Development of sustained release/long acting products for TB

开发结核病缓释/长效产品

• 批准号: 10989407
• 负责人: J. Victor Garcia-Martinez
• 金额: $ 69.97万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10989407
• 关键词: Development; sustained; release; long; acting; Development; sustained; release; long; acting

In 2020, 10 million people developed tuberculosis (TB) and 1.5 million people died from TB, marking the first time TB deaths rose in over a decade.1,2 Approximately one-fourth of the world's population has a latent TB infection (LTBI) with the potential for reactivation. These billions of people serve as an ever-present source of new TB cases, independent of ongoing transmission events 3. For people with LTBI, the greatest risk factor for developing TB is HIV co-infection. HIV-infection increases the risk of latent TB reactivation by 20-fold. Further, TB is the leading cause of death of HIV positive individuals. It is thus critical to develop LTBI treatments that are compatible with HIV treatments.4 Short-course, rifamycin-based, 3- or 4-month latent TB infection treatment regimens are preferentially recommended over 6- or 9-month isoniazid monotherapy.5 A single-drug LTBI therapy with a four-month rifampin or rifabutin regimen has been show efective when taken consistently.6- 8 While rifabutin has not been studied in a randomized trial for latent TB treatment, it has reduced potential for drug-drug interactions, which makes it more suitable for treatment of Mtb/HIV coinfections compared to other rifamycins.9-13 Non-adherence to drug regimens has grave consequences and can lead to loss of therapeutic effectiveness and the development of drug resistance.14,15 Long acting (LA) parenteral drug formulations that provide sustained drug release over weeks or months have the potential to reduce dosing frequency such that only one or a few injections of the drug formulation could be sufficient for LTBI treatment. This would dramatically increase treatment compliance and efficacy of treatment16-18. Recently, we developed long-acting formulation of the anti-TB drug rifabutin (RFB) based on In Situ Forming Implant (ISFI) technology (RFB-ISFI). RFB-ISFI is injectable, forms an implant after subcutaneous injection, provides sustained release of RFB for 16 weeks, and is highly effective in mouse models of TB prevention and treatment of acute TB infection (Kim et al 2022). Due to the biocompatible and biodegradable nature of the ISFI polymer, the implant does not need to be removed at the end of treatment. However, if adverse events such as toxicity, drug-drug interactions, or an allergic response occurs, the implant can be safely removed. Drug release properties of ISFI formulations can be manipulated by changes in composition of the liquid formulation and adjusted to meet the specific needs of a given treatment. The scientific premise of this proposal is that the highly effective RFB-ISFI formulation we developed can be used for treatment of LTBI. Our ultimate goal is to develop an injectable formulation, that can be administered once every two months bi-monthly or less frequently and be effective for LTBI treatment, including patients on antiretroviral therapy. To accomplish this goal, we have assembled an outstanding, multi- disciplinary team of investigators with combined demonstrated expertise in animal models, including non-human primates, for studying TB disease and treatment, LA drug delivery systems, pharmacokinetics (PK) analysis, clinical pathology, and biostatistics that will work collaboratively to accomplish the following specific aims.

2020年，1000万人发生结核病（TB），有150万人死于结核病，这是第一个 时间结核病死亡人数在十多年中增加了。1,2大约世界人口的四分之一具有潜在的结核病 感染（LTBI）具有重新激活的潜力。这十亿人是永远存在的来源 新的结核病案件，独立于正在进行的传输事件3。 开发结核病是HIV共感染。 HIV感染将潜在TB重新激活的风险增加20倍。更远， 结核病是艾滋病毒阳性个体死亡的主要原因。因此，开发LTBI治疗至关重要 与艾滋病毒治疗兼容。4短期，基于利由霉素的，3或4个月的潜在结核病感染 优先建议在6个月或9个月的异念珠菌单一疗法上使用治疗方案。5单药 始终如一地进行四个月的利福平或利福布丁治疗的LTBI治疗已表现出效率。6-- 8虽然尚未在一项潜在结核病治疗的随机试验中研究利法布丁，但它的潜力降低了 与其他相比 利法米霉素。9-13对药物方案的不遵守有严重的后果，可能导致失去 治疗有效性和耐药性的发展。14,15长作用（LA）肠胃外药物 在数周或几个月内提供持续药物释放的配方有可能减少剂量 频率使得只有一种或几次药物制剂可以足以进行LTBI治疗。 这将显着提高治疗的依从性和治疗功效16-18。最近，我们开发了 基于原位形成植入物（ISFI）技术的抗TB药物利法布丁（RFB）的长效配方 （RFB-fisti）。 RFB-fisfi是可注射的，在皮下注射后形成植入物，可持续释放 RFB持续16周，并且在预防结核病的小鼠模型中非常有效 （Kim等2022）。由于ISFI聚合物的生物相容性和可生物降解性，植入物不得 需要在治疗结束时去除。但是，如果不良事件，例如毒性，药物相互作用， 或发生过敏反应，可以安全地去除植入物。 ISFI制剂的药物释放特性 可以通过液体配方组成的变化来操纵并进行调整以满足特定需求 给定的治疗。该提议的科学前提是高效的RFB-fistiulation 我们开发的可用于治疗LTBI。我们的最终目标是开发一种可注射的配方， 可以每两个月一次或更少一次一次管理一次，并且对LTBI治疗有效， 包括接受抗逆转录病毒疗法的患者。为了实现这一目标，我们组装了一个出色的，多的 纪律调查员的纪律团队在包括非人类在内的动物模型中展示了专业知识 灵长类动物，用于研究结核病疾病和治疗，LA药物输送系统，药代动力学（PK）分析， 临床病理和生物统计学将共同起作用以实现以下特定目标。