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目的通过Box-Behnken效应面优化法筛选处方,制备生物素介导的阿霉素和槲皮素的复方脂质体。方法采用薄膜分散法制备槲皮素脂质体,通过硫酸铵梯度法主动包载阿霉素。分别以磷脂与胆固醇质量比(X1)、脂质与槲皮素质量比(X_2)、硫酸铵浓度(X_3)和孵育温度(X_4)为考察指标,以阿霉素(doxorubicin,DOX)包封率(Y_1,wEE/%)、槲皮素(quercetin,QUE)包封率(Y_2,wEE/%)及粒径(Y_3,d/nm)为评价指标;采用四因素三水平Box-Behnken效应面优化法筛选脂质体处方;测定优化脂质体的粒径、zeta电位和外观形态并考察脂质体的稳定性。结果最优化处方工艺为磷脂与胆固醇质量比为3.48∶1;磷脂与槲皮素质量比为26∶1;硫酸铵浓度为0.15 mol·L~(-1);阿霉素孵育温度为50℃;载药脂质体的平均粒径为148.5 nm;zeta电位为-23.1 m V;15 d内泄露率小于20%。结论采用Box-Behnken实验设计法优化处方所得数学模型预测性良好,可以用于复方阿霉素/槲皮素脂质体的处方优化。
OBJECTIVE To prepare biotin-conjugated doxorubicin and quercetin compound liposomes by Box-Behnken effect surface optimization. Methods Quercetin liposomes were prepared by thin film dispersion method, and doxorubicin was actively encapsulated by ammonium sulfate gradient method. The phospholipid and cholesterol mass ratio (X1), lipid to quercetin mass ratio (X_2), ammonium sulfate concentration (X_3) and incubation temperature (X_4) were used as indexes and doxorubicin (DOX) (Y_1, wEE /%), quercetin (QUE) entrapment efficiency (Y_2, wEE /%) and particle size (Y_3, d / nm) were used as the evaluation indexes. The four factors and three levels of the Box-Behnken effect Surface optimization method was used to screen liposomal prescription. The particle size, zeta potential and morphology of the liposomes were optimized and the stability of the liposomes was investigated. Results The optimized formulation was that the mass ratio of phospholipid to cholesterol was 3.48:1, the mass ratio of phospholipid and quercetin was 26:1, the concentration of ammonium sulfate was 0.15 mol·L -1, the doxorubicin incubation temperature was 50 ℃ ; The average diameter of drug-loaded liposomes was 148.5 nm; zeta potential was -23.1 mV; and the leakage rate within 15 days was less than 20%. Conclusion The mathematical model optimized by Box-Behnken experimental design has good predictability and can be used for the prescription optimization of compound doxorubicin / quercetin liposomes.