Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

6. Project II: Pharmacokinetic of transmucosal nasal delivered midazolam – impact of adjuvants
Table 6-6: Pharmacokinetic parameters of α-hydroxymidazolam following i.v. (Dormicum ® 1 mg/ml,
1 mg) and nasal application of midazolam (1 mg, Preparation 1 to 3 and 3 mg, Preparation 4 and 5);
n=8, (SD): standard deviation
Preparation
Nr.
T max
[min]
C max
[µg/l]
AUC 0-∞
[µg *min/l]
T 1/2
[min]
Cal
[l/min]
F
1 mg
i.v.
--- 22.5
(11.6)
1.7
(0.8)
293.8
(73.0)
118.0
(23.4)
3.6
(0.8)
100%
1 mg nasal
1 39.4
(11.2)
2 35.6
(7.8)
3 41.3
(10.6)
1.4
(0.4)
1.4
(0.6)
1.5
(0.6)
305.0
(67.0)
316.6
(129.5)
311.0
(81.6)
131.0
(27.6)
146.7
(33.1)
142.2
(41.8)
3.4
(0.8)
3.6
(1.3)
3.4
(0.8)
104%
(9.0)
106%
(11.5)
106%
(11.5)
3 mg
nasal
4 41.3
(13.3)
5 33.3
(13.3)
3.8
(1.2)
4.4
(1.3)
292.5*
(81.6)
279.5*
(53.0)
122.8
(41.4)
112.3
(9.8)
3.7
(1.0)
3.7
(0.6)
100%
(18.2)
97%
(14.5)
* dose adjusted AUC
Reaction Time (RT) and Interstimulus Interval (ISI) were assessed by Computer-controlled selfadjusting
reaction time test (CRTT). Figure 6-11 displays RT and ISI assessed during the test runs
(day 1 before predose run) and predose (all study days). Mean inter test difference of RT and ISI
was 19 ± 9 ms and 22 ± 10 ms, respectively. Delta RT and delta ISI refer to the difference of the
assessed RT and ISI at 20 min, 120 min, and 240 min after midazolam administration and the
corresponding parameter assessed previous to midazolam administration.
850
800
test run
predose
750
700
Time [ms]
650
600
550
500
450
400
test 1 test 2 test 3 day 1 day 2 day 3 day 4 day 5 day 6
RT 653 615 591 581 564 548 530 519 502
ISI 745 720 681 652 626 603 594 580 569
Figure 6-11: Three test runns and predose RT and ISI assessed by CRTT. Overall mean inter test
difference of RT and ISI was 19 ± 9 ms and 22 ± 10 ms, respectively (n=8).
Katja Suter-Zimmermann Page 75 of 188 University of Basel, 2008