- Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, dizziness, discomfort, nasal drainage and bad taste usually accompany subject received midazolam and diazepam via the nasal route. The purpose of this study was to evaluate the use of a new alcohol-free microemulsion system as a carrier for diazepam or midazolam given intranasally. Midazolam (base) or diazepam was solubilized in the microemulsion to obtain a high drug concentration of 25 mg/g (2.5% by weight), to provide 2.5 mg drug in 100 µl spray (d ≈ 1.00 g/ml). The nasal ab-sorption of both drugs from the same microemulsion formulation (containing 20% aqueous phase) was found to be fairly rapid after administration of 0.4 mg/kg to rabbits. The absolute bioavailability of diazepam after intranasal ad-ministration using this formulation was 33.45% ± 12.36% and the t max was 18.33 ± 23.09 min, which was twice longer than the t max obtained after midazolam administration, 9.25 ± 6.75 min. The pharmacokinetic parameters of midazolam in W/O (20% water) microemulsion and their comparison with midazolam in O/W (50% water) microemulsion have shown that both formulations resulted in a relatively short time to reach the peak plasma level (t max), that is, 9.25 ± 6.75 min and 6.75 ± 5.67 min, respectively. However, the peak plasma levels (C max) and the absolute bioavailability (F A) of midazolam were significantly higher after administration of the W/O formulation than those obtained after application of O/W formulation, i.e., 46.62 ± 17.38 µg/ml vs. 15.44 ± 4.00 µg/ml, and 35.19% ± 11.83% vs. 19.83% ± 16.32%, re-spectively. Our results suggest that the new microemulsion system may be useful for getting rapid-onset of midazolam and diazepam following intranasal administration, resulting in reasonable peak plasma levels and bioavailability, but most importantly, providing a high measure of tolerability and comfort.