黄芩素固体分散体的制备、表征及体内外释药研究

doi:10.16431/j.cnki.1671-7236.2024.05.037

摘要/Abstract

摘要： 【目的】改善黄芩素(baicalein,BAI)的溶解性能,提高其溶出度和生物利用度,扩大其临床应用。【方法】本研究以聚乙烯己内酰胺-聚乙烯乙酸酯-聚乙二醇接枝共聚物(Soluplus)为载体,采用旋转蒸发法制备黄芩素固体分散体(BAI-ASD),并对其进行表征,包括:利用粉末X射线衍射(PXRD)中特征衍射峰的位置、强度等信息,初步判断固体分散体是否制备成功;利用差示扫描量热(DSC)进行热性质研究;利用傅里叶红外光谱(FT-IR)分析分子间相互作用;利用扫描电子显微镜(SEM)观察微观形貌。通过溶出试验考察其体外释药性能,在此基础上考察鸡口服BAI-ASD的药动学特征。【结果】旋转蒸发法产物的PXRD中无BAI的晶体衍射峰,同时DSC中也无明显的吸热峰,表明成功制备了BAI-ASD,且BAI在ASD中以无定形态存在。体外溶出结果显示,BAI在240 min内的累积溶出仅为6.62%,药物与载体比例为1∶9和2∶8时ASD的累积溶出提高,240 min内的累积溶出分别为29.89%和52.67%。稳定性研究结果显示,BAI-ASD在45 ℃,75% RH条件下,90 d内稳定性良好。药动学结果显示,鸡灌胃给药24 h内BAI-ASD的峰浓度(C_max(0-24))和药时曲线下面积(AUC_(0-24))分别为(5.20±0.82)μg/mL和(17.03±0.67)μg·h/mL,分别为BAI的1.91和2.64倍。【结论】以Soluplus为载体利用旋转蒸发法制备的BAI-ASD稳定性良好,可有效提高BAI的累积溶出和口服生物利用度。

关键词: 黄芩素(BAI); 无定形固体分散体; Soluplus; 累积溶出度; 生物利用度

Abstract: 【Objective】 The aim of this study was to improve the solubility of baicalein (BAI),enhance its dissolution and bioavailability,and expand its clinical application.【Method】 Solid dispersion of baicalein (BAI-ASD) was prepared by rotary evaporation using polyethylene caprolactam-polyethylene acetate-polyethylene glycol graft copolymer (Soluplus) as the carrier,and it was characterized including that:Using the position and intensity of the characteristic diffraction peaks in powder X-ray diffraction (PXRD) to preliminarily determine whether the solid dispersion was successfully prepared;Differential scanning calorimetry (DSC) was used to study thermal properties;Fourier transform infrared spectroscopy (FT-IR) was used to analyze intermolecular interactions;Scanning electron microscopy (SEM) was used to observe the microscopic topography.The in vitro release performance was investigated by dissolution test,and the pharmacokinetic characteristics of oral BAI-ASD in chickens were investigated.【Result】 There was no crystal diffraction peak of BAI baicalein in PXRD and no obvious endothermic peak in DSC,indicating that the baicalein solid dispersion BAI-ASD was successfully prepared,and BAI baicalein existed in an amorphous form in the solid dispersion ASD.The results of in vitro dissolution showed that the cumulative dissolution of baicalein BAI within 240 min was only 6.62%,and the cumulative dissolution of solid dispersion ASD was significantly increased when the ratio was 1∶9 and 2∶8,and the cumulative dissolution within 240 min was 29.89% and 52.67%,respectively.The stability study results showed that BAI-ASD had good stability within 90 days at 45 ℃ and 75% RH.The pharmacokinetic results showed that the peak concentration (C_max(0-24)) and area under the curve (AUC_(0-24)) of BAI-ASD within 24 h of intragastric administration were (5.20±0.82) μg/mL and (17.03±0.67) μg·h/mL,respectively,which were 1.91 and 2.64 times of BAI,respectively.【Conclusion】 BAI-ASD,a solid dispersion of baicalein prepared by rotary evaporation with Soluplus as the carrier,had good stability,which could effectively improve the cumulative dissolution and oral bioavailability of BAI.

Key words: baicalein(BAI); amorphous solid dispersion; Soluplus; cumulative dissolution; bioavailability

中图分类号:

S859.7

高建亭, 路晨月, 师鑫潮, 何欣. 黄芩素固体分散体的制备、表征及体内外释药研究[J]. 中国畜牧兽医, 2024, 51(5): 2169-2177.

GAO Jianting, LU Chenyue, SHI Xinchao, HE Xin. Preparation,Characterization and in vitro and in vivo Drug Release of Baicalein Solid Dispersion[J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(5): 2169-2177.

参考文献

[1] 严红梅,祁秀秀,秦海芳.基于纳米混悬技术的黄芩素制剂研究[J].化学试剂,2021,43(7):889-894. YAN H M,QI X X,QIN H F.Evaluation on preparation process of baicalein nanosuspensions[J].Chemical Reagents,2021,43(7):889-894.(in Chinese)
[2] 冯倩倩,陈淼,何嘉丽,等.黄芩素抗菌作用研究进展[J].宜春学院学报,2022,44(9):21-24. FENG Q Q,CHEN M,HE J L,et al.Rearch progess on antibacterial effect of baicalein[J].Journal of Yichun University,2022,44(9):21-24.(in Chinese)
[3] 施高翔,邵菁,汪天明,等.黄芩及其有效成分抗菌作用新进展[J].中国中药杂志,2014,39(19):3713-3718. SHI G X,SHAO J,WANG T M,et al.New advance in studies on antimicrobal activity of Scutellaria baicaleinsis and its effective ingredients[J].China Journal of Chinese Materia Medica 2014,39(19):3713-3718.(in Chinese)
[4] YIN B,LI W,QIN H,et al.The use of Chinese skullcap (Scutellaria baicalensis) and its extracts for sustainable animal production[J].Animals (Basel),2021,11(4):1039.
[5] 云宝仪,周磊,谢鲲鹏,等.黄芩素抑菌活性及其机制的初步研究[J].药学学报,2012,47(12):1587-1592. YUN B Y,ZHOU L,XIE K P,et al.Antibacterial activity and mechanism of baicalein[J].Acta Pharmaceutica Sinica,2012,47(12):1587-1592.(in Chinese)
[6] 余诗强,蒋林树,熊本海.黄芩素结构与生物学功能关系研究进展[J].动物营养学报,2021,33(6):3106-3114. YU S Q,JIANG L S,XIONG B H.Research progress on relationship between structure and biological functions of baicalein[J]. Chinese Journal of Animal Nutrition,2021,33(6):3106-3114.(in Chinese)
[7] ZHOU Y,DONG W,YE J,et al.A novel matrix dispersion based on phospholipid complex for improving oral bioavailability of baicalein:Preparation,in vitro and in vivo evaluations[J].Drug Delivery,2017,24(1):720-728.
[8] 刘洋,杨丽,张鑫,等.葛根芩连复方环境中黄芩素的中药生物药剂学分类系统属性研究[J].中国中药杂志,2019,44(17):3653-3661. LIU Y,YANG L,ZHANG X,et al.Research on attributes of biopharmaceutics classification system for Chinese materia of baicalein in Gegen Qinlian decoction environment[J].China Journal of Chinese Materia Medica,2019,44(17):3653-3661.(in Chinese)
[9] 韩贝贝,孙春萌.固体分散技术在中药制剂中的应用进展[J].广东化工,2022,49(20):105-107. HAN B B,SUN C M.Application progress of solid dispersion technology in Chinese materia medica preparation[J]. Guangdong Chemical Industry,2022,49(20):105-107.(in Chinese)
[10] 肖娟,石志锋,刘佳,等.样品质量控制对X射线衍射测量结果的影响[J].应用化学,2023,40(5):720-729. XIAO J,SHI Z F,LIU J,et al.Effect of sample quality control on X-ray diffraction measurement results[J].Chinese Journal of Applied Chemistry,2023,40(5):720-729.(in Chinese)
[11] YONG H M,BI F Y,LIU J,et al.Preparation and characterization of antioxidant packaging by chitosan,D-α-tocopheryl polyethylene glycol 1000 succinate and baicalein[J].International Journal of Biological Macromolecules,2020,153(C):102361.
[12] 蔡萍.延胡索乙素三元固体分散体的制备及稳定性研究[D].南昌:江西中医药大学,2022. CAI P.Preparation and stability study of ternary solid dispersion of tetrahydropalmatine[D].Nanchang:Jiangxi University of Traditional Chinese Medicine,2022.(in Chinese)
[13] TAMBE S,JAIN D,MERUVA S K,et al.Recent advances in amorphous solid dispersions:Preformulation,formulation strategies,technological advancements and characterization[J].Pharmaceutics,2022,14(10):2203.
[14] 仝萌.热熔挤出技术制备黄芩素固体分散体及其体内外评价研究[D].南京:南京中医药大学,2021. TONG M.Study on preparation of baicalein solid dispersion by hot-melt extrusion technology and its evaluation in vivo and in vitro[D].Nanjing:Nanjing University of Chinese Medicine,2021.(in Chinese)
[15] 刘沛,常金花,薛禾菲,等.不同制备工艺对薯蓣皂苷元固体分散体体外溶出、物相特征、体内药动学的影响[J].中成药,2023,45(2):349-357. LIU P,CHANG J H,XUE H F,et al.Effects of different preparation processes on in vitro dissolution,phase characteristics and in vivo pharmacokinetics of diosgenin solid dispersions[J].Chinese Traditional Patent Medicine,2023,45(2):349-357.(in Chinese)
[16] NANDI U,AJIBOYE A L,PATEL P,et al.Preparation of solid dispersions of simvastatin and Soluplus using a single-step organic solvent-free supercritical fluid process for the drug solubility and dissolution rate enhancement[J].Pharmaceuticals,2021,14(9):846.
[17] 林健,李智欢,吴志红.碳量子点黄芩素复合物对金黄色葡萄球菌抑菌作用的研究[J].九江学院学报,2022,37(2):92-97. LIN J,LI Z H,WU Z H.Antibacterial effect of carbon quantum dots-baicalein composite on Staphylococcus aureus[J].Journal of Jiujiang University,2022,37(2):92-97.(in Chinese)
[18] STAVROULA N,RODANTHI M E,PANAGIOTIS B,et al.Evaluation of dissolution enhancement of aprepitant drug in ternary pharmaceutical solid dispersions with Soluplus^® and Poloxamer 188 prepared by melt mixing[J].Science,2019,1(1):48.
[19] 程佳慧,赵强,张领,等.新型聚合物Soluplus制备水飞蓟素固体分散体及体外评价[J].承德医学院学报,2021,38(1):30-34. CHENG J H,ZHAO Q,ZHANG L,et al.Preparation of silymarin solid dispersions from a novel polymer Soluplus and its in vitro evaluation[J].Journal of Chengde Medical College,2021,38(1):30-34.(in Chinese)
[20] LIU P,ZHOU J Y,CHANG J H,et al.Soluplus-mediated diosgenin amorphous solid dispersion with high solubility and high stability:Development,characterization and oral bioavailability[J].Drug Design,Development and Therapy,2020,14:2959-2975.
[21] AMANDA K P M,LUKE S,ATHANAS K,et al.Producing amorphous solid dispersions via co-precipitation and spray drying:Impact to physicochemical and biopharmaceutical properties[J].Journal of Pharmaceutical Sciences,2018,107(1):187-191.
[22] LAMICHHANE S,SEO J E,KEUM T,et al.Enhancing solubility and bioavailability of coenzyme Q₁₀:Formulation of solid dispersions using Soluplus^® as a carrier[J].Archives of Pharmcal Research,2022,45(1):29-37.
[23] CESÁREO J J D L,JOSÉ I P,EULALIA G,et al.Enhancement of albendazole dissolution properties using solid dispersions with Gelucire 50/13 and PEG 15000[J].Journal of Drug Delivery Science and Technology,2017,42:1773-2247.
[24] 曹麒麟,韩晓璐,高静,等.提高难溶性药物生物利用度的研究进展[J].湖北科技学院学报(医学版),2021,35(4):352-356. CAO Q L,HAN X L,GAO J,et al.Research progress in improving the bioavailability of poorly soluble drugs[J].Journal of Hubei University of Science and Technology(Medical Sciences),2021,35(4):352-356.(in Chinese)
[25] RAO Q,QIU Z,HUANG D,et al.Enhancement of the apparent solubility and bioavailability of Tadalafil nanoparticles via antisolvent precipitation[J].European Journal of Pharmaceutical Sciences,2019,128:222-231.