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: 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
• 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' 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

 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(申请人提供)：内耳疾病需要新的治疗选择，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，包括使用标签外的类固醇，缺乏安全性和有效性数据。这些特别方法往往无法达到预期的结果；这一结果可能是由于内耳暴露的药物不足和可变。奥比斯生物科学公司的缓释内耳给药平台Unison具有显著改善各种耳科疾病的治疗效果的潜力，在一次经济高效的鼓室内注射后，可在内耳维持精确和治疗性药物水平超过三十(30)天。Unison平台由两部分组成：(1)载药微球--采用奥比斯公司获得专利的精密颗粒制造技术--可实现药物释放的精确控制；(2)新型快速成膜剂(FFA)，可用作微球注射的稀释剂和将微球固定在圆窗膜(RWM)上的薄膜，使微球能够在一个多月的时间内连续将药物有效载荷输送到内耳。第一个使用Unison平台的产品是ORB-202，这是一种用于治疗类固醇反应性耳聋的缓释倍他米松。成功获得FDA批准后，ORB-202将取代目前的临床做法，即在几周内间隔几周多次鼓室内注射含水混悬剂，这是一种痛苦、不便且往往无效的治疗方法。在SBIR第一阶段，Orbis成功开发了Unison和ORB-202的原型。奥比斯使用其专利的精密颗粒制造技术成功地包裹和控制了倍他米松的体外释放，倍他米松是一种有效的糖皮质激素。与此同时，Orbis开发了一种能够将微球固定在RWM中超过30天的FFA，并证明了这种新型FFA在小鼠身上是无毒的。SBIR第二阶段提案的目的是证明ORB-202在小动物和大动物的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计划第三阶段的IND备案做准备。Orbis将首次在豚鼠体内建立ORB-202的体内外相关性 以及ORB-202组件的货架稳定性测试(目标1)。随后，Orbis将使用急性耳毒性模型(AIM 2)对ORB-202在豚鼠身上的安全性、药理学和毒理学进行表征。最后，Orbis将在大型动物绵羊模型(目标3)中建立ORB-202的剂量-反应曲线，以表征内耳液体体积接近人类大小的动物的剂量需求。在完成这个第二阶段的SBIR计划后，奥比斯将确定ORB-202的安全性和有效性，以实现内耳中类固醇的稳定浓度，无论是大的还是小的都是如此 动物模型，从而将所得到的配方定位于启用IND的临床前试验。