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

使用超长效注射平台克服药物滥用障碍。

• 批准号: 10586277
• 负责人: Nitin Joshi
• 金额: $ 25.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586277
• 关键词: Buprenorphine; Chemicals; Creativeness; Data; Development; Diffusion; Disease; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Engineering; Excision; Exhibits; FDA approved; Focal Infection; Formulation; Fostering; Goals; Histologic; Human; Hydrophobicity; Image; Implant; In Situ; In Vitro; Inflammation; Injectable; Kinetics; Lamivudine; Liquid substance; Magnetic Resonance Imaging; Mission; Modeling; Molecular Weight; Naltrexone; Nature; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Polymers; Process; Public Health; Rattus; Relapse; Research; Risk; Scanning Electron Microscopy; Solid; Solvents; Structure-Activity Relationship; Subcutaneous Injections; Substance Use Disorder; Tenofovir; Therapeutic; Therapeutic Agents; Time; United States National Institutes of Health; Water; acamprosate; biomaterial compatibility; clinically relevant; compliance behavior; crosslink; density; evidence base; high risk; hydrophilicity; improved; in vivo; innovation; medication-assisted treatment; nalmefene; particle; polycaprolactone; prevent; side effect; subcutaneous; substance abuse treatment; substance use; substance use treatment

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.

药物使用障碍（SUD）是一种复发状况，需要药物治疗数年。长的- 作用注射剂和植入物改善了患者对用于SUD的药物的依从性。两者 纳曲酮和丁丙诺啡虽然植入物显示出明显更长的释放，但与注射剂相比， 他们需要手术干预以插入/去除，容易出现局部感染和炎症，并且具有 亚最佳药代动力学（PK）。纳曲酮和丁丙诺啡的长效注射剂仅提供30 药物释放的天数是亚最佳的，因为SUD是一种复发状况，通常需要治疗 几年。此外，先前开发了用于SUD的长效注射剂导致显着初始爆发 该药物的释放，并且仅在30-60天后达到稳定的血浆水平，这增加了侧面的风险 效果。尽管明显未满足对SUD治疗的超长注射措施，但 临床相关的药物，包括纳曲酮，丁丙诺啡，丙甲酸酯和纳米芬，使其极为极为 难以制定其超长的注射剂。我们最近设计了无溶剂和可注射的 从超低分子量的原位交联仓库（ISCD），液体聚合物形成密集的网眼 - 整齐的工作和实现了亲水性药物的超长递送。实体整体仓库集成了 注射性和可检索性的独特优势。我们在此应用程序中的总体目标是（i）探索 该平台在体外和体内进行超长作用的可行性，以及（ii）评估 具有不同亲水性的其他相关治疗剂的负载和体外释放。我们的中心假设 是ISCD密集的网格网络将最大程度地减少水流/外排，并结合最小的初始 由于ISCD的无溶剂性质引起的爆发将实现长期持续药物释放。我们的长期目标是 利用此ISCD平台来开发有前途的超长注射剂 SUD的处理。为了实现我们的整体目标，我们将追求以下特定目标：1）最大化 naltrexone在ISCD中加载，调子释放动力学，2）评估纳曲酮加载的ISCD的生物相容性， 并确定降解，3）评估与SUD相关的其他治疗剂的负载和体外释放。 我们认为，本应用程序中提出的研究具有创新性，因为它专注于新的注射剂 配方，其中超低分子量聚合物经历化学转化以形成密集 网格，它限制了水流/外排，因此释放了药物。另外，聚合物的液态降低 溶剂的需求，防止由于ISFI中观察到的溶剂交换过程而导致的高爆发。 利用这个创新的平台，我们将是第一个展示纳曲酮和其他纳曲酮的长效版本的人 从注射平台开始至少4-6个月与SUD相关的治疗剂，从而为 为SUD患者开发超长作用疗法。