前药策略协同离子导入促进双氢睾酮透皮吸收

摘要

Objective To enhance the transdermal delivery of dihydrotestosterone(DHT)and to make the delivery controlla⁃ble,which would enable personalized administration of DHT to pediatric patients. Methods A hydrosoluble,ionizable prodrug of DHT,dihydrotestosterone dimethylglycine ester hydrochloride(DHT-DG),was synthesized,characterized and its physicochemical properties were determined. DHT And DHT-DG were formulated into hydrogel,respectively,and the transdermal delivery of each compound across fresh porcine ear skin with or without iontophoresis was evaluated. Results Application of current(0.5 mA/cm2)to 2.5%DHT-DG hydrogel for 8 h enabled(226.91±45.62)nmol/cm2 accumulative amounts of DHT-DG across fresh porcine ear skin, which was much higher than the amount of DHT delivered from 2.5%DHT hydrogel without iontophoresis,(10.45±3.63)nmol/cm2. More than 80%delivered amount of DHT-DG was hydrolyzed into its parent drug DHT. The steady state flux of DHT-DG was found af⁃ter the application of iontophoresis for 2 h,and the accumulative amounts of DHT-DG could be modulated by drug concentration and current intensity. Conclusion Combination strategy of iontophoresis and prodrug can enable fast controllable transdermal delivery of DHT.%目的：加快双氢睾酮（DHT）透皮递送速率并实现速率可调，方便儿童患者个体化给药。方法合成并鉴定了水溶性离子化的前体药物双氢睾酮二甲基甘氨酸酯盐酸盐（DHT-DG），并对其进行了物理化学性质考察；将DHT和DHT-DG制成水凝胶后，以新鲜离体猪耳皮肤作为生物屏障，考察两种凝胶在被动扩散和离子导入情况下的透皮吸收。结果2.5%DHT-DG水凝胶施加0.5 mA/cm2电流，8 h后皮肤累积透过量为（226.91±45.62）nmol/cm2，远大于单独水凝胶的被动透过量〔（10.45±3.63）nmol/cm2〕，且吸收的DHT-DG有≥80%水解为其原药DHT。离子导入DHT-DG在2 h后出现稳态流，且累积透过量可通过药物浓度和电流强度调控。结论通过合成水溶性离子化前体药物DHT-DG，并结合离子导入技术，可实现DHT快速可控地透皮递送。