Predictive Drug Release from a Tunable Injectable Capsule

可调节注射胶囊的预测药物释放

基本信息

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
项目类别：
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

项目摘要

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.

项目概要数百万人受到慢性病的影响，并且由于寿命的延长，这一数字还将继续上升期望。这些疾病，包括湿性年龄相关性黄斑变性 (AMD)，依赖于频繁的局部治疗注射用于疾病管理。为获得最大治疗效果，需要频繁注射与护理障碍相关，包括患者不适、高昂的治疗费用和并发症的风险。临床需要减少注射频率，同时保持这些慢性病的治疗效果。疾病，以改善这些患者的治疗结果和生活质量。本项目的总体目标是开发一种可调谐、可注射、可生物降解的微胶囊输送装置，该装置有潜力维持释放不同分子量的治疗药物至少 12 个月。理论建模将结合体外和体内实验研究，优化微胶囊系统并预测治疗释放。在目标 1 中，将使用两种方法调节微胶囊的孔隙率来调整治疗效果发布。释放不同分子量的治疗药物，包括抗 VEGF（血管内皮生长因子）和曲安奈德 (TA)，将进行至少 12 个月的评估。治疗释放率和将通过使用 ELISA、超高性能液体评估样品来进行体外生物活性评估色谱 (UPLC)、内皮细胞管形成测定以及视网膜炎症标志物的抑制细胞。将完善依赖于孔隙率和药物尺寸的药物释放的计算机模型。在目标 2 中，微胶囊外聚合物层的厚度将被调节以调节治疗释放。长期释放抗 VEGF 和 TA 的速率和生物活性将在体外进行评估。计算机模型将得到完善并经验证药物释放取决于胶囊层厚度。在目标 3 中，微胶囊的生物相容性和将在体内评估治疗药物的药代动力学分布。首先对微胶囊进行评估 1个月以获得短期生物相容性。然后，荧光标记的治疗剂将被加载到优化的微胶囊并与空白胶囊和仅治疗对照进行 12 个月的比较。荧光光度法将用于定量评估随时间释放的治疗浓度，并将与在研究结束时对提取的眼组织进行测定。结果将与已发表的研究进行比较以获得有效的治疗浓度。这项研究还将提供 12 个月的体内安全性数据。计算机中的模型将被改进，包括玻璃体和视网膜中治疗浓度的测量，以预测体内分布与胶囊中药物的释放相关。此外，还将开发一种计算工具用于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规模。该项目的目标是开发一种可调谐药物输送装置有可能将注射次数减少到每年一次，从而改善 AMD 或其他疾病患者的生活质量依赖局部注射治疗的慢性疾病。