Long-acting injectable ketamine for improved substance use disorder (SUD) treatment without dissociative effects.

项目摘要/摘要 在美国，有2200多万人患有药物使用障碍(SUD)。肥皂水是 一种慢性疾病的集合，通常以寻求毒品的行为为特征，表现为 物质沉迷和狂欢，然后是戒断，以及导致强迫症的渴望状态 复发，通常是由不遵守治疗药物引起的。尽管对SUD进行了数十年的研究 原因和治疗，2021年有超过10.8万美国人死于药物过量，其中大部分涉及阿片类药物。 现有的药理学sud治疗只是作为滥用药物的替代品或暂时改善。 禁欲，但不能减少与SUD相关的渴望。尽管存在着压倒性的上瘾危机，但很少有人 治疗方法是存在的，而那些可用的治疗方法的疗效很低。迫切需要新的药物治疗方法 需要的。最近的研究表明，致精神病的化合物(PC)可以减少药物 依赖。这种药物滥用的停止与神经再生的诱导有关，并增加了 神经可塑性，个人电脑的一个标志。作为一种个人电脑，氯胺酮有望成为一种更好的sud药物疗法，可以 减少食欲，促进永久康复，治疗非阿片类肥皂；然而，目前可用 制剂有几种副作用，包括镇静、解离效应和滥用倾向。 CP110将氯胺酮包裹在聚合物微粒中，随着时间的推移，这些微粒会以聚合物的形式缓慢释放药物 会退化。随着时间的推移，这种低水平的缓慢释放将减少副作用。每月的行政管理将 减少不依从性，改善固位，提供更好的患者结果。长期目标是 开发一种新的SUD药物疗法，将改善戒酒，治疗不合规的患者，减少 并有效地治疗那些没有有效药物治疗的肥皂水。我们的假设 长期给予低水平的氯胺酮将提供比目前可用的更好的安全性 氯胺酮配方，同时提高依从性。释放低水平的氯胺酮也会延长时间。 神经可塑性增强，据信能提供更永久的恢复。具体目标如下 1)验证氯胺酮在大鼠体内28天的释放，2)验证CP110的疗效并证明 减少大鼠体内的解离。本项目的目标是继续开发CP110，这是一种新型的、长期的、 有效注射(LAI)氯胺酮制剂，通过体内验证保持治疗水平28天 药代动力学和显示减少解离。在第二阶段，我们将进行一项新的调查 FDA申请所需的药物(IND)使能研究。因此，这里提出的研究是重要的。 支持CP110未来临床计划的先例。CP110的市场批准可以解决2.7美元的问题 十亿美元的全球SUD市场，满足未得到满足的医疗需求，改进SUD疗法，以提供更好的 患者的治疗结果。

PROJECT SUMMARY / ABSTRACT There are more than 22 million individuals in the United States with a substance use disorder (SUD). SUDs are a collection of chronic disorders often characterized by drug-seeking behavior manifesting as a cycle of substance intoxication and binging, followed by withdrawal, and craving states that contribute to compulsive relapses, often driven by non-compliance with treatment medications. Despite decades of research into SUD causes and treatment, more than 108,000 Americans died from drug overdoses in 2021, most involving opioids. Existing pharmacological SUD treatments merely act as a substitute for the misused drug or temporarily improve abstinence but do not reduce the cravings associated with SUD. Despite the overwhelming addiction crisis, few therapies exist, and those that are available have low efficacy. Novel pharmacological treatments are urgently needed. Recent research has suggested that psychoplastogenic compounds (PCs) can reduce drug dependence. This drug abuse cessation is linked to the induction of neuritogenesis and increased neuroplasticity, a hallmark of PCs. As a PC, ketamine promises to be a better SUD pharmacotherapy that can reduce cravings, promote permanent recovery, and treat non-opioid SUDs; however, currently available formulations have several adverse side effects including sedation, dissociative effects, and abuse liability. CP110 encapsulates ketamine in polymer microparticles that slowly release the drug over time as the polymer degrades. This slow release at low levels over time will reduce side effects. The monthly administration will reduce non-adherence and improve retention and provide better patient outcomes. The long-term goal is to develop a new SUD pharmacotherapeutic that will improve abstinence, treat non-compliant patients, reduce cravings, and effectively treat those SUDs that have no effective pharmacological treatments. Our hypothesis is that delivering ketamine at a low level over time will offer a better safety profile than currently available ketamine formulations while improving adherence. Releasing ketamine at low levels will also lengthen the time of neuroplasticity enhancement that is believed to provide more permanent recovery. The Specific Aims are as follows: 1) Validate ketamine release over 28-days in rats, and 2) Validate efficacy of CP110 and demonstrate reduced dissociation in rats. The objective of this project is to continue development of CP110, a novel, long- acting injectable (LAI) ketamine formulation that maintains therapeutic levels for 28-days by validating in vivo pharmacokinetics and demonstrating reduced dissociation. In Phase II, we will conduct an investigational new drug (IND) enabling studies required for an FDA application. Hence, the studies proposed here are important precedents to support a future clinical program for CP110. Market approval for CP110 could address the $2.7 billion global SUD market and fulfill the unmet medical need of an improved SUD therapeutic to provide better therapeutic outcomes for patients.