Precision Betamethasone Microspheres for Transtympanic Delivery & SSNHL Treatment

用于经鼓膜输送的精密倍他米松微球

基本信息

批准号：
8902728
负责人：
Nathan H Dormer
金额：
$ 76.07万
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 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8902728
关键词：
Acute Adverse effects Affect Agreement Ambulatory Care Facilities American Animal Model Animals Auditory Brainstem Responses Autoimmune Process Betamethasone 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 Foundations Funding Future Glucocorticoids Goals Grant Health Personnel Histology Human In Vitro Injection of therapeutic agent Investments Label Labyrinth Lead Legal patent Length Liquid substance Marketing Measures Medicine Membrane Meniere&apos s Disease Methods Microspheres Modeling Mus Outcome Pain Patients Perilymph Pharmaceutical Preparations Pharmacologic Substance Pharmacology and Toxicology 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 study programs prototype public health relevance response round window safety testing stability testing

项目摘要

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，医生使用临时治疗方法，包括使用以下药物。标签外类固醇，缺乏安全性和有效性数据这些临时方法常常无法达到预期的结果；这一结果可能归因于奥比斯生物科学公司的药物暴露不足和变化。缓释内耳药物输送平台 Unison 具有在单次成本后三十 (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- 有效的鼓室内注射由以下部分组成：(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，以及 (2) 新型快速薄膜 -成型剂（FFA）既作为微球注射的稀释剂，又作为将微球固定在圆窗膜（RWM）上的薄膜，使微球能够在一个多月内持续将其药物有效负载输送到内耳。使用 Unison 平台的产品是 ORB-202，一种用于治疗类固醇反应性耳部疾病的缓释倍他米松。一旦 FDA 成功批准，ORB-202 将取代倍他米松。目前的临床实践是在数周内间隔多次鼓室内注射水悬浮液，这种治疗方法痛苦、不方便且通常无效。在 SBIR 第一阶段，Orbis 成功开发了 Unison 原型，Orbis 使用了其原型。 Orbis 获得专利的精密颗粒制造技术，成功封装并控制倍他米松（一种强效糖皮质激素类固醇）的体外释放。开发了一种能够在 RWM 中固定微球超过三十 (30) 天的 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 在体内的安全性和有效性。 Orbis 将首先建立小型和大型动物的临床前模型，并与 FDA 举行 IND 前会议，为 SBIR 项目第三阶段的 IND 申请做准备。 ORB-202 在豚鼠中的相关性随后，Orbis 将使用急性耳毒性模型来表征 ORB-202 在豚鼠中的安全性、药理学和毒理学（目标 2）。 ORB-202 在大型动物绵羊模型中的剂量反应曲线（目标 3），以表征内耳液量接近完成该 II 期 SBIR 计划后，Orbis 将确定 ORB-202 在内耳中实现类固醇浓度稳定至少三十 (30) 天的安全性和有效性。大的动物模型，从而将所得制剂用于支持 IND 的临床前试验。