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）：目前治疗突发性感音神经性听力损失（SSNHL）的方法没有将内耳药物浓度维持在适当的治疗窗口内足够长的时间以达到治疗效果。一种新的长期、有控制地向内耳释放糖皮质激素的给药系统将极大地改善SSNHL的治疗选择。我们提出的策略是使用精密颗粒制造（PPF）来制造装载倍他米松的微球，用于经鼓室注射、圆窗膜定位和内耳缓释。我们方法的核心优势是PPF技术允许精确控制颗粒大小，形状，材料和释放速率。我们的长期目标是将ppf激活的倍他米松微球通过腹腔输送，使其成为SSNHL患者的标准治疗方案。我们假设微球可以在RWM上保留两周，倍他米松的释放可以维持在治疗剂量的25% （~55 ng/天）。我们期望这种新方法能够使倍他米松的治疗浓度维持在内耳水平，这将大大提高SSNHL治疗的安全性和有效性，超过目前可用的选择。我们的研究团队将首先开发和表征微球大小与倍他米松释放谱之间的关系，以确定实现长期、控制释放到内耳的可行性（目标1）。然后，我们将确定最佳的微球固定策略，使RWM定位至少14天，毒性最小（目标2）。结果将是微球能够维持精确的倍他米松剂量，并在RWM上坚持足够的时间。在确定该方法的可行性后，我们将在II期中证明我们能够精确控制小型（小鼠）和大型（绵羊）动物模型中内耳倍他米松浓度的药代动力学特征。这种PPF给药策略解决了剂量准确性和长期释放的问题。此外，基于PPF的包封具有很强的适应性，可以作为多种药物的跨腹膜给药平台。这种独特的策略具有成为治疗SSNHL的标准护理的巨大潜力。

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