Bioavailability and tolerability of intranasal diazepam in healthy adult volunteers

SummaryIntranasal therapy has been proposed as an alternative for the management of seizure emergencies. The bioavailability, dose proportionality and tolerability of a supersaturated intranasal formulation of diazepam (DZP) solubilized in a glycofurol–water cosolvent system was investigated. Eight healthy volunteers were randomized into a single-blind, three-way crossover study to compare 5 and 10 mg intranasal DZP doses of the investigational formulation with a 5 mg dose of a DZP solution (DZP injectable, 5 mg/mL) administered intravenously. Treatments were separated by a two-week washout period. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 48 h post-dose and assayed by HPLC. Visual analog scales (VAS) were used to assess tolerability (1-tolerable; 10-extremely intolerable) and pain (1-no pain; 4-extreme pain) at predefined time points. Following the 5 and 10 mg doses, the median tmax were 20 and 30 min and the mean Cmax were 134.3 ± 62 and 247.6 ± 61 ng/mL. Estimated bioavailability was 75% for both doses. Pain scores of 2 and 2.3 were observed following the 5 and 10 mg doses; tolerability scores were 4.4 and 4.7. Pain and tolerability scores returned to baseline within 10 h. Our formulation provided reasonable bioavailability, but was not well tolerated.