非洛地平纳米脂质载体在大鼠体内的药动学与药效学研究

Study on pharmacokinetics and pharmacodynamics of felodipine nanostructured lipid carriers in rats

目的研究非洛地平(FLD)纳米脂质载体(FLD-NLCs)在大鼠体内的药动学特征以及对高血压模型大鼠的血压控制效果。方法以山嵛酸甘油酯(Compritol 888 ATO)作为固体脂质,聚乙二醇-15羟基硬脂酸酯(Solutol HS 15)作为液体脂质,泊洛沙姆188(Poloxamer 188)作为表面活性剂,使用高压均质技术制备FLD-NLCs,并对FLD-NLCs的理化性质进行评价,考察FLD-NLCs在不同pH介质溶液中的稀释稳定性以及体外释药特性;研究FLD原料药和FLD-NLCs的细胞跨膜转运性质;比较FLD混悬剂和FLD-NLCs经大鼠口服给药后的体内药动学及药效学。结果FLD-NLCs的平均粒径为(126.8±3.3)nm,多聚分散系数(PDI)为(0.184±0.005),Zeta电位为(-26.3±0.6)mV,在透射电镜下可观察到FLD-NLCs呈球形,均匀分散;FLD-NLCs经不同pH介质溶液稀释后稳定性良好,在不同pH介质溶液中均表现为双相释药特征,且药物释放速率无明显差异;FLD-NLCs能有效提高药物的跨膜转运能力;与FLD混悬剂相比,大鼠口服给予FLD-NLCs后显著提高了药物生物利用度,可长时间有效控制血压。结论FLD-NLCs能显著提高药物的生物利用度,有效控制血压,对非洛地平的临床应用具有重要价值。

Objective To study the pharmacokinetic characteristics of felodipine(FLD)nanostructured lipid carriers(FLD-NLCs)in rats and their blood pressure control effects in hypertensive rats.Methods Compritol 888 ATO was used as solid lipid,Solutol HS 15 was used as liquid lipid,and Poloxamer 188 was used as surfactant.By using high-pressure homogenization method,FLD-NLCs were prepared,and the physical and chemical properties were evaluated.The dilution stability and in vitro release characteristics of FLD-NLCs in different pH media were investigated.The cell transmembrane transport properties of FLD and FLD-NLCs were studied,and the in vivo pharmacokinetics and pharmacodynamics of FLD suspensions and FLD-NLCs after oral administration in rats were compared.Results The average particle size of FLD-NLCs was(126.8±3.3)nm,PDI was(0.184±0.005),and Zeta potential was(-26.3±0.6)mV.Under transmission electron microscope,the FLD-NLCs could be observed in a spherical distribution.The FLD-NLCs had good stability in different pH media solutions,and exhibited biphasic drug release characteristics in different pH media.There was no significant difference in drug release rate.The FLD-NLCs could effectively improve the transmembrane transport capacity of drugs.Compared with FLD suspensions,the FLD-NLCs could significantly improve the bioavailability after oral administration in rats and the blood pressure can be controlled effectively for a long time.Conclusion The FLD-NLCs could significantly improve the bioavailability and control blood pressure,which was of great significance for the secondary development and utilization of felodipine.