Ototoxicity protection with intratympanic steroid implant

描述（由申请方提供）：化疗诱导的耳毒性是由给药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损失和/或耳鸣（耳朵中的连续振铃）。一些最常见的引起耳毒性的药物是抗生素和抗癌药物，如顺铂。顺铂通常用于治疗各种癌症，包括成神经管细胞瘤、成神经细胞瘤、骨肉瘤和睾丸癌、卵巢癌、宫颈癌、膀胱癌、肺癌和头颈癌，并且被认为是使用中最具耳毒性的药物之一。开发耳保护治疗以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，因为他们更容易患上药物引起的永久性听力损失。该I期SBIR提案涉及制造基于类固醇的治疗性治疗，用于保护免受化疗诱导的耳毒性。该提案的具体目标为鼓室内植入类固醇制剂的早期开发提供了路线图。该提案的具体目标有三个方面：首先，将开发治疗制剂的初始组成，以纳入所需的治疗剂量。其次，将利用体外分析表征开发的治疗制剂。这些研究将产生具有已知治疗剂量和预测体内给药持续时间的先导制剂。第三，将使用适当的动物模型表征治疗制剂，以确定体内药物释放和功效。O-Ray的研究人员团队是唯一有资格执行本文提出的工作的团队，并且在耳科、药物开发和药物输送方面具有成功开发本产品的专业知识。O-Ray的科学家们已经成功地开发出了目前正在临床上使用的治疗配方。这包括眼内持续释放类固醇植入物，其能够从单次植入起维持抗炎性玻璃体内药物水平长达3年。该项目的第II阶段将包括完成最终制剂，用于在GMP条件下进行规模放大，检测这些制剂的稳定性和无菌性，以及在两个种属中进行GLP药代动力学动物研究，这些研究足以获得研究性新药豁免。这项工作的完成将最终促进与公司合作伙伴的合作，以获得我们开发产品的许可。 公共卫生相关性：化疗诱导的耳毒性是对内耳的损伤，其导致显著的使人衰弱的副作用，例如患者的永久性听力损失和/或耳鸣（耳朵中的连续铃声）。一些最常见的引起耳毒性的药物是抗生素和抗癌药物，如顺铂，对儿童患者听力的损害最严重。该I期SBIR提案涉及开发基于类固醇的治疗性治疗，以保护免受化疗诱导的耳毒性。

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.