Transdermal Naltrexone for Opiate Addiction and Alcoholism

描述（由申请人提供）：根据2008年全国药物使用和健康调查（NSDUH）， 720万美国人需要治疗物质相关疾病（SRDs），其中很大一部分需要治疗阿片类止痛药、海洛因和酒精成瘾。纳曲酮（NTX）是一种阿片类拮抗剂，目前以口服片剂形式用于帮助维持阿片类药物成瘾者处于无药状态。NTX也被fda批准用于治疗酒精依赖。大量的临床证据表明，NTX治疗对戒烟有好处，尤其是对女性。在苯丙胺依赖个体中也观察到非常有趣的临床试验数据，这一点尤其重要，因为苯丙胺依赖没有fda批准的治疗方案。90年代用NTX治疗成瘾者的成功率各不相同；然而，目前的临床NTX治疗正在基于人类药物遗传数据进行优化。30天贮存注射该药物已被批准用于治疗阿片类药物成瘾和酒精中毒；然而，严重注射部位反应（蜂窝织炎、脓肿和坏死）的上市后报告最近要求患者更新警告。透皮给药系统比其他给药系统有许多改进。贴片不需要吞咽，消除了口服副作用；它们也不需要用注射器穿刺皮肤，从而消除了疼痛和病人看医生的时间。通过皮肤的渗透使药物直接进入体循环，避免了第一次通过效应，减少了胃副作用和肝损害药物滥用者和酗酒者的肝损害作用。经皮给药对成瘾者和酗酒者是可取的，以帮助减少与口服/贮存注射疗法相关的副作用，并提高依从性。NTX本身不具备必要的物理化学性质，不能使治疗剂量的药物通过人体皮肤屏障。微针增强透皮给药是一种有效和无痛的方法，可以增加包括NTX在内的许多药物的皮肤渗透。微针产品目前处于疫苗开发的后期临床试验阶段，但这一提议的产品将是首个用于多日缓释全身治疗的微针输送系统。我们假设NTX联合微针治疗将提供NTX的治疗性透皮给药率。原型贴片的初步筛选将在尤卡坦微型猪药代动力学研究中完成，以验证体外开发的贴片系统在体内的性能良好（剂量范围研究）。该提案的最终研究将是一组关键的动物GLP皮肤毒理学研究，以评估最终贴片的皮肤刺激和致敏潜力。这些最终数据将用于申请IND，以便在项目结束时开始I期临床试验。我们将研制出一种适销对路的、安全的药物，这将大大有助于治疗成瘾。

DESCRIPTION (provided by applicant): According to the National Survey of Drug Use and Health (NSDUH) of 2008, 7.2 million Americans are in need of treatment for Substance-Related Disorders (SRDs), and a large proportion of those need treatment for opiate pain reliever, heroin, and alcohol addiction. Naltrexone (NTX), an opioid antagonist, is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. NTX is also FDA-approved for the treatment of alcohol dependence. Substantial clinical evidence exists for the benefits of NTX treatment in smoking cessation, especially in women. Very intriguing clinical trial data has also been observed in amphetamine-dependent individuals, which is especially important as methamphetamine dependence has no FDA-approved treatment options. Treatment with NTX in the 90's produced variable success rates in addicts; however, current clinical NTX therapy is being optimized based on human pharmacogenetic data. A 30-day depot injection of the drug has been approved for the treatment of opiate addiction and alcoholism; however, postmarketing reports of serious injection site reactions (cellulitis, abscess, and necrosis) have recently required patient warning updates. Transdermal delivery systems offer a number of improvements over other delivery systems. Patches do not require swallowing, eliminating oral side effects; nor do they require skin puncture by syringe needles, eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect, decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers and alcoholics. Transdermal delivery of NTX is desirable for addicts and alcoholics in order to help reduce side effects associated with oral/depot injection therapies and improve compliance. NTX itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. Microneedle-enhanced transdermal delivery is an efficient and painless method for increasing the skin permeation of many drugs, including NTX. Microneedle products are currently in late-stage clinical trials for vaccine development, but this proposed product would be the first microneedle delivery system for multiple day sustained release systemic treatment. We hypothesize that NTX in combination with microneedle treatment will provide a therapeutic transdermal delivery rate of NTX. The initial screening of the prototype patch will be completed in a Yucatan miniature pig pharmacokinetic study to verify that the patch system developed in vitro performs well in vivo (dose ranging study). The final studies for this proposal will be a group of critical GLP dermatotoxicology studies in animals to assess skin irritation and sensitization potential of the final patches. This final data will be used to apply for an IND, so that a Phase I clinical trial may begin at the end of this project. We will create a marketable and safe drug that will significantly aid in the treatment of addiction.