Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

6. Project II: Pharmacokinetic of transmucosal nasal delivered midazolam – impact of adjuvants
6 Project II: Pharmacokinetic of transmucosal nasal
delivered midazolam – impact of adjuvants
6.1 Introduction
Fast onset of action, complete independence of ingestion, and the needle-less application render
nasal application of midazolam to a convenient alternative to common application modes
[Bjorkman, et al. 1997; Goepfert 1996; Malinovsky, et al. 1995; Münte 2002; Tschirch, et al. 2006;
Uygur-Bayramicli, et al. 2002]. Although no nasal midazolam preparation is commercially available,
numerous authors report on successful nasal delivery of midazolam. In most studies and case
reports, Dormicum ® for i.v. application is instilled nasally. Often the volumetric capacity of the nose
(0.1 ml to 0.4 ml per nostril [Penkler 2001]) is exceeded and therefore, a portion of the nasal
administered preparation is swallowed. Consequently, the resulting pharmacokinetic profile is a
combination of nasal and gastrointestinal drug absorption.
To minimize the volume to be applied for nasal delivery of midazolam, preparations with higher
concentration than 5 mg/ml midazolam need to be provided. Addition of solubilization enhancers
(e.g., cyclodextrins) facilitates compounding of midazolam preparations with increased midazolam
concentrations; this allows delivering therapeutic doses by instilling minimized volumes into nasal
cavities.
The solubilization enhancing effect of cyclodextrins, by forming inclusion complexes, is well
established (see chapter 4.3 and Project I). However, the impact of cyclodextrins on
pharmacokinetics of transmucosal delivered drugs is controversially discussed [Illum 2002] and is
assumed to depend on the drug cyclodextrin ratio, as well as on the solubility and the permeation
ability of the compound.
Mucociliary clearance restricts contact time of nasal administered preparations and nasal mucosa;
consequently the period for transmucosal nasal drug absorption is limited. For efficient drug
uptake, absorption promoting or bioadhesive excipients are added to preparations for transmucosal
nasal drug delivery. Chitosan features both, bioadhesion and absorption promoting (see chapter
4.4.3). In addition, Zerrouk et al. showed the synergistic effect of cyclodextrins and chitosan on
drug absorption [Zerrouk et al., 2006].
The aim of this clinical trial was to characterize the impact of the vehicle (RMβCD and chitosan
hydrochloride) and the application modality (e.g., one-sided versus two-sided nasal administration)
on pharmacokinetics of transmucosal nasal delivered midazolam. Pharmacokinetic and
pharmacodynamic parameters of i.v. delivered midazolam (Dormicum ® , Roche) and nasally applied
midazolam (5 different preparations) were assessed in healthy volunteers.
Katja Suter-Zimmermann Page 61 of 188 University of Basel, 2008