目的 制备土木香内酯(ATL)生物黏附微球,对其进行质量表征、体外释放机制研究以及治疗大鼠溃疡性结肠炎(UC)的药效学评价。
方法 采用乳化溶剂挥发法制备ATL生物黏附微球,并对其进行形态、粒径、黏附性、包封率、载药量、X射线衍射(XRD)以及差示扫描量热(DSC)等一系列表征;测定其体外释放度,进行方程拟合,探讨释药机制;以
![]()
唑酮诱导大鼠UC模型,研究ATL生物黏附微球结肠溶胶囊对UC的治疗作用。
结果 ATL生物黏附微球扫描电镜下圆整,表面粗糙且存在溶剂挥发后留下的大量微孔;粒径为(205.95±2.72) μm;黏附性为(91.33±2.52)%;包封率为(95.54±0.62)%;载药量为(42.62±0.29)%;XRD和DSC结果表明,ATL大部分以无定型分子状态分散于微球中;体外释放24 h可达89%,为扩散与溶蚀共同作用,以扩散为主;装入结肠溶胶囊给药后,可显著改善UC模型大鼠体重下降、便血、拉稀、结肠缩短、脾脏水肿等症状并缓解UC模型大鼠的结肠病理损伤,显著减少UC模型大鼠中髓过氧化物酶(MPO)和肿瘤坏死因子α(TNF-α)的表达,提高炎性因子白介素-4(IL-4)与白介素-13(IL-13)的表达。
结论 制备的ATL生物黏附微球载药量高,将其装入结肠溶胶囊口服后,提高了炎症部位的局部给药浓度,对UC模型大鼠有显著的治疗作用,具有良好的应用前景。
Abstract
OBJECTIVE To prepare alantolactone(ATL) bioadhesive microspheres and investigate its quality characterization,in vitro release mechanism and effects on the ulcerative colitis in rats model. METHODS ATL bioadhesive microspheres were prepared by solvent emulsification and volatilization method, and a series of characterizations such as morphology, particle size, adhesion, encapsulation efficiency, drug loading, X-ray diffraction(XRD) and differential scanning calorimetry(DSC) were carried out. The drug release rate in vitro was measured, and the equations were fitted to explore the drug release mechanism. Rat model of ulcerative colitis (UC) was induced by oxazolone to explore the ATL-OCSDDS therapeutic effects on UC rats. RESULTS Scanning electron microscopy(SEM) results showed ATL microspheres were round with rough surface and intensive micropores left after the solvent evaporating. The average particle size of the ATL bioadhesive microspheres was (205.95±2.72) μm, the adhesion was( 91.33±2.52)%, the encapsulation efficiency was (95.54±0.62)%, and the drug loading was (42.62±0.29)%, respectively. XRD and DSC results indicated that most of the ATL were dispersed in the microspheres in amorphous state. The release in vitro reached 89% within 24 h, with the synergistic effects of drug diffusion and skeleton dissolution, mainly diffusion. Administration of ATL microsphere colon-soluble capsules could significantly improve the weight loss, blood in the stool, diarrhea, colon shortening, and spleen edema in UC model rats. It could obviously relieve the colon pathological damage in UC model rats, reduce the expression of myeloperoxidase(MPO) and tumor necrosis factor-α(TNF-α) in UC rats, and increase the expression of IL-4 and IL-13. CONCLUSION The ATL bioadhesive microspheres are successfully prepare with high drug loading. It could increase the local administration concentration in the inflammatory site after oral administration in colon-soluble capsules and have positive therapeutic effects on UC model rats, which has a meaningful application prospect.
关键词
土木香内酯 /
生物黏附微球 /
口服结肠定位释药系统 /
溃疡性结肠炎
{{custom_keyword}} /
Key words
alantolactone /
bioadhesive microsphere /
oral colon specific drug delivery system /
ulcerative colitis
{{custom_keyword}} /
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] KESHTELI A H, MADESN K L, DIELEMAN L A. Diet in the pathogenesis and management of ulcerative colitis: a review of randomized controlled dietary interventions. Nutrients, 2019, 11(7):1498. DOI: 10.3390/nu11071498.
[2] WANG K, LIN A, MA M Y, et al. Therapeutic effect of compound heparin oral colon targeting capsules on ulcerative colitis in rats . Chin Pharm J (中国药学杂志), 2011, 46(22):1723-1726.
[3] BURRI E, MAILLARD M H, SCHOEPFER A M, et al. Treatment algorithm for mild and moderate-to-severe ulcerative colitis: an update. Digestion, 2020,101(Suppl.1):2-15.
[4] AGGAEWAL A, SABOL T, VAZIRI H. Update on the use of biologic therapy inulcerative colitis. Curr Treat Options Gastroenterol, 2017, 15(1):155-167.
[5] CHEN F, LIU Q, XIONG Y, et al. Current strategies and potential prospects of nanomedicine-mediated therapy in inflammatory bowel disease. Int J Nanomed, 2021, 16:4225-4237.
[6] LI H, FAN C, LU H, et al. Protective role of berberine on ulcerative colitis through modulating enteric glial cells-intestinal epithelial cells-immune cells interactions. Acta Pharm Sin B(药学学报 英文), 2020, 10(3):447-461.
[7] CAPRILLI R, VISCIDO A, LATELLA G. Current management of severe ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol, 2007, 4(2):92-101.
[8] LI W, XU W. Progress of Traditional Chinese Medicine in the Treatment of Ulcerative Colitis . J Jinzhou Med Univ (锦州医科大学学报),2022,43(2):108-112.
[9] ZHANG X X, JIN J W, LIU C H, et al. Effect of Nrf2 / HO-1 signaling pathway in intestinal protection by Sishen Pills against ulcerative colitis in mice . China J Chin Mater Med (中国中药杂志), 2021, 46(16):4187-4192.
[10] ZHU L, SHEN H, GU P Q, et al. Effects of baicalin on the inflammation and apoptosis in ulcerative colitis rats relating to PI3K/AKT pathway . China J Tradit Chin Med Pharm (中华中医药杂志),2017,32(9):4001-4004.
[11] ZHANG C L, ZHANG S, HE W X, et al. Baicalin may alleviate inflammatory infiltration in dextran sodium sulfate-induced chronic ulcerative colitis via inhibiting IL-33 expression. Life Sci, 2017, 186: 125-132. DOI: 10.1016/j.lfs.2017.08.010.
[12] CHEN Q Y, DUAN X Y, FAN H, et al. Oxymatrine protects against DSS-induced colitis via inhibiting the PI3K/AKT signaling pathway. Int Immunopharmacol, 2017, 53: 149-157. DOI:10.1016/j.intimp.2017.10.025.
[13] LV J, ZHANG Y H, TIAN Z Q, et al. Astragalus polysaccharides protect against dextran sulfate sodium-induced colitis by inhibiting NF-κB activation. Int J Biol Macromol, 2017, 98: 723-729. DOI:10.1016/j.ijbiomac.2017.02.024.
[14] REN Y, YUE B, YU Z L, et al. Research progress on pharmacological effects of alantolactone. Acad J Shanghai Univ Tradit Chin Med (上海中医药大学学报), 2019, 33(6):82-87.
[15] CHEN H L, LIN S C, LI S M, et al. Alantolactone alleviates collagen-induced arthritis and inhibits Th17 cell differentiation through modulation of STAT3 signalling. Pharm Biol, 2021,59(1):134-145.
[16] LEE J Y, KIM S B, CHUN J, et al. High body clearance and low oral bioavailability of alantolactone, isolated from Inula helenium, in rats: extensive hepatic metabolism and low stability in gastrointestinal fluids. Biopharm Drug Dispos, 2016, 37(3): 156-167.
[17] XU R, PENG Y, WANG M, et al. Intestinal Absorption of Isoalantolactone and Alantolactone, Two Sesquiterpene Lactones from Radix Inulae, Using Caco-2 Cells. Eur J Drug Metabol Pharmacokinet, 2019, 44(2):295-303.
[18] REN Y J, YUE B, REN G, et al. Activation of PXR by alantolactone ameliorates DSS-induced experimental colitis via suppressing NF-κB signaling pathway. Sci Rep, 2019, 9(1):16636. DOI:10.1038/s41598-019-53305-z.
[19] JIAO Y, PANG X, LIU M, et al. Recent progresses in bioadhesive microspheres via transmucosal administration. Colloids Surf B Biointerfaces, 2016, 140:361-372. DOI:10.1016/j.colsurfb.2015.12.049.
[20] TIAN Z K, GAO W X, WU L, et al. Research progress in bioadhesive microspheres both at home and abroad. Mod Tradit Chin Med Mater Med World Sci Technol (世界科学技术-中医药现代化), 2012, 14(2):1481-1484.
[21] TAO Y, LU Y, SUN Y. Development of mucoadhesive mi-crospheres of acyclovir with enhanced bioavailability. Int J Pharm, 2009, 378 (1-2):30-36.
[22] QIAN Y Y, ZHANG L H, GUO L W, et al. Studies on baicalin ethylcellulose microspheres for intranasal administration . China J Chin Mater Med (中国中药杂志), 2014, 39(24):4787-4791.
[23] ZHOU H M, CHEN Y Z, XIA J. Study on the preparation and mucoadhesive property of benzoyl metronidazole bioadhesive microspheres. China Pharm (中国药师), 2008, 11(8):895-897.
[24] JIANG M, LI G H, L X J, et al. Study on sustained release and release mechanism of nerve growth factor from chitosan /β-glycerophosphate thermosensitive hydrogel containing amino-carbon nanotubes . Chin J New Drugs(中国新药杂志),2019,28(2):190-194.
[25] ZHANG L H, CAO N, WANG Y W, et al. Improvement of oxazolone-induced ulcerative colitis in rats using andrographolide. Molecules, 2020, 25(1):76. DOI:10.3390/molecules25010076.
[26] ZHANG Q, CHEN X N, TIAO W W, et al. Comparative study on dissolution in vitro of cryptotanshinone and tanshinone ⅡA in Fufang Danshen adhesive pellets and ordinary pellets . Tianjin J Tradit Chin Med (天津中医药), 2019, 36(4):408-412.
[27] RITGER P L, PEPPAS N A. A simple equation for description of solute release I. Fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Controlled Release, 1987, 5(1):23-26.
[28] ZHANG X M, HUANG M S, FAN C J, et al. Recent advances in animal models of ulcerative colitis . J Basic Chin Med (中国中医基础医学杂志), 2022, 28(1):157-160.
[29] WANG Q, TIAN H, LIU L J, et al. Establishment of model about ulcerative colitis and the mechanism of colitis-related inflammatory responses . Acta Neuropharmacol (神经药理学报), 2014, 4(5):15-23.
[30] ZHENG L H, WANG X, WANG L J, et al. Effect of Yuchang Suppository on inflammatory factors in rats with ulcerative colitis. Jilin J Chin Med (吉林中医药), 2019, 39(6):780-783.
[31] DING L H, JIA Y X, CHENG Y X, et al. Effect of Shenling Baizhu San on expressions of IL-13, IL-23 and COX-2, CREB in ulcerative colitis rats with spleen deficiency and dampness . Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2018, 24(11):67-72.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
PDF(1931 KB)
