姜黄素自胶束化固体分散体制备及其体内药动学研究

Preparation and in vivo pharmacokinetics of curcumin self-micellizing solid dispersions

目的制备姜黄素自胶束化固体分散体,并考察其体内药动学。方法溶剂蒸发法制备自胶束化固体分散体,测定其累积溶出率、饱和溶解度、稳定性、理化性质、自胶束化性能。12只大鼠随机分为2组,分别灌胃给予姜黄素及其自胶束化固体分散体的0.5%CMC-Na混悬液(100 mg/kg),于0.083、0.167、0.25、0.5、0.75、1、2、3、4、6、8、12、24 h采血,UPLC法测定姜黄素血药浓度,计算主要药动学参数。结果自胶束化固体分散体呈圆球形,表面光滑,分散均匀,无粘连,60 min内累积溶出率为(90.31±2.24)%,饱和溶解度为(583.17±16.78)μg/mL,粒径为22 nm,PDI为0.048,Zeta电位绝对值为1.2,在6个月内稳定性良好。姜黄素以无定形状态存在,与载体(F127、TPGS)之间可能发生氢键效应。与原料药比较,自胶束化固体分散体C_(max)、AUC_(0~t)、AUC_(0-∞)升高(P<0.01),t_(max)、t_(1/2)延长(P<0.01),相对生物利用度增加至7.05倍。结论自胶束化固体分散体可改善姜黄素体外溶出度、体内生物利用度。

AIM To prepare curcumin self-micellizing solid dispersions and to investigate their in vivo pharmacokinetics.METHODS Solvent evaporation method was adopted in the preparation of self-micellizing solid dispersions,after which the accumulative dissolution rate,saturated solubility,stability,physicochemical properties and self-micellizing properties were determined.Twelve rats were randomly assigned into two groups and given intragastric administration of the 0.5%CMC-Na suspensions of curcumin and its self-micellizing solid dispersions(100 mg/kg),respectively,after which blood collection was made at 0.083,0.167,0.25,0.5,0.75,1,2,3,4,6,8,12,24 h,UPLC was adopted in the plasma concentration determination of curcumin,and main pharmacokinetic parameters were calculated.RESULTS The spherical self-micellizing solid dispersions demonstrated smooth surfaceand uniform dispersion without adhension,whose accumulative dissolution rate within 60 min,saturated solubility,particle size,PDI,absolute value of Zeta potential were(90.31±2.24)%,(583.17±16.78)μg/mL,22 nm,0.048 and 1.2,respectively,along with good stability within 6 months.Curcumin existed in an amorphous state,which might occured hydrogen-bonding effect between carriers(F127,TPGS).Compared with raw medicine,the self-micellizing solid dispersions displayed increased C_(max),AUC_(0~t),AUC_(0-∞)(P<0.01),and prolonged t_(max),t_(1/2)(P<0.01),the relative bioavailability was enhanced to 7.05 times.CONCLUSION Self-micellizing solid dispersion can improve the in vitro dissolution rate and in vivo bioavailability of curcumin.