Topical Middle Ear Drug Delivery without Tympanic Membrane Puncture

无需鼓膜穿刺的局部中耳给药

• 批准号: 9135610
• 负责人: Mika Shimoji
• 金额: $ 22.58万
• 依托单位: OTOMAGNETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135610
• 关键词: 5 year old; Academy; Acute; Address; American; Anesthesia procedures; Animal Model; Animals; Antibiotics; Auditory Brainstem Responses; Auditory Threshold; Blood specimen; C3H/HeJ Mouse; Cells; Child; Childhood; Chinchilla (genus); Chronic; Clinical; Collaborations; Control Groups; Data; Deposition; Devices; Dose; Drug Delivery Systems; Drug Kinetics; Ear; Effectiveness; Erythema; External auditory canal; Family Practice; Funding; Future; General Anesthesia; Goals; Grant; Guidelines; Health; Health system; Hearing; High Pressure Liquid Chromatography; Hour; Infiltration; Inflammation; Inflammatory; Magnetism; Maryland; Mass Spectrum Analysis; Measurement; Measures; Medical; Methods; Modeling; Office Visits; Operative Surgical Procedures; Otitis Media; Otitis Media with Effusion; Otolaryngology; Pediatric Surgical Procedures; Pediatrics; Pharmaceutical Preparations; Phase; Protocols documentation; Puncture procedure; Pus; Rattus; Recurrence; Research; Risk; Rodent Model; Safety; Seeds; Serum; Side; Small Business Innovation Research Grant; Steroids; Symptoms; System; Technology; Testing; Therapeutic Effect; Topical application; Treatment Effectiveness; Tube; Tympanic membrane; Tympanostomy; United States; Visit; Visual; Work; arm; associated symptom; base; cytokine; design; drinking water; ear infection; effusion; four-arm study; improved; innovation; middle ear; particle; pediatrician; prednisolone; restoration; success

DESCRIPTION (provided by applicant): The ultimate goal of the project is to transform the treatment of chronic middle ear inflammations in children, and to reduce the reliance on surgery and typmanostomy tubes. To do so, we are developing a first-line topical non-invasive treatment that can deliver therapy to the middle ear without tympanic membrane puncture, surgery, or general anesthesia. Ear infections are the leading cause of child visits to pediatricians. Approximately 20% of children with acute otitis media (AOM) progress on to chronic otitis media with effusion (COME). Surgery and tympanostomy tube placement under general anesthesia for treatment of recurrent AOM or COME is the most common pediatric surgical procedure requiring anesthesia in the United States. There are no effective non-surgical treatments for COME, nor are there any medical treatments that block the progression of AOM to COME. Our system works by using magnetic forces to selectively deliver medical therapy across the intact tympanic membrane and into the middle ear. Systemic steroids have shown short-term effectiveness for treatment of COME, but long term steroid use has major drawbacks and risks and is not recommended clinically by the American Academies of Pediatrics. Our system enables concentrated topical delivery of steroids (and antibiotics) to the middle ear, and will minimize symptoms associated with systemic steroid administration. In this SBIR Phase I we will demonstrate that magnetic delivery of the steroid prednisolone resolves middle ear effusion and inflammation, as compared to systemic steroids and to no-treatment controls. The first phase I aim will investigate the clearance of middle ear effusion, by visual inspection and by quantitative measures of middle ear inflammation (cytokines, inflammatory cell infiltration, etc). Aim 2 will assess hearing improvement by auditory brainstem response (ABR) measurements. Aim 3 will verify that topical magnetic delivery reduces steroid concentration in blood serum as compared to systemic administration. All three aims will be carried out in a recognized small animal model of COME (in C3H/HeJ mice). The number of animals in the study has been chosen to achieve ≥ 95% confidence hypothesis testing for all three aims. In phase II we will examine a second recognized animal model of COME (e.g. chinchilla), and will initiate safety and pharmacokinetic/dynamic (PK/PD) studies. We agree with reviewers that it important for our system to be able to treat both middle ear infections as well as middle ear inflammation and effusion. We are acutely aware of the clinical need to address both aspects and would like to note that we already have an active and funded grant from the FDA's Pediatric Device Consortium at Children's to show that our method can clear middle ear infections. As part of that grant, we have shown that our method can reliably clear middle ear infections in a recognized rodent model of acute otitis media.

描述（由适用提供）：该项目的最终目标是改变儿童慢性中耳感染的治疗，并减少对手术和打字机的依赖。为此，我们正在开发一种一线局部非侵入性治疗，可以在不鼓膜膜穿刺，手术或全身麻醉的情况下向中耳提供治疗。耳朵感染是儿童探访儿童的主要原因。大约20％的患有急性中耳炎（AOM）的儿童以效率（来）继续前进到慢性中耳炎。在全身麻醉下进行手术和鼓膜造口术管，以治疗复发性AOM或CAME是最常见的小儿外科手术，需要在美国麻醉。没有有效的非手术治疗方法，也没有任何药物阻止未来AOM的进展。我们的系统通过使用磁力在完整的鼓膜膜上和中耳中有选择性地提供医疗疗法。全身性类固醇对COME的治疗显示出短期有效性，但是长期使用类固醇具有主要的缺点和风险，并且不建议由美国儿科学院临床临床。我们的系统可以使类固醇（和抗生素）的集中局部递送到中耳，并将与全身类固醇给药相关的符号最小化。在SBIR I期中，我们将证明类固醇泼尼松龙的磁性递送与全身类固醇和无治疗控制相比，可以解决中耳泡沫和感染。第一阶段的目标将通过视觉检查和中耳感染的定量测量（细胞因子，炎症细胞浸润等）来研究中耳泡沫的清除率。 AIM 2将通过听觉脑干响应（ABR）测量评估听力改善。 AIM 3将验证与全身给药相比，局部磁性递送会降低血清中的类固醇浓度。这三个目标将在公认的Come（C3H/HEJ小鼠）中进行。该研究中的动物数量已被选择以实现所有三个目标的95％置信度假设检验。在第二阶段，我们将检查第二个公认的Come动物模型（例如Chinchilla），并启动安全性和药代动力学/动力学（PK/PD）研究。我们同意审稿人的观点，对于我们的系统来说，能够治疗中耳感染以及中耳感染和积液很重要。我们敏锐地意识到要解决这两个方面的临床需求，并想指出，我们已经从FDA的儿童小儿装置财团中获得了积极的资助，以表明我们的方法可以清除中耳感染。作为该赠款的一部分，我们表明我们的方法可以在公认的急性中耳炎啮齿动物模型中可靠地清除中耳感染。