Surmounting substance use disorder using an ultra-long acting injectable platform.

物质使用障碍(SUD)是一种复发性疾病，需要几年的药物治疗。长- 代理注射剂和植入物改善了患者对用于SUD的药物的依从性。对两个人都是 纳曲酮和丁丙诺啡，尽管植入物表现出显著长于注射剂的释放， 它们需要手术干预才能插入/取出，容易发生局部感染和炎症，并且 次优药代动力学(PK)。纳曲酮和丁丙诺啡长效注射剂仅提供30 药物释放天数，这是次优的，因为SUD是一种复发的情况，通常需要治疗 好几年了。此外，以前开发的用于SUD的长效注射剂导致显著的初始猝发 药物释放，只有在30-60天后才能达到稳定的血药浓度，这增加了副作用的风险 效果。尽管对用于SUD治疗的超长效注射剂的需求明显未得到满足，但 临床相关药物，包括纳曲酮、丁丙诺啡、氨基己酸酯和纳美芬，使其 很难配制他们的超长效注射剂。我们最近设计出了一种无溶剂和可注射的 现场交联库(ISCD)来自一种超低分子量液体聚合物，它形成了致密的网状聚合物- 整洁，能够超长时间输送亲水性药物。坚固的整体式仓库集成了 可注射性和可回收性的独特优势。我们在本申请中的总体目标是：(I)探索 该平台用于纳曲酮超长效体内外给药的可行性研究，以及(Ii)评价 具有不同亲水性的其他SUD相关治疗药物的载药和体外释放。我们的中心假设 是ISCD的密集网状网络将最大限度地减少水的流入/排出，这与最小的初始 由于ISCD的无溶剂性质而产生的猝发，将实现药物的长期缓释。我们的长期目标是 利用这一ISCD平台开发有希望的治疗药物的超长效注射剂 SUD的治疗。为实现总体目标，我们将追求以下具体目标：1)最大限度地 纳曲酮在ISCD中的载量，并调整释放动力学，2)评价纳曲酮ISCD的生物相容性， 并确定降解情况，以及3)评估与SUD相关的其他治疗药物的载量和体外释放。 在我们看来，这项申请中提出的研究是创新的，因为它专注于一种新的注射剂 配方，其中超低分子量聚合物经历化学转化以形成稠密的 这限制了水的流入/排出，从而限制了药物的释放。此外，聚合物的液态避免了 需要溶剂，防止由于溶剂交换过程而导致的高爆裂释放，如ISFI中所观察到的。 利用这一创新平台，我们将率先展示纳曲酮和其他药物的长效释放 在可注射平台上进行至少4-6个月的SUD相关治疗，从而为 针对sud患者的超长效疗法的发展。

Substance use disorder (SUD) is a relapsing condition and demands pharmacotherapy for several years. Long- acting injectables and implants have improved patient adherence to medications used for SUD. For both naltrexone and buprenorphine, although implants exhibit significantly longer release, compared to injectables, they require surgical intervention for insertion/removal, are prone to local infection and inflammation, and have sub-optimal pharmacokinetics (PK). Long-acting injectables of naltrexone and buprenorphine only provide 30 days of drug release, which is sub-optimal, as SUD is a relapsing condition and typically demands therapy for several years. Additionally, previously developed long-acting injectables for SUD result in significant initial burst release of the drug, and a steady plasma level is attained only after 30-60 days, which increases the risk for side effects. Despite the clear unmet need for an ultra-long-acting injectable for SUD treatment, hydrophilicity of clinically relevant drugs, including naltrexone, buprenorphine, acamprosate, and nalmefene makes it extremely difficult to formulate their ultra-long-acting injectables. We have recently engineered a solvent-free and injectable in situ crosslinking depot (ISCD) from an ultra-low molecular weight, liquid polymer which forms a dense mesh- neatwork and enables ultra-long-lasting delivery of hydrophilic drugs. The solid monolithic depot integrates the unique advantages of injectability and retrievability. Our overall objectives in this application, are to (i) explore the feasibility of this platform for ultra-long-acting delivery of naltrexone in vitro and in vivo, and (ii) evaluate loading and in vitro release of other SUD related therapeutics with varying hydrophilicity. Our central hypothesis is that the dense mesh network of ISCD will minimize water influx/efflux and this combined with minimal initial burst due to solvent-free nature of ISCD will achieve long-term sustained drug release. Our long-term goal is to utilize this ISCD platform for developing ultra-long-acting injectables of promising therapeutic agents for the treatment of SUD. To achieve our overall objectives, we will pursue the following specific aims: 1) maximize naltrexone loading in ISCD, and tune release kinetics, 2) evaluate biocompatibility of naltrexone-loaded ISCD, and determine degradation, and 3) evaluate loading and in vitro release of other therapeutics relevant to SUD. The research proposed in this application is innovative, in our opinion, because it focuses on a new injectable formulation, wherein an ultra-low molecular weight polymer undergoes chemical transformation to form a dense mesh, which limits water influx/efflux and hence the drug release. Additionally, liquid state of the polymer obviates the need for solvent, preventing high burst release due to solvent exchange process, as observed in ISFI. Utilizing this innovative platform, we will be the first to demonstrate long-acting release of naltrexone and other SUD related therapeutics for at least 4-6 months from an injectable platform, thereby opening new horizons for development of ultra-long-acting therapies for SUD patients.