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Chitosan: A Unique Pharmaceutical Excipient
ABSTRACT
Chitosan is a natural polymer obtained by deacetylation of chitin. Chitin is the second most abundant
polysaccharides in nature after cellulose. The main commercial sources of chitin are the shell wastes of shrimp,
crab, lobster, krill, and squid. It is a biologically safe, non-toxic, biocompatible, and biodegradable polysaccharide.
Being a bioadhesive polymer and having antibacterial activity, chitosan is a good candidate for site-specific drug
delivery. The aim of this review is to provide an insight into the many potential applications of chitosan as a
pharmaceutical excipient. Various investigations carried out recently are reported, although references to
research performed on chitosan prior to the recent reviews have also been included where appropriate. The first
part of this review concerns the chemical structure, preparation and properties, product characterization, and
pharmaceutical grade of chitosan. The second part contains the recent applications of chitosan in ophthalmic,
nasal, oral (sublingual, buccal, periodontal), gastrointestinal, colon-specific, vaginal, and transdermal drug
delivery. It also includes its application as a mucosal-vaccine carrier.
INTRODUCTION
Chitosan is a hydrolyzed (deacetylated) derivative of chitin, a biopolymer widely distributed in nature and
biologically safe.1,2 This polymer exhibits several favorable properties, such as biodegradability and
biocompatibility.1 It also has mucoadhesive properties due to its positive charges at neutral pH that enable an
ionic interaction with the negative charges of sialic acid residues of the mucus. 3,4 Some of which include binding,
disintegrating, and tablet coating properties. Numerous studies have demonstrated that chitosan and its
derivatives (N-trimethyl chitosan, mono-N-carboxymethyl chitosan) are effective and safe absorption enhancers to
improve mucosal (nasal, peroral) delivery of hydrophylic macromolecules, such as peptides, proteins, and
heparins. The polymer has also been investigated as a potential adjuvant for swellable controlled drug delivery
systems. Chitosan exhibits a myriad of biological actions, namely hypocholesterolemic, antimicrobial, and woundhealing properties. Low toxicity coupled with wide applicability makes it a promising candidate not only for the
purpose of drug delivery for a host of drug moieties (anti-inflammatories, peptides, etc) but also as a biologically
active agent. Chitosan nano-and micro-particles are also suitable for controlled drug release. Association of
vaccines to some of these particulate systems has shown to enhance the antigen uptake by mucosal lymphoid
tissues, thereby inducing strong systemic and mucosal immune responses against the antigens.
STRUCTURAL FORMULA & PREPARATION OF CHITIN & CHITOSAN
Chitin is similar to cellulose both in chemical structure and in biological function as a structural polymer. The
crystalline structure of chitin has been shown to be similar to cellulose in the arrangements of inter- and intrachain
hydrogen bonding (Figure 1). It has been proposed to define chitosan and chitin as soluble or insoluble in 0.1 M
acetic acid, respectively, or by degree of deacetylation. >20% of deacetylation is the proposed definition of
chitosan.5-7 Chitosan is made by alkaline N-deacetylation of chitin. The term chitosan does not refer to a uniquely
defined compound; it merely refers to a family of copolymers with various fractions of acetylated units. It consists
of two types of monomers; chitin-monomers and chitosan-monomers. Chitin is a linear polysaccharide consisting
of (1-4)-linked 2-acetamido-2-deoxy-b-D-glucopyranose. Chitosan is a linear polysaccharide consisting of (1-4)linked 2-amino-2-deoxy-b-D-glucopyranose.8,9
Commercial chitin and chitosan consists of both types of monomers. Chitosan is found in nature, to a lesser
extent than chitin, in the cell walls of fungi. Chitin is believed to be the second most abundant biomaterial after
cellulose. The annual biosynthesis of chitin has been estimated to 109 to 1011 tons. Chitin is widely distributed in
nature. Among several sources, the exoskeleton of crustaceans consist of 15% to 20 % chitin of dry weight. Chitin
found in nature is a renewable bioresource.8,10,11 Chitin and chitosan are both prepared using the common
process illustrated and described in Figure 2.
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PRODUCT CHARACTERIZATION
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Chitosan can be described in general by the following parameters:








degree of deacetylation in %,
dry matter in %,
ash in %,
protein in %,
viscosity in Centipoise,
intrinsic viscosity in ml/g,
molecular weight in g/mol, and
turbidity in NTU units.
All of these parameters can be adjusted to the application for which chitosan is being used. The deacetylation is
very important to get a soluble product. In general, the solubility of heteroglucans are also influenced by the
distribution of the acetyl groups, the polarity and size of the monomers, distribution of the monomers along the
chain, the flexibility of the chain, branching, charge density, and molecular weight (50,000 to 2,000,000 Da) of the
polymer. Viscosity (10 to 5000 cp) can be adjusted to each application by controlling the process parameters.
SPECIFICATIONS & CHARACTERISTICS OF PHARMACEUTICAL-GRADE CHITOSAN
The pharmaceutical requirements for chitosan include: a white or yellow appearance (powder or flake), particle
size < 30 �m, density between 1.35 and 1.40 g/cm3, a pH of 6.5 to 7.5, moisture content < 10%, residue on
ignition <0.2%, protein content <0.3%, degree of deacetylation 70% to 100%, viscosity <5 cps, insoluble matter
<1%, heavy metals (As) <10 ppm, heavy metals (Pb) <10 ppm, and no taste and smell.13
APPLICATIONS OF CHITOSAN
Ophthalmic
Delivery
Various studies showed the potential of chitosan-based systems for improving the retention and biodistribution of
drugs applied topically onto the eye. In addition to its low toxicity and good ocular tolerance, chitosan exhibits
favorable biological behavior, such as bioadhesion, permeability-enhancing properties, and interesting physicochemical characteristics, which make it a unique material for the design of ocular drug delivery vehicles.14 Various
formulations have been prepared like chitosan gels, chitosan-coated colloidal systems, and chitosan
nanoparticles. The results reported until now have provided evidence of the potential of chitosan gels for
enhancing and prolonging the retention of drugs on the eye surface. In contrast, chitosan-based colloidal systems
were found to work as transmucosal drug carriers, either facilitating the transport of drugs to the inner eye
(chitosan-coated colloidal systems containing indomethacin) or their accumulation into the corneal/conjunctival
epithelia (chitosan nanoparticles containing ciclosporin). The microparticulate drug-carrier (microspheres) seems
a promising means of topical administration of acyclovir to the eye. 15
Nasal
Delivery
The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. 16 Chitosan drug delivery systems,
such as microspheres, liposomes, and gels, have been demonstrated to have good bioadhesive characteristics
and swell easily when in contact with the nasal mucosa. Bioavailability and residence time of the drugs that are
administered via the nasal route can be increased by bioadhesive drug delivery systems. Various chitosan salts
(chitosan lactate, chitosan aspartate, chitosan glutamate, and chitosan hydrochloride) showed nasal sustained
release of vancomycin hydrochloride.17 Chitosan delivery systems (such as microspheres) have the ability to
increase the residence time of drug formulations in the nasal cavity, thereby providing the potential for improved
systemic medication.18 Diphtheria toxoid (DT) associated to chitosan microparticles results in protective systemic
and local immune response against DT, and enhances significant IgG production after nasal administration. 19
Bioadhesive chitosan microspheres of pentazocine for intranasal systemic delivery significantly improved
bioavailability with sustained and controlled blood level profiles compared to intravenous, oral administration. 20
The nasal absorption of insulin after administration in chitosan powder was the most effective formulation for
nasal delivery of insulin in sheep compared to chitosan nanoparticles and chitosan solution. 21 Different types of
nasal vaccine systems have been described to include cholera toxin, microspheres, nanoparticles, liposomes,
attenuated virus and cells, and outer membrane proteins (proteosomes). Nasal formulations induced significant
serum IgG responses similar to and secretory IgA levels superior to what was induced by a parenteral
administration of the vaccine.22
Buccal
Delivery
An ideal buccal delivery system should stay in the oral cavity for a few hours and release the drug in a
unidirectional way toward the mucosa in a controlled- or sustained-release fashion. Mucoadhesive polymers will
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prolong the residence time of the device in the oral cavity. Bilayered devices will ensure the release of the drug
occurs in a unidirectional way. 23,24
Chitosan is an excellent polymer to be used for buccal delivery because it has muco/bioadhesive properties and
can act as an absorption enhancer. Directly compressible bioadhesive tablets of ketoprofen containing chitosan
and sodium alginate in the weight ratio 1:4 showed sustained release 3 hours after intraoral (sublingual site of
rabbits) drug administration.25 Buccal tablets based on chitosan microspheres containing chlorhexidine diacetate
showed a prolonged release of the drug in the buccal cavity. The loading of chlorhexidine into chitosan is able to
maintain or improve the antimicrobial activity of the drug. The improvement is particularly high against Candida
albicans. This is important for a formulation whose potential use is against buccal infections. Drug-empty
microparticles have an antimicrobial activity due to the chitosan itself. 26 The buccal bilayered devices (bilaminated
films, bilayered tablets) using a mixture of drugs (nifedipine and propranolol hydrochloride) and chitosan, with or
without anionic crosslinking polymers (polycarbophil, sodium alginate, gellan gum), demonstrated that these
devices show promising potential for use in controlled delivery of drugs to the oral cavity. 27 Bioadhesive tablets of
nicotine containing 0% to 50% w/w glycol chitosan produced the good adhesion. 28
Periodontal
Delivery
Local delivery of drugs and other bioactive agents directly into the periodontal pocket has received a lot of
attention lately. For example, for moderate to severe periodontal diseases, antimicrobial agents are used to
eradicate and/or suppress the plaque bacteria. However, systemic administration of these drugs has certain
disadvantages, such as the necessity for frequent dosing to maintain the drug concentrations at the therapeutic
level in the plasma, poor patient compliance, super infections caused by resistant organisms, and gastrointestinal
and systemic side-effects.29,30 An ideal formulation should be easy to deliver, have good retention at the target
site, and provide sustained release of the drug. Muco/bioadhesive polymers increase the residence time of the
formulation in the oral cavity. This will enhance drug penetration, localize the drug for local therapy, target the
diseased tissue, and improve efficacy and acceptability. 31
Being a muco/bioadhesive polymer, chitosan is considered a good candidate for drug delivery in the oral
cavity.32,33 In addition to its non-toxicity, biocompatibility, and biodegradability, chitosan itself possesses
antibacterial activity.34 The antibacterial activity of chitosan could be due to the electrostatic interactions between
the amine groups of chitosan and the anionic sites on bacterial cell wall because of the presence of carboxylic
acid residues and phospholipids.35 Chitosan is a biologically safe polymer and prolongs the adhesion time of oral
gels and drug release from them. Chitosan also inhibits the adhesion of Candida albicans to human buccal cells
and has antifungal activity. Chitosan gel and chitosan film containing chlorhexidine gluconate for local delivery
were developed. Chitosan itself showed antifungal activity. Also, a prolonged release was observed with chitosan
films.36 A monolayer and multilayered film of chitosan/PLGA containing ipriflavone were showed to prolong drug
release for 20 days in vitro.37
Gastrointestinal
(Floating)
Drug
Delivery
Floating systems have a density lower than the density of the gastric juice. Thus, gastric residence time and
hence the bioavailability of drugs that are absorbed in the upper part of the GI tract will be improved. Intragastric
floating dosage forms are useful for the administration of drugs that have a specific absorption site, area insoluble
in the intestinal fluid, or area used for the treatment of gastric diseases. Chitosan granules having internal cavities
were prepared by deacidification. When added to acidic (pH 1.2) and neutral (deionized distilled water) media,
these granules were immediately buoyant and provided a controlled release of the candidate drug prednisolone.
Both chitosan granules and chitosan-laminated preparations could be helpful in developing drug delivery systems
that will reduce the effect of gastrointestinal transit time. Floating hollow microcapsules of melatonin produced
have an interesting gastroretentive controlled-release delivery system for drugs. Release of the drug from these
microcapsules was greatly retarded with release lasting for several hours (1.75 to 6.7 hours in simulated gastric
fluid), depending on processing factors. Most of the hollow microcapsules developed tended to float over
simulated biofluids for more than 12 hours.38
Peroral
Drug
Delivery
Because of the mucoadhesive properties of chitosan and most of its derivatives, a presystemic metabolism of
peptides on the way between the dosage form and the absorption membrane can be strongly reduced. Based on
these unique features, the coadministration of chitosan and its derivatives leads to a strongly improved
bioavailability of many perorally given peptide drugs, such as insulin, calcitonin, and buserelin. 39 Unmodified
chitosan proved to display a permeation-enhancing effect for peptide drugs. A protective effect for polymerembedded peptides toward degradation by intestinal peptidases can be achieved by the immobilization of enzyme
inhibitors on the polymer. Serine proteases are inhibited by the covalent attachment of competitive inhibitors, such
as the Bowman-Birk inhibitor; metallo-peptidases are inhibited by chitosan derivatives displaying complexing
properties, such as chitosan-EDTA conjugates. Chitosan films are an alternative to pharmaceutical tablets. 40 The
mucoadhesive property of chitosan gel could be enhanced by threefold to sevenfold by admixing of chitosanglycerylmono-oleate. Drug release from the gel followed a matrix diffusion controlled mechanism. 41
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Chitosan is an excellent candidate for the treatment of oral mucositis. Its bioadhesive and antimicrobial properties
offer the palliative effects of an occlusive dressing and the potential for delivering drugs, including anticandidal
agents.42 A novel mucoadhesive DL-lactide/glycolide copolymer (PLGA) nanosphere system to improve peptide
absorption and prolong the physiological activity following oral administration was prepared. The chitosan-coated
nanosphere reduced significantly the blood calcium level compared with uncoated nanospheres, and the reduced
calcium level was sustained for a period of 48 hours. 43 Nifedipine embedded in a chitosan matrix in the form of
beads showed prolonged-release of drug compared to granules.44
Intestinal
Drug
Delivery
Sustained intestinal delivery of drugs, such as 5-fluorouracil (choice for colon carcinomas) and insulin (for
diabetes mellitus), seems to be a feasible alternative to injection therapy. 45 A formulation was developed that
could bypass the acidity of the stomach and release the loaded drug for long periods into the intestine by using
the bioadhesiveness of polyacrylic acid, alginate, and chitosan. Bromothymol blue was taken as a model drug.
The formulation exhibited bioadhesive property and released the drug for an 80-day period in vitro.
Chitosan/calcium alginate microcapsules containing nitrofurantoin (NF) showed sustained release of drug. Drug
release into the gastric medium is found to be relatively slow compared to that into the intestinal medium. 46
Colon
Delivery
Chitosan was used in oral drug formulations to provide sustained release of drugs. Recently, it was found that
chitosan is degraded by the microflora that are available in the colon. As a result, this compound could be
promising for colon-specific drug delivery. Chitosan was reacted separately with succinic and phthalic anhydrides.
The resulting semisynthetic polymers were proved for colon-specific, orally administered drug delivery systems.
Systems for colon delivery containing acetaminophen (paracetamol), mesalazine (5-ASA), sodium diclofenac, and
insulin have been studied and showed satisfactory results.48-51
Vaginal
Delivery
Chitosan, modified by the introduction of thioglycolic acid to the primary amino groups of the polymer, embeds
clotrimazole, an imidazole derivative widely used for the treatment of mycotic infections of the genitourinary tract.
By introducing thiol groups, the mucoadhesive properties of the polymer were strongly improved, and this resulted
in an increased residence time of the vaginal mucosa tissue (26 times longer than the corresponding unmodified
polymer), guaranteeing a controller drug release in the treatment of mycotic infections. 52 Vaginal tablets of
chitosan containing metronidazole, acriflavine, and other excipients showed adequate release and good adhesion
properties.53,54
Transdermal
Delivery
Chitosan has good film-forming properties. The drug release from the devices are affected by the membrane
thickness and cross-linking of the film.55 Chitosan-alginate poly electrolyte complex (PEC) has been prepared in
situ in beads and microspheres for potential applications in packaging, controlled release systems, and wound
dressings.56 Chitosan gel beads are a promising biocompatible and biodegradable vehicle for treatment of local
inflammation. Chitosan gel beads containing the anti-inflammatory drug prednisolone showed sustained release
of drug with reduced inflammation indexes that resulted in improved therapeutic efficacy. 57
Chitosan membranes with different permeability to propranolol hydrochloride obtained by controlled cross-linking
with glutaraldehyde were used to regulate the drug release in the devices. Chitosan gel was used as the drug
reservoir. The drug-release profiles showed that drug delivery is completely controlled by the devices. The rate of
drug release was found to be dependent on the type of membrane used. 58 A combination of chitosan membrane
and chitosan hydrogel containing Lidocaine hydrochloride, a local anesthetic, is a good transparent system for
controlled drug delivery and release kinetics.59
Vaccine
Delivery
Various chitosan-antigen nasal vaccines have been prepared. These include cholera toxin, microspheres,
nanoparticles, liposomes, attenuated virus and cells, and outer membrane proteins (proteosomes). They induced
significant serum IgG responses similar to and secretory IgA levels superior to what was induced by a parenteral
administration of the vaccine.60 Chitosan microparticles are very promising mucosal vaccine delivery systems.
Significant systemic humoral immune responses were found after nasal vaccination with diphtheria toxoid
associated to chitosan microparticles. Diphtheria toxoid associated to chitosan microparticles results in protective
systemic and local immune response against diphtheria toxoid after oral vaccination, and in significant
enhancement of IgG production after nasal administration. 61 Chitosan microspheres cross-linked with
glutaraldehyde were loaded by bovine serum albumin (BSA) and diphtheria toxoid and showed tissue
compatibility with a long-lasting drug delivery system in wistar rats for several days.62
CONCLUSION
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Chitosan is an abundant natural polymer obtained by alkaline N-deacetylation of chitin. The physical and chemical
properties of chitosan, such as inter- and intramolecular hydrogen bonding and the cationic charge in acidic
medium, makes this polymer attractive for the development of conventional and novel pharmaceutical products.
Chitosan has favorable biological properties, such as non-toxicity, biocompatibility, biodegradability, and
antibacterial characteristics.
Chitosan has unique properties of bioadhesion, absorption enhancement by increasing the residence time of
dosage forms at mucosal sites, inhibiting proteolytic enzymes, and increasing the permeability of various drugs
across mucosal membranes. Chitosan is degraded by the microbial flora that are present in the colon; as a result,
chitosan is a good candidate for site-specific drug delivery. Low toxicity coupled with wide applicability makes it a
promising candidate not only for the purpose of drug delivery for a host of drug moieties (anti-inflammatory,
peptides, etc), but also as a biologically active agent. These multiform aspects of chitosan parallel to those as a
drug carrier make it a unique polymer in the pharmaceutical field and indicate that its potential applications may
be even wider than those currently examined and reported to date.
______________
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