Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

5. Project I: Development of preparations for transmucosal nasal midazolam delivery
5 Project I: Development of preparations for
transmucosal nasal midazolam delivery
5.1 Introduction
The key issue in development of preparations for transmucosal nasal midazolam delivery is the
relatively poor and highly pH-dependent solubility of midazolam. Solubilization enhancers ideally
promote midazolam solubility independent of pH. Several approaches to enhance solubility of
midazolam have been described in literature (see Table 4-1). Knoester et al. proposed a nasal
midazolam preparation based on propylene glycol and benzyl alcohol [Knoester, et al. 2002] and
other groups enhanced midazolam solubility by different cyclodextrin derivatives [Loftsson, et al.
2001; Roelofse, et al. 2000]. Loftsson et al. accentuated the importance of keeping the drug
cyclodextrin ratio close to one and just adding as much cyclodextrin as required for drug
solubilization. To investigate drug release from cyclodextrin complexes porous semi-permeable
cellophane membranes with defined pore size (i.e., molecular weight cut off, MWCO) are used.
The residence time on the nasal mucosa of nasal delivered preparations is limited and therefore
drug uptake has to proceed before the preparation is removed by mucociliary clearance.
Chitosan is reported to promote transmucosal nasal drug absorption by bioadhesion (prolongation
of contact time) and transient opening of tight junctions (penetration enhancer). In a study with
12 healthy volunteers Illum et al. demonstrated penetration enhancing effect of chitosan in
transmucosal nasal delivery of morphine [Illum, et al. 2002].
In order to discover eventual stability problems as early as possible, accelerated stability testing is
accomplished already during development of pharmaceutical preparation. According to the current
guideline of the International Conference on Harmonization (ICH), accelerated stability testing
provides preliminary information about the compound and the vehicle. For the approval of a
medicinal product, authorities generally require data from real-time stability testing [Gil-Alegre et
al., 2001]. To determine the shelf life of a medicinal product, real time stability testing at the
intended storage conditions has to be accomplished. As the determined shelf life is dependent of
packaging, real time stability testing has to be generated with the bottled product.
This project comprises the development and in vitro characterization of midazolam preparations for
transmucosal nasal midazolam delivery. Providing of stability data was prerequisite to use the
developed preparations in clinical trials (Project II and Project III).
Katja Suter-Zimmermann Page 45 of 188 University of Basel, 2008