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.

物质使用障碍 (SUD) 是一种复发性疾病，需要数年的药物治疗。长的- 作用注射剂和植入物提高了患者对 SUD 药物的依从性。对于两者 纳曲酮和丁丙诺啡，尽管与注射剂相比，植入剂的释放时间明显更长， 它们需要手术干预来插入/取出，容易发生局部感染和炎症，并且有 药代动力学 (PK) 次优。纳曲酮和丁丙诺啡的长效注射剂仅提供 30 药物释放天数，这是次优的，因为 SUD 是一种复发性疾病，通常需要治疗 几年。此外，之前开发的 SUD 长效注射剂会导致显着的初始爆发 药物释放，并且仅在 30-60 天后才能达到稳定的血浆水平，这增加了副作用的风险 影响。尽管用于 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、阿坎酸和纳美芬，使其极其 很难配制其超长效注射剂。我们最近设计了一种无溶剂且可注射的 原位交联库（ISCD）由超低分子量液体聚合物形成致密的网状结构 整洁并能够超持久地输送亲水性药物。坚固的整体式仓库集成了 具有独特的可注射性和可回收性优点。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超长效递送纳曲酮的可行性，以及（ii）评估 其他具有不同亲水性的 SUD 相关治疗剂的负载和体外释放。我们的中心假设 ISCD 的密集网状网络将最大限度地减少水的流入/流出，并且这与最小的初始初始值相结合 由于ISCD的无溶剂性质，爆裂将实现药物的长期持续释放。我们的长期目标是 利用该 ISCD 平台开发有前途的治疗药物的超长效注射剂 SUD 的治疗。为了实现我们的总体目标，我们将追求以下具体目标：1）最大化 ISCD 中的纳曲酮负载，并调整释放动力学，2) 评估负载纳曲酮的 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，该申请中提出的研究具有创新性，因为它专注于一种新的注射剂 配方中，超低分子量聚合物经过化学转化形成致密的 网状结构，限制水的流入/流出，从而限制药物的释放。此外，聚合物的液态避免了 对溶剂的需求，防止由于溶剂交换过程而导致的高爆发释放，如 ISFI 中观察到的。 利用这个创新平台，我们将率先展示纳曲酮和其他药物的长效释放 通过注射平台进行 SUD 相关治疗至少 4-6 个月，从而为 为 SUD 患者开发超长效疗法。