Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

6. Project II: Pharmacokinetic of transmucosal nasal delivered midazolam – impact of adjuvants
Transmucosal nasal midazolam absorption was promoted by chitosan hydrochloride. Chitosan
hydrochloride modified absorption kinetics (C max and t max ) of nasally applied midazolam (3 mg), but
overall systemic bioavailability was not enhanced.
Furthermore, smaller ranges for AUC, t max , and C max observed after nasal administration of 3 mg
(Preparation 5) refer to less interindividual variability and therefore reproducible pharmacokinetics.
Bioequivalence testing was performed for all assessed pharmacokinetic parameters (AUC, t max ,
and C max ) following nasal administration of Preparation 4 (reference preparation) and Preparation 5
(test preparation). None of the tested parameters (AUC, t max , and C max ) following nasal
administration of Preparation 5 fulfilled the requirements of the EMEA for bioequivalence.
Accordingly, bioequivalence was not confirmed for Preparation 4 (3 mg midazolam, no chitosan
hydrochloride) and Preparation 5 (3 mg midazolam, 0.5% chitosan hydrochloride).
Chitosan hydrochloride (Preparation 5) promoted absorption kinetics of nasally applied midazolam
and significant higher midazolam serum concentrations were faster achieved. Chitosan
hydrochloride proved valuable penetration enhancer abilities in transmucosal nasal midazolam
delivery. Chitosan hydrochloride potentially facilitates optimization of nasal midazolam preparation
for indications requiring fast onset of therapeutic effects (e.g., status epilepticus). Chitosan
containing nasal midazolam preparations are a promising therapeutic alternative to i.v. delivered
midazolam for the treatment of status epilepticus. Providing reliable anticonvulsive therapy the
more intense nasal irritation, of chitosan containing nasal midazolam preparation (Preparation 5) is
of secondary importance compared to the benefit of needle-free drug delivery.
The congruent metabolite profile after nasal and i.v. administration of 1 mg midazolam supports the
presumption of direct midazolam uptake through nasal mucosa into the systemic circulation. Apart
from slightly earlier peak concentration after i.v. administration, the metabolite profiles after nasal
and i.v. administration of 1 mg midazolam are congruent. In addition, the constant AUC (dose
adjusted) of α-hydroxymidazolam following nasal and i.v. administration of midazolam attests
effective bypassing of the first-pass metabolism. Thus, serum concentration time profiles of the
midazolam metabolites (α-hydroxymidazolam and 4-hydroxymidazolam) demonstrated exclusive
transmucosal absorption of nasally applied midazolam.
Nasal administration of 0.1 ml prevented swallowing of the nasally delivered preparation,
gastrointestinal midazolam uptake, and reduction of systemic bioavailability by hepatic first-pass
metabolism. Consequently, the assessed pharmacokinetic parameters characterized pure
transmucosal nasal midazolam delivery.
This interpretation of metabolite profiles is in accordance with the findings of Heizmann et al., who
demonstrated higher plasma levels for α-hydroxymidazolam following oral administration of
midazolam compared to i.v. midazolam delivery [Heizmann et al., 1983]. Illum et al. were the first
who proved direct transmucosal nasal drug uptake based on the characterization of drug and
metabolite concentration time profiles [Illum, et al. 2002].
Katja Suter-Zimmermann Page 80 of 188 University of Basel, 2008