Pharmaceutical Manufacturing Handbook: Production and

662 NASAL POWDER DRUG DELIVERY
Chitosan microspheres were shown to enhance nasal bioavailability of several
peptide drugs such as insulin and goserelin. A simple chitosan – insulin powder formulation
provided about 20% of absolute insulin bioavailability in sheep [96] .
Improved bioavailability (of 44%, in rats) was obtained when insulin was loaded
into chitosan microspheres prepared with ascorbyl palmitate as cross - linking agent
[91] . Chitosan microspheres have also been shown to improve nasal goserelin
absorption providing about 40% bioavailability relative to goserelin intravenous
application [9] .
Krauland et al. [93] prepared the microparticles with thiolated chitosan (chitosan -
TBA; chitosan – 4 - thiobutylamidine conjugate) intended for nasal peptide delivery.
During the preparation process microparticles were stabilized by the formation of
inter - and intramolecular cross - linking via disulfi de bonds. Chitosan – TBA microparticles
were characterized by improved swelling ability and displayed 3.5 - fold higher
insulin bioavailability compared to unmodifi ed chitosan microparticles.
Besides the polymer derivatization, combining the polymers in microsphere
preparations can result in improved drug delivery and absorption characteristics.
Hyaluronic acid – chitosan microspheres appeared to improve the absorption of
incorporated gentamicin compared to the individual polymers, assembling the
mucoadhesive potential of both polymers and the penetration - enhancing effect of
chitosan [51, 52] .
Chitosan microparticulate systems have also been investigated for vaccine nasal
delivery and have proven to induce strong systemic and mucosal immune responses
[18, 21, 76] .
5.7.4.1
Preparation Methods
The design of bioadhesive microspheres includes selection of the most suitable
preparation method, considering the nature of the drugs and polymers used as well
as the route of administration. A number of methods for the preparation of microspheres
have been described in the literature [3, 97] . In the scope of nasal delivery,
the fi rst microspheres in use were starch and dextran microspheres, prepared by an
emulsion polymerization technique employing epichlorohydrine as a cross - linking
agent [55, 56, 59, 60, 62, 81] . Currently techniques based on solvent removal, such
as solvent evaporation [41, 51, 66, 93, 98] and solvent extraction [88, 99] , are most
frequently in use. There are tree processes involved in such microensapsulation
procedures: the preparation of emulsion, solvent removal, and separation of the
particles obtained. Selection of the type of (oil - and - water) emulsion system (O/W,
W/O, W/O/W, W/O/O, etc.) depends on the physicochemical properties of the drug
and polymer used. After the preparation of stable emulsion, solvent is removed from
the system at high or low temperature, at low pressure, or by addition of another
solvent that enables the extraction of polymer solvent to the continuous phase.
Hardened microspheres are then washed, centrifuged, and lyophilized.
Emulsion techniques are suitable for the preparation of microspheres intended
for nasal delivery since they allow controlling the size of the particles. Freiberg and
Zhu [97] reviewed solvent evaporation process parameters (e.g., polymer concentration,
viscosity, stirring rate, temperature and percentage of emulsifying agent) affecting
microsphere size. It can be assumed that the particle size is directly proportional
to polymer concentration and inversely proportional to stirring rate and percentage
of emulsifying agent [41, 88] , while there is a nonlinear correlation between particle