松萝酸纳米混悬剂制备及其体内药动学研究

Preparation and in vivo pharmacokinetics of usnic acid nanosuspensions

目的制备松萝酸纳米混悬剂,并考察其体内药动学。方法高压均质法制备纳米混悬剂。以稳定剂种类、稳定剂用量、均质压力、均质次数为影响因素,粒径、PDI、Zeta电位为评价指标,单因素试验优化制备工艺。在扫描电镜下观察纳米混悬剂形态,测定溶解度、体外释药。12只大鼠分别灌胃给予松萝酸及其纳米混悬剂的0.5%CMC-Na混悬液(15 mg/kg),于0、0.25、0.5、1、2、2.5、3、4、6、8、10、12 h采血,HPLC法测定松萝酸血药浓度,计算主要药动学参数。结果最佳条件为稳定剂(泊洛沙姆188)用量100 mg,均质压力80 MPa,均质次数12次。所得纳米混悬剂呈球形或类球形,平均粒径为185.19 nm,PDI为0.089,Zeta电位为-34.08 mV,溶解度为92.47μg/mL,60 min内累积溶出度为90.46%。与原料药、物理混合物比较,纳米混悬剂t_(max)缩短(P<0.01),t_(1/2)延长(P<0.01),C_(max)、AUC_(0~t)、AUC_(0~∞)升高(P<0.01),口服生物利用度提高至3.09倍。结论纳米混悬剂可改善松萝酸溶解度和溶出度,促进其口服吸收。

AIM To prepare usnic acid nanosuspensions to investigate their in vivo pharmacokinetics.METHODS The nanosuspensions were prepared by high-pressure homogenization method.With stabilizer type,stabilizer consumption,homogenization pressure and homogenization frequency as influencing factors,particle size,PDI and Zeta potential as evaluation indices,the preparation process was optimized by single factor test.The morphology of nanosuspensions were observed under scanning electron microscope,and the solubility and in vitro drug release were determined.Twelve rats were given intragastric administration(15 mg/kg)of the 0.5%CMC-Na suspensions of usnic acid and its nanosuspensions,respectively,after which blood collection was made at 0,0.25,0.5,1,2,2.5,3,4,6,8,10,12 h,HPLC was adopted in the plasma concentration determination of ursolic acid,and main pharmacokinetic parameters were calculated.RESULTS The optimal conditions were 100 mg for stabilizer(poloxamer 188)consumption,80 MPa for homogenization pressure,and 12 times for homogenization frequency.The obtained spherical or spherical-like nanosuspensions demonstrated the average particle size,PDI,Zeta potential,solubility and accumulative dissolution rate within 60 min of 185.19 nm,0.089,-34.08 mV,92.47μg/mL and 90.46%,respectively.Compared with the raw medicine and physical mixture,the nanosuspensions displayed shortened t_(max)(P<0.01),prolonged t_(1/2)(P<0.01)and increased C_(max),AUC_(0-t) and AUC_(0-∞)(P<0.01),and the oral bioavailability was enhanced to 3.09 times.CONCLUSION Nanosuspensions can improve the solubility and disolution rate of usnic acid,and promote its oral absorption.