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

项目总结/摘要 在美国，有超过2200万人患有物质使用障碍（SUD）。SUD是 一系列慢性疾病，通常以寻求药物的行为为特征，表现为一个周期， 物质中毒和暴食，随后是戒断，以及导致强迫性行为的渴望状态 复发，通常是由于不遵守治疗药物。尽管对SUD进行了数十年的研究， 原因和治疗，2021年有超过108，000名美国人死于药物过量，其中大多数涉及阿片类药物。 现有的药物SUD治疗仅作为滥用药物的替代品或暂时改善 戒断，但不减少与SUD相关的渴望。尽管成瘾危机势不可挡， 治疗是存在的，并且那些可用的治疗具有低功效。新的药物治疗迫切需要 needed.最近的研究表明，精神可塑性化合物（PC）可以减少药物 依赖这种药物滥用的停止与神经突发生的诱导有关， 神经可塑性，这是PC的标志。作为一种PC，氯胺酮有望成为一种更好的SUD药物疗法， 减少渴望，促进永久恢复，并治疗非阿片类药物SUD;然而，目前可用 制剂具有几种不利的副作用，包括镇静、分离作用和滥用倾向。 CP 110将氯胺酮封装在聚合物微粒中，随着时间的推移， 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。每月的管理将 减少不依从性，改善保留，并提供更好的患者结果。长期目标是 开发一种新的SUD药物，将改善禁欲，治疗不依从的患者，减少 渴望，并有效地治疗那些没有有效药物治疗的SUD。我们的假设 随着时间的推移以低水平递送氯胺酮将提供比目前可用的更好的安全性 氯胺酮制剂，同时提高依从性。低浓度释放氯胺酮也会延长 增强神经可塑性的方法，被认为可以提供更持久的恢复。具体目标为 如下：1）大鼠中氯胺酮在28天内释放，2）抑制CP 110的疗效，并证明 降低大鼠的解离。该项目的目标是继续开发CP 110，一种新型的，长期的， 通过体内验证，作用注射（LAI）氯胺酮制剂可维持治疗水平28天 药代动力学和证明解离减少。在第二阶段，我们将进行一项新的研究 FDA申请所需的IND研究。因此，这里提出的研究是重要的 支持CP 110未来临床项目的先例。CP 110的市场批准可以解决2.7美元的 全球SUD市场，并满足改进SUD治疗的未满足医疗需求，以提供更好的 患者的治疗效果。

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.