The preparation of dexamethasone sodium phosphate multivesicular liposomes thermosensative hydrogel and its impact on noise-induced hearing loss in the Guinea pigs
The preparation of dexamethasone sodium phosphate multivesicular liposomes thermosensative hydrogel and its impact on noise-induced hearing loss in the Guinea pigs
复制标题
地塞米松磷酸钠多囊脂质体热敏水凝胶的制备及其对噪声性豚鼠听力损失的影响
DOI：
10.1016/j.yexcr.2019.111755
复制
发表时间：
2020-02-01
影响因子：
3.7
通讯作者：
Dai, Chunfu
中科院分区：
文献类型：
--
作者：
Li, Yu;Zhang, Ru;Dai, Chunfu
目的：本研究的目的是建立地塞米松磷酸钠多囊脂质体温敏凝胶目的：研究DEX-MVLs-Gel（DEX-MVLs-Gel）给药系统的药效学、药代动力学和安全性，并探讨DEX-MVLs-Gel对噪声暴露豚鼠听力的保护作用。采用复乳法制备DEX-MVL制剂，并在DEX-MVL中加入P407和P188制备DEX-MVL凝胶。选用20只成年白化病豚鼠建立噪声性听力损失动物模型。分别用浓度为20、6和2 mg/mL的DEX-MLVs-Gel和5 mg/mL地塞米松磷酸钠（DEX-P）溶液处理动物后，评估听力功能、外周淋巴液中药物浓度和毛细胞形态。结果：20 mg/mL DEX-MVL-凝胶治疗组在4、8、16和24 kHz频率下的ABR阈值测量为47.5 +/- 5.2、48.3 +/- 4.1、48.4 +/- 4.1、48.5 +/- 4.1、4.5 +/-4.1 55.8 +/- 3.8和57.5 5 +/- 5.2 dB SPL。在20 mg/mL DEX-MVL-凝胶处理组和对照组之间在每个频率下观察到统计学显著性（均P < 0.05），在2 mg/mL和6 mg/mL DEX-MVL-凝胶处理组之间在4和8 kHz频率下观察到统计学显著性（均P < 0.05）。高效液相色谱法（HPLC）检测结果显示，鼓室内注射后第1、3、7天各组外周淋巴液中药物浓度均逐渐降低。结论：高浓度（20 mg/mL）的DEX-MVLs-Gel对噪声性听力损失豚鼠有明显的保护作用。所制备的DEX-MVL-凝胶在豚鼠外周淋巴液中可有效维持3-7 d，且无明显耳毒性。
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.