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  

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

作　　者：刘万路 LIU Wan-lu(Weihai Ocean Vocational College,Weihai 264300,China)

机构地区：[1]威海海洋职业学院,山东威海264300

出　　处：《中草药》2023年第19期6253-6263,共11页Chinese Traditional and Herbal Drugs

基　　金：国家自然科学青年基金项目(51804021)。

摘　　要：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NarPC-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(tmax)提前至(0.95±0.14)h,半衰期(t1/2)增加至(6.85±0.71)h,达峰浓度(Cmax)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。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-PCDPs: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 NarPC-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(tmax)of Nar-PC-DPs was shift to(0.95±0.14)h,half-life period(t1/2)was extend to(6.85±0.71)h,peak concentration(Cmax)was increased to 3.25 times and oral bioavailability was enhanced to 3.79 times.Conclusion Nar-PCDPs increased the solubility of naringenin,promoted the drug dissolution and enhanced oral bioavailability.

关 键 词：柚皮素 磷脂酰胆碱复合物 滴丸 Box-Behnken设计-效应面法 体外溶出 药动学行为 

分 类 号：R283.6[医药卫生—中药学]