Precision Betamethasone Microspheres for Transtympanic Delivery & SSNHL Treatment

用于经鼓膜输送的精密倍他米松微球

• 批准号: 9132197
• 负责人: Nathan H Dormer
• 金额: $ 73.81万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132197
• 关键词: Acute; Adverse effects; Affect; Agreement; Ambulatory Care Facilities; American; Animal Model; Animals; Auditory Brainstem Responses; Autoimmune Process; Betamethasone; Biological Sciences; Capital; Cavia; Characteristics; Clinical; Cochlea; Data; Development; Dexamethasone; Disease; Disease Progression; Dose; Drug Controls; Drug Delivery Systems; Drug Exposure; Drug Formulations; Drug Kinetics; Drug Prescriptions; Ear; Encapsulated; Exposure to; FDA approved; Film; Formulation; Foundations; Funding; Future; Glucocorticoids; Goals; Grant; Health; Health Personnel; Histology; Human; In Vitro; Injection of therapeutic agent; Investments; Label; Labyrinth; Lead; Legal patent; Length; Liquid substance; Marketing; Measures; Medicine; Membrane; Meniere' s Disease; Methods; Microspheres; Modeling; Mus; Outcome; Pain; Patients; Perilymph; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Pharmacotherapy; Phase; Physicians; Positioning Attribute; Pre-Clinical Model; Preparation; Procedures; Safety; Sensorineural Hearing Loss; Serum; Sheep; Small Business Innovation Research Grant; Steroids; Suspension substance; Suspensions; System; Technology; Therapeutic; Time; Tinnitus; Tissues; Toxic effect; Toxicology; United States National Institutes of Health; Variant; aqueous; clinical practice; cost; cost effective; dosage; effective therapy; evidence base; improved; in vivo; inner ear diseases; innovation; meetings; middle ear; novel; ototoxicity; particle; preclinical trial; programs; prototype; response; round window; safety testing; stability testing

 DESCRIPTION (provided by applicant): New treatment options are needed for inner ear disorders including Meniere's disease, sensorineural hearing loss, autoimmune inner ear disease, and tinnitus. In the absence of FDA-approved drugs, physicians use improvised treatments, including the administration of off-label steroids, which lack safety and efficacy data These ad hoc approaches often fail to achieve the desired outcomes; a result potentially attributable to insufficient and variable drug exposure in the inner ear. Orbis Biosciences's extended-release inner ear drug delivery platform, Unison, has the potential to significantly improve treatment for a wide-range of otic disorders by maintaining precise and therapeutic drug levels in the inner ear for more than thirty (30) days after a single, cost-effective intratympanic injection. The Unison platform is a composite of: (1) drug-loaded microspheres - produced using Orbis' patented Precision Particle Fabrication technology - that allow for precise control of drug release, and (2) a novel Fast Film- forming Agent (FFA) that severs as both a diluent for microsphere injection and a film that holds the microspheres to the Round Window Membrane (RWM), allowing the microspheres to continuously deliver their drug payload to the inner ear for over a month. The first product to use the Unison platform is ORB-202, an extended release betamethasone for the treatment of steroid-responsive otic disorders. Upon successful FDA approval, ORB-202 will replace the current clinical practice of multiple intratympanic injections of aqueous suspensions spaced over the course of several weeks, a treatment that is painful, inconvenient, and often ineffective. Under SBIR Phase I, Orbis successfully developed a prototype of Unison and ORB-202. Orbis used its patented Precision Particle Fabrication technology to successfully encapsulate and control the in vitro release of betamethasone, a potent, glucocorticoid steroid. Concurrently, Orbis developed a FFA capable of affixing microspheres in the RWM for over thirty (30) days and demonstrated that this novel FFA was non-toxic in mice. The objective of this SBIR Phase II proposal is to demonstrate the safety and efficacy of ORB-202 in preclinical models for both small and large animals and to hold a pre-IND meeting with the FDA in preparation for an IND-filing during Phase III of this SBIR program. Orbis will first establish the in vitro-in vivo correlation of ORB-202 in guinea pigs along with shelf stability testing of the ORB-202 components (Aim 1). Subsequently, Orbis will characterize the safety, pharmacology, and toxicology of ORB-202 in guinea pigs using an acute ototoxicity model (Aim 2). Finally, Orbis will establish the dose-response curve of ORB-202 in a large animal, sheep model (Aim 3), to characterize the dose requirements in an animal with inner ear fluid volume near the size of the human. At the completion of this Phase II SBIR program, Orbis will have established the safety and efficacy of ORB-202 to achieve steady concentration of steroid in the inner ear for a minimum of thirty (30) days in both small and large animal models, thereby positioning the resultant formulation for IND-enabling preclinical trials.

 描述（由申请人提供）：内耳疾病需要新的治疗方案，包括梅尼埃病、感音神经性听力损失、自身免疫性内耳疾病和耳鸣。在没有 FDA 批准的药物的情况下，医生使用临时治疗，包括使用标签外类固醇，但缺乏安全性和有效性数据。这些临时方法往往无法达到预期的结果；该结果可能归因于内耳药物暴露不足且变化多端。 Orbis Biosciences 的缓释内耳药物递送平台 Unison 具有在单次经济高效的鼓室内注射后三十 (30) 天以上维持内耳精确治疗药物水平的潜力，可显着改善多种耳部疾病的治疗。 Unison 平台由以下部分组成：(1) 载药微球 - 使用 Orbis 的专利精密颗粒制造技术生产 - 可以精确控制药物释放；(2) 一种新型快速成膜剂 (FFA)，既可用作微球注射的稀释剂，又可用作将微球固定在圆窗膜 (RWM) 上的薄膜，使微球能够持续释放其药物成分。 药物有效负载到达内耳一个多月。第一个使用 Unison 平台的产品是 ORB-202，这是一种缓释倍他米松，用于治疗类固醇反应性耳部疾病。一旦 FDA 成功批准，ORB-202 将取代目前在几周内多次鼓室内注射水悬浮液的临床实践，这种治疗是痛苦的、不方便的，而且往往无效。 在 SBIR 第一阶段，Orbis 成功开发了 Unison 和 ORB-202 的原型。 Orbis 利用其获得专利的精密颗粒制造技术成功封装并控制了倍他米松（一种强效糖皮质激素类固醇）的体外释放。与此同时，Orbis 开发了一种能够将微球固定在 RWM 中三十 (30) 天以上的 FFA，并证明这种新型 FFA 对小鼠无毒。该 SBIR II 期提案的目的是证明 ORB-202 在小型和大型动物临床前模型中的安全性和有效性，并与 FDA 举行 IND 前会议，为该 SBIR 项目 III 期期间的 IND 申请做准备。 Orbis将首先在豚鼠中建立ORB-202的体外-体内相关性 以及 ORB-202 成分的货架稳定性测试（目标 1）。随后，Orbis 将使用急性耳毒性模型（目标 2）来表征 ORB-202 在豚鼠中的安全性、药理学和毒理学。最后，奥比斯将在大型动物绵羊模型中建立 ORB-202 的剂量反应曲线（目标 3），以表征内耳液量接近人类大小的动物的剂量需求。 完成该 II 期 SBIR 计划后，Orbis 将确定 ORB-202 的安全性和有效性，以在小耳和大耳中实现类固醇浓度稳定至少三十 (30) 天。 动物模型，从而将所得制剂用于支持 IND 的临床前试验。