双黄连速释口腔崩解片与分散片的制备及体内药代动力学评价

Preparation and in vivo pharmacokinetic evaluation of Shuanghuanglian immediate-release orally disintegrating tablets and dispersible tablets

关键词:  速释制剂  口腔崩解片  分散片  药代动力学  双黄连制剂  UPLC-Q-Orbitrap-MS

Key words:  immediate-release preparation  orally disintegrating tablet  dispersible tablet  pharmacokinetics  Shuanghuanglian preparation  UPLC-Q-Orbitrap-MS

摘要:

[目的] 研究开发双黄连口腔崩解片（SHL-ODT）与双黄连分散片（SHL-DT）来实现快速起效，提高生物利用度。[方法] 采用液质联用技术对双黄连中成分进行定性鉴定，为药代动力学定量成分的选择奠定实验基础。制备两种速释口服制剂，并进行表征、体外溶出度及药代动力学研究。[结果] 新绿原酸、绿原酸、芦丁、连翘酯苷A、木犀草苷、黄芩苷、连翘苷和千层纸素A-7-O-β-D-葡萄糖醛苷8种化合物被选为药代动力学研究的指标成分。SHL-ODT崩解时间为（52.91±2.21） s，SHL-DT平均分散时间为（119.8±2.31） s，两者崩解时间、分散均匀度、硬度、质量变化、脆性及溶出度均符合并高于《中国药典》（2020年版）要求。体外溶出度实验显示，SHL-ODT和SHL-DT中主要成分（绿原酸、黄芩苷、连翘苷）的溶出度均达到98%。药代动力学分析表明，SHL-ODT中连翘苷的C_max、T_max和AUC_（0-t）分别为双黄连普通片（SHL-OT）的2.44倍、0.69倍和1.87倍（P<0.05）；SHL-DT中连翘苷的C_max、T_max和AUC_（0-t）分别为SHL-OT的2.26倍（P<0.05）、0.56倍和2.12倍（P<0.01）。相比SHL-ODT，SHL-DT的AUC更大。[结论] 两种速释口服双黄连制剂显著提高了起效速度和药物生物利用度，为临床提供了更安全高效的双黄连制剂选择。

Abstract:

[Objective] Shuanghuanglian orally disintegrating tablets（SHL-ODT） and dispersible tablets（SHL-DT） were developed to achieve rapid onset of action and improve bioavailability. [Methods] Liquid chromatography-mass spectrometry（LC-MS） technique was used to qualitatively identify the components in SHL and to lay the experimental foundation for the selection of components for pharmacokinetic quantification. Two immediate-release oral formulations were prepared and subjected to characterization，in vitro dissolution and pharmacokinetic studies. [Results] Eight compounds，neochlorogenic acid，chlorogenic acid，rutin，forsythoside A，luteoloside，baicalin，phillyrin，and oroxylin A 7-O-beta-D-glucuronide，were selected as the index components for pharmacokinetic studies. The disintegration time of SHL-ODT was（52.91±2.21） s，and the average dispersion time of SHL-DT was（119.8±2.31） s. Both formulations met and exceeded the relevant requirements for disintegration time，dispersion uniformity，hardness，weight variation，brittleness，and dissolution rate as specified in the Chinese Pharmacopoeia（2020 edition）. In vitro dissolution experiments showed that the dissolution rates of the major components（neochlorogenic acid，baicalin，phillyrin） in SHL-ODT and SHL-DT were both approximately 98%. Pharmacokinetic analysis indicated that the C_max，T_max，and AUC_（0-t） of forsythiaside in SHL-ODT were 2.44 times，0.69 times，and 1.87 times（P<0.05） higher than those of SHL ordinary tablets（SHL-OT），respectively. In SHL-DT，the C_max，T_max，and AUC_（0-t） of phillyrin were 2.26 times（P<0.05），0.56 times，and 2.12 times（P<0.01） higher than those of SHL-OT，respectively. Additionally，SHL-DT showed a higher AUC compared to SHL-ODT. [Conclusion] Both fast-release oral SHL formulations significantly enhanced the onset of action of the drug and bioavailability，providing a safer and more efficient alternative for clinical application of SHL preparations.