Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

5. Project I: Development of preparations for transmucosal nasal midazolam delivery
Table 5-3 and Figure 5-5 summarize midazolam release from RMβCD-midazolam complexes
assessed by permeation experiments with semi-permeable cellophane membranes (SpectraPro ® ,
MWCO 2000).
Table 5-3: Midazolam release (µg/min ± SD) from RMβCD-midazolam complexes. Total midazolam
concentration was 5 mg/ml, 15 mg/ml, and 30 mg/ml and RMβCD was added in equimolar amount and
threefold amount of midazolam (base). Drug release experiments were accomplished in triplicates
Total midazolam
Ratio RMβCD to midazolam
concentration No RMβCD 1 to 1 1 to 3
5 mg/ml 1.067 ± 0.058 µg/min 0.850 ± 0.354 µg/min 0.150 ± 0.050 µg/min
15 mg/ml --- 1.133 ± 0.808 µg/min ---
30 mg/ml --- 1.375 ± 0.436 µg/min 0.567 ± 0.306 µg/min
Midazolam release decrease with addition of RMβCD and is 1.067 ± 0.058 µg/min,
0.850 ± 0.354 µg/min, and 0.150 ± 0.050 µg/min for midazolam 5 mg/ml, 5 mg/ml with equimolar
RMβCD, and 5 mg/ml with threefold molar amount of RMβCD, respectively.
For 30 mg/ml observed midazolam release was 1.375 ± 0.436 µg/min and 0.567 ± 0.306 µg/min for
30 mg/ml midazolam with equimolar RMβCD, and 30 mg/ml with threefold molar amount of
RMβCD, respectively. The observed midazolam release was not proportional to the total
midazolam concentration present in the donor compartment. Half of the midazolam concentration
(15 mg/ml midazolam solved with equimolar amount of RMβCD) did not result in half of midazolam
release compared with the release of 30 mg/ml midazolam solved with equimolar amount of
RMβCD.
Midazolam release did not correlate with the total midazolam concentration in the donor
compartment. Three fold amount of RMβCD did considerably reduce midazolam release for both
tested (total) midazolam concentrations 5 mg/ml and 30 mg/ml.
Katja Suter-Zimmermann Page 52 of 188 University of Basel, 2008