Predictive Drug Release from a Tunable Injectable Capsule

可调节注射胶囊的预测药物释放

• 批准号: 10586224
• 负责人: Katelyn E Swindle-Reilly
• 金额: $ 57.27万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586224
• 关键词: Adverse event; Affect; Age related macular degeneration; Anti-Inflammatory Agents; Biological Assay; Bolus Infusion; Cells; Chitosan; Chronic; Chronic Disease; Clinical; Coupled; Data; Degenerative polyarthritis; Device Designs; Devices; Differential Equation; Disease; Disease Management; Disease Progression; Drug Delivery Systems; Drug Kinetics; Drug Modelings; Drug or chemical Tissue Distribution; Encapsulated; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Experimental Designs; Eye; Eye diseases; Fluorophotometry; Frequencies; Goals; Healthcare Systems; In Vitro; Individual; Infection; Inflammation; Injectable; Injections; Label; Life Expectancy; Liquid Chromatography; Malignant Neoplasms; Measurement; Measures; Methods; Microcapsules drug delivery system; Modeling; Molecular Weight; Oral; Oral Administration; Oryctolagus cuniculus; Patient-Focused Outcomes; Patients; Performance; Persons; Pharmaceutical Preparations; Polymers; Porosity; Property; Publishing; Quality of life; Research; Retina; Risk; Safety; Salts; Sampling; Specific qualifier value; System; Techniques; Testing; Theoretical model; Therapeutic; Therapeutic antibodies; Thick; Time; Tissues; Treatment Cost; Treatment Efficacy; Treatment outcome; Triamcinolone Acetonide; Tube; Vascular Endothelial Growth Factors; Vision; Work; adverse event risk; barrier to care; bevacizumab; biomaterial compatibility; caprolactone; capsule; common treatment; compliance behavior; computerized tools; controlled release; cost; design; drug distribution; experimental study; improved; in silico; in vivo; inflammatory marker; innovation; mathematical model; novel; pharmacokinetic model; pre-clinical; prevent; small molecule; standard of care; symptom management; therapeutically effective

PROJECT SUMMARY Millions of people are affected by chronic conditions, and the number will continue to rise due to increased life expectancy. These diseases, including wet age-related macular degeneration (AMD), rely on frequent local injections for disease management. Frequent injections required for maximum therapeutic efficacy are associated with barriers to care including patient discomfort, high treatment costs, and risk of complications. There is a clinical need to reduce injection frequency while maintaining treatment efficacy for these chronic diseases to improve treatment outcomes and quality of life for these patients. The overall objective of this project is to develop a tunable, injectable, biodegradable microcapsule delivery device that has the potential to sustain release of therapeutics of varying molecular weights for at least 12 months. Theoretical modeling will be combined with in vitro and in vivo experimental studies to optimize the microcapsule system and predict therapeutic release. In Aim 1, microcapsule porosity will be modulated using two methods to tune therapeutic release. Release of therapeutics of varying molecular weights, including anti-VEGF (vascular endothelial growth factor) and triamcinolone acetonide (TA), will be evaluated at least 12 months. Therapeutic release rates and bioactivity will be assessed in vitro by evaluating samples using ELISA, Ultra Performance Liquid Chromatography (UPLC), endothelial cell tube formation assays, and inhibition of inflammatory markers in retinal cells. An in silico model for drug release dependent on porosity and drug size will be refined. In Aim 2, microcapsule outer polymer layer thickness will be modulated to tune therapeutic release. Long-term release rates and bioactivity of anti-VEGF and TA will be evaluated in vitro. The in silico model will be refined and validated for drug release dependent on capsule layer thickness. In Aim 3, microcapsule biocompatibility and pharmacokinetic distribution of the therapeutics will be evaluated in vivo. The microcapsule will first be evaluated for 1 month for short-term biocompatibility. Then, fluorescently labeled therapeutics will be loaded into optimized microcapsules and compared to blank capsules and therapeutic only controls for 12 months. Fluorophotometry will be used to quantitatively assess therapeutic concentrations released over time and will be compared to assays conducted on extracted ocular tissues at study termination. Results will be compared to published studies for effective therapeutic concentrations. This study will also provide 12 month in vivo safety data. The in silico model will be refined to include measurements of therapeutic concentrations in the vitreous and retina to predict in vivo distribution coupled to drug release from a capsule. Additionally, a computational tool will be developed for optimizing capsule layer thickness and porosity for specified release duration, pharmacokinetic tissue distribution, and therapeutic size. The goal of this project is to develop a tunable drug delivery device with the potential to reduce injections to one time per year, improving the quality of life for patients with AMD or other chronic diseases that rely on local injections for treatment.

项目摘要 数以百万计的人受慢性病的影响，由于寿命的增加，人数将继续增加 期待。这些疾病，包括与年龄相关的黄斑变性（AMD），依赖于频繁的局部 注射疾病管​​理。最高治疗功效所需的经常注射是 与护理障碍有关，包括患者不适，高治疗费用和并发症的风险。 临床需要减少注射频率，同时维持这些慢性的治疗效果 改善这些患者的治疗结果和生活质量的疾病。该项目的总体目标 是开发一种可调的，可注射的，可生物降解的微胶囊输送设备，有可能维持 至少12个月的不同分子量的疗法释放。理论建模将是 结合体外和体内实验研究，以优化微胶囊系统并预测 治疗释放。在AIM 1中，将使用两种调整治疗方法调节微胶囊孔隙率 发布。释放不同分子量的治疗学，包括抗VEGF（血管内皮生长 因子）和曲安赛乙酰乙烯苷（TA）至少将评估至少12个月。治疗释放率和 通过使用ELISA，超级性能液体评估样品，将在体外评估生物活性。 色谱（UPLC），内皮细胞管的形成测定和视网膜中炎症标志物的抑制 细胞。将完善的用于释放药物释放的硅模型将得到完善。在AIM 2中， 微胶囊外聚合物层厚度将被调制以调整治疗性释放。长期发布 抗VEGF和TA的速率和生物活性将在体外评估。中的硅模型将被完善，并且 验证了释放药物释放的依赖胶囊层厚度。在AIM 3中，微胶囊生物相容性和 治疗剂的药代动力学分布将在体内评估。微胶囊将首先评估 短期生物相容性1个月。然后，将荧光标记的治疗剂加载到优化 微胶囊，与空白胶囊和治疗性对照进行比较12个月。荧光测定法 将用于定量评估随着时间的时间释放的治疗浓度，并将与 研究终止时对提取的眼组织进行的测定。结果将与已发表的研究进行比较 有效的治疗浓度。这项研究还将提供12个月的体内安全数据。在硅中 模型将被完善，包括对玻璃体和视网膜中治疗浓度的测量以预测 体内分布与从胶囊中释放药物释放。此外，将开发一个计算工具 为了优化指定释放持续时间的胶囊层厚度和孔隙率，药代动力学组织 分布和治疗尺寸。该项目的目的是开发一个可调的药物输送设备 将注射量减少到每年一次的潜力，改善AMD或其他患者的生活质量 依靠局部注射进行治疗的慢性疾病。