Naltrexone Prodrugs for Transdermal Delivery

纳洛酮是一种阿片类拮抗剂，目前以口服片剂形式使用，以帮助维持阿片类成瘾者处于无毒状态。最近，纳洛酮已被指示为治疗酒精依赖的辅助药物，并据报道可减少某些酒精中毒人群的酒精渴望。纳洛酮的透皮递送对于阿片类成瘾者和酗酒者是理想的，以帮助减少与口服治疗相关的副作用并提高依从性。纳洛酮本身不具有允许治疗剂量的药物穿过人体皮肤屏障的基本物理化学性质。我们计划继续设计和合成比纳洛酮更具有皮肤渗透性的衍生物（前药），以制造治疗上成功的药物递送系统。我们假设纳曲酮的前药将提高纳曲酮的经皮递送速率，并且这些前药将成为研究经皮通量和并行代谢的定量结构-渗透性关系（QSPR）的优秀研究工具。这些前药应该改善纳洛酮通过皮肤的递送速率，因为它们比纳洛酮更亲脂，结晶更少，因此更可溶。该项目的具体目标包括：（1）合成一系列纳曲酮前药，其设计用于阐明前药的经皮通量和同时代谢的基本QSPR，（2）表征纳曲酮前药的物理化学参数，包括分子量、分子体积、亲脂性、氢键势、熔点、熔化热和在所选溶剂中的溶解度，（3）测量纳洛酮前药在体外通过人皮肤的渗透和同时代谢，（4）表征纳洛酮前药在豚鼠体内的药代动力学，和（5）表征最有希望的纳洛酮前药在猪体内的药代动力学。我们的体外数据与体内模型的相关性将有助于建立一个可靠的QSPR数据库，以及帮助确定最有前途的前药，最终人类使用。

Naltrexone, an opioid antagonist, is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. Most recently, naltrexone has been indicated as an adjunct in the treatment of alcohol dependence, as well as reported to reduce alcohol craving in certain alcoholic populations. Transdermal delivery of naltrexone is desirable for opioid addicts and alcoholics in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. We plan to continue designing and synthesizing derivatives (prodrugs), which are more skin permeable than naltrexone, in order to make a therapeutically successful drug delivery system. We hypothesize that prodrugs of naltrexone will improve the transdermal delivery rate of naltrexone, and that these prodrugs will make excellent research tools for investigating quantitative structure- permeability relationships (QSPRs) for transdermal flux and concurrent metabolism. These prodrugs should improve naltrexone delivery rates across the skin, because they are more lipophilic, less crystalline, and therefore more soluble than naltrexone. The specific aims of this project include: (1) to synthesize a series of naltrexone prodrugs designed to elucidate fundamental QSPRs for transdermal flux and concurrent metabolism of the prodrugs, (2) to characterize the physicochemical parameters of the naltrexone prodrugs, including molecular weight, molecular volume, lipophilicity, hydrogen-bonding potentials, melting points, heats of fusion, and solubilities in select solvents, (3) to measure the naltrexone prodrugs' penetration and concurrent metabolism through human skin in vitro, (4) to characterize the pharmacokinetics of the naltrexone prodrugs in guinea pigs in vivo, and (5) to characterize the pharmacokinetics of the most promising naltrexone prodrugs in pigs in vivo. Correlation of our in vitro data with the in vivo models will aid in the creation of a reliable QSPR database, as well as help to identify the most promising prodrug for eventual human use.