目的 制备iv用高载药量甘草次酸纳米混悬剂(GA-NSPs),并对其在SD大鼠体内的药动学行为进行研究。方法 将甘草次酸、聚乙二醇-聚己内酯(PEG2000-PCL2000)按质量比5:1,以微沉淀联合高压均质的方法制成GA-NSPs。相同剂量(50.00 mg/kg)的GA-NSPs分别以ig和尾iv的方式给药,于给药后0.08、0.25、0.5、1、2、4、8、12、24、36、48 h经大鼠眼球后静脉丛取血,血浆经过处理后,HPLC法测定各组SD大鼠给药后不同时间点血浆药物浓度。色谱柱为Symmetryshield C₁₈(250 mm×4.6 mm,5μm),流动相为乙腈-0.1%磷酸水(梯度洗脱),柱温25℃,体积流量1.00 mL/min,紫外检测波长254 nm,进样量50.00μL。结果 GA-NSPs的平均粒径为298.1 nm,载药量为(77.40±0.93)%。大鼠血浆低、中、高3个浓度的方法回收率分别为(116.6±3.8)%、(88.8±1.3)%和(83.0±1.5)%,日内、日间精密度RSD均小于5%。GA-NSPs尾iv组的C_max是ig组的8.13倍,GA-NSPs尾iv组的AUC值是ig组的1.28倍。结论 制备的GA-NSPs稳定性好,可同时满足ig和iv给药的要求。药动学研究结果提示,iv GA-NSPs可能更多地向肝、脾等网状内皮系统分布,利于对保肝和对肝脏疾病的治疗。

Objective To prepare glycyrrhetinic acid nanosuspensions (GA-NSPs) with high drug payload and investigate their pharmacokinetics in SD rats. Methods The GA-NSPs were prepared by microprecipitation combined with high pressure homogenization method, using glycyrrhetinic acid and PEG 2000-PCL 2000 (5:1, weight ratio) in formulation. GA-NSPs were ig and iv administered respectively at the same dose of 50.00 mg/kg. At 0.08, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 h after administration, the blood was collected from the eye venous plexus of the rats, pretreated to remove plasma protein and analyzed using HPLC. Symmetry shield C₁₈ (250 mm×4.6 mm, 5 μm) column was used, and the mobile phase was composed of acetonitrile and 0.1% phosphoric acid (gradient elution at the flow rate of 1.00 mL/min). The analysis was performed at 25℃ and monitored at 254 nm (UV detector). The analyte (50.00 μL) was injected for HPLC assay. Results The average particle size of glycyrrhetinic acid nanosuspensions was 298.1 nm and the drug loading of GA-NSPs was (77.40±0.93)%. The recovery rates of rat plasma with low-, mid-, and high-concentration were (116.6±3.8)%, (88.8±1.3)%, and (83.0±1.5)%, respectively, and the inter- and intra-day precisions of the method were good (RSD < 5%). The C_max of GA-NSPs iv injection group was 8.13-fold as that of ig administration group, and the AUC of GA-NSPs iv injection group was 1.28 times as that of ig administration group. Conclusion GA-NSPs have good stability and could be ig administrated or intravenously injected for in vivo study or clinic use. The results of the pharmacokinetic studies indicate that GA-NSPs tend to go to reticulloendothelial system such as liver and spleen after iv injection, thus benefit the therapy of liver diseases.