method has a few drawbacks, including incomplete removal of solvents, un-reacted
excipients, etc. Overall, the efficacy of this method can be improved via the proper
choice of dispersing phase, continuous phase, phase ratio, and surfactants.
Chitosan-PEG nanocapsules prepared through the emulsion route for the oral
delivery of peptides resulted in stable nanoparticles with improved in vitro stability
[103]. Likewise, various other carbohydrates such as dextran, hyaluronan, and
starch have also been prepared as stable nanoformulations by adopting the emulsion
route [32, 132]. Crosslinking of gelatin using transglutaminase is a novel concept.
Fuchs et al. detailed the interaction in gelatin–glutaminase crosslinking, and proposed it to be stronger and more biocompatible than the conventionally used
glutaraldehyde for gelatin nanoparticle production. [133].
3.2 Ionic Gelation
This technique, which works through the complexation between oppositely
charged molecules, has gained wide attention due its simple and mild processing
routes. In this method, the polymer solution is added to an oppositely charged ionic
solution, resulting in ionic gelation followed by precipitation, yielding spherical
particles. Particle size is mainly dictated by the polymer and crosslinker
concentrations. One of the main advantages of this technique is its reduced toxicity
due to the reversible physical crosslinking by electrostatic interaction rather than
chemical crosslinking, which eliminates the use of harsh chemicals. However, the
same is also disadvantageous, since this results in particles with poor mechanical
stability [16, 35, 86, 87].
Studies have reported a better encapsulation for poorly soluble drugs like 1,4dihydroxyanthraquinone (DHA) by forming complexes between anionic starch and
cationic cyclodextrin derivatives via ionic gelation [36]. Similarly, chitosan
nanoparticles prepared using the polyanionic crosslinker tripolyphosphate resulted
in stable nanoparticles with better encapsulation efficiency and reduced toxicity,
with BSA as a model drug [134]. Zorzi et al. developed new hybrid nanoparticles
via ionic gelation between cationized gelatin and the anionic polysaccharides,
dextran sulfate and chondroitin sulfate for delivery of plasmid DNA (pEGFP) to
the ocular surface [63]. Ionically crosslinked casein nanoparticles loaded with the
anti-androgen flutamide, showed satisfactory entrapment efficiency with a positive
zeta potential, good colloidal stability, and prolonged in vitro drug release. After
intravenous administration into rats, pharmacokinetic parameters revealed that
flutamide-loaded casein nanoparticles were well tolerated without any side effects
and showed a longer circulation time relative to flutamide-free solution, suggesting
that ionically crosslinked casein nanoparticles may have a promising future as
carriers for hydrophobic drugs [1].
Proteins and Carbohydrates as Polymeric Nanodrug Delivery Systems. . .
259
excipients, etc. Overall, the efficacy of this method can be improved via the proper
choice of dispersing phase, continuous phase, phase ratio, and surfactants.
Chitosan-PEG nanocapsules prepared through the emulsion route for the oral
delivery of peptides resulted in stable nanoparticles with improved in vitro stability
[103]. Likewise, various other carbohydrates such as dextran, hyaluronan, and
starch have also been prepared as stable nanoformulations by adopting the emulsion
route [32, 132]. Crosslinking of gelatin using transglutaminase is a novel concept.
Fuchs et al. detailed the interaction in gelatin–glutaminase crosslinking, and proposed it to be stronger and more biocompatible than the conventionally used
glutaraldehyde for gelatin nanoparticle production. [133].
3.2 Ionic Gelation
This technique, which works through the complexation between oppositely
charged molecules, has gained wide attention due its simple and mild processing
routes. In this method, the polymer solution is added to an oppositely charged ionic
solution, resulting in ionic gelation followed by precipitation, yielding spherical
particles. Particle size is mainly dictated by the polymer and crosslinker
concentrations. One of the main advantages of this technique is its reduced toxicity
due to the reversible physical crosslinking by electrostatic interaction rather than
chemical crosslinking, which eliminates the use of harsh chemicals. However, the
same is also disadvantageous, since this results in particles with poor mechanical
stability [16, 35, 86, 87].
Studies have reported a better encapsulation for poorly soluble drugs like 1,4dihydroxyanthraquinone (DHA) by forming complexes between anionic starch and
cationic cyclodextrin derivatives via ionic gelation [36]. Similarly, chitosan
nanoparticles prepared using the polyanionic crosslinker tripolyphosphate resulted
in stable nanoparticles with better encapsulation efficiency and reduced toxicity,
with BSA as a model drug [134]. Zorzi et al. developed new hybrid nanoparticles
via ionic gelation between cationized gelatin and the anionic polysaccharides,
dextran sulfate and chondroitin sulfate for delivery of plasmid DNA (pEGFP) to
the ocular surface [63]. Ionically crosslinked casein nanoparticles loaded with the
anti-androgen flutamide, showed satisfactory entrapment efficiency with a positive
zeta potential, good colloidal stability, and prolonged in vitro drug release. After
intravenous administration into rats, pharmacokinetic parameters revealed that
flutamide-loaded casein nanoparticles were well tolerated without any side effects
and showed a longer circulation time relative to flutamide-free solution, suggesting
that ionically crosslinked casein nanoparticles may have a promising future as
carriers for hydrophobic drugs [1].
Proteins and Carbohydrates as Polymeric Nanodrug Delivery Systems. . .
259