Biodegradable microfuses to enable the safe and compliant long-term interval dosing of 5HT2A agonists

可生物降解的微熔丝可实现 5HT2A 激动剂安全、合规的长期间隔给药

• 批准号: 10372879
• 负责人: Glenn Madison Walker
• 金额: $ 18.25万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372879
• 关键词: Acetates; Acids; Address; Affect; Agonist; Autopsy; Cellulose; Centers of Research Excellence; Characteristics; Clinical; Clinical Research; Clinical Trials; Creativeness; Devices; Dose; Drug Delivery Systems; Drug Kinetics; Effectiveness; Electrons; Ensure; Exposure to; Film; Goals; Grant; Growth; Hallucinogens; Histopathology; Immune response; Immunocompetent; Implant; In Vitro; Ingestion; Investigation; Ketamine; Kinetics; Letters; Liquid substance; Lysergic Acid Diethylamide; Major Depressive Disorder; Medical; Medical Care Costs; Mental Depression; Mental disorders; Microfluidics; Microscopy; Mississippi; Modality; Moods; Mus; Natural Products; Needles; Neurosciences; Occupational; Organ; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiologic pulse; Pluronics; Polymers; Population; Positioning Attribute; Psychiatry; Psychotherapy; Regimen; Reporting; Research; Research Personnel; Resistance; Scanning; Schedule; Series; Serum; Site; Structure; Suicide attempt; Surface; Symptoms; System; Technology; Therapeutic; Time; Toxicology; Translating; Treatment Protocols; Trocars; Universities; Walkers; Work; alternative treatment; base; biomaterial compatibility; caprolactone; clinical investigation; clinical translation; commercialization; compliance behavior; cost; craving; depressive symptoms; disabling symptom; effective therapy; experience; follow-up; high reward; high risk; implantation; improved; in vitro Assay; in vivo; innovation; microdevice; phthalates; polycaprolactone; preclinical study; prevent; prototype; psychologic; reduce symptoms; social; subcutaneous; suicide rate; technology development; treatment-resistant depression

Abstract There is an urgent unmet medical need to develop therapeutic options for the ~50% of depression patients suffering from treatment-resistant depression, a form of depression resistant to treatment by existing psycho- and pharmaco-therapies. Classical psychedelics, such as the 5HT2A agonists lysergic acid diethylamide (LSD) and psilocybin, have re-emerged as a treatment option for patients with depression that is treatment-resistant. Recent clinical trials highlight the potential effectiveness of 5HT2A agonists to improve mood and psychotherapeutic growth in treatment-resistant depression patients, even in those who have failed a median of 4 previous medications in their lifetime. Accordingly, the FDA recently granted “Breakthrough Therapy” designation to psilocybin for treatment-resistant depression. The improvements associated with 5HT2A agonist pharmacotherapy last for weeks to months, a marked increase relative to ketamine, but administration requires a 6-8-hr psychological support session, an approach which is unlikely to scale. Moreover, many patients find their symptoms recur and need repeat administration. ‘Microdosing’ – ingesting subperceptual doses of psychedelics every 3-7 days to improve mood and/or creativity – represents an alternative, potentially long-term treatment option. Microdosing has become prominent in the lay public, with recent scientific studies corroborating anecdotal claims that it improves mood, energy levels, social connectedness, and decreases craving for addictive substances. However, there are a gamut of practical barriers that stymie further investigation of 5HT2A agonists microdosing in the clinical setting, including: low compliance with the complicated dosing regimen, high risk of diversion of controlled substances, and difficulty and cost administering the long-term treatment regimens in controlled settings. Here, we propose to overcome the above limitations by developing a bioresorbable microdosing implant (MDI) composed of “microfluidic fuses”, or µfuses, that enables long-term, intermittent delivery of sub-perceptual microdoses of 5HT2A agonists. The µfuses are composed of a 70:30 mixture of Cellulose Acetate Phthalate (CAP) and Pluronic® F-127 (P) polymers which form a surface-eroding film. CAPP µfuses will be embedded in a slowly biodegrading polycaprolactone (PCL) body and sit atop 5HT2A agonist- containing drug reservoirs in series. As the CAPP µfuse erodes, the reservoirs will be exposed to the surrounding fluid and release pulses of 5HT2A agonist, where the timing between pulses is controlled by the distance between reservoirs beneath the µfuse. We will develop the CAPP µfuse technology in two aims. 1) Microfabricate and validate the function of µfuse devices in vitro. 2) Characterize the in vivo pharmacokinetics and biocompatibility of prototype µfuse devices in immune-competent, healthy mice. Successful development of this technology will enable unprecedented studies into the merits of 5HT2A microdosing as a therapeutic strategy to overcome treatment-resistant depression.

抽象的 为约 50% 的抑郁症患者开发治疗方案是一项迫切且未得到满足的医疗需求 患有难治性抑郁症，这是一种对现有心理治疗有抵抗力的抑郁症。 和药物治疗。经典迷幻药，例如 5HT2A 激动剂麦角酸二乙酰胺 (LSD) 和裸盖菇素，已重新成为治疗耐药的抑郁症患者的治疗选择。 最近的临床试验强调了 5HT2A 激动剂在改善情绪和改善情绪方面的潜在功效。 难治性抑郁症患者的心理治疗增长，即使是那些中位数失败的患者 一生中曾服用过 4 种药物。因此，FDA 最近授予“突破性疗法” 指定裸盖菇素用于治疗难治性抑郁症。与 5HT2A 激动剂相关的改善 药物治疗持续数周至数月，相对于氯胺酮显着增加，但给药需要 6-8 小时的心理支持课程，这种方法不太可能扩大规模。而且，很多患者发现 他们的症状反复出现，需要重复给药。 “微剂量”——摄入亚知觉剂量的 每 3-7 天使用迷幻药来改善情绪和/或创造力——代表一种替代方案，可能是长期的 治疗选择。最近的科学研究证实，微剂量在普通公众中已经变得很突出 传闻称它可以改善情绪、精力水平、社交联系，并减少对食物的渴望 成瘾物质。然而，存在一系列实际障碍阻碍了 5HT2A 的进一步研究 临床环境中的激动剂微剂量，包括：对复杂给药方案的依从性低、高 受控物质转移的风险以及实施长期治疗方案的难度和成本 在受控设置中。在这里，我们建议通过开发一种生物可吸收的材料来克服上述限制 微剂量植入物 (MDI) 由“微流体保险丝”或 µfuse 组成，可实现长期、间歇性 5HT2A 激动剂的亚感知微剂量的递送。 µfuses 由 70:30 的混合物组成 邻苯二甲酸醋酸纤维素 (CAP) 和 Pluronic® F-127 (P) 聚合物可形成表面侵蚀膜。计算机辅助应用程序 µfuse 将嵌入缓慢生物降解的聚己内酯 (PCL) 体内，并位于 5HT2A 激动剂的顶部 - 含有串联的药物储存器。当 CAPP µfuse 腐蚀时，储层将暴露在周围环境中 5HT2A激动剂的液体和释放脉冲，其中脉冲之间的时间由之间的距离控制 µfuse 下方的水库。我们将出于两个目标开发 CAPP µfuse 技术。 1) 微加工和 体外验证 µfuse 器件的功能。 2) 表征体内药代动力学和生物相容性 在具有免疫能力的健康小鼠中进行原型微熔丝装置的研究。该技术的成功开发将 能够对 5HT2A 微剂量作为治疗策略的优点进行前所未有的研究，以克服 难治性抑郁症。