Rapid-onset intranasal delivery of anticonvulsants: pharmacokinetic and pharmacodynamic evaluation in rabbits

Intranasal (IN) administration is a promising approach for rapid-onset deli very of medications. In order to assess the feasibility of this approach fo r the emergency treatment of status epilepticus, three anticovulsants, i.e. diazepam (DZ), clonazepam (CZ), and a monocarbamate-based new compound (MC A) were studied in rabbits for the pharmacokinetics (PK) and pharmacodynami c (PD) response following intravenous (IV) and IN administrations. The anim als were intranasally dosed with DZ (1 mg/kg), CZ (0.2 mg/kg), and MCA (5 m g/kg), dissolved in 200 mu l of vehicle consisting of propylene glycol (PG) , ethanol (EtOH), and water in the presence or absence of 1% sodium glycoch olate (SGC) using single and repeated dosing schedules. Both DZ and CZ were absorbed very rapidly from 1% SGC/60% PG-30% EtOH-10% Water after IN singl e application; the T-max's were less than 2 min. The absorption rate of MCA was relatively slower with the peak time of 13-32 min. The bioavailability of single IN administration for DZ, CZ, and MCA determined over the first 2 or 4 h was found to be 77, 45, and 79%, respectively. The peak plasma lev el of DZ increased linearly with increasing the volume fraction of EtOH in the ternary cosolvent (20% to 60%). A repeated IN application of DZ, 5 min after the first dose, doubled the C-max and AUC(0-2 h) values of the first one, whereas those of CZ and MCA resulted in an increase of 73-94% of the f irst dose. A single IN application of DZ- and CZ-containing formulations pr oduced a PD response within 1.5 min, which was comparable to that of an IV injection. These results suggest that single or repeated IN applications of DZ, CZ, and MCA in a hydroalcoholglycolic formulation might represent a vi able approach to achieving a rapid systemic absorption of these anticonvuls ants during the emergency treatment of status epilepticus and other types o f seizures. (C) 2000 Elsevier Science B.V. All rights reserved.