Improved Method of Drug Delivery to the Inner Ear

内耳药物输送的改进方法

• 批准号: 7948601
• 负责人: Kevin S. Li
• 金额: $ 20.89万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7948601
• 关键词: Adrenal Cortex Hormones; Adverse effects; Adverse event; Animal Model; Animals; Body Surface; Body Temperature; Catheters; Cells; Chemicals; Chronic; Cidofovir; Complex; Computer Systems Development; Deposition; Development; Dexamethasone; Diffusion; Distal; Dose; Drug Controls; Drug Delivery Systems; Electrodes; Eustachian Tube; Evaluation; External Ear; External auditory canal; Gel; Goals; Health Care Costs; Hearing problem; Hydrogels; In Vitro; Infusion Pumps; Injection of therapeutic agent; Iontophoresis; Kinetics; Knowledge; Labyrinth; Lead; Liquid substance; Literature; Mechanics; Membrane; Metabolic Clearance Rate; Methods; Modeling; Molecular; Needles; Pharmaceutical Preparations; Polymers; Pump; Risk; Sol-Gel Phase Transitions; Solutions; Source; Structure; System; Technology; Temperature; Therapeutic Agents; Time; Toxic effect; Transition Temperature; Tympanic membrane; base; copolymer; drug clearance; drug discovery; effective therapy; electric field; hearing impairment; implant coating; improved; in vivo; in vivo Model; inner ear diseases; middle ear; novel; ototoxicity; physical property; public health relevance; residence; round window

DESCRIPTION (provided by applicant): The existing methods of drug delivery to the inner ear such as the deposition of therapeutic agents in the middle ear on the round window membrane (RWM) by intratympanic injections are not very effective. Systemic corticosteroid therapy is also problematic due to systemic side effects. Intracochlear injections provide more precise dosing but are not long lasting that effective treatments may require multiple dosing, this increasing the risks of damaging the cochlear. Other methods of intratympanic and intracochlear delivery such as the use of catheters, pumps (e.g., osmotic pump, infusion pump), injectors, and drug coated implants are complicated due to the complex mechanics involved. Because of the challenges in inner ear drug delivery, many inner ear disorders cannot be treated effectively. With the recent advances in drug discovery of new chemical entities and new knowledge in hearing disorders, there is an unmet need to effectively deliver drugs to the inner ear. The objective of the present project is to develop a robust, long- lasting, and safe method of drug delivery to the inner ear using a sustained release temperature sensitive gel and controlled delivery using iontophoresis. A temperature sensitive gel system that is a liquid at room temperature to conform on the round window niche and solidify at body temperature will first be evaluated to provide sustained baseline inner ear delivery via the RWM. This gel will be placed in the middle ear by intratympanic injection, and has a significant advantage over the conventional intratympanic injection method. To enhance drug delivery from the gel to the inner ear on an as-needed basis, iontophoresis will be used. In addition to enhance drug delivery, iontophoresis will also be used to replenish the drug in the gel when needed over the treatment. Iontophoresis will be performed with the electrode placed in the external ear in electrical contact with the tympanic membrane, which in turn is in contact with the gel system in the middle ear, with the gel in the middle ear serves as both the drug depot and a conduit of the electric current from the electrode in the external ear to the RWM. The ultimate goal of the project is to develop a drug delivery platform for inner ear delivery that is effective and well tolerated while easy to administer. PUBLIC HEALTH RELEVANCE: There is an unmet need to develop a robust, long lasting, and safe drug delivery method for the inner ear to take advantage of the new knowledge in the treatment of hearing disorders. The present project will begin the development of a drug delivery method using a temperature sensitive hydrogel that is a solution at room temperature but gel in the middle ear for sustained drug delivery to the inner ear. Iontophoresis will then be developed that can be applied noninvasively to the external ear for controlled drug delivery from this hydrogel on an as-needed basis. It is believed that this method can allow convenient and safe treatment of inner ear diseases.

描述（由申请人提供）：现有的内耳给药方法，如鼓室内注射将治疗剂沉积在中耳的圆窗膜（RWM）上，效果不是很好。由于全身副作用，全身皮质类固醇治疗也存在问题。耳蜗内注射提供更精确的剂量，但持续时间不长，有效的治疗可能需要多次给药，这增加了损害耳蜗的风险。其他鼓室内和耳蜗内给药的方法，如导管、泵（如渗透泵、输液泵）、注射器和药物包被植入物的使用，由于涉及复杂的力学，是复杂的。由于内耳给药困难，许多内耳疾病无法得到有效治疗。随着新化学实体药物的发现和听力疾病治疗的新进展，如何有效地将药物输送到内耳是一个尚未满足的需求。本项目的目标是开发一种强大的，持久的，安全的药物输送到内耳的方法，使用缓释温敏凝胶和离子电泳控制输送。首先将评估一种温度敏感凝胶系统，该系统在室温下为液体，符合圆形窗口壁龛，并在体温下固化，以通过RWM提供持续的基线内耳输送。这种凝胶将通过鼓室内注射的方式放置在中耳内，与传统的鼓室内注射方法相比具有显著的优势。为了在需要的基础上加强药物从凝胶到内耳的输送，离子电泳将被使用。除了加强药物输送，离子透入也将用于补充凝胶中的药物在治疗期间需要时。离子导入将电极放置在外耳中，与鼓膜电接触，鼓膜又与中耳中的凝胶系统接触，中耳中的凝胶既充当药物库，又充当电流从外耳电极到RWM的管道。该项目的最终目标是开发一种有效、耐受性良好、易于管理的内耳给药平台。