Preparation Of Breviscapine Loaded TPGS Polymeric Micelles And Pharmacokinetics And Pharmacodynamics Evaluation In Rats

Object:To prepare breviscapine-loaded TPGS polymeric micelles and study the release characteristics in vitro and pharmacokinetics and pharmacodynamics in rats.Methods:1.Preparation of Bre/TPGS:The film solvent diffusion method war used to prepare polymeric micelles.Single factor analysis was used to study the effect of reaction conditions by diameter,entrapment efficiency and drug loading of the polymeric micelles.The optimal reaction conditions were determined by L₉?3³?orthogonal table experiment with the ratio of drug to drug carrier,hydration time and hydration temperature.2.Characterization and sustained release of Bre/TPGS:Transmission electron microscopy?TEM?was used to observe morphology of polymeric micelles.The micelles size,distribution and stability were analyzed by Nano particle and Zeta potential analysis instrument.Dynamic dialysis was used to study the release behavior of the polymeric micelles in vitro.3.Pharmacokinetics study of Bre/TPGS:SD rats were treated by tail vein i.v.injection with commercial injection and Bre/TPGS.The concentration of scutellarin in rats was measured by HPLC.After drug administration of the rats,blood was collected at the scheduled time point and the plasma concentration was measured.Then,we made the blood solubility-time curve.The pharmacokinetic parameters of commercial breviscapine powder injection and Bre/TPGS were obtained by software3P97.4.Pharmacodynamics study of Bre/TPGS:The rat model of carotid artery thrombosis was induced by ferric chloride.We studied five groups as test samples for thrombolysis including the model group?given equal volume of saline?,commercial breviscapine powder injection group?1 mg/kg?and the micellar group?0.5,1,2 mg/kg?.Results:The optimal preparation process of Bre/TPGS micelles was as follows:the ratio of drug to drug carrier,hydration time and hydration temperature was 7:100?quality ratio?,37?and 2h.Bre/TPGS were spherical or near spherical.The average diameter,zeta potential,entrapment efficiency and drug loading of the polymeric micelles were?20±2.62?nm,0 mV,?90±2.14?%and?5.8±0.19?%,respectively.The polymeric micelles had a slow release in vitro.After i.v administration of commercial injection and Bre/TPGS 10mg/kg,the main pharmacokinetic parameters parameters were as follows:AUC_0-t were 293.6?g/mL·min and 491.0?g/mL·min respectively.T_1/2were 59.3 min and 762.1 min,C_max were 15.7?g/mL and 9.5?g/mL,respectively.Pharmacokinetic results showed that the drug group containing breviscapine had a thrombolytic effect on FeCl₃-induced carotid artery thrombosis in rats,and the thrombolysis rate in the Bre/TPGS group was stronger than that of the commercial injection group.Conclusions:Bre/TPGS polymer micelles with small particle size,uniform distribution and good breviscapine effect were prepared in this experiment.The polymer micelles exhibited higher T_1/2 and AUC_0-t and showed more effective thrombolytic effect,compared with the commercial breviscapine powder Injection.