椒姜凝胶贴膏的体外释药动力学与药效学评价

In Vitro Pharmacokinetics and Pharmacodynamic Evaluation of Jiaojiang Cataplasms

目的:研究椒姜凝胶贴膏的体外动力学并对其药效学进行评价,为该制剂的开发提供可行性依据。方法:采用改良的Franz扩散池法进行体外释放与透皮试验,分别以半透膜和离体小鼠皮肤作为透过屏障,采用高效液相色谱法(HPLC)测定指标成分羟基-α-山椒素、人参皂苷Rb1及6-姜辣素的含量,以评价椒姜凝胶贴膏的释放与经皮渗透效果。6-姜辣素和羟基-α-山椒素检测的流动相为水-乙腈-甲醇(2∶1∶1),检测波长280 nm;人参皂苷Rb1检测的流动相为乙腈-0.1%磷酸水溶液(31∶69),检测波长203 nm。建立小鼠肠麻痹模型,动物随机分为5组,即假手术组、模型组、多潘立酮组(3.9 mg·kg^(-1))及椒姜凝胶贴膏高、低剂量组(6.2,3.1 g·kg^(-1),以生药量计),观察椒姜凝胶贴膏对模型动物胃肠推进功能的影响。结果:椒姜凝胶贴膏中羟基-α-山椒素,6-姜辣素及人参皂苷Rb1在24 h的平均释放速率分别为16.41,4.23,4.15μg·cm^(-2)·h^(-1);体外透皮试验中24 h平均透过速率分别为2.31,0.64,0.29μg·cm^(-2)·h^(-1);皮肤滞留量分别为19.56,3.59,1.61μg。根据Ritger-Peppas方程,确定羟基-α-山椒素、人参皂苷Rb1及6-姜辣素的释放为非Fick扩散。椒姜凝胶贴膏高剂量组对模型小鼠小肠摩擦损伤术后的肠功能具有一定改善作用,可以促进肠蠕动,促进小肠推进率(P<0.05)。结论:椒姜凝胶贴膏具有体外释放和透皮性能,体外释放符合Higuchi方程,经皮渗透行为符合零级动力学方程,其对术后的小肠功能有改善作用,可提高小肠推进功能,初步说明该制剂具有一定的临床开发价值。

Objective:To study the in vitro kinetics of Jiaojiang cataplasms and evaluate its pharmacodynamics,so as to provide a feasible basis for the development of this preparation.Method:The improved Franz diffusion cell was used for the in vitro release in semipermeable membrane and transdermal absorption in in vitro mouse skins.The contents of hydroxy-α-sanshool,6-gingerol,ginsenoside Rb1 were determined by high performance liquid chromatography(HPLC),to evaluate the in vitro release and transdermal absorption of Jiaojiang cataplasms.The mobile phase of 6-gingerol and hydroxy-α-sanshool was wateracetonitrile-methanol(2∶1∶1)with the detection wavelength of 280 nm.The mobile phase of ginsenoside Rb1 was acetonitrile-0.1%phosphoric acid aqueous solution(31∶69)with the detection wavelength of 203 nm.A mouse intestinal paralysis model was established,and mice were randomly divided into five groups,namely sham operation group,model group,domperidone group(3.9 mg·kg^(-1))and high-and low-dose groups of Jiaojiang cataplasms(6.2,3.1 g·kg^(-1),measured by crude drug dosage),to observe the effect of this preparation on gastrointestinal propulsion function.Result:Average release rates of hydroxy-α-sanshool,6-gingerol and ginsenoside Rb1 at 24 h were 16.41,4.23,4.15μg·cm^(-2)·h^(-1),the average transdermal rates of them at 24 h were2.31,0.64,0.29μg·cm^(-2)·h^(-1),their skin retention values were 19.56,3.59,1.61μg,respectively.According to the Ritger-Peppas equation,the release of hydroxy-α-sanshool,6-gingerol,ginsenoside Rb1 was non-Fick diffusion.The high-dose group of Jiaojiang cataplasms could improve intestinal function of model mice after small intestinal friction injury,and promote intestinal peristalsis and small intestinal propulsion rate(P<0.05).Conclusion:Jiaojiang cataplasms has in vitro release and transdermal properties,the in vitro release conforms to Higuchi equation,and transdermal absorption behavior conforms to zero-order kinetic equation,which can improve the postoperative function of the small intestine and the propulsion function of small intestine.It preliminarily indicates that the preparation has certain clinical development value.