Improved Method of Drug Delivery to the Inner Ear

描述(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是有问题的。耳蜗腔内注射提供了更精确的剂量，但持续时间不长，有效的治疗可能需要多次剂量，这增加了损害耳蜗的风险。其他鼓室内和鼓室内给药的方法，如使用导管、泵(如渗透泵、输液泵)、注射器和药物涂层植入物，由于涉及的复杂机制而复杂。由于内耳给药方面的挑战，许多内耳疾病无法有效治疗。随着新化学物质的药物发现和听力障碍的新知识的最新进展，有效地将药物输送到内耳的需求尚未得到满足。本项目的目标是开发一种强大、持久和安全的药物内耳给药方法，使用缓释温度敏感凝胶和使用离子导入控制给药。温度敏感凝胶系统是室温下的液体，在圆窗壁龛上符合并在体温下固化，将首先进行评估，以通过RWM提供持续的基线内耳给药。这种凝胶将通过鼓室内注射放置在中耳内，与传统的鼓室内注射方法相比具有明显的优势。为了在需要的基础上加强药物从凝胶到内耳的传递，将使用离子导入。除了加强药物输送，离子导入还将用于在治疗过程中需要时补充凝胶中的药物。离子导入将通过放置在外耳的电极与鼓膜电接触来执行，鼓膜又与中耳的凝胶系统接触，中耳的凝胶既是药库，也是电流从外耳的电极到RWM的管道。该项目的最终目标是开发一种有效、耐受性好、易于管理的内耳给药平台。 公共卫生相关性：开发一种强大、持久和安全的内耳给药方法，以利用新知识治疗听力障碍，是一个尚未得到满足的需求。本项目将开始开发一种药物输送方法，使用一种温度敏感的水凝胶，这种水凝胶是室温下的溶液，但在中耳形成凝胶，用于将药物持续输送到内耳。然后将开发出离子导入技术，它可以非侵入性地应用于外耳，以便根据需要从这种水凝胶中控制药物输送。认为该方法可以方便、安全地治疗内耳疾病。

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.