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

描述（由申请人提供）：成瘾每年花费美国5000亿美元。麻醉成瘾尤其令人担忧，因为静脉药物滥用（IVDA）也会促进艾滋病毒的传播。减少IVDA对降低艾滋病毒发病率至关重要。由于约75%的IVDA与阿片类药物有关，因此对阿片类药物成瘾的有效治疗应能显著降低IVDA并降低艾滋病毒传播率。纳曲酮与标准行为疗法联合使用可显著降低阿片成瘾患者的复发率，缩短治疗时间。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治疗（DOT）。该项目的重点是开发一种新的药物依从性监测系统，该系统可以完全独立于DOT，实际监测麻醉成瘾者是否确实定期口服纳曲酮。在这个专利系统中，无害的“标记剂”（从FDA“公认安全”列表中选择）与活性药物成分（例如纳曲酮）一起“包装”成“智能”药物配方。药物被摄入并进入胃后，药物被释放并迅速代谢为挥发性代谢物。呼气中挥发性代谢物的检测证实了口服药物的摄入。我们之前建立了这个系统，旨在准确评估人类的依从性，在技术上是可行的。值得注意的发展发现包括：1)二级（20）醇（例如，2-丁醇）是由酒精脱氢酶代谢的优良标记物（ADH不受遗传多态性的影响，与同型异构体不同），以产生呼出的挥发性酮（例如，2-丁酮），2)微型气相色谱-金属氧化物传感器（mGC-MOS）已经创建，用于测量人体呼吸中的酮，3)多种标记物可以很容易地纳入系统，以监测几种药物的粘附性。4)食物不会干扰系统。我们现在建议专门调整和扩展这一核心技术，以管理阿片类药物成瘾的艾滋病毒/艾滋病患者。为此，将实现以下两个目标：目标1：使用4种一般类型的药物配方策略，创建8种基于SMART胶囊的纳曲酮系统。将制备模型纳曲酮（50毫克）配方，其中含有GRAS标记剂，2-丁醇（25或40毫克），并进行初步稳定性研究：类型1)疏水系统，类型2)亲水性系统，类型3)反胶束系统，类型4)油包水微乳液系统（1-6个月）。目的2：在UF临床与转化科学研究所（CTSI）筛选最佳纳曲酮处方并检测mGC-MOS在健康志愿者中的性能。采用双盲、随机、交叉研究设计，在口服从Aim 1或阳性对照（7-12个月）中选择的3种有前途的纳曲酮制剂后，确定2-丁醇（标记剂）和2-丁酮（代谢物）的呼气浓度（通过mGC-MOS和气相色谱-质谱[GC-MS]测量）与时间的关系。

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.