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

摘要 有一个迫切的未满足的医疗需求，以发展治疗方案的约50%的抑郁症患者 患有难治性抑郁症，一种对现有精神病患者的治疗有抵抗力的抑郁症， 和药物治疗。经典的致幻剂，如5 HT 2A激动剂麦角酰二乙胺（LSD） 和裸盖菇素，已经重新成为治疗抑郁症患者的一种治疗选择。 最近的临床试验强调了5 HT 2A激动剂改善情绪和 在难治性抑郁症患者中，即使在那些中位 一生中曾服用过4种药物。因此，FDA最近批准了“突破性疗法” 指定为裸盖菇素治疗难治性抑郁症。与5 HT 2A激动剂相关的改善 药物治疗持续数周至数月，相对于氯胺酮显著增加，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。此外，许多患者发现 他们的症状复发，需要重复给药。“微剂量”-注射次知觉剂量的 每3-7天服用一次迷幻药，以改善情绪和/或创造力-代表了一种替代方案，可能是长期的 治疗选择微剂量已成为突出的外行公众，与最近的科学研究证实， 传闻称，它可以改善情绪，能量水平，社会联系，并减少对食物的渴望。 成瘾物质然而，存在各种各样的实际障碍，阻碍了对5 HT 2A的进一步研究 在临床环境中，激动剂微量给药，包括：对复杂给药方案的依从性低， 受管制物质转移的风险，以及长期治疗方案管理的困难和费用 在受控的环境中。在这里，我们建议通过开发生物可吸收的 微剂量植入物（MDI）由“微流体熔断器”或µ熔断器组成， 递送亚感知微剂量的5 HT 2A激动剂。µ保险丝由70：30的 邻苯二甲酸醋酸纤维素（CAP）和Pluronic® F-127（P）聚合物，形成表面腐蚀膜。Capp µfuses将嵌入缓慢生物降解的聚己内酯（PCL）体内，并位于5 HT 2A激动剂上， 包含串联的药物储存器。随着CAPP µ熔断器的腐蚀，储液器将暴露在周围环境中 5 HT 2A激动剂的液体和释放脉冲，其中脉冲之间的时间由5 HT 2A激动剂与液体之间的距离控制。 微熔丝下方的储液器。我们将从两个方面开发CAPP µfuse技术。1)微制造和 在体外验证µfuse器械的功能。2)表征体内药代动力学和生物相容性 在免疫功能正常的健康小鼠中使用原型µfuse器件。这项技术的成功开发将 使前所未有的研究5 HT 2A微量给药的优点，作为一种治疗策略，以克服 难治性抑郁症

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.