Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

6. Project II: Pharmacokinetic of transmucosal nasal delivered midazolam – impact of adjuvants
Figure 6-10 shows the serum concentration time profiles of α-hydroxymidazolam (main metabolite
of midazolam) following i.v. and nasal delivery of 1 mg midazolam (Preparation 1, 2, and 3) and
nasal delivery of 3 mg midazolam (Preparation 4 and 5).
5.0
α-hydroxy-midazolam serum concentration [ug/L]
4.0
3.0
2.0
1.0
α-hydroxy-m idazolam , i.v. (1m g)
α-hydroxy-m idazolam , P1 (1m g)
α-hydroxy-m idazolam , P2 (1m g)
α-hydroxy-m idazolam , P3 (1m g)
α-hydroxy-m idazolam , P4 (3m g)
α-hydroxy-m idazolam , P5 (3m g)
0.0
- 60 120 180 240 300 360
Time [min]
Figure 6-10: Serum concentration of α-hydroxymidazolam after i.v. (Dormicum ® ) and nasal delivery of
1 mg midazolam (Preparation 1, 2, and 3) and nasal delivery of 3 mg midazolam (Preparation 4 and 5);
P: Preparation.
Table 6-6 summarizes pharmacokinetic parameters of α-hydroxymidazolam following i.v.
(Dormicum ® , 1 mg) and nasal application of midazolam (1 mg by Preparation 1, 2, and 3 and 3 mg
by Preparation 4 and 5).
There is no significant difference between dose adjusted AUC of α-hydroxymidazolam following i.v.
and nasal delivery of 1 mg midazolam (Dormicum ® , Preparation 1, 2, and 3) and nasal delivery of
3 mg midazolam (Preparation 4 and 5). Following nasal midazolam administration, maximal α-
hydroxymidazolam serum concentrations were reached after 33.3 ± 13.3 min (Preparation 5) and
41.3 ± 13.3 min (Preparation 4). Following i.v. midazolam administration maximal α-
hydroxymidazolam serum concentrations were reached 22.5 ± 11.6 min after midazolam injection.
Maximal 4-hydroxymidazolam (second midazolam metabolite) concentration detected were
0.6 µg/l, 0.2 µg/l following nasal delivery of 3 mg midazolam and administration of 1 mg midazolam
(i.v. and nasal), respectively. Often, 4-hydroxymidazolam was detected, but below LOQ (0.2 µg/l),
see Appendix 10.3.7.
Katja Suter-Zimmermann Page 74 of 188 University of Basel, 2008