叶黄素纳米混悬剂制备及其体内药动学研究

Preparation and in vivo pharmacokinetics of lutein nanosuspensions

目的 制备叶黄素纳米混悬剂,并考察其体内药动学。方法 纳米沉淀法制备纳米混悬剂。以白蛋白浓度、吐温-80浓度、均质压力、均质次数为影响因素,粒径、PDI为评价指标,单因素试验优化处方,在扫描电镜下观察形态,进行晶型分析,测定溶解度、体外溶出、稳定性。18只大鼠随机分为3组,分别灌胃给予叶黄素、物理混合物、叶黄素纳米混悬剂的0.5%CMC-Na混悬液(30 mg/kg),于0、5、15、30、45、60、90、120、240、360、480 min采血,HPLC法测定叶黄素血药浓度,计算主要药动学参数。结果 最佳处方为叶黄素用量30 mg,白蛋白浓度1.5%,吐温-80浓度0.75%,均质压力80 MPa,均质次数8次。所得纳米混悬剂呈球形,平均粒径为(208.71±9.26)nm, PDI为0.114±0.017,Zeta电位为-(23.15±1.60)mV。原料药以无定形状态存在于纳米混悬剂中。纳米混悬剂溶解度相较于原料药增加至46.12倍,360 min内累积溶出度达95%,90 d内稳定性良好。与原料药、物理混合物比较,纳米混悬剂tmax缩短(P<0.05),Cmax、AUC0~t、AUC0~∞升高(P<0.01),相对生物利用度相较于原料药增加至3.71倍。结论 白蛋白纳米混悬剂可改善叶黄素溶解度,促进其溶出、口服吸收。

AIM To prepare lutein nanosuspensions and to investigate their in vivo pharmacokinetics.METHODS Nanoprecipitation method was adopted in the preparation of nanosuspensions.With albumin concentration,Tween-80 concentration,homogenization pressure and homogenization frequency as influencing factors,particle size and PDI as evaluation indices,the formulation was optimized by single factor test,after which crystalline form analysis was made,and the solubility,in vitro dissolution,stability were determined.Eighteen rats were randomly assigned into three groups and given intragastric administration of the 0.5%CMC-Na suspensions of lutein,physical mixture and lutein nanosuspensions(30 mg/kg),respectively,after which blood collection was made at 0,5,15,30,45,60,90,120,240,360,480 min,HPLC was adopted in the plasma concentration determination of lutein,and main pharmacokinetic parameters were calculated.RESULTS The optimal formulation was determined to be 30 mg for lutein consumption,1.5%for albumin concentration,0.75%for Tween-80 concentration,80 MPa for homogenization pressure,and 8 times for homogenization frequency.The obtained spherical nanosuspensions demonstrated the average particle size,PDI and Zeta potential of(208.71±9.26)nm,0.114±0.017 and-(23.15±1.60)mV,respectively.Raw medicine existed in the nanosuspensions in an amorphous state.The solubility of nanosuspensions was increased to 46.12 times as compared with that of raw medicine,whose accumulative dissolution rate reached 95%within 360 min,along with good stability within 90 d.Compared with raw medicine and physical mixture,the nanosuspensions displayed shortened t max(P<0.05)and increased C max,AUC 0-t,AUC 0-∞(P<0.01),the relative bioavailability was enhanced to 3.71 times as compared with that of raw medicine.CONCLUSION Nanosuspensions can improve the solubility of lutein and promote its dissolution,oral absorption.