天冬酰胺酶纳米微球的药代动力学和生物等效性初步研究

目的研究载天冬酰胺酶（asparaginase, AAS）自组装透明质酸-聚乙二醇（hyaluronic acid-graft-poly ethylene glycol, HA-g-PEG）/羟丙基-β-环糊精（hydroxypropyl-beta-cyclodextrin, HPCD）纳米微球（self-assembly HA-g-PEG/HPCD hollow nanospheres loaded with AAS, AHHPs）在雄性SD大鼠体内的药代动力学和生物等效性。方法采用自组装方法制备AHHPs, 考察AHHPs的透射电镜、粒径、Zeta电位、包封率，分别测定大鼠静脉注射给予AHHPs和游离AAS后，不同时间点大鼠血浆样品中AAS的活性。采用DAS 2.1.1软件计算药动学参数，对AHHPs和游离AAS进行生物等效性评价。结果制得的AHHPs平均粒径为（367.43±2.72） nm，Zeta电位为（-15.70±1.25）mV，平均包封率为(66.03 ± 3.81)%。AHHPs和游离AAS大鼠静脉注射给药后，AHHPs和游离AAS的主要药动学参数：药时曲线下面积AUC_{(0-48 h)}分别为（162.06±4.01） U/mL·h和（46.38±1.98） U/mL·h，AUC_(0-∞)分别为（203.74±12.91） U/mL·h和（51.44 ±3.01） U/mL·h，平均驻留时间MRT_{(0-72 h)}分别为（4.35±0.06） h和（1.76±0.06） h, MRT_(0-∞)分别为（7.53±1.05） h和（2.44±0.29） h，药峰浓度C_max分别为（30.37±0.43） U/mL和（26.06±0.88） U/mL,达峰时间T_max分别为（0.75±0.00） h和（0.08±0.00） h。与游离AAS比较，AHHPs的AUC_{(0-48 h)}、AUC_(0-∞)、MRT_{(0-72 h)} 、MRT_(0-∞)、C_max和T_max分别提高了3.5倍、4.0倍、2.5倍、3.1倍、1.2倍和9.4倍。AUC_{(0-48 h)}、AUC_(0-∞)和C_max的90%置信区间分别为72.6%~74.0%、72.3%~73.7%、94.7%~96.3%。结论 AHHPs延长了AAS在大鼠体内的生物半衰期，提高了AAS在大鼠体内的生物利用度，且AHHPs与游离AAS不具有生物等效性。

英文摘要:

Objective To determine the pharmacokinetics and bioequivalence of self-assembled hyaluronic acid-graft-poly (ethylene glycol)/hydroxypropyl-beta-cyclodextrin hollow nanospheres loaded with asparaginase (AHHPs) in SD rats. Methods AHHPs were prepared and observed under transmission electron microscopy. Its size, Zeta potential and entrapment efficiency were detected. Asparaginase (AAS) activities were measured after intravenous injection of AHHPs or free AAS in rats. The pharmacokinetic parameters were calculated using software DAS 2.1.1 for bioequivalence assessment. Results The self-prepared AHHPs had an average particle size of (367.43±2.72) nm, Zeta potential of (-15.70±1.25) mV, and average entrapment efficiency of (66.03 ± 3.81)%. The intravenous injection of AHHPs and free AAS produced an area under concentration-time Curve (AUC)_{(0-48 h)} of (162.06±4.01) U/mL·h and (46.38±1.98) U/mL·h, AUC_(0-∞) of (203.74±12.91) U/mL·h and (51.44±3.01) U/mL·h, mean residence time (MRT)_{(0-72 h)}of (4.35±0.06) h and (1.76±0.06) h, MRT_(0-∞) of (7.53±1.05) h and (2.44±0.29) h, peak concentration (C_max) of (30.37±0.43) U/mL and (26.06±0.88) U/mL, and time to peak concentration (T_max) of (0.75±0.00) h and (0.08±0.00) h, respectively. Compared with free AAS, the AUC_{(0-48 h)}, AUC_(0-∞), MRT_{(0-72 h)}, MRT_(0-∞), C_max and T_max of AHHPs increased by 3.5, 4.0, 2.5, 3.1, 1.2 and 9.4 times, respectively. The 90% confidential intervals of AUC_{(0-48 h)}, AUC_(0-∞) and C_max of the tested formulation were 72.6%-74.0%, 72.3%-73.7%, 94.7%-96.3%, respectively. Conclusion AHHPs can improve the bioavailability of AAS, extending its biological half-life in rats. AHHPs and free AAS are not bioequivalent.

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