Transdermal Codrugs for Treatment of Alcoholism

描述（由申请人提供）： 纳洛酮目前以口服片剂形式用作治疗酒精依赖的辅助药物，以及帮助维持阿片类药物成瘾者处于无毒状态。纳洛酮的透皮递送是期望的，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。这个问题可以通过设计和合成比纳洛酮更具有皮肤渗透性的衍生物（共药物）来解决。共同药物或相互前药由化学连接在一起的两种协同药物组成，以改善一种或两种药物的药物递送性质。安非他酮是一种成功的戒烟治疗药物，被选为与纳洛酮相关的药物。同时治疗酒精和烟草成瘾是至关重要的，因为这种常见的并发症中存在生物化学和行为因果联系，以及酗酒者因烟草相关疾病而死亡的高死亡率。阿片类成瘾者也可能受益于这种治疗组合，因为他们的吸烟率和共同滥用率很高。假设纳洛酮和安非他酮以共药物形式的化学组合将提高药物的经皮递送速率。该项目的具体目标是：（1）合成一系列的纳洛酮、6-β-纳洛醇、安非他酮和羟基安非他酮共药物，其设计用于阐明经皮通量和随后的生物转化率的定量结构-活性关系（QSARS），（2）表征共药物的物理化学性质，包括分子体积、亲脂性、氢键势、熔点、熔化热，水解动力学和在所选溶剂中的溶解度，（3）测量共同药物在体外人皮肤中的渗透和生物转化速率，和（4）表征共同药物在豚鼠体内的药代动力学。这些目标将有助于确定关键参数的优化透皮联合药物的设计。体外数据与体内模型的相关性将有助于建立可靠的QSAR数据库，这对于帮助确定临床使用的最佳联合药物是必要的。

DESCRIPTION (provided by applicant): Naltrexone is currently used in oral tablet form as an adjunct in the treatment of alcohol dependence, as well as to help maintain opioid addicts in a drug-free state. Transdermal delivery of naltrexone is desirable 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. This problem may be solved by designing and synthesizing derivatives (co-drugs) which are more skin permeable than naltrexone. A co-drug or mutual pro-drug consists of two synergistic drugs chemically linked together, in order to improve the drug delivery properties of one or both drugs. Bupropion, a successful smoking cessation treatment, is the drug chosen for linkage to naltrexone. Simultaneous treatment of alcohol and tobacco addiction is vital, because of the biochemical and behavioral causal links in this common co-morbidity, as well as alcoholics' high death rate from tobacco-related diseases. Opioid addicts may also benefit from this treatment combination, because of their high prevalence of smoking and co-abuse. The hypothesis is that chemical combinations of naltrexone and bupropion in a co-drug form will improve the transderrnal delivery rate of the drugs. The specific aims of this project are: (1) to synthesize a series of naltrexone, 6-beta-naltrexol, bupropion, and hydroxybupropion codrugs designed to elucidate quantitative structure-activity relationships (QSARS) for transdermal flux and subsequent bioconversion rates, (2) to characterize the physicochemical properties of the co-drugs, including molecular volume, lipophilicity, hydrogen-bonding potentials, melting points, heats of fusion, hydrolysis kinetics, and solubilities in select solvents, (3) to measure the co-drugs' penetration and bioconversion rates in human skin in vitro, and (4) to characterize the pharmacokinetics of the co-drugs in guinea pigs in vivo. These objectives will help to identify the critical parameters involved in the optimization of transdermal co-drug designs. Correlation of the in vitro data with the in vivo model will aid in the creation of a reliable QSAR database that is necessary to help identify the best co-drugs for clinical use.