基于甘草酸增溶作用的葛根素分散片研究
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摘要
基于甘草酸可在水溶液中形成胶束从而起增溶作用,筛选葛根素与甘草酸最佳配伍比例,制备葛根素-甘草酸分散片,考察葛根素溶出度。通过比较葛根素与甘草酸质量比为7∶1,6∶1,5∶1,4∶1,3∶1,2∶1时的胶束溶液的粒径、Zate电位及葛根素的溶出量,得出二者质量比为5∶1时,胶束粒径最小,分布均匀,葛根素的溶出量最大,确定葛根素与甘草酸质量比5∶1为最佳配伍比例。采用单因素和正交试验优化葛根素-甘草酸分散片最佳处方组成为:葛根素100.0 mg,甘草酸20.0 mg,交联聚维酮为崩解剂24.0 mg,微晶纤维素为填充剂135.0 mg,羟丙基甲基纤维素为黏合剂18.0 mg,硬脂酸镁为润滑剂2.7 mg,片重300.0 mg。采用HPLC测定分散片中葛根素含量,葛根素在15.5～248 mg·L~(-1)线性关系良好(r=0.999 8),精密度高(RSD<2.0%),重复性好(RSD<2.0%),回收率为101.1%,RSD 0.89%,不同批次葛根素-甘草酸分散片中葛根素的量无明显差异。以人工胃液为溶出介质时,葛根素-甘草酸分散片在15 min内葛根素的溶出度可达到85%以上;以磷酸盐缓冲液(pH 6.8)为溶出介质时,与葛根素分散片比较,葛根素-甘草酸分散片中葛根素的体外溶出速率更快,30 min内累计溶出度达99.8%,因此,借助甘草酸的增溶作用制备葛根素-甘草酸分散片可提高葛根素的体外溶出。
Based on the fact that glycyrrhizic acid can form micelles in aqueous solution and play a role in solubilization, the optimal compatibility ratio between puerarin and glycyrrhizic acid was screened to prepare puerarin-glycyrrhizic acid dispersible tablets and investigate the dissolution of puerarin. The particle size, Zate potential and puerarin dissolution were compared among the micellar solutions with mass ratio of 7∶1, 6∶1, 5∶1, 4∶1, 3∶1 and 2∶1(puerarin to glycyrrhizic acid), and it was found that when the mass ratio of puerarin and glycyrrhizic acid was 5∶1, the micelle showed smallest particle size, uniform distribution, and largest puerarin dissolution, so mass ratio of 5∶1 was determined as the optimal condition. The formulation of puerarin-glycyrrhizic acid dispersible tablets was optimized by single factor and orthogonal test: puerarin 100.0 mg, glycyrrhizin 20.0 mg, polyvinylpolypyrrolidone 24.0 mg as disintegrating agent, microcrystalline cellulose 135.0 mg as stuffing bulking agent, hydroxypropyl methyl cellulose 18.0 mg as adhesive agent, magnesium stearate 2.7 mg as lubricant, and tablet weight of 300.0 mg. High-performance liquid chromatography(HPLC) method was used to determine the content of puerarin in dispersible tablets. Puerarin showed a good linear relationship(r=0.999 8) in the range of 15.5-248 g·L~(-1), with high precision(RSD<2.0%) and good repeatability(RSD<2.0%), and the recovery rate was 101.1%, RSD 0.89%. There was no significant difference in the quantity of puerarin in different batches of puerarin-glycyrrhizic acid dispersible tablets. When the artificial gastric juice was used as the dissolution medium, the dissolution of puerarin in puerarin-glycyrrhizic acid dispersible tablets could reach over 85% within 15 min. When phosphate buffer(pH 6.8) was used as the dissolution medium, the dissolution of puerarin in the puerarin-glycyrrhizic acid dispersible tablets had a faster dissolution rate in vitro, 99.8% in 30 min. Therefore, puerarin-glycyrrhizic acid dispersible tablets could improve the dissolution of puerarin in vitro due to the solubilization effect of glycyrrhizic acid.
Based on the fact that glycyrrhizic acid can form micelles in aqueous solution and play a role in solubilization, the optimal compatibility ratio between puerarin and glycyrrhizic acid was screened to prepare puerarin-glycyrrhizic acid dispersible tablets and investigate the dissolution of puerarin. The particle size, Zate potential and puerarin dissolution were compared among the micellar solutions with mass ratio of 7∶1, 6∶1, 5∶1, 4∶1, 3∶1 and 2∶1(puerarin to glycyrrhizic acid), and it was found that when the mass ratio of puerarin and glycyrrhizic acid was 5∶1, the micelle showed smallest particle size, uniform distribution, and largest puerarin dissolution, so mass ratio of 5∶1 was determined as the optimal condition. The formulation of puerarin-glycyrrhizic acid dispersible tablets was optimized by single factor and orthogonal test: puerarin 100.0 mg, glycyrrhizin 20.0 mg, polyvinylpolypyrrolidone 24.0 mg as disintegrating agent, microcrystalline cellulose 135.0 mg as stuffing bulking agent, hydroxypropyl methyl cellulose 18.0 mg as adhesive agent, magnesium stearate 2.7 mg as lubricant, and tablet weight of 300.0 mg. High-performance liquid chromatography(HPLC) method was used to determine the content of puerarin in dispersible tablets. Puerarin showed a good linear relationship(r=0.999 8) in the range of 15.5-248 g·L~(-1), with high precision(RSD<2.0%) and good repeatability(RSD<2.0%), and the recovery rate was 101.1%, RSD 0.89%. There was no significant difference in the quantity of puerarin in different batches of puerarin-glycyrrhizic acid dispersible tablets. When the artificial gastric juice was used as the dissolution medium, the dissolution of puerarin in puerarin-glycyrrhizic acid dispersible tablets could reach over 85% within 15 min. When phosphate buffer(pH 6.8) was used as the dissolution medium, the dissolution of puerarin in the puerarin-glycyrrhizic acid dispersible tablets had a faster dissolution rate in vitro, 99.8% in 30 min. Therefore, puerarin-glycyrrhizic acid dispersible tablets could improve the dissolution of puerarin in vitro due to the solubilization effect of glycyrrhizic acid.
引文
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[23] 马鸿雁, 李霞, 李楠, 等. 甘草及其活性成分的表面活性比较研究[J]. 现代药物与临床, 2011, 26(3): 227.
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[25] 赵金龙,汤顺莉,陈国铭,等.基于系统药理学的葛根芩连汤治疗2型糖尿病作用机制探讨[J].中国实验方剂学杂志,2018,24(12):199.
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[30] 陈艳琰, 曹玉洁, 唐于平, 等. 甘草调和大黄“泻下攻积”作用的量-毒-效关系研究 [J]. 中国中药杂志,2019,doi:10.19540/j.cnki.cjcmm.20190117.003.
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[32] 张娜, 胡丽娟, 徐红欣, 等. 中药分散片制备工艺的研究进展[J]. 中国医院药学杂志, 2011, 31(11): 930.
[33] 于蓓蓓, 闫雪生, 张丹丹, 等. 星点设计-效应面法优化黄独素B分散片的制备工艺[J]. 中药材, 2017(10): 2390.
[34] 江茂源, 张臻, 石金凤, 等. 基于甘草中2种成分同时测定的附子理中丸溶出行为研究[J]. 中国中药杂志, 2018, 43(5):952.
[35] 何昱, 钟涛, 陈龙, 等. 不同粒度甘草超微粉甘草酸溶出情况的比较[J]. 中成药, 2011, 33(1):171.
[2] 中国医学科学院药物研究所. 中草药现代研究[M]. 北京:北京医科大学、中国协和医科大学联合出版社, 1995: 258.
[3] 伟唯, 江培. 葛根素药理作用研究进展[J]. 黑龙江医药, 2014, 27(1): 51.
[4] 汪群红, 章灵芝, 徐文伟, 等. 葛根素的药理作用与不良反应分析[J]. 中华中医药学刊, 2015(5): 1185.
[5] 程博琳, 苗明三. 葛根现代研究及应用特点分析[J]. 中医学报, 2014(7): 1014.
[6] Zhou Y X, Zhang H, Peng C. Puerarin: a review of pharmacological effects[J]. Phytother Res, 2014, 28(7): 961.
[7] 李其国. 葛根素注射剂不良反应分析和处理对策[J]. 临床合理用药杂志, 2011, 4(5): 7.
[8] 徐俊,许颖琦,邓海欣,等.葛根素注射液所致临床发热反应的系统评价[J].今日药学,2014,24(3):152.
[9] 解晓帅, 董运茁, 穆殿平, 等. 葛根素注射液临床使用安全性的评价研究[J]. 中国中药杂志, 2018, 43(19): 3956.
[10] Yue P F, Yuan H L, Zhu W F, et al. The study to reduce the hemolysis side effect of puerarin by a submicron emulsion delivery system[J]. Biol Pharm Bull, 2008, 31(1): 45.
[11] 王洪宝, 郭琳, 关勇彪. 葛根素注射液致急性血管内溶血的临床特征和发病机制及其安全应用[J]. 药物不良反应杂志, 2010, 12(2): 109.
[12] 邓烨, 孙新. 葛根素的药理作用及不良反应[J]. 临床医药文献电子杂志, 2017, 4(5): 955.
[13] 唐扬检. 葛根素注射液致药物不良反应分析[J]. 临床合理用药杂志, 2015,28: 110.
[14] 王震, 何含杰. 中药野葛的药理作用和临床应用研究进展[J]. 安徽农业科学, 2015,43(24): 52.
[15] 吴正红, 朱延勤, 严汉英, 等. 葛根素的溶解性及高分子聚合物助溶作用的研究[J]. 药学与临床研究, 1999, 7(1): 9.
[16] 王成, 刘玉玲, 谷士杰. 葛根素的溶解性及其络合助溶的研究[J]. 中国药学杂志, 1993, 28(5): 294.
[17] 杨璇, 王妍, 王宝华, 等. 甘草酸对葛根素增溶作用的实验研究[J]. 天津中医药, 2015, 32(5): 304.
[18] 钟慧, 朱源, 余江南, 等. 难溶性天然药物增溶方法的研究进展[J]. 中国中药杂志, 2014, 39(17): 3226.
[19] Yi T, Tang D, Wang F, et al. Enhancing both oral bioavailability and brain penetration of puerarin using borneol in combination with preparation technologies[J]. Drug Deliv, 2017, 24(1): 422.
[20] 吴立军. 天然药物化学[M]. 北京: 人民卫生出版社, 2011: 293.
[21] 陈璐, 许润春, 邹文铨, 等. 甘草-青黛药对配伍的增溶作用考察[J]. 中国实验方剂学杂志, 2012, 18(23): 17.
[22] 杨璇. 甘草对葛根、黄芩增溶作用和机理的研究[D]. 北京:北京中医药大学, 2013.
[23] 马鸿雁, 李霞, 李楠, 等. 甘草及其活性成分的表面活性比较研究[J]. 现代药物与临床, 2011, 26(3): 227.
[24] 郭友立. 葛根芩连汤沉淀物溶出度及盐酸小檗碱、葛根素配伍肠吸收变化的研究[D]. 广州:南方医科大学, 2010.
[25] 赵金龙,汤顺莉,陈国铭,等.基于系统药理学的葛根芩连汤治疗2型糖尿病作用机制探讨[J].中国实验方剂学杂志,2018,24(12):199.
[26] Korenaga M, Hidaka I, Nishina S, et al. A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice [J]. Liver Int, 2015, 31(4): 552.
[27] Lu Y, Meng Q, Zhang G, et al. Clozapine-induced hepatotoxicity in rat hepatocytes by gel entrapment and monolayer culture [J]. Toxicol In Vitro, 2008, 22(7): 1754.
[28] Han S, Sun L, He F, et al. Anti-allergic activity of glycyrrhizic acid on IgE-mediated allergic reaction by regulation of allergy-related immune cells [J]. Sci Rep, 2017, 7(1): 7222.
[29] Kalaiarasi P, Kaviarasan K, Pugalendi K V. Hypolipidemic activity of 18β-glycyrrhetinic acid on streptozotocin-induced diabetic rats [J]. Eur J Pharmacol, 2009, 612(1): 93.
[30] 陈艳琰, 曹玉洁, 唐于平, 等. 甘草调和大黄“泻下攻积”作用的量-毒-效关系研究 [J]. 中国中药杂志,2019,doi:10.19540/j.cnki.cjcmm.20190117.003.
[31] 中国药典. 四部[S]. 2015: 3.
[32] 张娜, 胡丽娟, 徐红欣, 等. 中药分散片制备工艺的研究进展[J]. 中国医院药学杂志, 2011, 31(11): 930.
[33] 于蓓蓓, 闫雪生, 张丹丹, 等. 星点设计-效应面法优化黄独素B分散片的制备工艺[J]. 中药材, 2017(10): 2390.
[34] 江茂源, 张臻, 石金凤, 等. 基于甘草中2种成分同时测定的附子理中丸溶出行为研究[J]. 中国中药杂志, 2018, 43(5):952.
[35] 何昱, 钟涛, 陈龙, 等. 不同粒度甘草超微粉甘草酸溶出情况的比较[J]. 中成药, 2011, 33(1):171.