Pharmacokinetics and pharmacodynamics of nasally delivered midazolam

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Nasal application of midazolam has been studied for a variety of indications. Due to the limited application volume, highly concentrated formulations are required to reach clinically relevant concentrations in adult patients. No data on the pharmacokinetics and pharmacodynamics of nasal midazolam formulations based on cyclodextrin and chitosan are available. WHAT THIS STUDY ADDS• Clinically effective midazolam concentrations can be reached within less than 10 min after nasal administration of highly concentrated formulations containing an equimolar amount of the solubilizer randomly methylatedb-cyclodextrin combined with the absorption enhancer chitosan. Immediate non-invasive application of such formulations in emergency treatment of seizure patients by lay persons could offer clinical benefits in situations where intravenous access cannot be quickly established. AIMSTo investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5-30 mg ml METHODSAn open-label sequential trial was conducted in eight healthy subjects receiving single doses of 1 mg and 3 mg intranasally and 1 mg midazolam intravenously. Pharmacokinetic parameters were obtained by non-compartmental and two-compartmental models. Pharmacodynamic effects of midazolam were assessed using VAS and a reaction time test. RESULTSMean bioavailability of midazolam after nasal administration ranged from 76 Ϯ 12% to 92 Ϯ 15%. With formulations delivering 1 mg midazolam, mean Cmax values between 28.1 Ϯ 9.1 and 30.1 Ϯ 6.6 ng ml -1 were reached after 9.4 Ϯ 3.2-11.3 Ϯ 4.4 min. With formulations delivering 3 mg midazolam, mean Cmax values were between 68.9 Ϯ 19.8 and 80.6 Ϯ 15.2 ng ml -1 after 7.2 Ϯ 0.7-13.0 Ϯ 4.3 min. Chitosan significantly increased Cmax and reduced tmax of midazolam in the high-dose formulation. Mean ratios of dose-adjusted AUC after intranasal and intravenous application for 1′-hydroxymidazolam were between 0.97 Ϯ 0.15 and 1.06 Ϯ 0.24, excluding relevant gastrointestinal absorption of intranasal midazolam. The pharmacodynamic effects after the low-dose nasal formulations were comparable with those after 1 mg intravenous midazolam. The maximum increase in reaction time by the chitosan-containing formulation delivering 3 mg midazolam was greater compared with 1 mg midazolam i.v. (95 Ϯ 78 ms and 19 Ϯ 22 ms, mean difference 75.5 ms, 95% CI 15.5, 135.5, P < 0.01). Intranasal midazolam was well tolerated but caused reversible irritation of the nasal mucosa. CONCLUSIONSEffective midazolam serum concentrations were reached within less than 10 min after nasal application of a highly concentrated midazolam formulation containing an equimolar amount of the solubilizer RMbCD combined with the absorption enhancer chitosan.

Intranasal Delivery of Two Benzodiazepines, Midazolam and Diazepam, by a Microemulsion System

“…Wermeling, et al [17] reported a half-life of 3.14 h after 5 mg IV dose of MDZ to healthy volunteers, and Haschke, et al [26] reported a half-life of 1.89 h after 1 mg IV dose of MDZ to human volunteers. Interestingly, t 1/2 values obtained in rats were much closer to our data than those obtained in humans, 55.4 min and 105.5 min for MDZ and DZP, respectively [27].…”

“…Optimal formulation should contain at least 2.5 mg of midazolam in 100 µl solution. Although more concentrated MDZ-HCl solutions [17,21,26] resulted in a relatively high bioavailability in healthy volunteers, the researchers reported that irritation ("burning" sensation) and pain occurred in all subject received midazolam, as well as symptoms like teary eyes, dizziness, and bad taste.…”

Efeitos anestésicos da administração intranasal ou intramuscular de cetamina S+ e midazolam em pomba-rola (Streptotelia sp.)

“…Este fator explica o curto período de latência observado no presente estudo, que foi semelhante à injeção intranasal de midazolam em canários (Vesal & Zare 2006) e cetamina e midazolam em periquitos (Vesal & Eskandari 2006). Alguns possíveis efeitos adversos da administração intranasal em aves incluem aerossaculite devido a contaminação dos sacos aéreos craniais devido a flora presente na cavidade nasal das aves A biodisponibilidade média do midazolam após administração intranasal varia de 76+12%, sendo a concentração sérica efetiva alcançada em menos de 10 minutos em crianças (Haschke et al 2010). Outros estudos revelaram menor biodisponibilidade em humanos (55-57%), entretanto, sendo maior do que as vias oral ou retal, pois não há o metabolismo de primeira passagem (Wallbergh et al 1991, Burstein et al 1997.…”

Nasal Delivery of Biopharmaceuticals

“…Therefore, this polymer improves the intranasal bioavailability of insulin and morphine [76,77]. Conversely, in a pharmacokinetic study, CS increased C max and decreased T max but also decreased the intranasal bioavailability of midazolam solubilized with a cyclodextrin [66]. Their utility as an absorption promoter might be mainly attributable to their ability to mask molecules by trapping them within their hydrophobic cavity and their ease of diffusion within the membrane [78,79].…”

“…They not only increase the solubility of hydrophobic drugs but also facilitate direct permeation through biological barriers because the overall hydrophobicity of the drug-cyclodextrin complex is higher than that of the molecule alone. This combination has been applied advantageously to intranasal administration of molecules such as midazolam [66] and granisetron [67].…”