A Breath-based Naltrexone Adherence Tool to Manage Narcotic-addicted HIV patients

描述(由申请者提供)：成瘾每年给美国造成5000亿美元的损失。吸毒成瘾尤其令人担忧，因为静脉吸毒(IVDA)也会促进艾滋病毒的传播。减少IVDA对于降低艾滋病毒发病率至关重要。由于75%的IVDA是阿片类药物，有效的阿片成瘾治疗应该会显著减少IVDA和降低艾滋病毒传播率。纳曲酮与标准行为疗法相结合，显著降低了阿片成瘾患者的复发率，缩短了治疗时间。然而，这种疗效依赖于严格的依从性，而监测这种依从性主要依赖于直接观察疗法(DOT)。该项目的重点是开发一种新型的用药依从性监测系统，该系统可以真实地监测吸毒者是否真的定期服用纳曲酮，完全独立于DOT。在这个专利系统中，无害的“标签”(选自FDA“公认的安全”名单)与活性药物成分(如纳曲酮)一起被“包装”成“智能”药物配方。在药物被摄取并进入胃后，标记物被释放并迅速代谢为挥发性代谢物。对呼气中挥发性代谢物的检测证实了口服药物的摄入。我们之前已经确定，这个旨在准确评估人体依从性的系统在技术上是可行的。值得注意的开发发现包括：1)仲丁醇(例如2-丁醇)是由酒精脱氢酶(ADH不受遗传多态影响，与异构体不同)代谢产生挥发酮(例如2-丁酮)在呼气中呼出的高级标记物，2)已经创建了微型气相色谱-金属氧化物传感器(MGC-MOS)来检测人体呼气中酮，3)多标记物可以容易地合并到系统中以监测几种药物的粘附性，以及4)食物不会干扰系统。我们现在建议具体调整和扩展这项核心技术，以管理感染艾滋病毒/艾滋病的阿片成瘾患者。为此，将实现以下2个目标：目标1：使用4种一般类型的药物配方策略创建8个智能胶囊纳曲酮系统。将制备包含Gras Tagant、2-丁醇(25或40 mg)的纳曲酮(50 Mg)模型制剂，并进行初步稳定性研究：类型1)疏水体系、类型2)亲水体系、类型3)反胶束体系和类型4)油包水微乳体系(1-6个月)。目的2：选择最佳的纳曲酮制剂，并在UF临床与翻译科学研究所(CTSI)的健康志愿者中测试MGC-MOS的性能。采用双盲、随机、交叉研究设计，将在口服从Aim 1或阳性对照(7-12个月)中选择的3种有希望的纳曲酮制剂后，确定2-丁醇(泰格特)和2-丁酮(代谢物)的呼气浓度(通过MGC-MOS和气相色谱-质谱仪[GC-MS]测量)与时间的关系。 公共卫生相关性：这一第一阶段SBIR计划的目标是开发一种新型的基于呼吸的用药依从性监测系统，该系统能够真实地监测患有艾滋病毒/艾滋病的阿片成瘾者是否定期服用(最终依从性)他们的口服纳曲酮，完全独立于直接观察治疗的需要。

DESCRIPTION (provided by applicant): Addiction annually costs America >$500B. Narcotic addiction is especially worrisome since intravenous drug abuse (IVDA) also promotes HIV transmission. Reducing IVDA is critical to lowering the incidence of HIV. Since >75% of IVDA is with opioids, effective treatment of opiate addiction should markedly reduce IVDA and lower HIV transmission rates. Naltrexone has markedly lowered relapse rates and shortened treatment time in opiate-addicted patients when combined with standard behavioral therapies. This efficacy, however, is dependent upon strict adherence, and monitoring this adherence relies primarily upon directly observed therapy (DOT). The focus of this program is to develop a novel medication adherence monitoring system that can realistically monitor whether narcotic addicts actually ingest their oral naltrexone on a regular basis, completely independent of DOT. In this patented system, innocuous "taggants" (chosen from FDA "Generally Recognized as Safe" list) are "packaged" with the active pharmaceutical ingredient (e.g., naltrexone) into a "smart" drug formulation. After the drug is ingested and enters the stomach, the taggant is released and rapidly metabolized to a volatile metabolite. Detection of the volatile metabolite in the breath verifies oral ingestion of the drug. We previously established that this system, directed at accurately assessing adherence in humans, is technically feasible. Notable development findings include: 1) secondary (2o) alcohols (e.g., 2-butanol) are superior taggants metabolized by alcohol dehydrogenase (ADH is not subject to genetic polymorphisms, unlike the isoform) to generate volatile ketones (e.g., 2-butanone) exhaled in breath, 2) a miniature gas chromatography-metal oxide sensor (mGC-MOS) has been created to measure ketones in human breath, 3) multiple taggants can be readily incorporated into the system to monitor adherence for several drugs, and 4) food does not interfere with the system. We now propose to specifically adapt and expand this core technology to manage opioid-addicted patients with HIV/AIDS. To that end, the following 2 aims will be achieved: Aim 1: Create 8 SMART capsule-based naltrexone systems using 4 general types of pharma formulation strategies. Model naltrexone (50 mg) formulations containing the GRAS taggant, 2-butanol (25 or 40 mg) will be prepared and preliminary stability studies executed: Type 1) hydrophobic system, Type 2) hydrophilic system, Type 3) reverse micelle system, and Type 4) water-in-oil microemulsion system (Months 1-6). Aim 2: Select the best naltrexone formulation and test mGC-MOS performance in healthy volunteers in the UF Clinical and Translational Science Institute (CTSI). Using a double blind, randomized, crossover study design, the relationship between the breath concentration (measured via mGC-MOS and gas chromatography mass spectroscopy [GC-MS]) of 2-butanol (taggant) and 2-butanone (metabolite) versus time will be determined after the oral administration of 3 promising naltrexone formulations selected from Aim 1 or a positive control (Months 7-12). PUBLIC HEALTH RELEVANCE: The goal of this Phase I SBIR program is to develop a novel breath-based medication adherence monitoring system that can realistically monitor whether opiate addicts with HIV/AIDS actually ingest (definitive adherence) their oral naltrexone on a regular basis, completely independent of the need for directly observed therapy.