Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

3. Midazolam
Table 3-2: Benefits and limitations of different administration routes for midazolam application
Administration Benefit
Oral
(solid form)
Oral
(liquid
preparation)
- convenient, painless application
- well accepted by patients
- individual dosing of syrup or drops
- well accepted (if bitter taste of midazolam is
masked)
- convenient, painless application
Limitation
- dose: 7.5 mg or 15 mg
- delayed onset of therapeutic effect
- inappropriate for emergency care
- only 30-50% bioavailability (relevant
interindividual variability)
- delayed onset of therapeutic effect
- children sometimes refuse oral
medication
- inappropriate for emergency care
- only 30-72% bioavailability (relevant
interindividual variability)
- no liquid oral midazolam preparation
commercially available in Europe
Rectal - no swallowing - not well accepted (adults and children)
- 10-20% of children refuse rectal
administration
Intravenous
Intramuscular
Nasal
- fast onset of therapeutic effect
- no swallowing
- emergency care (if veins are accessible)
- fast onset of therapeutic effect
- no swallowing
- fast onset of therapeutic effect
- no swallowing
- painful
- veins are not accessible during status
epilepticus
- children and some adults detest
injections
- painful
- risk of tissue necrosis at the site of
injection
- individual dosing is limited
- no nasal preparation commercially
available
3.4.1 Pharmacokinetic parameters of transmucosal delivered midazolam
In Table 3-3 pharmacokinetic parameters of transmucosal delivered midazolam are summarized. It
has to be taken in consideration, that for transmucosal nasal midazolam delivery different
formulations were used.
Several clinical investigators have used midazolam solution for injection at a concentration of
5 mg/ml (Dormicum ® , 5 mg/ml) for nasal delivery [Bjorkman et al., 1997; Burstein, et al. 1997;
Connors and Terndrup 1994; Fösel 1996; Goepfert 1996; Ljung and Andreasson 1996; Ljungman
2000; Malinovsky et al., 1995; Münte 2002; Tolksdorf and Eick 1991; Uygur-Bayramicli et al.,
2002]. In the cited studies, doses of 0.06 mg/kg to 0.6 mg/kg midazolam were administered by
instilling Dormicum ® (5 mg/ml) into the nose. The administered volume reached from 0.1 ml to 5 ml
according to the bodyweight of patients. By exceeding the commonly recommended application
volumes of 0.05 ml to 0.2 ml, the excess formulation tends draining off into the nasopharynx, where
it is swallowed. The swallowed portion of the nasally delivered midazolam dose is absorbed in the
Katja Suter-Zimmermann Page 28 of 188 University of Basel, 2008