氢化可的松琥珀酸钠口服结肠靶向pH敏感型水凝胶的药动学与药效学研究

Study on Pharmacokinetics and Pharmacodynamics of Oral Colon Targeted pH-Sensitive Hydrogel of Hydrocortisone Sodium Succinate

目的对氢化可的松琥珀酸钠(hydrocortisone sodium succinate,HSS)口服结肠靶向pH敏感型水凝胶(oral colon targeted pH-sensitive hydrogel of HSS,HSS-GEL)进行药动学与药效学研究。方法考察HSS-GEL与HSS在大鼠体内血药浓度变化;建立2,4,6-三硝基苯磺酸(2,4,6-trinitrobenzene sulfonic acid,TNBS)诱导小鼠溃疡性结肠炎(ulcerative colitis,UC)模型,以小鼠疾病活动指数(disease activity index,DAI)、结肠长度、髓过氧化酶活性(myeloperoxidase,MPO)和脏器指数为指标,考察了HSS-GEL的结肠炎治疗作用。结果HSS-GEL的Tmax、Cmax和AUC与HSS比较均有统计学差异(P<0.01),其中HSS-GEL的Tmax比HSS明显延长,药物吸收入血时间明显延后;HSS-GEL组Cmax与HSS的Cmax相比明显降低;HSS-GEL组AUC是同等剂量HSS的39.38%,表明将HSS制成HSS-GEL口服后药物入血量明显减少;造模后小鼠由于炎症反应,DAI、MPO活性和脏器指数均升高,结肠缩短,给予HSS-GEL治疗后,小鼠DAI、MPO活性和部分脏器指数与TNBS组相比均明显降低(P<0.05或P<0.01);而TNBS+HSS-GEL组小鼠MPO活性和部分脏器指数降低程度明显大于TNBS+HSS组,表明HSS-GEL对TNBS诱导的小鼠UC有很好的治疗作用,且效果优于HSS。结论制备的HSS-GEL具有良好的结肠靶向性与结肠炎治疗效果。

OBJECTIVE To study the pharmacokinetics and pharmacodynamics of oral colon targeted pH-sensitive hydrogel of hydrocortisone sodium succinate(HSS-GEL).METHODS The plasma concentration changes of HSS-GEL and HSS in the mice were investigated;2,4,6-trinitrobenzene sulfonic acid(TNBS)-induced mouse model of ulcerative colitis(UC)was established,disease activity index(DAI),colon length,myeloperoxidase(MPO)and organ index were used as indicators to investigate the therapeutic effect of HSS-GEL on colitis.RESULTS The results showed that the Tmax,Cmax and AUC of HSS-GEL were significantly different from those of HSS(P<0.01).The Tmax of HSS-GEL was significantly longer than that of HSS,and the time of drug absorption into the blood was significantly delayed.The Cmax of HSS-GEL group was significantly lower than that of HSS.The AUC of the HSS-GEL group was 39.38%of the same dose of HSS,indicating that the amount of the drug absorbed into blood was significantly reduced after the HSS was made into HSS-GEL orally.After modeling,DAI,MPO activity and organ index were increased,while the colon was shortened due to the inflammatory reaction,with the treatment of HSS-GEL,DAI,MPO activity and some organ index of mice were significantly decreased comparing with TNBS group(P<0.05 or P<0.01).The degree of reduction of MPO activity and some organ indexes of the mice in the TNBS+HSS-GEL group were significantly greater than those in the TNBS+HSS group,indicating that HSS-GEL had good therapeutic effect on TNBS-induced ulcerative colitis,and the effect was better than that of HSS.CONCLUSION The HSS-GEL prepared has good colon targeting characteristic and colitis treatment effect.