Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

4. Compounding of nasal midazolam preparations
4.4.2 Applications of chitosan
Chitosan is a multifunctional excipient with a wide rang of industrial applications (e.g., flocculant for
wastewater clarification, chelating of heavy metals, clarification of fruit juices and beers, and
fungicide in agriculture) [Shahidi and Abuzaytoun 2005]. Further, in food industry, chitosan is a
popular dietary supplement, particularly in Japan. In addition, chitosan is used for ophthalmic
applications, such as contact lens coating or as the contact lenses material itself and in cosmetic
industry chitosan is also a very popular excipient (e.g., for hair care products).
Chitosan is a versatile excipient for miscellaneous pharmaceutical applications. Chitosan is
adjuvant in direct compressed tablets, for controlled release matrix tablets, in the process of wet
granulation, in gels, films, and emulsions, as well as wetting and coating agent, and for the
production of microspheres and microcapsules. Chitosan is used also in newer research areas like
nasal vaccine delivery and DNA delivery [van der Lubben et al., 2001; Xu et al., 2004]. The
European Pharmacopoeia describes the requirements for chitosan hydrochloride used in
pharmaceutical products.
4.4.3 Chitosan in transmucosal nasal drug delivery
Davis et al. were the first to demonstrate the cationic polymer chitosan to promote the
transmucosal adsorption of challenging drugs, particularly with regard to improved nasal delivery.
In animal and human models, chitosan generated a remarkably higher bioavailability [Davis and
Illum 2003]. Illum et al found, that the addition of chitosan to a nasal formulation of insulin caused
plasma glucose to fall to 43% of basal level compared to 83% without the addition of chitosan [Illum
et al., 1994]. Similar effects on bioavailability have been achieved for polar low-molecular-weight
drugs (e.g., morphine and antimigraine drugs). Chitosan is an effective nasal absorption enhancer
in liquid and powder formulations. Chitosan improve bioavailability in nasal and pulmonal drug
delivery [Illum 1998; Illum et al., 2002; Martinac et al., 2005; Yu et al., 2004].
In liquid formulations for nasal drug delivery, concentrations of 0.5-1.0% chitosan proved to
promote absorption [Davis and Illum 2003].
Unlike common penetration enhancers, chitosan is neither membrane active nor a classical
surfactant and is not transmucosal absorbed. The clearance of chitosan formulations from the
nasal cavity of sheep and humans has been shown to be significantly slower compared with
aqueous solutions [Soane et al., 1999; Soane et al., 2001].
The mucoadhesion results of the interaction between the linear cationic polysaccharide chitosan
and the negatively charged mucosa. This mechanism decelerates the nasal clearance [Aspden et
al., 1997].
The extended time of contact of the formulation and the nasal mucosa favors the transmucosal
drug absorption [Pavis et al., 2002]. Studies with CaCo-2 cell monolayer suggest cationic polymers
(e.g., chitosan) to modify permeability of the monolayer by interaction with the gating mechanism of
tight junction, causing a transient opening [Artursson et al., 1994]. Dodane et al. demonstrated
Katja Suter-Zimmermann Page 40 of 186 University of Basel, 2008