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

摘要 为约50%的抑郁症患者开发治疗方案是一种迫切的未得到满足的医疗需求 患有难治性抑郁症，这是一种对现有精神病患者的治疗有抵抗力的抑郁症 和药物疗法。经典迷幻剂，如5HT2A激动剂麦角酸二乙胺(LSD) 和裸盖菇素，已经重新成为治疗耐药抑郁症患者的一种治疗选择。 最近的临床试验强调了5HT2A激动剂改善情绪和改善情绪的潜在有效性 难治性抑郁症患者的心理治疗增长，即使在那些未能达到 在他们的生命中有4次之前的药物。因此，FDA最近批准了“突破性疗法” 指定裸盖菇素治疗难治性抑郁症。与5HT2A激动剂相关的改善 药物治疗持续几周到几个月，与氯胺酮相比明显增加，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 他们的症状会复发，需要重复给药。“微量剂量”--摄取潜意识剂量的 每隔3-7天服用一次迷幻药以改善情绪和/或创造力--这是一种潜在的长期替代疗法 治疗选项。最近的科学研究证实，微量注射在普通公众中已经变得突出起来。 坊间传闻称，它可以改善情绪、能量水平、社交联系，并减少对 令人上瘾的物质。然而，有一系列的实际障碍阻碍了对5HT2A的进一步研究 激动剂在临床环境中的微量应用，包括：依从性低，给药方案复杂，依从性高 转移受控物质的风险，以及实施长期治疗方案的困难和费用 在受控设置中。在这里，我们建议通过开发一种生物可再吸收材料来克服上述限制 微剂量植入物(MDI)由“微流控熔丝”或微熔丝组成，可实现长期、间歇性 递送亚知觉剂量的5HT2A激动剂。熔断器由70：30的混合物组成 醋酸纤维素邻苯二甲酸酯(CAP)和Pluronic®F-127(P)聚合物，可形成表面腐蚀膜。CAPP 微熔断器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- 含有串联的药物储藏库。随着CAPP熔断器的腐蚀，储水池将暴露在周围 5HT2A激动剂的液体和释放脉冲，其中脉冲之间的定时由之间的距离控制 保险丝下方的蓄水池。我们将在两个目标下开发CAPP微熔丝技术。1)微制造和 在体外验证µFUSE器件的功能。2)体内药代动力学和生物相容性研究 在免疫能力良好的健康小鼠身上进行了大量的实验。这项技术的成功开发将 使对5HT2A微剂量作为一种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。

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.