Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

5. Project I: Development of preparations for transmucosal nasal midazolam delivery
midazolam concentration [mg/ml]
50.0
45.0
40.0
35.0
30.0
25.0
20.0
15.0
10.0
5.0
0.0
w ater 10% HPbCD 10% RMbCD 10% HPgCD
midazolam 9.1 26.2 33.1 40.8
Figure 5-3: Saturated midazolam concentration in water,
10% RMβCD, 10% HPβCD, and 10% HPγCD (n=3).
Midazolam solubility was
9.1 mg/ml, 26.2 mg/ml,
33.1 mg/ml, and 40.8 mg/ml in
water, 10% HPβCD, 10% RMβCD,
and 10% HPγCD, respectively.
The calculated ratio of cyclodextrin
and midazolam in the saturated
solutions was 1 to 1.13, 1 to 1.33,
and 1 to 1.97 for HPβCDmidazolam,
RMβCD-midazolam,
and
HPγCD-midazolam
complexes, respectively. Figure
5-3 displays the solubility of
midazolam without and with
solubilization
enhancer
(10% HPβCD, 10% RMβCD, and
10% HPγCD).
Midazolam release [ug/min]
5.3.2 Drug Release
2.00
1.80
1.60
1.40
1.20
1.00
0.80
0.60
0.40
0.20
0.00
Dormicum
(5mg/ml)
.
10mg/ml
midazolam,
equimolar RMbCD
10mg/ml
midazolam, 20%
RMbCD
Midazolam release in preliminary
drug release studies was
1.258 µg/min, 1.150 µg/min, and
0.461 µg/min from Dormicum ®
(5 mg/ml midazolam), 10 mg/ml
midazolam solubilized with
equimolar amount of RMβCD (4%)
and 10 mg/ml midazolam
solubilized with 20% RMβCD,
respectively.
Midazolam release did not
correlate with the total midazolam
concentration. In Figure 5-4 the
results of the preliminary drug
release study is displayed.
Figure 5-4: Midazolam Release from Dormicum ® (5 mg/ml
midazolam), 10 mg/ml midazolam solubilized with
equimolar amount of RMβCD (4%) and 10 mg/ml midazolam
solubilized with 20% RMβCD.
Katja Suter-Zimmermann Page 50 of 188 University of Basel, 2008