Precision Particle Fabrication-enabled Betamethasone-loaded Microspheres for Tran

用于 Tran 的精密颗粒制造负载倍他米松的微球

• 批准号: 8396087
• 负责人: Cory Berkland
• 金额: $ 28.71万
• 依托单位: ORBIS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-06 至 2013-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8396087
• 关键词: Address; Adhesives; American; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Betamethasone; Biocompatible; Biotechnology; Caliber; Caring; Clinical; Clinical Trials; Complete Hearing Loss; Data; Diffuse; Disease; Dose; Drug Controls; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Engineering; Ensure; Film; Glucocorticoids; Goals; Histology; Human; Immobilization; In Vitro; Injection of therapeutic agent; Kansas; Kinetics; Labyrinth; Length; Marketing; Measures; Medical; Membrane; Microspheres; Modeling; Mus; Needles; Oranges; Particle Size; Pharmaceutical Preparations; Phase; Positioning Attribute; Principal Investigator; Research; Safety; Scientist; Sensorineural Hearing Loss; Shapes; Sheep; Steroids; Surface; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Time; Toxic effect; Universities; Work; base; clinical practice; controlled release; design; dosage; experience; improved; middle ear; mouse model; novel; novel strategies; particle; professor; round window; safety study; success; treatment duration; treatment strategy

DESCRIPTION (provided by applicant): Current approaches to treat sudden sensorineural hearing loss (SSNHL) do not maintain inner ear drug concentrations within an appropriate therapeutic window for sufficient lengths of time to achieve therapeutic effect. A novel delivery system for long-term, controlled release of glucocorticoid steroids to the inner ear would constitute a dramatic improvement in SSNHL treatment options. Our proposed strategy uses Precision Particle Fabrication (PPF) to create betamethasone-loaded microspheres for transtympanic injection, round window membrane (RWM) localization, and sustained-release to the inner ear. The central advantage of our approach is that PPF technology allows for precise control of particle size, shape, material, and release rates. Our long-term goal is for transtympanic delivery of PPF-enabled betamethasone-loaded microspheres to be the standard-of-care for people who suffer from SSNHL. We hypothesize that microspheres can be retained on the RWM for two weeks and that betamethasone release can be maintained within 25% of a therapeutic dose (~55 ng/day). We expect that this novel approach will enable sustained levels of therapeutic concentrations of betamethasone to the inner ear that will dramatically improve the safety and efficacy of SSNHL treatments over currently available options. Our research team will first develop and characterize the relationship between the microsphere size and betamethasone release profiles to establish the feasibility of achieving long-term, controlled release to the inner ear (Aim 1). We will then determine the optimal microsphere immobilization strategy to enable RWM localization for a minimum of 14 days with minimal toxicity (Aim 2). The result will be microspheres that sustain a precise betamethasone dose and adhere to the RWM for sufficient time. After establishing the feasibility of this approach, we will, in Phase II, demonstrate our ability to precisely control the pharmacokinetic profile of inner ear betamethasone concentrations in small (mouse) and large (sheep) animal models. This PPF- enabled drug-delivery strategy addresses issues of dosage accuracy and long-term release. In addition, PPF- based encapsulation is highly adaptable and can serve as a transtympanic delivery platform for multiple drug classes. This unique strategy has significant potential to become the standard-of-care for treatment of SSNHL. PUBLIC HEALTH RELEVANCE: Current approaches to treat sudden sensorineural hearing loss (SSNHL) do not maintain inner ear drug concentrations within an appropriate therapeutic window for sufficient lengths of time to achieve therapeutic effect. A novel delivery system for long-term, controlled release of glucocorticoid steroids to the inner ear would constitute a dramatic improvement in SSNHL treatment options. Our proposed strategy uses Precision Particle Fabrication (PPF) to engineer glucocorticoid-loaded microspheres that are designed to remain localized to the round-window membrane of the inner ear and provide controlled and sustained release of the therapeutic throughout the treatment period.

描述（由申请人提供）：当前治疗突然的感觉性听力损失（SSNHL）的方法不会在适当的治疗窗口内保持内耳药物的浓度，以实现足够长的时间来实现治疗作用。长期，受控糖皮质固醇对内耳的新型输送系统将构成SSNHL治疗方案的显着改善。我们提出的策略使用精确的颗粒制造（PPF）来创建替伯米松的微球，用于跨抑制注射，圆形窗户（RWM）定位，并持续到内耳。我们方法的核心优势是PPF技术允许精确控制粒径，形状，材料和释放速率。我们的长期目标是用于施用PPF支持替他米松的微球的倍跨输送，是患有SSNHL的人的标准护理。我们假设微球可以在RWM上保留两个星期，并且可以将倍他米松释放维持在治疗剂量的25％以内（〜55 ng/day）。我们预计这种新颖的方法将使替代替他的替他的替代替补替代的治疗浓度能够大大提高SSNHL治疗的安全性和功效，而不是当前可用的选择。我们的研究团队将首先发展并表征微球大小和倍他米松释放曲线之间的关系，以确定在内耳内实现长期，受控释放的可行性（AIM 1）。然后，我们将确定最佳的微球固定策略，以使RWM定位至少14天，而毒性最小（AIM 2）。结果将是维持精确倍替米松剂量并遵守RWM的微球。在建立了这种方法的可行性之后，我们将在第二阶段证明我们能够精确控制小（小鼠）和大型（绵羊）动物模型中内耳倍硫塞松浓度的药代动力学特征的能力。这项启用PPF的药物输送策略解决了剂量准确性和长期释放问题。此外，基于PPF的封装具有高度适应性，可以用作多种药物类别的三个跨性传递平台。这种独特的策略具有成为SSNHL治疗标准的重要潜力。 公共卫生相关性：当前治疗突然的感觉性听力损失（SSNHL）的方法不会在适当的治疗窗口内保持内耳药物的浓度，以实现足够的时间来实现治疗作用。长期，受控糖皮质固醇对内耳的新型输送系统将构成SSNHL治疗方案的显着改善。我们提出的策略使用精确的颗粒制造（PPF）来设计糖皮质激素负载的微球，这些微球旨在保持到内耳的圆形窗膜，并在整个治疗期间提供治疗性的受控和持续释放。

项目成果

Evaluation of a transtympanic delivery system in Mus musculus for extended release steroids.

• DOI: 10.1016/j.ejps.2018.01.020
• 发表时间: 2019-01-01
• 期刊: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
• 作者: Dormer NH;Nelson-Brantley J;Staecker H;Berkland CJ
• 通讯作者: Berkland CJ