Naltrexone Prodrugs for Transdermal Delivery

描述(由申请人提供)：酗酒和鸦片成瘾会给美国和世界其他地区的人带来与健康相关的重大问题和社会成本。因此，研究和开发改善药物和酒精滥用的药物治疗方法是非常重要的。纳曲酮是一种阿片类拮抗剂，目前以口服片剂的形式使用，以帮助阿片成瘾者保持无毒状态。最近，纳曲酮被表明是治疗酒精依赖的辅助药物，据报道，它还可以减少某些酗酒人群的酒精渴求。对于阿片成瘾者和酗酒者来说，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。我们计划继续设计和合成比纳曲酮更具皮肤渗透性的前药，以制造一个治疗上成功的药物输送系统。我们推测纳曲酮前药和前药与微针联合治疗将提高纳曲酮的透皮吸收速率，这些前药将成为研究透皮通量的定量结构-通透性关系(QSPR)以及结合微针增强的通量优化的极佳研究工具。这些前体药物/微针应该可以提高纳曲酮在皮肤上的释放率，因为它们具有优化的物理化学性质，可以更快地扩散。本项目的具体目标包括：(1)合成一系列纳曲酮和纳曲醇(活性代谢物)前体药，旨在阐明使用微针和不使用微针时优化透皮吸收的基本QSPR；(2)表征药物的理化参数，包括分子量、分子体积、亲脂性、氢键电位、熔点、熔点、熔化热和在选定溶剂中的溶解度；(3)测量药物在微针和未使用微针的情况下经人体皮肤的渗透和并行生物转化；(4)表征药物在微针和未使用微针的豚鼠体内的药代动力学。我们的体外数据与体内模型的关联将有助于为使用和不使用微针的透皮前药建立可靠的QSPR数据库，并有助于确定最终用于人类的最有前途的前药/微针系统。

DESCRIPTION (provided by applicant): Alcoholism and opiate addiction lead to major health-related problems and societal costs for people in the United States and the rest of the world as well. Therefore, research and development for improved pharmacologic treatments for drug and alcohol abuse are very important. 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 prodrugs, which are more skin permeable than naltrexone, in order to make a therapeutically successful drug delivery system. We hypothesize that prodrugs of naltrexone and prodrugs in combination with microneedle treatment will improve the transdermal delivery rate of naltrexone, and that these prodrugs will make excellent research tools for investigating quantitative structure-permeability relationships (QSPR) for transdermal flux and optimization of flux in combination with microneedle enhancement. These prodrugs/microneedles should improve naltrexone delivery rates across the skin because of optimized physicochemical properties for faster diffusion. The specific aims of this project include: (1) to synthesize a series of naltrexone and naltrexol (active metabolite) prodrugs designed to elucidate fundamental QSPRs for transdermal flux optimization with and without microneedle use, (2) to characterize the physicochemical parameters of the drugs, including molecular weight, molecular volume, lipophilicity, hydrogen-bonding potentials, melting points, heats of fusion, and solubilities in select solvents, (3) to measure the drugs' penetration and concurrent bioconversion through human skin in vitro with and without microneedle use, and (4) to characterize the pharmacokinetics of the drugs in guinea pigs in vivo with and without microneedle use. Correlation of our in vitro data with the in vivo model will aid in the creation of a reliable QSPR database for transdermal prodrugs with and without microneedle use, as well as help to identify the most promising prodrug/microneedle system for eventual human use.