中草药2026，Vol.57Issue(17)：6766-6778,13.DOI:10.7501/j.issn.0253-2670.2026.17.010
高乌甲素自胶束化固体分散体缓释片的制备、药动学及毒动学研究
Preparation,pharmacokinetics and toxicokinetics study of lappaconitine-self-micellizing solid dispersion sustained-release tablets
摘要
Abstract
Objective Lappaconitine-self-micellizing solid dispersion sustained-release tablets(Lap-SMSD-SRT)was prepared,and investigated its pharmacokinetics and toxicokinetics in vivo.Methods Lap-SMSD powder was prepared by solvent evaporation method,and its basic physicochemical properties were also studied.The influence of hydroxypropyl methyl cellulose(HPMC)K4M dosage,carboxymethyl starch sodium(CMS-Na)dosage and lactose dosage on the drug release behavior of Lap-SMSD-SRT were investigated by single factor experiments.Composite score of cumulative release rate at 2,6,12 h was used as response value,Box-Behnken design-response surface method(BBD-RSM)was employed to optimize formulation of Lap-SMSD-SRT.The release behavior of lappaconitine hydrobromide tablets,lappaconitine tablets and Lap-SMSD-SRT were compared.Six beagle dogs were used to study the pharmacokinetic behavior by a three-period crossover trial,and the relative bioavailability of Lap-SMSD-SRT was calculated.Three level of low,medium,high(0.75,1.50,2.25 mg/kg)dose groups of Lap-SMSD-SRT were set up,and compared the plasma concentration of lappaconitine after the first and last administration with a 4-week dosing period and a 4-week recovery period.Then the toxicokinetic parameters were calculated.The living condition of Beagle dogs was observed,and the hematology and biochemical indexes were also examined.Results The dosage ratio of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer(Soluplus)to lappaconitine in Lap-SMSD powder was 5∶1,and quickly became into micelles with particle size of(29.44±2.01)nm when dispersed in water.Optimal formulation of Lap-SMSD-SRT:HPMC K4M dosage was 19.09％,CMS-Na dosage was 15.59％,and lactose dosage was 22.63％.The cumulative release rate of Lap-SMSD-SRT at 2,6,12 h were 26.50％,61.67％and 93.67％,respectively.Pharmacokinetic results showed that the peak time(tmax)of Lap-SMSD-SRT was delayed to(6.20±1.61)h,the half-life(t1/2)was prolonged to(9.13±2.64)h,the peak concentration(Cmax)was enhanced to(123.94±46.77)ng/mL,and the relative bioavailability was enhanced to 5.21-fold.No significant accumulation of lappaconitine was observed in Beagle dogs at each dose of Lap-SMSD-SRT.There might be slight effect on the blood system and liver in the medium-dose and high-dose groups of Lap-SMSD-SRT,but these symptoms disappeared during the 4-week recovery period.Conclusion The preparation process of Lap-SMSD-SRT was reproducible,and the formulation exhibited obvious sustained-release characteristics,significantly enhanced the in vivo absorption of lappaconitine,and showed good safety.关键词
高乌甲素/自胶束化固体分散体/缓释片/Box-Behnken设计-响应面法/生物利用度/药动学/毒动学Key words
lappaconitine/self-micellizing solid dispersion/sustained-release tablets/Box-Behnken design-response surface method/bioavailability/pharmacokinetics/toxicokinetics分类
医药卫生引用本文复制引用
王丽,王凯,韩淑华,刘广辉,高小玲,宋沛然,薛佳琦..高乌甲素自胶束化固体分散体缓释片的制备、药动学及毒动学研究[J].中草药,2026,57(17):6766-6778,13.基金项目
2024年度河南省科技攻关项目(242102110111) （242102110111）
