OBJECTIVE The aim of this study is to establish the dexamethasone sodium phosphate multivesicular liposomes thermosensative hydrogel (DEX-MVLs-Gel) drug delivery system and to analyze the pharmacodynamics, pharmacokinetics and safety of DEX-MVLs-Gel as well as to explore whether the prepared DEX-MVLs-Gel can protect the hearing in the guinea pigs following noise exposure. METHODS DEX-MVLs formulations were constructed by double emulsion method, and the DEX-MVLs-Gel was prepared after adding P407 and P188 into the DEX-MVLs. A total of 20 adult albino guinea pigs were chosen to establish the animal models with noise-induced hearing loss. After animals were treated with DEX-MVLs-Gel at concentrations of 20, 6 and 2 mg/mL, and 5 mg/mL Dexamethasone Sodium Phosphate (DEX-P) solution, respectively, the hearing function, drug concentration in the peripheral lymph fluid, and hair cell morphology were assessed. RESULTS The ABR threshold of the 20 mg/mL DEX-MVLs-Gel treated group at the frequencies of 4, 8, 16 and 24 kHz were measured as 47.5 ± 5.2, 48.3 ± 4.1, 55.8 ± 3.8 and 57.5 5 ± 5.2 dB SPL, respectively. Statistical significances were noted between the 20 mg/mL DEX-MVLs-Gel treated group and control group at each frequency (all P < 0.05), between the 2 mg/mL and 6 mg/mL DEX-MVLs-Gel treated groups at the frequencies of 4 and 8 kHz (both P < 0.05). High Performance Liquid Chromatography (HPLC) demonstrated that the drug concentrations in the peripheral lymph in all groups were gradually decreased on the 1st, 3rd and 7th d after intratympanic injection. Scattered hair cell loss could be observed mainly in the basal and middle turn in the saline administrated group and the 20 mg/mL DEX-MVLs-Gel administration group, and the hair cell loss was not identified in the apical turn. CONCLUSIONS A high concentration (20 mg/mL) of DEX-MVLs-Gel exerts significant protective effects upon the guinea pigs with noise-induced hearing loss. The prepared DEX-MVLs-Gel can be effectively maintained in the peripheral lymph fluid of guinea pigs for 3-7 d and MVLs-Gel causes no obvious ototoxicity.

中文翻译：

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地塞米松磷酸钠多囊脂质体热敏水凝胶的制备及其对豚鼠噪声性听力损失的影响。

目的本研究的目的是建立地塞米松磷酸钠多囊脂质体热敏水凝胶（DEX-MVLs-Gel）给药系统，并分析DEX-MVLs-Gel的药效学，药代动力学和安全性，并探讨是否制备了DEX-MVLs-Gel。噪声暴露后，DEX-MVLs-Gel可以保护豚鼠的听力。方法采用双乳化法制备DEX-MVLs配方，在PEX-MVLs中加入P407和P188，制备DEX-MVLs-Gel。总共选择了20只成年的白化豚鼠，以建立噪声引起的听力损失的动物模型。用浓度分别为20、6和2 mg / mL和5 mg / mL的地塞米松磷酸钠（DEX-P）溶液的DEX-MVLs-Gel处理动物后，听觉功能 评估外周淋巴液中的药物浓度和毛细胞形态。结果20 mg / mL DEX-MVLs-Gel治疗组在4、8、16和24 kHz频率下的ABR阈值分别为47.5±5.2、48.3±4.1、55.8±3.8和57.5 5±5.2 dB SPL ， 分别。在各频率下，在20 mg / mL DEX-MVLs-Gel处理组与对照组之间的统计学意义（均P <0.05），在2 mg / mL至6 mg / mL DEX-MVLs-Gel处理组之间，具有统计学意义。频率为4和8 kHz（均为P <0.05）。高效液相色谱法（HPLC）显示，在鼓膜内注射后第1、3和7天，所有组的外周淋巴中的药物浓度均逐渐降低。盐水给药组和20 mg / mL DEX-MVLs-Gel给药组的散发性毛细胞丢失主要发生在基底和中部回旋处，而在心尖回旋中未发现毛细胞丢失。结论高浓度（20 mg / mL）的DEX-MVLs-Gel对豚鼠产生了明显的保护作用，其噪声引起的听力损失。所制备的DEX-MVLs-Gel可以有效地维持在豚鼠的外周淋巴液中3-7天，而MVLs-Gel不会引起明显的耳毒性。