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

基本信息

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
项目类别：
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

项目摘要

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。一种将糖皮质激素类固醇长期控制释放到内耳的新型输送系统将极大地改善 SSNHL 的治疗选择。我们提出的策略使用精密颗粒制造（PPF）来创建负载倍他米松的微球，用于经鼓室注射、圆窗膜（RWM）定位和持续释放到内耳。我们方法的核心优势是 PPF 技术可以精确控制颗粒尺寸、形状、材料和释放速率。我们的长期目标是通过鼓膜递送支持 PPF 的倍他米松微球，成为 SSNHL 患者的护理标准。我们假设微球可以在 RWM 上保留两周，并且倍他米松的释放可以维持在治疗剂量的 25% 以内（约 55 ng/天）。我们预计，这种新方法将使内耳倍他米松的治疗浓度保持在持续水平，与目前可用的选择相比，这将显着提高 SSNHL 治疗的安全性和有效性。我们的研究团队将首先开发并表征微球尺寸与倍他米松释放曲线之间的关系，以确定实现内耳长期受控释放的可行性（目标 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 天且毒性最小（目标 2）。结果将是维持精确的倍他米松剂量并在 RWM 上粘附足够时间的微球。在确定这种方法的可行性后，我们将在第二阶段展示我们在小型（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的能力。这种基于 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 的封装具有高度适应性，可以作为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。公共卫生相关性：目前治疗突发感音神经性听力损失 (SSNHL) 的方法无法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。一种将糖皮质激素类固醇长期控制释放到内耳的新型输送系统将极大地改善 SSNHL 的治疗选择。我们提出的策略使用精密颗粒制造（PPF）来设计负载糖皮质激素的微球，这些微球旨在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。