Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

5. Project I: Development of preparations for transmucosal nasal midazolam delivery
with 1.0 M sodium hydroxide), containing no solubilization enhancer, 10% RMβCD, 10% HPβCD,
or 10% HPγCD. The suspensions were equilibrated at room temperature for 3 days. The
suspensions were filtered (0.45 µm) and midazolam content assessed by HPLC. All samples were
prepared in triplicates.
5.2.4 Drug Release
For drug release of midazolam from RMβCD-midazolam complexes aqueous solutions trough
semi-permeable cellophane membranes, diffusion cells (see Figure 5-1) were used. A semipermeable
cellophane membrane (Spectra/Por ® Dialysis Tubing, MWCO 2000 from regenerated
cellulose) was inserted into diffusion cells with a surface area of 2.3 cm 2 .
In a preliminary drug release study Dormicum ® 5 mg/ml, 10 mg/ml midazolam solubilized with
20% RMβCD, and 10 mg/ml midazolam solubilized with equimolar amount of RMβCD (4%) were
filled in donor compartments.
For drug release 5 mg/ml midazolam in water; 5 mg/ml, 15 mg/ml, and 30 mg/ml midazolam solved
with equimolar amount of RMβCD; and 5 mg/ml and 30 mg/ml midazolam with threefold molar
amount of RMβCD were filled into donor compartment. Osmolality of all preparations for midazolam
release studies was adjusted to 300mOsmol/kg with sodium chloride.
The receiver compartment contained 0.9% sodium chloride in water. Both compartments contained
8.0 ml and were stirred during the release experiments (see Figure 5-1 A and B). The diffusion
cells were immersed in a water bath maintained at 37°C. Samples were withdrawn from the
receptor compartment replaced with aliquots of 0.9% sodium chloride. Midazolam release per
minute was assessed from the slope of the midazolam concentration time plot.
A
B
Figure 5-1 A and B: Picture of a diffusion cell (A) and 2 diffusion cells mounted, ready for drug release
experiment. The arrow indicates the position of the cellulose membrane.
Katja Suter-Zimmermann Page 47 of 188 University of Basel, 2008