| The purpose of this research work was to develop a rapid-onset systemically effective intranasal delivery system of an anticonvulsant, diazepam for use in acute treatment of status epilepticus. The microemulsion formulations formulated using MiglyolRTM 812 and ethyl lauarate as oil phase; Span 20, sodium dioctyl sulfosuccinate and LabrasolRTM as surfactant; and TranscutolRTM P, phenylethanol and ethanol as cosurfactant provided sufficient DZ solubility (60-98 mg/mL), excellent chemical stability after 2 months of storage at 6, 25 and 45°C, and acceptable permeation rate (3.2 x 10-6 - 4.4 x 10-6 cm/sec) across rabbit nasal mucosa.;In the simultaneous plasma PK and brain distribution studies, the profiles of DZ were evaluated in the plasma and six regions of the brain, i.e. olfactory bulb, olfactory tract, anterior, middle, and posterior segments of cerebrum and cerebellum following IV (1 mg/kg) and IN (2 mg/kg) administration in rabbits and rats using selected DZ microemulsion comprising 1% sodium glycocholate/15% ethyl laurate-25% LabrasolRTM-37.5% TranscutolRTM P-12.5% ethanol-10% water. After IN administration, the DZ was rapidly absorbed into the systemic circulation, and readily and homogenously distributed into brain tissues with a tmax of 5-10 min in rats and rabbits. The bioavailability of DZ in the rat model brain (67.6%) and plasma (68.4%) was 32-47% higher than those observed in rabbit brain (45.9%) and plasma (51.6%). The nearly similar AUCbrain/AUCplasma ratios in rats and 12% lower AUCbrain/AUCplasma ratios observed in rabbits after IN administration than that obtained after IV administration indicates that lipophilic DZ molecules reached the brain predominantly from the blood by crossing the blood-brain barrier after IN administration with no significant direct nose-to-brain transport via olfactory epithelium. The results of toxicity studies demonstrated absence of adverse effects on the cilia and epithelial layer of rabbit nasal mucosa after nasal administration of multiple doses once a day for seven consecutive days. In conclusion, the ethyl laurate-LabrasolRTM based DZ microemulsion system showing a tmax of 2-10 min and bioavailability of 51-68% is a very promising approach to the development of a rapid onset intranasal delivery system of DZ for use in the treatment of convulsive attack phenomena of epilepsies. |
