Pharmaceutical Manufacturing Handbook: Production and

MICROSPHERES AS NASAL DRUG DELIVERY DEVICES 661
to swell readily in contact with nasal mucosa and to have good bioadhesive properties
[65] . An in vitro release study using a Franz diffusion cell on levodopa - loaded
gelatin microspheres showed prolonged drug release as compared to drug alone
[88] . Negatively and positively charged gelatin microspheres intended for nasal and
intramuscular delivery of salmon calcitonin were prepared by Morimoto et al. [10] .
Both types of microspheres enhanced nasal absorption of salmon calcitonin compared
to the solution. Positively charged gelatin microspheres seamed to exhibit
greater enhancing effect on nasal absorption than negatively charged gelatin microspheres.
Recently gelatin and gelatin – poly(acrylic acid) microspheres were studied
with respect to oral and nasal delivery of oxprenolol [89] . Combining the gelatin
with poly(acrylic acid) resulted in microspheres with improved bioadhesive properties.
Also, nasal administration of gelatin – poly(acrylic acid) microspheres resulted
in improved bioavailability of the drug compared to nasal administration of the drug
solution.
Polyacrylate Microspheres Cross - linked polyacrylate microspheres as nasal
powder delivery systems have been investigated in several studies [39, 41, 90] . Microspheres
were produced by spray drying and emulsifi cation methods and their nasal
drug delivery potential has been evaluated only in vitro. Carbopol 934P microspheres
were shown to have the best bioadhesive properties compared to other
hydrophilic microspheres prepared with polyvinyl alchohol, chitosan, and hydroxypropylmethyl
cellulose [41] . Improved permeation - enhancing effect of polycarbophil
microparticles was obtained when microparticles were prepared with the
thiolated polycarbophil and the permeation mediator glutathione [68] .
Chitosan Microspheres As a specifi c chitosan - based delivery system, chitosan
microspheres have been extensively studied and number of reports has verifi ed their
potential regarding nasal drug delivery [9, 21, 25, 41, 53, 73, 91, 92] . Chitosan microspheres
have been prepared by the emulsifi cation solvent evaporation method [51,
52, 93] , emulsifi cation cross - linking process [91] , spray drying method [25, 53] , and
ionic gelation process [94] . They have been shown to signifi cantly reduce mucociliary
clearance from the nasal cavity of sheep and humans compared to solutions [83,
85] . The bioadhesive properties of chitosan microspheres were shown to be inversely
proportional to particle size: Among chitosan microspheres in the size class between
50 and 200 μ m, smaller microspheres appeared to swell faster than large microspheres,
providing a more powerful mucoadhesive system [41] .
A modulated release rate of drug from the swellable chitosan microspheres has
been achieved with cross - linking agents such as glutaraldehyde [95] , citric acid [92] ,
ascorbic acid, or ascorbyl palmitate [91] that reacted with chitosan forming covalent
bonds with chitosan amino groups. However, to maintain the bioadhesive properties
of cross - linked chitosan microspheres, the amount of cross - linking agent should be
optimized [95] .
Chitosan molecular weight has also been reported to infl uence drug release. Jiang
et al. [94] studied Bordetella bronchiseptica dermonecrotoxin (BBD) release from
chitosan microspheres prepared by tripolyphosphate ionic gelation. It has been
shown that the BBD release rate increased with chitosan molecular weight decrease.
It has been explained by the weaker BBD interaction with chitosan of lower molecular
weight and lower content of free amine groups, responsible for their interaction.