二氢杨梅素混合胶束的制备、表征及药动学研究

Dihydromyricetin mixed micelles:Preparation characterization and pharmacokinetic study

目的 制备二氢杨梅素混合胶束(DMY-MMs),考察口服药动学行为,并计算口服吸收相对生物利用度。方法 通过单因素试验确定主要影响因素的筛选区间,Box-Behnken设计-响应面法优化DMY-MMs处方。透射电镜观察DMY-MMs微观形态,X-射线粉末衍射法分析晶型,透析法考察DMY-MMs体外释药行为。SD大鼠分别ig给予二氢杨梅素和DMYMMs,比较药动学行为和吸收相对生物利用度。结果 DMY-MMs最佳处方为:载-药用量比为7.6∶1,Soluplus与TPGS用量比为6.4∶1,水化时间为2 h。包封率、载药量、粒径及Zeta电位分别为(90.21±1.60)%、(10.43±0.21)%、(68.14±7.23)nm和(1.07±0.26)mV。DMY-MMs外貌为类球形,并以无定型态存在于DMY-MMs冻干粉中。DMY-MMs体外释药行为符合Weibull模型,释药方程为lnln[1/(1-M_(t)/M_(∞))]=0.639 7lnt-1.781 1(r=0.978 4)。药动学结果显示,DMY-MMs半衰期(t_(1/2))延长至(4.11±1.07)h,C_(max)增加至4.41倍,相对生物利用度提高至5.18倍。结论 DMY-MMs改变了二氢杨梅素体内药动学行为,显著促进了口服吸收。

Objective To prepare dihydromyricetin mixed micelles(DMY-MMs),and evaluate oral pharmacokinetic behavior and calculate its relative oral bioavailability.Methods Single factor tests were used to determine the screening interval of the main influencing factors,and Box-Behnken design-response surface methodology was employed to optimize prescriptions of DMY-MMs.Transmission electron microscope(TEM)was employed to observe its microscopic appearance.Crystal form of lyophilized powder was analyzed by X-ray powder diffraction(XRPD).Release behavior of DMY-MMs in vitro was investigated by dialysis method.SD rats in each group were administered intragastrically with dihydromyricetin and DMY-MMs,respectively.Pharmacokinetics and relative bioavailability were also compared.Results Optimal formulation of DMY-MMs:carrier to drug ratio was 7.6∶1,Soluplus to TPGS ratio was 6.4∶1,and hydration time was 2 h.Envelopment efficiency,drug loading,particle size and Zeta potential were(90.21±1.60)%,(10.43±0.21)%,(68.14±7.23)nm and(1.07±0.26)mV,respectively.Appearance of DMY-MMs was spherical,dihydromyricetin changed into an amorphous form in DMY-MMs lyophilized powder.Release behavior in vivo of DMY-MMs was in accordance with Higuchi model,and drug release equation was lnln[1/(1-M_(t)/M_(∞))]=0.6397lnt-1.7811(r=0.9784).Pharmacokinetics of DMY-MMs showed that t_(1/2) was prolonged to(4.11±1.07)h,C_(max) was enhanced to 4.41-fold and oral relative bioavailability was increased to 5.18-fold.Conclusion DMY-MMs changed pharmacokinetic behavior of dihydromyricetin in vivo and significantly promoted its oral absorption.