耳后注射异硫氰酸荧光素标记葡聚糖的可能转运途径

目的 探讨耳后注射异硫氰酸荧光素标记的葡聚糖(FITC-Dextran)进入内耳的可能途径.方法 以异硫氰酸荧光素标记的葡聚糖(分子量为3 000~5 000,20 μl)为示踪剂,将200只出生24 h内的昆明乳鼠随机分为耳后对照组[5 mg/ml的葡聚糖(Dextran)20 μl耳后注射]、耳后实验组(5 mg/ml的FITC-Dextran 20 μl 耳后注射)、肌注对照组(5 mg/ml的葡聚糖20 μl 肌肉注射)、肌注实验组(5 mg/ml FITC-Dextran 20 μl 肌肉注射),每组50只;于给药后0 min、5 min、15 min、30 min、1 h、3 h、5 h、7 h、12 h、24 h处死动物,取其头颅做冰冻切片,应用激光共聚焦成像技术观察分析荧光示踪剂在乙状窦、内淋巴囊及耳蜗的分布及强度变化,以实验组与相应对照组荧光强度比值为强度值.结果 肌注实验组乙状窦在给药后3 h、内淋巴囊及耳蜗在给药后12 h可检测到荧光强度轻度增高,其余各部位各时间点均未检测出明显荧光增强.耳后实验组耳后注射示踪剂后,乙状窦、内淋巴囊分别在给药后即刻、耳蜗在给药后30 min可观察到荧光信号,随后荧光强度随时间延长依次升高,乙状窦、内淋巴囊、耳蜗的荧光强度达峰值时间分别为给药后5~15、30、60 min,到12小时强度均再次小幅度升高.结论 药物在耳后注射较肌肉注射更易于进入内淋巴液,可能径路为:示踪剂首先通过局部循环和局部渗透至乙状窦内富集,随后通过乙状窦与内淋巴囊间的脉络关系进入内淋巴液,最终逆内淋巴浓度梯度作用于内耳.     

Insoluble Powder Formulation as an Effective Nasal Drug Delivery System

Purpose. To evaluate the utility of insoluble powder formulation for nasal systemic drug delivery. Methods. To compare the efficacy of liquid and powder formulations, the nasal absorption of drugs was examined in rats using hydrophilic compounds with various molecular weights (MW) such as phenol red, cyanocobalamin, and fluorescein isothiocyanate (FITC)-Dextrans, and several kinds of powder. Intranasal residence time was also compared among the different formulations. Results. All the drugs examined were absorbed through the nasal mucosa to varying extent; their systemic bioavailability decreased with increasing MW. Insoluble calcium carbonate (CaCO₃) powder formulation provided increased absorption of drugs over the wide range of MW from 354 to 77,000 Da. In the case of phenol red, intranasal administration as a CaCO₃ powder formulation resulted in a plasma concentration profile similar to that of an intravenous bolus dose due to its very rapid and complete absorption from the nasal cavity. Furthermore, improved bioavailability of FITC-Dextran (MW 4,400; FD-4) was also achieved with other insoluble powders as well as CaCO₃, but not with soluble powders such as lactose, d-sorbitol, and d-mannitol. Insoluble powder formulation prolonged the residence time of FD-4 within the nasal cavity. Conclusions. Insoluble powder formulations improve nasal bioavailability predominantly by retarding drug elimination from the absorption site and appear to be effective for nasal systemic drug delivery.