Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

8 Overall discussion
considered as unfavorable. Consequently, by applying only equimolar amounts of RMβCD (2%,
4%, and 12% to solubilize 5 mg/ml, 10 mg/ml, and 30 mg/ml midazolam) the pH of the nasal
preparations could not be adapted to physiologic pH due to limited midazolam solubility. Despite
low pH of the tested preparations (pH 3 to 4), no volunteer did rate the nasal administration as
painful and nasal irritation was reversible within 30 minutes.
As the proposed preparations are not supposed for long term therapies but for sporadic application
(e.g., treatment of status epilepticus and procedural anxiolysis or sedation) some reversible local
irritation may be tolerable.
For transmucosal nasal drug delivery there is no recommendation whether the dose is preferably
administered one-sided or two-sided. Commercially available nasal preparations for systemic
treatment (e.g., Zomig ® nasal, AstraZeneca, Zug, Switzerland) are supplied in unit dose systems
for one-sided administration. The blood vessels inside the lining of the nose become engorged in a
cyclic fashion, which causes congestion and then decongestion of the linings of each side of the
nose. This so-called ‘nasal cycle’ is detectable in about 80% of the population [Hasegawa and Kern
1977]. The impact of this nasal cycle on transmucosal nasal drug delivery is unknown. Against this
background two-sided nasal drug delivery may be preferable even though one-sided and two-sided
nasal administration of a given midazolam dose (1 mg) resulted in identical serum concentration
time profiles.
Katja Suter-Zimmermann Page 100 of 188 University of Basel, 2008