Transdermal Naltrexone for Opiate Addiction and Alcoholism

透皮纳曲酮治疗阿片成瘾和酒精中毒

• 批准号: 8519709
• 负责人: Audra L. Stinchcomb
• 金额: $ 69.6万
• 依托单位: ALLTRANZ, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519709
• 关键词: Abscess; Adverse effects; Alcohol abuse; Alcohol dependence; Alcoholism; American; Amphetamines; Analgesics; Animals; Blood Circulation; Cellulitis; Clinical; Clinical Trials; Data; Deglutition; Development; Diagnostic; Dose; Drug Formulations; Drug Kinetics; Drug abuse; Drug usage; FDA approved; Family suidae; Funding; Health; Heroin; Heroin Abuse; Heroin Dependence; Human; In Vitro; Individual; Injection Site Reaction; Injection of therapeutic agent; Investigational Drugs; Investigational New Drug Application; Lead; Methamphetamine dependence; Methods; Naltrexone; Narcotic Antagonists; Necrosis; Needles; Opiate Addiction; Opiates; Opioid; Oral; Pain; Painless; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phase I Clinical Trials; Physicians; Plasma; Population; Preparation; Property; Public Health; Puncture procedure; Reporting; Research; Rest; Skin; Staging; Stomach; Substance-Related Disorders; Surveys; Syringes; System; Tablets; Testing; Therapeutic; Toxic effect; Toxicology; Translational Research; United States; Update; Visit; Woman; Work; addiction; alcohol craving; alcohol use disorder; alcoholism therapy; base; cost; drug abuser; drug addiction pharmacotherapy; improved; in vivo; irritation; liver injury; meetings; pre-clinical; problem drinker; prototype; research and development; screening; skin irritation; smoking cessation; success; vaccine development

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.

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（SRD），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。纳洛酮（NTX）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。NTX也被FDA批准用于治疗酒精依赖。大量临床证据表明NTX治疗对戒烟有益，尤其是女性。在苯丙胺依赖者中也观察到了非常有趣的临床试验数据，这一点尤其重要，因为甲基苯丙胺依赖没有FDA批准的治疗方案。在90年代用NTX治疗在成瘾者中产生了不同的成功率;然而，目前的临床NTX治疗正在基于人类药物遗传学数据进行优化。该药物的30天长效注射剂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）的上市后报告最近需要更新患者警告。 经皮递送系统提供了优于其它递送系统的许多改进。贴片不需要吞咽，消除了口腔副作用;也不需要用注射器针头刺穿皮肤，消除了疼痛和患者就医。通过皮肤的渗透允许药物直接进入体循环，避免首过效应，减少肝脏受损药物滥用者和酗酒者的胃副作用和肝损伤效应。 NTX的经皮递送对于成瘾者和酗酒者是理想的，以帮助减少与口服/贮库注射疗法相关的副作用并提高依从性。NTX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。针头增强经皮给药是一种有效和无痛的方法，用于增加许多药物的皮肤渗透，包括NTX。微针产品目前正处于疫苗开发的后期临床试验阶段，但该拟议产品将是第一个用于多日持续释放全身治疗的微针递送系统。我们假设NTX与微针治疗组合将提供NTX的治疗性透皮递送速率。原型贴剂的初步筛选将在尤卡坦小型猪药代动力学研究中完成，以验证体外开发的贴剂系统在体内表现良好（剂量范围研究）。本提案的最终研究将是一组动物关键GLP皮肤毒理学研究，以评估最终贴剂的皮肤刺激和致敏潜力。该最终数据将用于申请IND，以便在本项目结束时开始I期临床试验。我们将创造一种可销售和安全的药物，这将大大有助于治疗成瘾。