Design of hydrogels of 5-hydroxymethyl tolterodine and their studies on pharmacokinetics, pharmacodynamics and transdermal mechanism

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• 作者：Wenhua Liu ; Lirong Teng ; Kongtong Yu ; Xiangshi Sun ; Chunyu Fan ; Chaoxing Long ; Na Liu ; Shuang Li ; Bing Wu ; Qingji Xu ; Fengying Sun ; ^{sunfengying@jlu.edu.cn} ; Youxin Li ; ^{liyouxin@jlu.edu.cn}
• 关键词：5-Hydroxymethyl tolterodine (5-HMT) ; Hydrogels ; Pharmacokinetics ; Pharmacodynamics ; Transdermal mechanism
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：530-541
• 全文大小：1960 K
• 卷排序：96

文摘

development, single-factor experiments were employed to evaluate the effect of adding different matrix, enhancers, 5-HMT, ethanol and glycerol on drug skin development, single-factor experiments were employed to evaluate the effect of adding different matrix, enhancers, 5-HMT, ethanol and glycerol on drug skin permeation. Finally, Carbopol 940 was selected as the gel matrix with N-methyl pyrrolidone (NMP) chosen as the enhancer. The relationship between time and the steady accumulative percutaneous amount (Q, μg cm− 2) of optimized 5-HMT hydrogels was Q4–12 h = 1290.8 t1/2 − 1227.7. The absolute bioavailability of 5-HMT hydrogels was 20.7% showed in pharmacokinetic study. No skin irritation was observed in 5-HMT hydrogels skin irritation study. In the pharmacodynamic study, the overactive bladder model was induced by 150 μg/kg of pilocarpine in rats. The significant effects of 5-HMT hydrogels on the inhibition of urine output on rat model were last to 12 h. The optimized 5-HMT hydrogels displayed prolonged pharmacological responses. 5-HMT hydrogels effectively avoided the metabolism difference of enzyme in bodies compared with tolterodine tablets, provided one single active compound in plasma to reduce the variability of having two active compounds. To further elucidate the transdermal mechanism, fourier transform infrared (FTIR) spectroscopy, differential scanning calorimeter (DSC) and activation energy measurements were used to study the transdermal routes and changes of stratum corneum during drug release.