异甘草素纳米混悬剂的制备及其体内药动学研究

Preparation and in vivo pharmacokinetics of isoliquiritigenin nanosuspensions

目的制备异甘草素纳米混悬剂,并评价其体内药动学。方法沉淀-高压均质法制备纳米混悬剂,考察稳定剂种类、药物与稳定剂比例、均质压力、均质次数对粒径、PDI的影响,测定粒径、Zeta电位、载药量、体外溶出。大鼠分别灌胃给予异甘草素、物理混合物、纳米混悬剂的0.5%CMC-Na混悬液(50 mg/kg),于0、0.5、0.75、1、1.5、2、3、4、6、8、10、12 h采血,HPLC法测定异甘草素血药浓度,计算主要药动学参数。结果最优处方为药物与稳定剂[PVP K30-泊洛沙姆188(1∶1)]比例1∶3,均质压力100 MPa,均质次数12次。所得纳米混悬剂呈球形,平均粒径为(163.5±6.8)nm,PDI为0.109±0.12,Zeta电位为(-34.1±2.6)mV,载药量为(24.36±0.83)%,45 min内累积溶出度为90.37%。与原料药、物理混合物比较,纳米混悬剂t_(max)缩短(P<0.01),C_(max)、AUC 0~t、AUC_(0~∞)升高(P<0.01),相对生物利用度增加至3.04倍。结论纳米混悬剂可有效改善异甘草素累积溶出度和口服生物利用度。

AIM To prepare isoliquiritigenin nanosuspensions and evaluate their pharmacokinetics in vivo.METHODS The nanosuspensions were prepared by precipitation-high pressure homogenization method,after which effects of stabilizer kind,drug-stabilizer ratio,homogenization pressure and homogenization frequency on particle size and PDI were investigated.Rats were given intragastric administration of the 0.5%CMC-Na suspensions of isoliquiritigenin and its nanosuspensions(50 mg/kg),respectively,after which blood collection was made at 0,0.5,0.75,1,1.5,2,3,4,6,8,10,12 h,HPLC was adopted in the plasma concentration determination of isoliquiritigenin,and main pharmacokinetic parameters were calculated.RESULTS The optimal formulation was determined to be 1∶3 for drug-stabilizer[PVP K30-Poloxamer 188(1∶1)]ratio,100 MPa for homogenization pressure,and 12 times for homogenization frequency.The obtained spherical nanosuspensions demonstrated the average particle size,PDI,Zeta potential,drug loading and accumulative release rate within 45 min were(163.5±6.8)nm,0.109±0.12,(-34.1±2.6)mV,(24.36±0.83)%and 90.37%,respectively.Compared with the raw medicine and physical mixture,the nanosuspensions displayed shortened t_(max)(P<0.01)and increased C_(max),AUC 0-t,AUC_(0-∞)(P<0.01),whose relative bioavailability was enhanced to 3.04 times.CONCLUSION Nanosuspensions can effectively improve the accumulative release rate and oral bioavailability of isoliquiritigenin.