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

关键词:  氢化可的松琥珀酸钠  pH敏感  口服结肠靶向给药系统  血药浓度  药效学

Key words:  hydrocortisone sodium succinate  pH-sensitive  oral colon-specific drug delivery system  plasma concentration  pharmacodynamics

摘要:

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T_max、C_max和AUC与HSS比较均有统计学差异(P<0.01)，其中HSS-GEL的T_max比HSS明显延长，药物吸收入血时间明显延后；HSS-GEL组C_max与HSS的C_max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。

Abstract:

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 T_max, C_max and AUC of HSS-GEL were significantly different from those of HSS(P<0.01). The T_max of HSS-GEL was significantly longer than that of HSS, and the time of drug absorption into the blood was significantly delayed. The C_max 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.