突发性感音神经性听力损失，常伴有耳鸣症状，严重影响患者的生活质量。目前的治疗方法，如通过静脉注射或鼓室内注射地塞米松和利多卡因等游离药物，面临着生物利用度低和药物清除快等局限性。为了应对这些挑战，本研究开发了一种联合药物递送系统，该系统结合了地塞米松微晶（Dexamethasone Microcrystals, DEX MCs）和负载利多卡因的聚乳酸-羟基乙酸共聚物非球形微颗粒（Lidocaine-loaded Poly (lactic-co-glycolic acid) Non-spherical Microparticles, LPNMs），可持续释放药物至内耳。本研究分别采用沉淀法和复乳-溶剂挥发法制备了DEX MCs和LPNMs，将二者混悬于透明质酸钠溶液中进行鼓室内注射。结果表明药物在豚鼠外淋巴液中的保留时间延长，药代动力学得到改善，可避免潜在的副作用。组织学评估没有观察到明显的内耳损伤，证实了这种联合药物递送系统具有良好的生物相容性。该联合药物递送系统可用作向内耳输送地塞米松和利多卡因的药库，为协同治疗伴有耳鸣的突发性感音神经性听力损失提供了一种极具潜力的给药策略。

本研究工作主要包含以下三个部分：

1.以地塞米松和利多卡因为原料药，分别采用沉淀法和复乳-溶剂挥发法制备了DEX MCs和LPNMs并对其理化性质进行了表征，随后将二者混悬于透明质酸钠溶液中构建DEX MCs + LPNMs联合给药系统。结果表明，利多卡因成功负载在LPNMs上，载药量和包封率分别达21.5 % ± 0.9 % 和75.3 % ± 3.2 %。透明质酸钠溶液增强了DEX MCs + LPNMs混悬液的分散性，使体系更加稳定。在体外释放研究中，LPNMs呈现出一定的缓释行为，其释放机制符合Fickian扩散。

2.在动物水平上，经鼓室注射DEX MCs + LPNMs混悬液后，考察微粒在圆窗膜的分布行为及药物在内耳外淋巴液中的药代动力学水平。光镜和扫描电镜图像表明，大量DEX MCs沉积在LPNMs表面，LPNMs和少量DEX MCs沉积在圆窗膜上，构成双系统、双药物联合的储库。药代动力学结果显示，透明质酸钠溶液提高了地塞米松的吸收效率，LPNMs的加入延长了地塞米松在外淋巴液存在的时间。相较于盐酸利多卡因溶液，LPNMs 作为药物储库呈现出明显的缓释效应，并可避免短时间外淋巴中利多卡因浓度骤升。

3. 在动物水平上考察了DEX MCs和LPNMs的生物相容性，为进一步的体内药效学研究奠定基础。结果表明，血管纹组织、柯蒂氏器、螺旋神经节等耳蜗组织维持了正常的结构和形态。耳蜗毛细胞形态完好，排列整齐，无融合或缺失等病理变化，说明DEX MCs及LPNMs具有良好的生物相容性。

Sudden sensorineural hearing loss (SSNHL) significantly impacts individuals’ quality of life, often accompanied by tinnitus. Current treatments, such as free drugs via intravenous or intratympanic (IT) administration of dexamethasone (DEX) and lidocaine, face limitations like low bioavailability and rapid drug clearance. To address these challenges, this research developed a local co-delivery system combining DEX microcrystals (DEX MCs) and lidocaine-loaded poly (lactic-co-glycolic acid) (PLGA) non-spherical microparticles (LPNMs) for sustained drug release in the inner ear. DEX MCs and LPNMs were prepared using the traditional precipitation technique and double emulsion-solvent evaporation, respectively. Then they were dispersed in sodium hyaluronate solution for IT injection. In vivo studies in guinea pigs demonstrated prolonged drug retention in the perilymph and improved pharmacokinetics, which may help to avoid potential side effects. Histological evaluation confirmed the good biocompatibility of this combined delivery system, with no significant inner ear damage observed. This co-delivery system can be used as a depot for delivering both DEX and lidocaine to the inner ear, offers a promising approach for the synergistic treatment of SSNHL associated with tinnitus.