Pharmacokinetics and pharmacodynamics of nasally delivered midazolam.
OBJECTIVE
To investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5-30 mg ml(-1)) complexed with cyclodextrin.


METHODS
An 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.


RESULTS
Mean bioavailability of midazolam after nasal administration ranged from 76 +/- 12% to 92 +/- 15%. With formulations delivering 1 mg midazolam, mean C(max) values between 28.1 +/- 9.1 and 30.1 +/- 6.6 ng ml(-1) were reached after 9.4 +/- 3.2-11.3 +/- 4.4 min. With formulations delivering 3 mg midazolam, mean C(max) values were between 68.9 +/- 19.8 and 80.6 +/- 15.2 ng ml(-1) after 7.2 +/- 0.7-13.0 +/- 4.3 min. Chitosan significantly increased C(max) and reduced t(max) 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 +/- 0.15 and 1.06 +/- 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 +/- 78 ms and 19 +/- 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.


CONCLUSIONS
Effective 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 RMbetaCD combined with the absorption enhancer chitosan.
Haschke
Manuel
M
Division of Clinical Pharmacology & Toxicology, University of Basel, Basel, Switzerland. mhaschke@uhbs.ch
Suter
Katja
K
Hofmann
Sarah
S
Witschi
Robert
R
Fröhlich
Johannes
J
Imanidis
Georgios
G
Drewe
Jürgen
J
Briellmann
Thomas A
TA
Dussy
Franz E
FE
Krähenbühl
Stephan
S
Surber
Christian
C
D000281:Administration, Intranasal; D000328:Adult; D019540:Area Under Curve; D001672:Biocompatible Materials / Q000008:administration & dosage; D001682:Biological Availability; D048271:Chitosan / Q000008:administration & dosage; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003505:Cyclodextrins / Q000008:administration & dosage; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
D001672:Biocompatible Materials; D003505:Cyclodextrins; D006993:Hypnotics and Sedatives; D048271:Chitosan; D008874:Midazolam