目的 制備iv用高載藥量甘草次酸納米混懸劑(GA-NSPs),并對其在SD大鼠體內(nèi)的藥動學(xué)行為進(jìn)行研究。方法 將甘草次酸、聚乙二醇-聚己內(nèi)酯(PEG2000-PCL2000)按質(zhì)量比5:1,以微沉淀聯(lián)合高壓均質(zhì)的方法制成GA-NSPs。相同劑量(50.00 mg/kg)的GA-NSPs分別以ig和尾iv的方式給藥,于給藥后0.08、0.25、0.5、1、2、4、8、12、24、36、48 h經(jīng)大鼠眼球后靜脈叢取血,血漿經(jīng)過處理后,HPLC法測定各組SD大鼠給藥后不同時間點(diǎn)血漿藥物濃度。色譜柱為Symmetryshield C₁₈(250 mm×4.6 mm,5μm),流動相為乙腈-0.1%磷酸水(梯度洗脫),柱溫25℃,體積流量1.00 mL/min,紫外檢測波長254 nm,進(jìn)樣量50.00μL。結(jié)果 GA-NSPs的平均粒徑為298.1 nm,載藥量為(77.40±0.93)%。大鼠血漿低、中、高3個濃度的方法回收率分別為(116.6±3.8)%、(88.8±1.3)%和(83.0±1.5)%,日內(nèi)、日間精密度RSD均小于5%。GA-NSPs尾iv組的C_max是ig組的8.13倍,GA-NSPs尾iv組的AUC值是ig組的1.28倍。結(jié)論 制備的GA-NSPs穩(wěn)定性好,可同時滿足ig和iv給藥的要求。藥動學(xué)研究結(jié)果提示,iv GA-NSPs可能更多地向肝、脾等網(wǎng)狀內(nèi)皮系統(tǒng)分布,利于對保肝和對肝臟疾病的治療。

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.