Long Acting Injectable Depots for TB Therapy

用于结核病治疗的长效注射剂

• 批准号: 10632118
• 负责人: Patrick S. Stayton
• 金额: $ 63.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-22 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10632118
• 关键词: Acceleration; Achievement; Acute; Address; Adherence; Antitubercular Agents; Architecture; Attenuated; Automation; Chemistry; Clinical; Clinical Trials; Cold Chains; Combination Drug Therapy; Complex; Cyclic GMP; Data; Dependence; Development; Dimethyl Sulfoxide; Dose; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Interactions; Drug resistance; Exhibits; Formulation; Freeze Drying; Future; HIV; HIV Seropositivity; HIV therapy; HIV/TB; High Prevalence; Image; Impairment; Implant; Individual; Infection; Injectable; Injections; Kinetics; Lead; Length; Libraries; Machine Learning; Maps; Modeling; Moxifloxacin; Mycobacterium tuberculosis; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Play; Polymer Chemistry; Polymers; Powder dose form; Prodrugs; Property; Refrigeration; Regimen; Robotics; Role; Running; Safety; Solubility; Stigmatization; Structure; Synthesis Chemistry; Technology; Testing; Therapeutic; Time; Tissues; Translations; Virulent; Viscosity; Water; Weight; biosafety level 3 facility; chronic infection; clinical development; co-infection; compliance behavior; cost; design; drug action; drug efficacy; drug release profile; experience; first-in-human; improved; innovation; lead candidate; lipophilicity; manufacture; monomer; mouse model; multidisciplinary; new technology; pharmacokinetics and pharmacodynamics; pill; prevent; product development; screening; social; solid state; therapy duration; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY/ABSTRACT Patient dosing adherence is often compromised by the complex pill regimes and long duration of current TB drug therapies. These challenges are exacerbated in settings for patients in many social and global settings where TB co-therapy with HIV positive patients is stigmatized. Long-acting drug delivery products should therefore play an important role to increase patient adherence and increase drug efficacy. This project will develop a new injectable depot technology that address a general target product profile that includes multiple-month delivery from a single injection, low volume and low viscosity formulations to reduce patient pain, combination drug formulation where required, sustained drug release with designable PK profiles, minimal initial and run-out burst release to increase safety and prevent drug resistance, and for global settings has low cost of goods and lowered cold-chain requirements. This depot technology also has the important translational product attributes of streamlined CMC and cGMP manufacturing that could lead to more rapid clinical development achievement. A new injectable depot product for TB therapy will be developed that is differentiated from current dispersal based formulation approaches by being a fully synthetic depot. The proposal is structured around 2 specific aims in the R61 phase and two further aims in the R33 phase: (1) Prodrug monomers made by synthetic chemistry are directly polymerized in a second synthetic step to create “drugamer” depot therapeutics that have the drugs built into the depot itself. Compared to current dispersion formulation approaches, the drugamers exhibit higher drug loading efficiencies, the ability to co-formulate drugs of different lipophilicities, and linear, individually tailorable PK profiles that minimize first- and last-week burst release. These PK profiles are kinetically controlled by the linker properties that are tied to the individual drugs, along with polymer architectural design. This aim will exploit a unique high throughput polymer library and screening platform at CSIRO Melbourne to identify lead injectable depot designs using bedaquiline and moxifloxicin as initial drug examples. Sophisticated LC-MS/MS PK characterization will assess the sustained PK profile together with PK/PK modeling. (2) Evolve and optimize depot lead candidates through efficacy in an initial TB model that allows higher throughput imaging characterization of activity. This will be followed by an Mtb model assessment and selection to a lead depot candidate; (3) Test and optimize the two lead drug depot candidates in an A/BSL3 Mtb model, by the criteria of PK/PD, efficacy and dose dependence, and dosing duration. The lead depot will also be characterized in accelerated stability studies to test whether they can avoid cold-chain storage. (4) Evaluate iterated up-selected depots in combination depots from mixing optimized bedaquiline and moxifloxacin depots, including dual PK profiling and PK/PD modeling. This same approach could also be expanded to develop future therapeutic products based on other combination drug depot designs. These favorable platform attributes motivate this this project as a potential new addition to the repertoire of anti-TB patient products.

项目总结/摘要 目前结核病药物的复杂药丸方案和长持续时间常常损害患者的给药依从性 治疗在许多社会和全球环境中，这些挑战在患者的环境中加剧， 与艾滋病毒阳性患者共同治疗结核病受到指责。因此，长效药物输送产品应发挥 对增加患者依从性和增加药物功效具有重要作用。该项目将开发一个新的 可注射贮库技术，其针对包括数月递送一般目标产品概况 从单次注射，低容量和低粘度配方，以减少患者疼痛，组合药物 需要时的制剂，具有可设计PK特征的持续药物释放，最小的初始和终止突释 释放以提高安全性并防止耐药性，并且对于全球环境来说，商品成本低，降低了 冷链要求。这种贮库技术还具有以下重要的转化产品属性： 简化的CMC和cGMP生产，可以导致更快的临床开发成果。一 将开发用于结核病治疗的新的可注射储库产品，其与目前基于分散的 作为一个完全合成的仓库，该提案围绕两个具体目标展开， R61阶段和R33阶段的两个进一步目标：（1）通过合成化学制备的前药单体， 在第二个合成步骤中直接聚合，以产生“drugamer”储库治疗剂， 进入仓库与目前的分散体制剂方法相比，药物释放剂表现出更高的药物活性。 装载效率，共同配制不同亲脂性药物的能力，以及线性的、可单独定制的 最大限度减少第一周和最后一周突释的PK特征。这些PK特征在动力学上受以下因素控制： 与单个药物相关的连接体性质，沿着聚合物结构设计。这一目标将利用 CSIRO墨尔本的一个独特的高通量聚合物库和筛选平台，用于识别可注射的铅 使用贝达喹啉和曲马多霉素作为初始药物实例的储库设计。复杂的LC-MS/MS PK 表征将评估持续PK特征以及PK/PK建模。(2)发展和优化 仓库通过初始TB模型的有效性领先候选者，该模型允许更高的吞吐量成像 活动的特征。随后将进行Mtb模型评估并选择主要仓库 （3）通过以下标准，在A/BSL 3 Mtb模型中测试和优化两种先导药物贮库候选物： PK/PD、疗效和剂量依赖性以及给药持续时间。铅库的特征还包括： 加速稳定性研究，以测试它们是否可以避免冷链储存。(4)评估迭代的向上选择 来自混合优化的贝达喹啉和利多卡因长效制剂的复方长效制剂，包括双重PK 分析和PK/PD建模。同样的方法也可以扩展到开发未来的治疗方法。 基于其他组合药物贮库设计的产品。这些有利的平台属性激发了这个这个 项目作为抗结核病患者产品库的潜在新补充。