Midazolam intranasal administration

Midazolam, Triazolam, and Flurazepam The feasibility of intranasal administration of midazolam, flurazepam, and triazolam has been studied and compared with oral absorption in dogs. There was a 3.4-fold increase in the Cmax after nasal administration, from 5.5-8.7ng/mL to 17.4-30.0 ng/mL. The mean tm showed comparable values for both routes. The Tnmx obtained after nasal administration of midazolam was found to be 15 min, as compared with the 15-45 min observed for oral dosing, while the Cmax after nasal administration was 6.5-20.3 ng/mL, as compared with 3.0-8.6ng/mL observed for the oral route. Like midazolam and triazolam, flurazepam also showed a shorter half-life, 15 min, as compared with 15 15 min with oral administration. The Cmax for oral administration was 0.14-0.59 ng/mL after nasal administration it was in the range of 2.6-11.1 ng/mL, a 16.4-fold increase. Since the gastrointestinal tract at bedtime is likely to be in the fed state, causing a twofold decrease in the absorption of midazolam and triazolam, the nasal route may be a better option for the treatment of amnesia, since these drugs cross the nasal mucosa effectively without the use of an absorption enhancer, as shown in these studies [108],... 

FIGURE 19 Fit of composite model to concentration-time data for midazolam and 1-hydroxymidazolam in one volunteer. Solid lines indicate the time course of midazolam concentrations ( ) and 1-hydroxymidazolamconcentrations ( ) after intravenous administration. Dotted lines indicate the time course of midazolam concentrations (A) and 1-hydroxymid-azolam concentrations ( ) after intranasal administration. (Reproduced from ref. Ill with permission of Blackwell Publishing.)... 

Burstein, A. H., Modica, R., Hatton, M., Forest, A., and Gengo, F. M. (1997), Pharmco-kinetics and pharmacodynamics of midazolam after intranasal administration, /. Clin. Pharmacol., 37,711-718. 

Gudmundsdottir H, Sigurjnsdottir JF, Masson M, et al. Intranasal administration of midazolam in a cyclodextrin based formulation bioavailability and clinical evaluation in humans. Pharmazie 2001 56(12) 963-966. 

In a double-blind, crossover, randomized trial in 10 healthy volunteers midazolam 0.2 mg/kg was given by nebulizer and liquid instillation nasally 5 days apart [30 ]. Plasma concentrations were greater after intranasal midazolam. Nasal instillation caused increased sedation but no difference in the time to sedation. There were no respiratory adverse events. Blood pressure and oxygen saturation fell in both groups (peak reduction at 15 minutes) but none required extra oxygen. Mean heart rate and diastolic pressure were increased. The incidence of unpleasant adverse effects was greater after intranasal midazolam, and nasal stinging, eye irritation, hiccups, and excessive secretions were common. One patient with asthma became wheezy after intranasal administration. 

Intranasal midazolam is a successful route of administration for sedating children. However, it can cause nasal burning, irritation, and lacrimation (24). In a study of an alternative route of administration, namely inhalation via a nebulizer, bronchospasm developed in two of the 10 patients studied. This formulation of midazolam has a pH of 3.0, and this was thought to be the reason it caused bronchospasm. 

Drug administration route Intranasal midazolam is used widely and successfully as pre-medication, particularly in children, avoiding first-pass metabolism and increasing systemic availability [29" ]. 

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