Transmucosal nasal drug delivery : systemic bioavailability of nasally applied midazolam

Suter-Zimmermann, Katja. Transmucosal nasal drug delivery : systemic bioavailability of nasally applied midazolam. 2008, PhD Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_8343


Transmucosal nasal drug delivery is a drug delivery option for challenging clinical situations where common drug administrations (e.g., intravenous, intramuscular, or oral) are inapplicable. For drugs with constricted oral bioavailability, due to degradation in the intestinal tract or hepatic first-pass metabolism, transmucosal nasal delivery is a convenient alternative to intravenous and intramuscular drug administration. The considerable blood flow, actually responsible for breath conditioning, benefits efficient systemic drug uptake and provides direct access to the systemic circulation for transmucosal absorbed drugs. Often, in nasal drug delivery the limited nasal capacity is disregarded and the instilled volumes exceed the limited capacity of the nose. Consequently, the administered preparations are partially swallowed and resulting pharmacokinetic characteristics refer to a combination of transmucosal nasal and gastrointestinal drug absorption. Due to low midazolam concentration, the commercially available preparations for intravenous administration (e.g. Dormicum , Roche) is inappropriate for transmucosal nasal midazolam delivery. For the optimization of transmucosal nasal midazolam delivery minimized administration volumes are essential to prevent swallowing of nasally administered preparations. Therefore, nasal preparations with enhanced midazolam concentrations need to be provided. In Project I different preparations for transmucosal nasal midazolam delivery were developed. The impact of vehicle and application modality on the pharmacokinetics of nasally applied midazolam was studied by administration of the developed preparations to healthy volunteers (Project II). The benefit of two nasal midazolam preparations for procedural anxiolysis in anxious patients undergoing MRI examinations was compared (Project III). Project I: Midazolam solubilization with RMβCD (randomized methylated-β-cyclodextrin, a cyclodextrin derivative) facilitated compounding of midazolam preparations adjusted to the limited volumetric capacity of the nose. RMβCD (added in equimolar or higher concentration to solubilize midazolam) reduced midazolam release in drug release studies with semi-permeable cellophane membranes (in vitro). Stability data affirmed shelf life of at leastmonths for RMβCD containing nasal midazolam preparations. Addition of chitosan hydrochloride (penetration enhancer) affected midazolam stability; therefore shelf life of the chitosan containing nasal midazolam preparation was reduced. The developed preparations for transmucosal nasal midazolam delivery were the basis to study the influence of the vehicle and the application modality on pharmacokinetics and systemic bioavailability of nasally applied midazolam (Project II).
Project II: Pharmacokinetic characteristics following nasal application of 1 mg midazolam
(Preparation 1, 2, and 3) and 3 mg midazolam (Preparation 4 and 5) were compared with
pharmacokinetic characteristics of 1 mg i.v. administered midazolam (Dormicum®, Roche). The
impact of RMbCD (solubilizer), chitosan hydrochloride (penetration enhancer) and the application
modality (one- versus two-sided nasal administration) was investigated in this open-label study with
healthy volunteers. Volunteers were asked to describe nasal midazolam administration and to
classify local irritation after nasal midazolam administration. Pharmacologic effects were assessed
by computer-controlled self-adjusting reaction time test (CRTT, recording reaction time and
interstimulus interval) and visual analog scale (VAS). Blood samples were serially obtained until
6 hours after midazolam administration. Serum concentrations of midazolam and two metabolites
(a-hydroxymidazolam and 4-hydroxymidazolam) were quantified by liquid chromatography-mass
spectrometry (LC-MS). Non-compartment and two-compartment pharmacokinetic modeling was
performed to estimate pharmacokinetic parameters. Bioequivalence testing was performed
according to the requirements of EMEA (European Agency for the Evaluation of Medicinal
Systemic bioavailability of nasally applied midazolam ranged from 78% (Preparation 5) to 93%
(Preparation 2), differences of bioavailability were not significant. After nasal administration of 1 mg
midazolam by Preparation 1, 2, and 3 mean Cmax was, 28.1 ± 9.1 mg/l, 30.1 ± 6.6 mg/l and
28.9 ± 5.4 mg/l, respectively. After nasal administration of 3 mg midazolam by Preparation 4 and 5
Cmax was, 72.6 ± 18.2 mg/l, and 82.2 ± 15.8 mg/l, respectively. Following nasal midazolam
administration tmax was between 7.1 ± 0.6 minutes (Preparation 5) and 11.7 ± 2.4 minutes
(Preparation 4). All tested nasal administration modalities to deliver 1 mg midazolam proved
bioequivalence. For Preparation 4 and Preparation 5 bioequivalence was not confirmed. The serum
concentration time profiles of the midazolam metabolites (a-hydroxymidazolam and 4-
hydroxymidazolam) demonstrated exclusive transmucosal absorption of nasally applied
midazolam. Swallowing of nasally delivered preparations was prevented and hepatic first-pass
effect successfully circumvented. Consequently, the assessed pharmacokinetic parameters
characterized pure transmucosal nasal midazolam delivery.
Neither RMbCD (equimolar to midazolam) nor application modality (one- or two-sided) changed
absorption kinetics of nasally administered midazolam, whereas chitosan hydrochloride promoted
absorption of nasally applied midazolam. Significant higher midazolam serum concentrations were
achieved faster. The outcome of the pharmacokinetic study emphasizes the decisive role of
minimized nasal application volume to prevent swallowing of nasally applied preparations and to
provide for exclusive transmucosal midazolam absorption.
Project III: In this randomized multicenter trial with 110 anxious and/or claustrophobic patients
undergoing MRI examinations, two nasal preparations for low-dose midazolam delivery,
Midazolam MD Nasal Spray 5 mg/ml (MD) and Midazolam UD Nasal Spray 1 mg (UD), were
compared. Nasal administration of 1 mg or 2 mg midazolam was provided before MRI examination.
Within both groups anxiety reduction was significant, but there was no difference in anxiety
reduction between the MD and UD group. Local irritation following administration of UD nasal spray
was slightly more intense than local irritation after administration of MD nasal spray.
Nasal delivery of low-dose midazolam is a safe therapy to provide procedural anxiolysis in patients
undergoing MRI examinations. The two compared low-dose midazolam preparations for
transmucosal nasal delivery of midazolam proved therapeutic equivalence. Hence, anxious and/or
claustrophobic patients equally benefit from procedural anxiolysis during MRI examinations
following administration of low-dose midazolam by MD nasal spray or UD nasal spray. Concerning
convenient handling, administration to laying patients, and hygienic aspects the new midazolam
nasal spray (UD) is superior to the commonly used midazolam multidose nasal spray (MD).
Overall, the presented nasal preparations facilitated characterization of exclusive transmucosal
nasal absorbed midazolam. In vivo neither RMbCD (equimolar to midazolam) nor administration
modality changed the pharmacokinetic profile of nasally applied midazolam. Chitosan
hydrochloride promoted nasal midazolam absorption but clinical relevance (e.g., for the treatment
of status epilepticus) is to be verified in further clinical investigations. High systemic bioavailability
of nasally applied midazolam demonstrated the veritable potential of transmucosal nasal drug
delivery as alternative to invasive drug administration.
Advisors:Surber, Christian
Committee Members:Imanidis, Georgios and Leuenberger, Hans
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Klinische Pharmazie (Drewe)
Item Type:Thesis
Thesis no:8343
Bibsysno:Link to catalogue
Number of Pages:188
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:13 Feb 2009 16:31

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