Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

5. Project I: Development of preparations for transmucosal nasal midazolam delivery
J = P * A * (c free midazolam )
(Equation 4)
Midazolam release (in vitro) did not correlate with the total midazolam concentration in the donor
compartment; consequently Equation 2 does not exactly correspond with data assessed in the drug
release studies. The results of the drug release studies suggest that only free midazolam
concentration controls permeation through the artificial membrane (see Equation 4). The more
RMβCD is available for midazolam complexation, the more midazolam release was reduced.
Consequently, to minimize the influence of RMβCD on midazolam release in vivo, equimolar
amount of RMβCD was used to solubilize midazolam in preparations for nasal midazolam delivery.
The pH of the developed preparations (Preparation 1 to 5) is not adjusted to physiologic pH. In the
nasal preparation proposed by Roelofse et al. (ratio cyclodextrin to midazolam was 5 to 1, for 20%
βCD to solubilize 10 mg/ml midazolam) pH was 5.8. The above discussed drug release studies are
in accordance with the outcome of in vitro investigations of Loftsson et Jarho [Loftsson 1995,
Jarho, 1996] and underline the importance of adequate cyclodextrin-compound ratio. Therefore,
cyclodextrin excess to solubilize midazolam was considered as inappropriate; even pH could have
been approached to physiologic pH.
Results of accelerated stability testing affirmed stability of midazolam solubilized with RMβCD.
Proven stability of midazolam enables the storage of the tested midazolam preparations at room
temperature. For all midazolam preparations with RMβCD (Preparation 2, 3, and 4) and without
RMβCD (Preparation 1a and 1b) stability data confirmed shelf life of 6 months. Preparation 5,
additionally containing chitosan hydrochloride, was not stable concerning midazolam content.
During 6 months storage at room temperature midazolam content decreased from originally
29.5 mg/ml to 25.1 mg/ml, not complying with the specified requirements for midazolam content.
Apparently, chitosan hydrochloride impaired midazolam stability. The preparation has to be
prepared immediately before use. Concerning pH, after 10 months storage Preparation 1b does not
comply with the specified limits for pH (3.0 to 3.5). As with arising pH midazolam risks to
precipitate, prolongation of shelf life for Preparation 1b is not reasonable. For Preparation 3
prolongation of shelf life from 6 months to at least 10 months is supported by long term stability
data.
Katja Suter-Zimmermann Page 58 of 188 University of Basel, 2008