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）的方法不能将内耳药物浓度维持在适当的治疗窗内足够长的时间以达到治疗效果。一种新的长期、控制释放糖皮质激素类固醇到内耳的递送系统将构成SSNHL治疗选择的显著改善。我们提出的策略使用精密粒子制造（PPF）来创建用于经鼓膜注射、圆窗膜（RWM）定位和持续释放到内耳的倍他米松负载微球。我们的方法的核心优势是PPF技术可以精确控制粒度、形状、材料和释放速率。我们的长期目标是经鼓膜递送PPF使能的倍他米松负载微球成为患有SSNHL的人的护理标准。我们假设微球可以在RWM上保留两周，并且betvastatin释放可以维持在治疗剂量的25%（约55 ng/天）内。我们预计，这种新的方法将使持续水平的治疗浓度的贝达松内耳，这将大大提高安全性和有效性SSNHL治疗目前可用的选项。我们的研究团队将首先开发和表征微球大小和betterone释放曲线之间的关系，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）。结果将是微球维持精确的倍他米松剂量并粘附到RWM足够的时间。在确定这种方法的可行性后，我们将在II期研究中证明我们有能力在小型（小鼠）和大型（绵羊）动物模型中精确控制内耳倍他米松浓度的药代动力学特征。这种支持PPF的药物输送策略解决了剂量准确性和长期释放的问题。此外，基于PPF的包封具有高度适应性，并且可以用作多种药物类别的经鼓膜递送平台。这种独特的策略具有成为SSNHL治疗标准的巨大潜力。 公共卫生关系：目前治疗突发性感音神经性听力损失（SSNHL）的方法不能将内耳药物浓度维持在适当的治疗窗内足够长的时间以实现治疗效果。一种新的长期、控制释放糖皮质激素类固醇到内耳的递送系统将构成SSNHL治疗选择的显著改善。我们提出的策略使用精密颗粒制造（PPF）来设计糖皮质激素负载微球，这些微球被设计为保持定位于内耳的圆窗膜，并在整个治疗期间提供治疗剂的受控和持续释放。

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