柚皮素磷脂酰胆碱复合物滴丸处方优化及口服药动学评价

目的 优化柚皮素磷脂酰胆碱复合物滴丸（naringenin-phosphatidylcholine complex dropping pills,Nar-PC-DPs）处方,考察口服药动学行为及生物利用度。方法 溶剂挥发法制备柚皮素磷脂酰胆碱复合物（naringenin-phosphatidylcholine complex,Nar-PC）。采用成型率和丸重差异为指标,单因素实验联合Box-Behnken效应面法筛选Nar-PC-DPs处方。扫描电子显微镜（SEM）观察Nar-PC-DPs微观形态,X射线粉末衍射法（XRPD）分析柚皮素在Nar-PC-DPs中存在状态,测定Nar-PC-DPs溶解度和体外释药情况。比格犬分别给予柚皮素原料药、Nar-PC和Nar-PC-DPs,测定血药浓度,计算主要药动学参数。结果 Nar-PC-DPs最佳处方工艺为聚乙二醇4000（PEG 4000）占基质百分比为49%,基质与Nar-PC质量比为5.2：1,滴距为8.2 cm。Nar-PC-DPs外观圆整、光滑。柚皮素在Nar-PC-DPs中以无定型形式存在,在不同介质中溶解度均明显增加。Nar-PC-DPs在60 min内累积溶出度为95.10%,储存稳定性良好。药动学结果显示,Nar-PC-DPs的达峰时间（t_max）提前至（0.95±0.14）h,半衰期（t_1/2）增加至（6.85±0.71）h,达峰浓度（C_max）增加至3.25倍,相对口服吸收生物利用提高至3.79倍。结论 Nar-PC-DPs增加了柚皮素溶解度,促进了药物溶出,提高了口服吸收生物利用度。

Formulation optimization of naringenin-phosphatidylcholine complex dropping pills and oral pharmacokinetics evaluation

Objective To optimize prescriptions of naringenin-phosphatidylcholine complex dropping pills (Nar-PC-DPs), and investigate its oral pharmacokinetic behavior and bioavailability. Methods Solvent evaporation method was employed to prepare naringenin-phosphatidylcholine complex (Nar-PC). Forming rate and weight difference were used as indexes, single factor investigation combined with Box-Behnken design response surface method was employed to investigate the optimal prescriptions of Nar-PC-DPs. Microscopic morphology of Nar-PC-DPs was observed by scanning electron microscope (SEM). Crystal form of naringenin in Nar-PC-DPs was analyzed by X ray powder diffraction (XRPD). Solubility and in vitro release behavior of Nar-PC-DPs were determined. Beagle dogs were administrated of naringenin suspension, Nar-PC and Nar-PC-DPs, respectively. Plasma concentrations were determined, and main pharmacokinetic parameters were calculated. Results Optimum prescriptions of Nar-PC-DPs:percentage of PEG 4000 in matrix was 49%, matrix to Nar-PC ratio was 5.2:1, dropping distance was 8.2 cm. Appearance of Nar-PC-DPs was round and smooth. Naringenin existed as an amorphous form in Nar-PC-DPs, and solubility in different media was enhanced greatly. Cumulative dissolution of Nar-PC-DPs reached 95.10% in 60 min, and storage stability was perfect. Pharmacokinetic results showed that the time to peak (t_max) of Nar-PC-DPs was shift to (0.95 ±0.14) h, half-life period (t_1/2) was extend to (6.85 ±0.71) h, peak concentration (C_max) was increased to 3.25 times and oral bioavailability was enhanced to 3.79 times. Conclusion Nar-PC-DPs increased the solubility of naringenin, promoted the drug dissolution and enhanced oral bioavailability.