Ototoxicity protection with intratympanic steroid implant

描述（由申请人提供）：化疗引起的耳毒性是由所给药物的副作用引起的内耳损伤。这可能会导致患者永久性听力丧失和/或耳鸣（耳鸣持续）。一些最常见的引起耳毒性的药物是抗生素和抗癌治疗药物，如顺铂。顺铂通常用于治疗多种癌症，包括髓母细胞瘤、神经母细胞瘤、骨肉瘤、睾丸癌、卵巢癌、宫颈癌、膀胱癌、肺癌和头颈癌，被认为是目前使用的最具耳毒性的药物之一。开发一种耳保护疗法来对抗化疗引起的听力损失将对患者的生活质量产生重大影响。这在治疗儿童时尤其重要，因为他们更容易受到药物引起的永久性听力损失的影响。这项I期SBIR提案涉及基于类固醇的治疗方法的制造，以防止化疗引起的耳毒性。本提案的具体目的是为鼓室内植入类固醇制剂的早期发展提供路线图。本建议的具体目的有三个：首先，将开发治疗制剂的初始组合物以纳入所需的治疗剂量。其次，所开发的治疗制剂将利用体外分析进行表征。这些研究将产生一种已知治疗剂量和预测体内给药时间的铅制剂。第三，将使用适当的动物模型对治疗制剂进行表征，以确定药物在体内的释放和功效。O-Ray的研究团队具有独特的资格来执行本文提出的工作，并且在耳科，药物开发和药物输送方面具有专业知识，可以成功开发该产品。O-Ray科学家已经成功开发出目前用于临床的治疗配方。这包括一种眼内缓释类固醇植入物，能够在单次植入后维持玻璃体内抗炎药物水平长达3年。该项目的第二阶段将包括完成最终配方，以便在GMP条件下扩大生产规模，测试这些配方的稳定性和无菌性，以及在两种物种中进行GLP药代动力学动物研究，足以获得新药研究豁免。这项工作的完成将最终促进与公司合作伙伴的合作，以获得我们开发的产品的许可。

DESCRIPTION (provided by applicant): Chemotherapy-induced ototoxicity is damage to the inner ear that is caused by the side effects of administered drugs. This can lead to permanent hearing loss and/or tinnitus (continuous ringing in the ear) in the patient. Some of the most common kinds of drugs causing ototoxicity are antibiotics and anti-cancer therapeutics such as cisplatin. Cisplatin is commonly used for the treatment of a variety of cancers, including medulloblastoma, neuroblastoma, osteosarcoma, and testicular, ovarian, cervical, bladder, lung, and head and neck cancers and is considered one of the most ototoxic drugs in use. The development of an otoprotective treatment to combat chemotherapy-induced hearing loss would have a significant impact on patient quality of life. This is particularly important when treating children as they are more susceptible to drug induced permanent hearing loss. This Phase I SBIR proposal involves the fabrication of steroid based therapeutic treatments for protection against chemotherapy induced ototoxicity. The specific aims of this proposal present a roadmap towards the early stage development of steroid formulations for intratympanic implantation. The specific aims of this proposal are threefold: First, the initial composition of the therapeutic formulation will be developed to incorporate the desired therapeutic dose. Second, the developed therapeutic formulation will be characterized utilizing in vitro analyses. These studies will produce a lead formulation with known therapeutic dose and predicted dosing duration in vivo. Third, the therapeutic formulation will be characterized using appropriate animal models in order to determine the drug release and efficacy in vivo. The team of investigators at O-Ray is uniquely qualified to perform the work proposed herein, and has expertise in otology, drug development and drug delivery for the successful development this product. O-Ray scientists have successfully developed therapeutic formulations that are currently being used in the clinic. This includes an intraocular sustained release steroid implant capable of maintaining anti-inflammatory intravitreal drug levels for periods of up to 3 years from a single implantation. Phase II of this project will involve completion of a final formulation for a scale up in manufactue in GMP conditions, the testing of stability and sterility of these formulations, and GLP pharmacokinetic animal studies in two species sufficient to lead to an Investigational New Drug Exemption. The completion of this work will ultimately facilitate a collaboration with a corporate partner for the licensing of our developed product. PUBLIC HEALTH RELEVANCE: Chemotherapy induced ototoxicity is damage to the inner ear which leads to significant debilitating side effects, such as permanent hearing loss and/or tinnitus (continuous ringing in the ear) in the patient. Some of the most common kinds of drugs causing ototoxicity are antibiotics and anti-cancer therapeutics such as cisplatin, and the damage to hearing is most severe in pediatric patients. This Phase I SBIR proposal involves the development of steroid based therapeutic treatments for protection against chemotherapy induced ototoxicity.