Topical Middle Ear Drug Delivery without Tympanic Membrane Puncture

项目描述（申请人提供）：项目的最终目标是改变儿童慢性中耳炎的治疗方式，减少对手术和压型造瘘管的依赖。为此，我们正在开发一种一线局部非侵入性治疗方法，可以在没有鼓膜穿刺、手术或全身麻醉的情况下将治疗传递到中耳。耳部感染是儿童去看儿科医生的主要原因。大约20%的急性中耳炎（AOM）患儿进展为慢性中耳炎伴积液（COME）。在美国，全麻下手术和鼓室造瘘置管治疗复发性AOM或COME是最常见的需要麻醉的儿科外科手术。没有有效的非手术治疗COME，也没有任何药物治疗可以阻止AOM向COME的进展。我们的系统工作原理是利用磁力选择性地将药物治疗穿过完整的鼓膜进入中耳。全身性类固醇已显示出治疗COME的短期有效性，但长期使用类固醇有主要的缺点和风险，美国儿科学会不推荐临床使用。我们的系统能够将类固醇（和抗生素）集中局部递送到中耳，并将与全身类固醇给药相关的症状降至最低。在这个SBIR I期研究中，我们将证明，与全身性类固醇和无治疗对照相比，类固醇强的松龙的磁性递送可以解决中耳积液和炎症。第一阶段的目的是通过目视检查和中耳炎症（细胞因子、炎症细胞浸润等）的定量测量来研究中耳积液的清除。目的2将通过听觉脑干反应（ABR）测量来评估听力的改善。目的3将验证与全身给药相比，局部磁性递送可降低血清中的类固醇浓度。所有这三个目标将在公认的小动物模型（C3H/HeJ小鼠）中进行。研究中选择的动物数量对所有三个目标都达到≥95%的置信度假设检验。在第二阶段，我们将研究第二种公认的COME动物模型（如栗鼠），并将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，即我们的系统能够治疗中耳感染以及中耳炎症和积液是很重要的。我们敏锐地意识到解决这两个方面的临床需求，并且想要指出的是，我们已经从FDA的儿童设备联盟获得了一项积极的资助，以表明我们的方法可以清除中耳感染。作为该资助的一部分，我们已经证明我们的方法可以可靠地清除公认的急性中耳炎啮齿动物模型中的中耳感染。

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.