柚皮素磷脂复合物纳米混悬剂制备及其体内药动学研究

Preparation and in vivo pharmacokinetics of nanosuspensions of naringenin phospholipids complex

目的制备柚皮素磷脂复合物纳米混悬剂,并考察其体内药动学。方法高压均质法制备磷脂复合物纳米混悬剂。以稳定剂种类、稳定剂与磷脂复合物用量比例、均质压力、均质次数为影响因素,粒径、PDI、Zeta电位为评价指标,单因素试验优化处方。在透射电镜下观察形态,进行X射线粉末衍射分析,测定溶解度、油水分配系数、磷脂复合物解离率、累积释放度。24只大鼠随机分为4组,分别灌胃给予柚皮素及其磷脂复合物、纳米混悬剂、磷脂复合物纳米混悬剂的0.5%CMC-Na混悬液(30 mg/kg),于0、0.25、0.5、1、1.5、2、3、4、5、6、8、10、12 h采血,HPLC法测定柚皮素血药浓度,计算主要药动学参数。结果最优处方为磷脂复合物用量50 mg,稳定剂PVP K30+TPGS(1∶1),稳定剂与磷脂复合物用量比例3∶1,均质压力100 MPa,均质次数10次。所得磷脂复合物纳米混悬剂呈类球形或椭圆形,平均粒径、PDI、Zeta电位分别为(260.53±25.86)nm、0.160±0.024、(-31.08±1.37)mV。柚皮素以无定型状态存在于磷脂复合物纳米混悬剂中,溶解度、油水分配系数、磷脂复合物解离率升高,4 h内累积释放度达90%以上。与原料药、纳米混悬剂比较,磷脂复合物纳米混悬剂t_(max)缩短(P<0.05),C_(max)、AUC_(0~t)、AUC_(0~∞)升高(P<0.05,P<0.01),相对生物利用度增加至4.38倍。结论磷脂复合物纳米混悬剂可提高柚皮素溶解度、溶出度,促进其体内吸收。

AIM To prepare the nanosuspensions of naringenin phospholipids complex,and to investigate their in vivo pharmacokinetics.METHODS High-pressure homogenization method was applied to preparing the nanosuspensions of phospholipids complex.With stabilizer type,stabilizer-phospholipids complex consumption ratio,homogeneous pressure and homogeneous frequency as influencing factors,particle size,PDI and Zeta potential as evaluation indices,the formulation was optimized by single factor test.The morphology was observed under transmission electron microscope,after which X-ray powder diffraction analysis was performed,solubility,oil-water partition coefficient,dissociation rate of phospholipids complex and accumulative release rate were determined.Twenty-four rats were randomly assigned into four groups and given intragastric administration of the 0.5%CMC-Na suspensions of naringenin and its phospholipids complex,nanosuspensions and nanosuspensions of phospholipids complex(30 mg/kg),respectively,after which blood collection was made at 0,0.25,0.5,1,1.5,2,3,4,5,6,8,10,12 h,HPLC was adopted in the plasma concentration determination of naringenin,and main pharmacokinetic parameters were calculated.RESULTS The optimal formulation was determined to be 50 mg for naringenin consumption,PVP K30+TPGS(1∶1)as stabilizer,3∶1 for stabilizer-phospholipids complex consumption ratio,100 MPa for homogeneous pressure,and 10 times for homogeneous frequency,respectively.The obtained spherical-like or oval nanosuspensions of phospholipids complex demonstrated the average particle size,PDI and Zeta potential of(260.53±25.86)nm,0.160±0.024 and(-31.08±1.37)mV,respectively.Naringenin existed in the nanosuspensions of phospholipids complex in an anamorphous state,along with increased solubility,oil-water partition coefficient and dissociation rate of phospholipids complex,and the accumulative release rate reached more than 90%within 4 h.Compared with raw medicine and nanosuspensions,the nanosuspensions of phospholipids complex displayed shortened t_(max)(P<0.05)and increased C_(max),AUC_(0-t),AUC_(0-∞)(P<0.05,P<0.01),the relative bioavailability was enhanced to 4.38 times.CONCLUSION The nanosuspensions of phospholipids can enhance naringenin’s solubility and dissolution rate,and promote its in vivo absorption.