Biomedical Engineering Reference
In-Depth Information
Separation and purification of particles were done by filtration/centrifugation followed by
successive washings with hot and cold water. The size of particles varied depending on the
compressed air pressure or spray-nozzle diameter, while the drug release profile was con-
trolled by using a cross-linking agent to harden these particles.
6.4.2.3 Aqueous Cross-Linking Gelation Method
Covalent chemical cross-linking and physical cross-linking in aqueous solution were both
used for the preparation of chitosan-based submicrometer-sized particles.
Examples of the chemical cross-linking method include the use of a carbodiimide cou-
pling reaction of chitosan with a PEG dicarboxylic acid as a water-soluble cross-linker in
aqueous medium at pH 6.5 [91]. Chitosan-based nanoparticles with a diameter of 4-24 nm
were formed. The average size of the particles in their swollen state was in the range of
50-120 nm. Particle size largely depended on the ratio of cross-linking and the molecular
weight of chitosan [91]. Because these chitosan particles are nanosized at neutral pH, they
are attractive candidates as delivery biomolecules for a variety of biomedical applications.
To avoid the possible toxicity of reagents and other undesirable effects, reversible physi-
cal cross-linking by electrostatic interaction, instead of chemical cross-linking, has been
explored to prepare fine chitosan nanoparticles. In this method, chitosan, as a polycation,
cross-linked with polyanion (i.e., TPP [92,93] and polyethyleneimine [94]) through electro-
static interactions. TPP is the most commonly used physical cross-linker. Recently, Csaba
et al. [92] prepared chitosan/TPP nanoparticles for oligonucleotide and plasmid DNA
delivery. Chitosan and TPP were separately dissolved in ultrapure water at different con-
centrations. Nanoparticles were formed instantaneously upon the dropwise addition of a
fixed volume of TPP solution to a fixed volume of chitosan solution under magnetic stir-
ring. Owing to the negligible toxicity of the carrier cross-linked by electrostatic interaction,
these nanoparticles showed high encapsulation efficiencies for plasmid DNA and oligo-
nucleotide. Gene expression of these particles was proved to be comparable to other effi-
cient gene delivery systems. In addition, this research showed that chitosan/TPP
nanoparticles were suitable for the simultaneous encapsulation and sustained release of
other active molecules together with DNA [92].
6.4.2.4 Spray Drying Method
Spray drying is a widely used technique for preparing capsules, granules, powders, and
agglomerates. This method involves the use of a spray dryer, mainly consisting of an atom-
izer and a drying chamber. Chitosan is first dissolved in aqueous acetic acid solution, drug
is dissolved or dispersed in the solution, and then a suitable cross-linking agent is added. This
solution or suspension is then atomized in a stream of hot air, which induces quick evapora-
t ion of solve nt f from t he d roplet s i in t he d r y i ng c h a mber, re su lt i ng i in t he for m at ion of m ic ropa r -
ticles. The obtained particles settle into a bottom collector, and are further dried in a vacuum
chamber or modified in separate experiments. Various process parameters have to be con-
trolled to obtain the desired size of particles. The size of the particles is determined by mea-
suring nozzle size, spray flow rate, atomization speed, and extent of cross-linking [18,84].
6.4.2.5 Sieving Method
A sieving method for preparing microparticles was included in the review by Agnihotri
et al. [18]. They reported their own novel method to produce chitosan microparticles [18].
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