Transdermal Codrugs for Treatment of Alcoholism

描述(由申请人提供)： 纳曲酮目前以口服片剂的形式用于酒精依赖的治疗，以及帮助阿片成瘾者保持戒毒状态。纳曲酮的透皮给药是可取的，以帮助减少与口服治疗相关的副作用，并提高依从性。纳曲酮本身并不具备让治疗剂量的药物通过人体皮肤屏障所需的基本物理化学性质。这个问题可以通过设计和合成比纳曲酮更具皮肤渗透性的衍生物(辅药)来解决。共用药物或互促药物由两种协同作用药物化学连接在一起，以改善其中一种或两种药物的给药性能。安非他酮是一种成功的戒烟治疗药物，是与纳曲酮联用的药物。同时治疗酒精和烟草成瘾是至关重要的，因为这种共同发病中的生化和行为因果联系，以及酗酒者死于与烟草有关的疾病的高死亡率。阿片成瘾者也可能从这种治疗组合中受益，因为他们吸烟和共同滥用的流行率很高。假设纳曲酮和安非他酮以联合药物的形式进行化学组合将提高药物的经皮给药速度。本项目的具体目标是：(1)合成一系列纳曲酮、6-β-纳曲醇、安非他酮和羟基安非他酮共用药物，旨在阐明透皮流量和随后的生物转化率的定量构效关系(QSAR)；(2)表征共用药物的物理化学性质，包括分子体积、亲脂性、氢键电位、熔点、熔融热、水解动力学和在选定溶剂中的溶解度；(3)测量共药物在人体皮肤中的渗透率和生物转化率，以及(4)表征共药物在豚鼠体内的药代动力学。这些目标将有助于确定涉及透皮共用药物设计优化的关键参数。体外数据与体内模型的关联将有助于创建可靠的QSAR数据库，这对于帮助确定临床使用的最佳辅助药物是必要的。

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.