution (pH 7 4). The diabetic rat model was established and blood glucose levels were measured using glucose oxidase (GOD PAP) method to evaluate the hypoglycaemic effects after subcutaneous administration of INS PCLA MP. The pharmacological bioavailability (PBA) of INS PCLA MP was calculated from the area above the curve (AAC) in contrast with INS solution. RESULTS The mean diameter of INS PCLA MP was 1 9 μm, while the encapsulation ratio of INS reached to 76 46%. Only 18 25% encapsulated INS was on the surface of the microparticles, it could be measured by “antibody capture” experiment. The in vitro release curve of INS PCLA MP consists of initial rapid release stage followed by slower exponential stage. In pharmacodynamic studies, after subcutaneous administration of INS PCLA MP 12 u·kg -1 , the hypoglycaemic effect was significant. The PBA of INS PCLA MP was 123 08%. CONCLUSION PCLA might become a new drug carrier material in the future.