PREPARATION OF ESTRADIOL SUBMICRON EMULSIONS TO IMPROVE BRAIN TARGETING THROUGH THE NASAL ROUTE IN RATS

摘要

Estradiol (E_2)-loaded submicron emulsions (SE) were prepared with the aim of improving brain targeting of E_2 through the nasal route. E_2-SE was administered to male Wistar rats, either intranasally or intravenously, at a dose of 0.48 mg kg~(-1). The levels of E_2 in the blood were investigated and the levels of E_2 in the cerebrospinal fluid (CSF) in rats were evaluated using the microdialysis method. The plasma levels achieved following intranasal administration (C_(max) 34.2 ± 8.8 ng·ml~(-1); AUC_(plasma) 4235.7 ± 1073.2 ng·min·ml~(-1)) were significantly lower than those after intravenous administration (C_(max) 123.4 ± 24.5 ng·ml~(-1); AUC_(pisama) 11632.2 ± 3902.3 ng·min·ml~(-1)), while the CSF concentrations achieved after intranasal administration (Cmax 97.3 ± 20.4 ng·ml~(-1); AUC_(csf) 17387.1 ±2294.5 ng·min·ml~(-1)) were significantly higher than those after intravenous administration (C_(max) 42.8 ± 18.6 ng·ml~(-1); AUC_(csf) 9505.1±4452.8 ng·min·ml~(-1)). The drug targeting index (DTI) for the nasal route was 5.0, and the drug targeting percentage (DTP%) was 80.1%. These results showed that the E_2 must be directly transported from the nasal cavity into the CSF in rats. In comparison with the E2 inclusion complex in our previous study, E_2-SE significantly improved the transport of E_2 into the CSF, and exhibited greater brain targeting efficiency.