11 28

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International Journal of Pharmaceutical and Applied Sciences/1 (1)/2010

11

Chitosan: A Novel Pharmaceutical Excipient
J. Shaji
1
*, V. Jain
1
, S. Lodha
1

1
Prin. K. M. Kundnani College of pharmacy,23, Jote Joy Building, Rambhau Salgaonkar Marg,
Cuffe Parade, Colaba, Mumbai 400005. India.

*Corresponding Author email: jshaji@rediffmail.com

Abstract:
This review focuses on the role of chitosan
and chitosan derivatives in drug delivery and
in pharmaceutical industries as excipients.
Chitin is one of the most abundant
polysaccharides found in nature. Chitosan
is a cationic natural polysaccharide obtained
by deacetylization of chitin and generally
considered as a safe, biocompatible and
biodegradable material. The use of chitosan
has been postulated in numerous areas of
biopharmaceutical research such as
mucoadhesion, permeation enhancement,
vaccine technology, gene therapy and
wound healing. Recent applications of
chitosan are in ophthalmic, nasal,
sublingual, buccal, periodontal,
gastrointestinal, colon-specific, vaginal,
transdermal drug delivery and mucosal-
vaccine and gene carrier. It can also be
used in the pharmaceutical industry in direct
tablet compression, as tablet disintegrant,
for the production of controlled release solid
dosage form or for the improvement of drug
dissolution
Keywords: Chitosan, chitin, derivatives of
chitosan, chitosan microspheres,
biodegradable polymer

1. Introduction:
Chitin is known biodegradable
natural polymers based on polysaccharides,
which is obtained from crustacean shell (e.g.
crab, shrimp, lobster), some insect (e.g. true
fly, Sulphur butterfly) and fungi like yeasts
and plants
1, 2.
Principally occurs in animals
of the phylum Arthopoda
2
.

Historically, in 1811, Prof. Henri
Braconnot, isolated fibrous substances from
mushroom and found it insoluble in aqueous acidic
solution. A decade later in 1823, Ojer named it
Chitin from Greek khiton meaning envelope
present in certain insects. In 1894, Hope Seyle
named it as chitosan. In 1930 to 1940, this
biopolymer of glucosamine gained much interest in
the field of medicine
3
.
Chitosan obtained from partial deacetylation of
chitin, is a polysaccharide comprising copolymers
of glucosamine and N-acetylglucosamine.
Chitosan is commercially available in several types
and grades that vary in molecular weight between
10000 and 1000000 and vary in degree of
deacetylation and viscosity
[1]
. Technically
speaking, Chitosan is a naturally occurring
substance that is chemically similar to cellulose
which is a plant fiber. Like plant fibers, Chitosan
possesses many of the same properties as fiber,
however unlike plant fiber; it has the ability to
significantly bind fat, acting like a "fat sponge" in
the digestive tract. It attracts the bio-hazardous
substances like greases, oils, heavy metals and
other potentially toxic substances from the water
and it is used for detoxifying water. Chitosan is
used for this purpose in water purification plants
throughout the nation
4
.

2. Chemical Structure:
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 intra chain
hydrogen bonding
5.
Chitosan is made
by alkaline N-deacetylation of chitin.
The term chitosan refers to a family of
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copolymers with various fractions of
acetylated units (fig.1, fig. 2). 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
5
.

Fig.1 Structure of chitin
Structure of the chitin molecule, showing two of the N-
Acetylglucosamine units that repeat to form long chains
in beta-1, 4 linkage.

Fig. 2 Structure of Chitosan
Chitosan is a linear polysaccharide composed of
randomly distributed -(1-4)-linked D-glucosamine
(deacetylated unit) and N-acetyl-D-glucosamine
(acetylated unit).

Fig. 3 Structure of Cellulose

3. Method of Manufacture And
Physicochemical Properties:

It is manufactured by chemically
treating the shells of crustaceans such as
shrimps and crabs. The process involves
separation of proteins by treating with alkali
and minerals such as calcium carbonate and
calcium phosphate by treatment with acid
3,
6
.

Initially the shells are deproteinized by
treatment with (3-5%) aqueous sodium
hydroxide solution. The resulting
product is neutralized and calcium is
removed by treatment with (3-5%)
aqueous Hydrochloric acid solution at
room temperature to precipitate chitin.
The chitin is dried and deacetylated to
give chitosan. This can be achieved by
treatment with 40-45% aqueous
sodium hydroxide solution at moderate
temperature (110 C) and the
precipitate is washed with water. The
crude sample is dissolved in 2% acetic
acid and the insoluble material is
removed. The resulting clear
supernatant solution is neutralized with
aqueous sodium hydroxide to give a
white precipitate of chitosan. It can be
further purified and ground to a fine
uniform powder or granules
7
.

4. Method of Manufacture And
Physicochemical Properties:

It is manufactured by
chemically treating the shells of
crustaceans such as shrimps and
crabs. The process involves
separation of proteins by treating with
alkali and minerals such as calcium
carbonate and calcium phosphate by
treatment with acid
3, 6
.

Initially the shells are deproteinized by
treatment with (3-5%) aqueous sodium
hydroxide solution. The resulting
product is neutralized and calcium is
removed by treatment with (3-5%)
aqueous Hydrochloric acid solution at
room temperature to precipitate chitin.
The chitin is dried and deacetylated to
give chitosan. This can be achieved by
treatment with 40-45% aqueous
sodium hydroxide solution at moderate
temperature (110 C) and the
precipitate is washed with water. The
crude sample is dissolved in 2% acetic
acid and the insoluble material is
removed. The resulting clear
supernatant solution is neutralized with
aqueous sodium hydroxide to give a
white precipitate of chitosan. It can be
further purified and ground to a fine
uniform powder or granules
7
.

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A. Niederhofer and B.W. Muller
8
have modified
the common method for the preparation of
chitosan. From low molecular weight fungi, with an
average molecular weight of 4.5*10
4
g/mol and a
numerical weight of 1.7*10
4
g/mol, it can be
directly extracted from the raw material without the
need of thermal or chemical polymerization.
Based on the solubility of low molecular chitosan
up to alkaline pH ranges, re-precipitation and
washing with ethanol is required to keep the low
molecular fraction with in the preparation .The use
of water for washing between the preparation
steps would cause solving and discarding the low
molecular chitosan.

Parameters Description
Powder or
flake
A white or
yellow
Particle size < 30 g
Density
1.35- 1.40
g/cm3
Ph 4.5 to 7.5
Moisture
content
> 10%
Residue on
ignition
< 0.2%
Protein content < 0.3%
Degree of
deacetylation
70% -100%
Viscosity < 5 cps
Insoluble
matter
< 0.5%
Chloride 10-20%
Heavy metals (As) < 10 ppm,
Heavy metals (Pb) < 10-ppm,
Sulphated ash 1.0%
Glass transition
temperature
203 C
Loss on drying 10 %
Table 1: characteristics of
pharmaceutical grade chitosan
Cps= centipoise, ppm= parts per million,
Characteristics required for pharmacutical
grade chitosan are shown in Table No. 1.

3.1 Molecular weight and degree of
deacetylation:

The molecular weight of chitosan ranges
from 1 x10
5
to 3 x10
5
, whereas average molecular
weight ranges from 3.8 x 10
3
to 2000 x 10
3
.
Degree of acetylation of chitosan ranges from 66%
to 99.8%.

3.2 Solubility:

Chitosan is sparingly soluble in water, practically
insoluble in ethanol (95%), other organic solvents
and neutral and alkaline solutions at pH
above 6.5
9
. It dissolves readily in dilute
and concentrated solution of most organic
acids and to some extent in mineral
inorganic acids. Upon dissolution, group of
the polymer becomes protonated,
resulting in a positively charged
polysaccharide (RNH
3
+
) and chitosan salts
(chloride, glutamate etc) that are soluble in
water. The solubility is affected by degree
of deacetylation
10
. Solubility is also
influenced by the addition of the salt to the
solution. The higher the ionic strength, the
lower is the solubility which is due to the
result of a salting out effect, which leads to
the precipitation of chitosan in solution
11
.

When chitosan is in solution, the repulsion
between the deacetylated units and their
neighbouring glucosamine units causes it
to exit in an extended conformation.
Addition of an electrolyte reduces this
effect and the molecule possesses a more
random, coil-like conformation
12
.

3.3 Viscosity (dynamic):

A wide range of viscosity types
are commercially available, owing to its
high molecular weight and linear,
unbranched structure, chitosan is an
excellent viscosity-enhancing agent in an
acidic environment. It acts as a
pseudoplastic material exhibiting a
decrease in viscosity with increasing rate
of shear
10
. Viscosity of chitosan solution
increases with increasing chitosan
concentration, decreasing temperature
and increasing degree of deacetylation
12
.

Acid 1%
concentratio
5%
concentratio
10%
concentratio
Visco
(Mpsa
pH Visco
(Mpsa
pH Visco
(Mpsa
pH
Acetic 260 .41 260 3.3 260 2.9
Adepic 190 4.1 -- -- -- --
Citric 35 3.0 195 2.3 215 2.0
Formic 240 2.6 185 2.0 185 1.7
Lactic 235 3.3 235 2.7 270 2.1
Malic 180 3.3 205 2.3 220 2.1
Malonic 195 2.5 -- -- -- --
Oxalic 12 1.8 100 1.1 100 0.8
Tartaric 52 2.8 135 2.0 160 1.7
Table1: Typical viscosity (dynamic)
values for chitosan 1%w/v solution in
different acids

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3.4 Safety:

Chitosan is widely used as an excipient in oral and
other pharmaceutical formulation, and also used
in cosmetics. It is regarded as nontoxic and non-
irritant material. It is biocompatible
13
with both
healthy and infected skin
14, 15
.
LD50 (mouse, Oral) : > 16g/kg
16

3.5 Cationic Polyamine:

Chitosan has high charge density at pH 6.5.
Positive charge of chitosan interacts strongly with
negative surface such as mineral oil carrying
negative charge. It forms gel with number of
multivalent ions at low pH range and also with
gluteraldehyde and chelates certain heavy
transition metals ions by residual amino group
17
.
It is used in controlled release technology
because of its ionic character along with reactive
functional group (Table1).

4. DERIVATIVES OF CHITOSAN
These are amphoteric in nature. They can
be prepared under heterogeneous
reaction condition using 2-sulfobenzoic
acid anhydride

4.1 Water-soluble derivatives of chitosan
at neutral pH:

Chitosan and its derivatives soluble in pH values
of lower than 6.0

may not be desirable for usage
in medicine, cosmetics and food
18
. To improve
its solubility at neutral pH, it is first derivatized
with substituents containing quaternary amino
group
19
, caboxymethylation and then sulfatation
by adding strongly hydrophilic

substituent
20
.

4.2 Quaternarized derivatives:

The simplest derivative is the trimethyl
ammonium salt of chitosan. A repeated
treatment of chitosan in N-methyl-2 pyrrolidone
containing sodium iodide and methyl iodide with
chloride ion in presence of sodium hydroxide
results into the trimethyl ammonium salt of
chitosan with high degree of substitution
21
.
Anionic changes of iodide with chloride ion are
necessary for stabilization. The resulting product
is water soluble at neutral pH
22
.

4.3 Caboxyalkylation:

The process of caboxyalkylation introduces
acidic group on the polymer backbone. This
derivative exhibits amphotericity due to the
presence of native amino group. These
derivatives also exhibit an isoelectric point as
that of other amphoteric molecules. Water
solubility is attained at pH values above or below
the isoelectric point. Formation of N-
carboxyalkylation uses carboxyaldehyde
in a reductive amination sequence
23
.
The reaction is carried out under
homogeneous condition provided that
the aldehyde used is water, allowing for
greater degree of substitution distribution
along the polymer back-bone. However,
sequential substitution giving rise to the
formation of bis-carboxymethyl
derivatives have been
observed using glyoxalic acid
24
.

4.4N- sulfonated derivatives of chitosan

25
. N-sulfonato-N,O-
carboxymethylchitosan: a novel polymeric
absorption enhancer for the oral delivery
of macromolecules
26
.

4.5 N-trimethylene chloride chitosan:

Hamman and coworkers showed that the
degree of quaternization of trimethylene
chloride influences its drug absorption-
enhancing properties
27, 28
. The charge on
chitosan has a role in providing intestinal
permeability. Hence, a quaternary
derivatized chitosan (N-trimethylene
chloride chitosan) is found to demonstrate
higher intestinal permeability than chitosan
alone. Polymers with higher degrees of
quaternization (> 22%) are able to reduce
the trans-epithelial electrical resistance
and thereby epithelial transport (in vitro) in
a neutral environment (pH 7.4). The
maximum reduction in trans-epithelial
resistance is found to be reached with
trimethylene chloride with a degree of
quaternization of 48%. This degree of
quaternization is optimum for in-vitro
transport of model drugs across a Caco-
2 monolayer.

4.6 Chitosan Esters:

Chitosan esters, such as chitosan
succinate and chitosan phthalate
have been used successfully as
potential matrices for the colon-
specific oral delivery of sodium
diclofenac. By converting the
polymer from an amine to a
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15
succinate form, the solubility profile is
changed significantly
29
. The modified
polymers are insoluble under acidic
conditions and act as sustained release
for the encapsulated agent under basic
conditions and also for colon-
targeted system
21
.
Miyazaki et al,

4.7 Chitosan conjugates: Guggi and
Bernkop attached an enzyme inhibitor to
chitosan. The resulting polymer retained
the mucoadhesivity of chitosan preventing
drug degradation by inhibiting enzymes
such as trypsin and chymotrypsin
30
. This
conjugated chitosan has promising role in
delivery of sensitive peptide drugs such as
calcitonin.

4.8 Stability and storage condition:
Chitosan powder is a stable material at
room temperature, although it is
hygroscopic after drying. It should be
stored in cool, dry place, preferably at a
temperature of 2-8
C. Chitosan is
incompatible with strong oxidizing agent
9
.

5. Application of Chitosan

5.1 Pharmaceutical Applications

5.1.1 Direct compressible excipients
and as binder:

Chitosan has an excellent property as
excipients for direct compression of tablets
where the additions of 50% chitosan result
in rapid disintigration. The degree of
deacetylation determine the extent of
moisture absorption
[31]
.Chitosan higher
then 5%, was superior to corn starch and
microcrystalline cellulose as a disintigrant
.The efficiency was dependent on
chitosan crystalinity, degree of
deacetylation, molecular weight and
particle size
[32]
. Chitosan is found to be
excellent tablet binder as compared to
other excipients with the rank order co-
relation for binder efficiency. Hydroxy
propyl methyl cellulose >chitosan> Methyl
cellulose>Sodium carboxy methyl
cellulose
33
.

5.1.2 Controlled release dosage forms:

Chitosan and chitosan derivatives, in
combination with other excipients are used
to give zero-order release profile. The rate
of release of drug from tablet was
found to some degree, to be
directly related to the amount and
type of chitosan used
34
.
35
who
found that, addition of sodium
alginate to the tablet preparation
gave the tablet an extended
release property. Similar results
had been found by Kawashima et
al,
36
who suggested that citric
acid can gel the chitosan and
thereby impart sustained release
properties.
Film coating of theophylline
granules with polyelectrolyte complex of
chitosan and sodium tripolyphosphate
37

has produced a controlled release system.

The rate of release of drug could be
controlled by pH. At low pH value the
reduce charge of the anionic
tripolyphosphate reduce the electrostatic
interaction in the complex and the film
network in loosen.
Akbuga
38
studied the influence of
physicochemical characteristics of drugs
on their release characteristics from
chitosan maleate matrix tablet and found
that the drug solubility, degree of ionization
and the molecular weight of the drug are
feature of importance.
Thiolated chitosan has
excellent cohesive properties. The
reduced thio functions on the chitosan
backbone enable thiolated chitosan
not only to form disulfide bond with
mucus glycoproteins, but also to form
inter as well as intra molecular
disulfide bonds. Such a crosslinking of
the polymeric chains results in high
stability of the drug carrier system
based on thiolated chitosan. In order
to improve therapeutic efficacy,
clotrimazole matrix tablets based on
chitosan-thioglycolic acid conjugate
and chitosan-4-thio-butyl-amidine
[chitosan-TBA] conjugates were
quantified. Both the thiolated chitosan
tablets remained stable during the
whole experiment [6 hrs] and no
disintegration could be observed.
However only the chitosan-TBA
conjugate was able to guarantee a
significant delay in the drug release in
comparison to unmodified chitosan,
leading to sustained release over a
much longer time period
39, 40
. The
release profile of salmon calcitonin
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matrix tablets based on chitosan-TBA
conjugate was determined. A pseudo zero
order release profile of salmon calcitonin over
the first 8 Hrs was observed in an artificial
intestinal fluid. During the experiment the
tablet swelled continuously, maintaining a
good cohesiveness and releasing a active
agent via a controlled diffusion process
41
.
These release studies, in which a peptide drug
was liberated, formed thiolated chitosan matrix
system permiting information concerning the
chemical events within the formulation to be
gained. Strong unintended interaction between
the polymeric matrix system and the peptide
drug could be excluded according to controlled
and sustained release profile
Cristian Tapia et al
42
have evaluated
the possibility of using mixtures and/or poly
electrolyte complexes from both chitosan-
alginate and chitosan-carrageenan system as
prolonged drug release systems. It has been
found that chitosan-alginate system is better
than the chitosan carrageen system as
prolonged drug release matrix because the
drug release is controlled at low percentage in
the formulation, the mean dissolution time is
high, and different dissolution profile could be
obtained by changing the mode of inclusion of
the polymers. Good arrangement between t
d

and k
f
/k
r
values for the system chitosan-
alginate was found, which means that the
swelling behavior of the polymer controlled the
drug release from the matrix. In case of the
system chitosan-carrageenan, the high
capacity of carrageenan promotes the entry of
water into the tablet and therefore the main
mechanism of drug release would be
disintegration instead of swelling of the matrix
42
.

5.1.3 Gel formulation:

Suitability of dried chitosan gels as vehicles for
the sustained release of the poorly soluble
drugs such indomethacin and papaverine
hydrochloride was studied. The drugs were
dispersed in the gel and showed zero order
release with 40% of the indomethacin
released into pH 7.4 buffer at 24 hours and
100% papaverine hydrochloride into 0.1N
hydrochloric acid at the same time interval
43
.
These results were confirmed by Krist et al
44

for lidocain release from chitosan
hydrochloride and the gels. It was found that
the degree of deacetylation of the chitosan
were important for the observed release
properties. The release profile of gels followed
almost zero order kinetics. Knapczyk
45

prepared gels from 93% and 66%
deacetylated chitosan with lactic acid
and found that the gels prepared from
the chitosan, with the highest degree
of deacetylation were more stable in
combination with drugs prepared with
less deacetylated chitosan.

5.1.4 Mucoadhesive property:

Takayama et al
46
have
investigated bioadhesive property and the
rate of release of a model drug from oral
tablet comprising chitosan and sodium
hyaluronate. It was found that tablets
produced from chitosan alone, were less
mucoadhesive than when produced from
sodium hyaluronate alone or when using
two polymers as a complex. The release
rate of drug was highly dependent upon
the weight fraction of chitosan in the tablet,
with a constant release rate being
obtained between 10 and 60 % of chitosan
and a rapid increase in release for higher
fraction.
Thiol-derivative of chitosan
improves mucoadhesive properties by the
formation of covalent bonds between thio
groups of the polymer and cysteine rich
sub domains of glycoproteins in the mucus
layer
47
.
These covalent bonds are
supposedly stronger than non-covalent
bonds, such as ionic interaction of
chitosan with anionic substrates of the
mucus layer; this theory was supported by
the results of tensile studies with tablets of
thiolated chitosan, which demonstrated
positive correlation between the degree of
modification with thiol bearing moieties
and the adhesive properties of the
polymer
48
.
Marta Roldo et al
49
have
evaluated the influence of the degree
of modification and the polymer chain
length on the mucoadhesive properties
and the swelling behavior of the
thiolated chitosan derivative obtained
via a simple one step reaction
between the polymer and 2-
iminothiolane. The conjugates differing
in molecular mass of the polymer
backbone and in amount of
immobilized thiol groups were
compressed into tablets. They were
investigated for their mucoadhesion
properties on freshly excised porcine
mucosa via tensile studies and rotating
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cylinder method. The obtained result
demonstrated that the total work of adhesion
of chitosan-TBA (4-thiobutyl-amidin)
conjugates can be improved by an increasing
number of covalently attached thiol groups;
100 fold increase compared to unmodified
chitosan was observed for a medium
molecular mass chitosan-TBA conjugate
exhibiting 264m thiol groups per gram
polymer. Also, the polymer chain length had
an influence on the mucoadhesive property of
the polymer. The medium molecular mass
polymer displayed a four fold improved
adhesion on the rotating cylinder compared to
the low molecular mass derivative
49
.

Miasakkinen et al
50
have studied
mucoadhesive properties of chitosan granules
to the human esophagus. Chitosan granules
were dispensed into gelatin capsules and
administered to 10-volunteers. The capsule
adhered initially to the distal esophagus. The
capsule shell started to disintegrate within 5
minutes, about two third of the radioactivity
remained detectable in the esophageal region
for 1.75 hour. This could be explained on the
basis of adherence not only on the gelatin
shell but also chitosan granules to the
esophageal mucosa
50
.
Mia Sakkinen et al
51
have studied in
vivo evidence of weather microcrystalline
chitosan formulation acted as gastro retentive
system in humans by gamma scintigraphic
evaluation of the fate of microcrystalline
chitosan granules in human stomach. It was
concluded that the in vivo mucoadhesion of
the formulation was erratic, and the
formulation studied were not reliable for gastro
retentive drug delivery systems.

5.1.5 Ophthalmic drug delivery:

Chitosan because of its low toxicity exhibits
favorable biological behavior, such as
bioadhesion, permeability enhancing
properties and interesting physico-chemical
characteristics, which make it a unique
material for the design of ocular drug delivery
vehicles
23
. The potential of chitosan-based
systems is for improving the retention and
biodistribution of drugs applied topically onto
the eye. Chitosan based formulations for
ophthalmic drug delivery are chitosan gels,
chitosan-coated colloidal systems, and
chitosan nanoparticles. Chitosan-based
colloidal systems are 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
cyclosporin)
[24]
. The micro-particulate
drug-carrier (micro-spheres) is a
promising means of topical
administration of acyclovir to the eye
25
.

5.1.6 Nasal drug delivery:

The nasal mucosa presents an ideal site
for bioadhesive drug delivery systems.
Chitosan based drug delivery systems,
such as micro spheres, liposomes and
gels have been demonstrated to have
good bioadhesive characteristics and swell
easily when in contact with the nasal
mucosa increasing the bioavailability and
residence time of the drugs to the nasal
route. Various chitosan salts such as
chitosan lactate, chitosan aspartate,
chitosan glutamate, and chitosan
hydrochloride are good candidates for
nasal sustained release of vancomycin
hydrochloride
26
. Nasal administration of
Diphtheria Toxoid (DT) incorporated into
chitosan microparticles results in a
protective systemic and local immune
response against DT with enhanced IgG
production. Nasal formulations have
induced significant serum IgG responses
similar to secretory IgA levels, which are
superior to parenteral administration of the
vaccine
27
.

Research showed bioadhesive
chitosan microspheres of pentazocine for
intranasal systemic delivery significantly
improved the bioavailability with sustained
and controlled blood level profiles
compared to intravenous and oral
administration
28
. Nasal absorption of
insulin after administration into chitosan
powder were found to be the most
effective formulation for nasal drug
delivery of insulin in sheep compared to
chitosan nanoparticles and chitosan
solution.

5.1.7 Buccal drug delivery:

An ideal buccal delivery system should
stay in the oral cavity for few hours
and release the drug in a unidirectional
way toward the mucosa in a controlled
or sustained-release fashion.
Mucoadhesive polymers prolong the
residence time of the device in the oral
cavity
29
, while bilayered devices
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18
ensure the release of the drug occurs in a
unidirectional way.

Chitosan is an excellent
polymer to be used for buccal delivery
because it has muco/bioadhesive properties
and can act as an absorption enhancer
30
.
Directly compressible bioadhesive tablets of
ketoprofen containing chitosan and sodium
alginate in the weight ratio of 1:4 showed
sustained release 3 hours after intraoral (into
sublingual site of rabbits) drug
administration
31
. Buccal tablets based on
chitosan microspheres containing
chlorhexidine diacetate gives prolonged
release of the drug in the buccal cavity
improving the antimicrobial activity of the
drug
32
. Chitosan microparticles with no drug
incorporated have antimicrobial activity due to
the chitosan. The buccal bilayered devices
(bilaminated films, palavered tablets) using a
mixture of drugs (nifedipine and propranolol
hydrochloride) and chitosan, with or without
anionic crosslinking polymers (polycarbophil,
sodium alginate, gellan gum) has promising
potential for use in controlled delivery in the
oral cavity
33
. Bioadhesive tablets of nicotine
containing 0% to 50% w/w glycol Chitosan
gives good adhesion
34
.

5.1.8 Periodontal Drug Delivery:

Local delivery of drugs and other bioactive
agents directly into the periodontal pocket has
received a lot of attention. For moderate to
severe periodontal diseases, antimicrobial
agents are used to eradicate and/ or suppress
the plaque bacteria
35
. However, systemic
administration of these drugs requires frequent
dosing to maintain the drug concentrations at
the therapeutic level in the plasma causing
poor patient compliance
36
. Chitosan itself
possesses antibacterial activity. Muco/
bioadhesive polymers increase the residence
time of the formulation in the oral cavity. This
enhances drug penetration, localizes the drug
for local therapy, target the diseased tissue
and improve efficacy and acceptability. The
antibacterial activity of chitosan is due to the
electrostatic interactions between the amine
groups of chitosan and the anionic sites on the
bacterial cell wall because of the presence of
carboxylic acid residues and phospholipids.
Chitosan inhibits the adhesion of Candida
albicans to buccal cells showing antifungal
activity
37
. Research shows that a monolayer
and multilayered film of chitosan/ PLGA
containing ipriflavone prolongs drug release
for 20 days in-vitro
38
.

5.1.9 Gastrointestinal drug delivery:

Chitosan granules having internal
cavities prepared by deacidification
when added to acidic and neutral media
are found buoyant and provided a
controlled release of the drug
prednisolone
39
. Floating hollow
microcapsules of melatonin showed
gastroretentive controlled-release
delivery system. Release of the drug
from these microcapsules is greatly
retarded with release lasting for 1.75 to
6.7 hours in simulated gastric fluid. Most
of the mucoadhesive microcapsules are
retained in the stomach for more than
10 hours (e.g.,
Metoclopramide and glipizide loaded chit
osan micro-spheres)
40
.

5.1.10 Peroral drug delivery:

As chitosan and most of its derivatives
has a mucoadhesive property, a
presystemic metabolism of peptides can
be strongly reduced leading to a strongly
improved bioavailability of many
perorally given peptide drugs, such as
insulin, calcitonin, and buserelin
41
.
Unmodified chitosan has a permeation-
enhancing effect for peptide drugs. A
protective effect for polymer-embedded
peptides towards degradation by
intestinal peptidases can be achieved by
the immobilization of enzyme inhibitors
on the polymer. The mucoadhesive
property of chitosan gel can be
enhanced by threefold to sevenfold by
admixing chitosan-glyceryl mono-oleate.
Drug release from the gel followed a
matrix diffusion controlled mechanism
43
.
Nifedipine embedded in a chitosan
matrix in the form of beads have
prolonged release of
drug compared to granules
43
.

5.1.11 Intestinal drug delivery:

Sustained intestinal delivery of drugs,
such as 5-fluorouracil (for colon
carcinomas) and insulin (for diabetes
mellitus), seems to be a feasible
alternative to parenteral therapy
44
. A
formulation of bromothymol blue using
bioadhesive polyacrylic acid, alginate
and chitosan bypassed the acidity of
the stomach and released the loaded
drug for a longer period of 80 days in-
I J PA S

19
vitro into the intestine. Chitosan/ calcium
alginate microcapsules containing
nitrofurantoin (NF) has sustained the release
of the drug
45
.

5.1.12 Vaginal drug delivery:

Chitosan, modified by the introduction of
thioglycolic acid to the primary amino groups
of the polymer, embeds clotrimazole, an
imidazole derivative, is widely used for the
treatment of mycotic infections of the
genitourinary tract. By introducing thiol groups,
the mucoadhesive properties of the polymer
are strongly improved and this is found to
increase the 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
48
. Vaginal
tablets of chitosan containing metronidazole
49

and acriflavine have showed adequate release
and good adhesion properties
50
.

5.1.13 Transdermal delivery:

Chitosan has good film-forming properties.
The drug release from the devices is affected
by the membrane thickness and cross-linking
of the film
51
. Chitosan-alginate polyelectrolyte
complex (PEC) has been prepared in-situ in
beads and microspheres for potential
applications in packaging, controlled release
systems and wound dressings
52
. Chitosan gel
beads are a promising biocompatible and
biodegradable vehicle for treatment of local
inflammation for drugs like prednisolone which
showed sustained release action improving
therapeutic efficacy
53
. The rate of drug
release was found to be dependent on the
type of membrane used
54
. 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
55
.
Microspheres of chitosan is used as a
controlled release delivery system either
for implantation or for oral delivery.
Generally such microspheres are
produced, either by an emulsification,
crosslinking processes or by use of
complexation between oppositely
charged macromolecules.

5.1.14 Enhanced dissolution with chitosan:

The dissolution of poorly soluble drugs is
critical for drug absorption. It has been found
that grinding of chitosan with poorly soluble
drugs, such as griseofulvin or prednisolone
enhances their dissolution properties
52
. For
low solubility acidic drugs, such as
indomethacin, it is possible to exploit the gel
forming reaction between the positively
charged amino sugar groups of
chitosan and the negatively charged
drug to increase the solubility of the
drugs and to control the release. Hou
et al
53
found that granules formed
from chitosan and indomethacin,
released the drug faster at a pH 7.5
after exposure to acidic pH in the
stomach, than if the granules had not
been exposed to lower pH. It was
thought that this was due to chitosan
swelling and gel formation at this low
pH. In comparison, if granules were
crosslinked with glutaraldehyde the
swelling and gel forming properties
diminished and a sustained release
was seen at intestinal pH.

5.1.15 Colonic drug delivery:

Chitosan has been used for the specific
delivery of insulin to the colon
54
. The
chitosan capsules were coated with
enteric coating (Hydroxy propyl methyl
cellulose phthalate) and contained, apart
from insulin, various additional
absorption enhancer and enzyme
inhibitor. It was found that capsules
specifically disintegrated in the colonic
region. It was suggested that this
disintegration was due to either the
lower pH in the ascending colon as
compared to the terminal ileum or to the
presence bacterial enzyme, which can
degrade the chitosan.

5.1.16 Microspheres and
microcapsules:

Nishioka et al
55
produced
glutaradehyde crosslinked chitosan
microsphere that contained cisplatin.
The drug loading efficiency increased
markedly with an increased chitosan
and chitin content and the sustained
release effect was enhanced with an
increase in the chitosan content from
1% to 5% and chitin content from 0-
1.5%. Similar microsphere were
prepared by Jameela and
I J PA S

20
Jayakrishna
56
containing Mitixantrone. Drug
release was found to be effectively controlled
by the degree of crosslinking, with only about
25% of the release over 36 days from
microspheres with a high degree of
crosslinking. The microspheres were not
biodegradable in the rat muscles. Akbuga and
Durmaz
57
prepared microspheres containing
furosemide from a w/o emulsion system.
Properties of microspheres were affected by
variables like concentration of chitosan, drug
concentration, crosslinking processes etc.
Microspheres crosslinked by tri-polyphosphate
have been shown to provide encapsulation of
the polypeptide salmon-calcitonin and a slow
release over 27 days
58
.
MI et al
59
produced chitosan
microsphers by two methods involving
interfacial acetylation and spray handling. The
microspheres contained oxytetracyclin and
were prepared with chitosan of 70-kDa, 700-
kDa and 2000-kDa molecular weight
respectively. The result showed that the higher
the molecular weight of the chitosan the more
sustained was the drug release rate. Similarly
chitosan microspheres encapsulating insulin
were prepared by Aideh et al
60
. The
microspheres were crosslinked interfacially by
ascorbyl palmitate. The release rate of the
drug was dependent on the amount of
chitosan in the microspheres and lasted up to
80 hours. Chitosan microspheres crosslinked
with the polyanion sodium tripolyphosphate
and with incorporated polyetheleneoxide, poly
propylene oxide, co-polymers were suggested
for use as carriers of proteins and vaccines for
oral delivery. The release of antigen was slow
with only 20 % of tetanus toxoids being
released after eighteen days
61
. Chitosan
microspheres have also been prepared by
emulsification- ionotropic gelation method,
which basically consist in raising the pH of the
emulsion system to render the chitosan
insoluble
62
.

Oppositely charged
polyelectrolytes would react rapidly in solution
to form, normally an insoluble precipitate. This
principle was investigated for the production of
chitosan microspheres, hence avoiding the
use of cross-linking agents.
Polk et al
63
reacted chitosan with
sodium alginate in presence of calcium
chloride and formed microcapsules with a
polyelectrolyte complex membrane, the rate of
release of albumin from these microcapsules
was dependent on alginate concentration and
chitosan molecular weight with an increase in
these two factors, decreasing the rate of
release of albumin. Remunane-Nopez and
Bodmeier
64
used a similar principal,
who prepared microspheres from
chitosan gelatin coacervates. Liu et
al
65
prepared porous microspheres by
gelling chitosan with sodium alginate
followed by freeze-drying. The drug
interlukine-II was incorporated into the
preformed microspheres by diffusion
from an external aqueous solution of
the drug. It was found that the drug
was released from microspheres in a
sustained manner and the drug
triggered the induction of cytotoxic T
lymphocyte more efficiently then free
drug due to the slow release of the
cytokinin.

5.1.17 Wound healing properties:

Efficacy of chitosan in the promotion of
wound healing was first reported in
1978
66
. Chitosan acetate films, which
were tough and protective, had the
advantage of good oxygen permeability,
high water absorptivity and slow
enzymatic degradation, there by
avoiding the need for repeated
application
66
.
Malettle et al
67
showed that
treating various dock tissues with
chitosan solutions resulted in the
inhibition of fibroplasias with enhanced
tissue regeneration. 3M Company has
marketed Tegasorb
TM
a wound-healing
product for human use, containing
chitosan as excipients.

5.1.18 Multiparticulate delivery
system:

H.Steckel and F. Mindermann-Nogly
68

have prepared chitosan pellets using the
extrusion/spheronization technology.
Microcrystalline cellulose was used as
additive in concentrations range from 0-
70 %. The powder mixture was extruded
using water and dilute acetic acid in
different powder to liquid ratios. The
study showed that chitosan pellets with
a maximum of 50 %(m/m) could be
produced with demineralized water as
granulating fluid. The mass fraction of
chitosan within in the pallets could be
increased to 100% by using dilute acetic
acid for the granulation step.

I J PA S

21
5.1.19 Absorption promotion properties:

Illum et al.
69
has shown that chitosan is able
to promote the transmucosal absorption of
small polar molecules and peptide and protein
drugs. In the ship model they found that the
addition of chitosan to a nasal formulation of
insulin caused the plasma glucose level to fall
to 43% of base level as compared to 83% of
base level, without the addition of chitosan.
Concurrently the plasma insulin levels,
increased from 34 mlu/l to 191 mlu/l and the
AUC increased seven fold. Similar result have
also been obtained for other small molecular
weight drugs that are polar in nature such as
morphin, antimigrain drugs, peptides such as
calcitonine, desmopressin, goserelin,
parathyroid hormone releasing hormone and
leuprolide. Studies in human volunteers
confirmed the results in sheeps,
70
when used
as a simple solution formulation with a
concentration 0.5-1%. Alternatively, chitosan
can be spray dried or formulated into chitosan
microspheres, such powder formulation are
superior to providing improved enhancement
of drug transport across the membrane as
compared to chitosan solutions. Rentel et al
71

reported that chitosan was able to enhance
the transmucosal absorption of the peptide 9-
desglycinamide 8-arginine vasopressin after
administration as a solution to intestinal loops
of rats. It was shown that the effect of chitosan
on the penetration of mannitol in caco-2 cells
was dependent on the alginate concentration
and the chitosan molecular weight
72, 73
.
It has been reported that chitosan
solution was able to increase upto fifty fold the
intestinal absorption of buserelin
74
.

Chitosan
derivative N-trimethyl chitosan chloride was
shown to be more soluble and hence easier to
formulate into solid oral dosage form than
chitosan itself
75
.
The mechanism of action of chitosan
in improving transport of drugs was thought to
be a combination of bioadhesion and a
transient opening of the tight junction in the
cell membrane to allow polar drug to pass
through
70
. It has been demonstrated by
gamma scintigraphy, that chitosan is
mucoadhesive with a nasal clearance time in
the order of 25, 40, and 80 minutes for a
control solution, a chitosan solution and a
chitosan powder, respectively after application
to the nasal cavity of human volunteers
70
. The
effect of chitosan on a model cell membrane
has demonstrated conclusively that chitosan,
most likely due to its positive charge, is able to
interact with the opening mechanism of the
tight junction as seen by a decrease in
zo-1 proteins and the change in the
cytoskeleton protein F-actin from a
filamentous to a globular structure
73,
75
.

Chitosan excels in enhancing
the transport of drugs across the cell
membrane. Its cationic polyelectrolyte
nature provides a strong electrostatic
interaction with mucus, negatively
charged mucosal surfaces and other
macromolecules such as DNA
76, 77
.
Chitosan has been used as a
delivery vehicle for nasal, ocular and
peroral drug delivery in order to prolong
contact time and improved drug
absorption
78
.
The permeation enhancing
effect of chitosan can be strongly
improved by the immobilization of thiol
groups. The uptake of fluorescence
labled bacitracin, for instance, was
improved 1.6 folds utilizing 0.5% of
chitosan-cystiene conjugatre instead of
unmodified chitosan
[79]
. In other studies
the permeation enhancing effect of
chitosan-TBA in comparision to the
permeation enhancing effect of
unmodified chitosan was done. The
uptake of the cationic marker compound
rhodamine 123 was 3 fold higher in the
presence of thiolated chitosan verses
unmodified Chitosan
80
.
A.polnok et al
134
showed
influence of methylation process on the
degree of quaternization of N-trimethyl
chitosan chloride. N-trimethyl chitosan
chloride (TMC) is a soluble chitosan
derivative that shows effective
enhancing properties for peptide and
protein drug transport across mucosal
membrane.
S.M. Vander and Merwe et al
81
prepared minitab and granules as
formulation for solid oral dosage form
for the delivery of peptide drugs with
the absorption enhancer N-trimethyl
chitosan chloride (TMC). Both the
optimized minitab and granule
formulation shows suitable release
profile for the delivery of peptides
drugs with TMC as absorption
enhancer in solid oral dosage forms.
Nimazerrouk et al
82
has investigated
the solubilizing and absorption
enhancing properties of naproxen
towards chitosan and polyvinyl
pyrollidone(PVP). Both carriers
I J PA S

22
improved drug dissolution and their
performance depend on the drug-polymer ratio
and the system preparation method. Chitosan
was more effective than PVP despite the
greater amorphizing power of PVP as
revealed by solid-state analysis. The 3/7(W/W)
drug-carrier co-ground system with chitosan
and PVP were the best product enabling,
respectively, an improvement of 4.8 and 3.6
times drug dissolution efficiency. Moreover,
the 3/7 (W/W) drug chitosan co-ground
product demonstrated an antiwrithing potency
2.4 times higher than that co-ground with PVP.
Thus, the direct compression properties and
anti-ulcerogenic activity, combined with the
demonstrated solubilizing power and
analgesic effect enhancing ability towards the
drug, make chitosan particularly suitable for
developing a reduced dose fast-releasing solid
oral dosage form of naproxen
83
.

5.1.20 Gene delivery:

Chitosan is a good candidate for gene
delivery system because positively charged
chitosan can be complexed with negatively
charged DNA
84, 85
. Chitosan can effectively
bind DNA and protect it from nuclease
degradation
86, 87
. It has advantage of not
necessitating sonication and organic solvents
for its preparation, thereby minimizing possible
damage to DNA during complexation. DNA
loaded chitosan microparticles were found to
be stable during storage
88
. The application of
DNA-chitosan nanospheres has advanced in
vitro DNA transfection research and the data
has showed their usefulness for gene delivery
89, 90
.
Erbacher et al
90
investigated chitosan
and lactosylated chitosan vectors for their
transfection efficiency of in hela cells in the
presence of 10% fetal salt serum and was
found comparable to that of another cationic
polymer, polyethylenemine. It was shown that
these vectors were poorly efficient in
transfecting galactose specific membrane
lectin (HepG2 cells). This was probably
caused by aggregation of the complexes due
to decrease of zeta potential after
lactocylation, accompanied by lower affinity of
the lactosylated polymer to DNA. Presence of
chloroquine, a weak base prevents lysosome
acidification
91
not improving transfection
efficiency. Park et al
92
have used
galactocylated chitosan graft-polyethylene
glycol as a DNA vector. DNA complexed with
GCP is stable and protected against enzyme
degradation with DNA. However, the
transfection efficiency using GCP/DNA
complexes is very low, mainly because
of interaction with plasma leading to
dissociation of GCP/DNA complexes.
This study was challenged by the data
of Gao et al
93
in different cell lines,
which supported positive use of low
molecular weight chitosan as a
modified vector for gean therapy.
Another approach to increase
transfection rate was to use chitosan
as a vector, consisting by preparing
trimethylated chitosan oligomers
through querternization of oligomeric
chitosan as demonstrated by Thanou
et al
94
Chitosan/DNA/ligand
complexes are used to increase
transfection rate. This system is based
on transferring receptor-mediated
endocytosis to carry exogenous DNA
into the cells to yield a higher
transfection rate. Compared to non-
modified chitosan, the method result in
four fold enhanced transfection
efficiency in HeLa cells and several
fold in H3K293
95
Yau and Liu have proposed a
DNA/N-dodecylated chitosan complex
and salt induced gean delivery (CS-12)
from dodecyl bromide and chitosan
(DNA-CS-12-PEC). Incorporating
dodecylated hydrolyze by DNAse can
be broken into fragments. On the other
hand, DNA dissociated from the
complex is well protected and remains
intact due to the protection from Dnase
offered by alkylated chitosan
96
.

Lee and
Kim et al
97, 98
proposed a
hydrophobically modify chitosan
(Mv=7.010
4
, degree of deacetylation
80%) with deoxycholic acid. Deoxycholic
acid is a main component of bile acid,
which is biologically the most detergent-
like molecule in the body. Since bile acid
can assemble in water, the deoxycholic
acid modified chitosan also self-
associate to form missiles of a mean
diameter of 160nm. The transfection of
COS-1 cells (Monkey kidney) with
chitosan self-aggregated-DNA
complexes were examined using the
plasmid encoding chlormphenicol acetyl
transferase. The transfection efficiency
of the complex is enhanced compared
to that achieved by naked DNA but
lower than that achieved by
lipofectamine.

I J PA S

23

Table 2: Application summary of the
chitosan

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Dosage for Drug
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Chitosan gel
Chitosan
Microparticle.
Chitosan
nanoparticles
Chitosan ophthalmic
film
Indomethacin
Acyclovir
Cyclosporine
2 Nasal drug
delivery system
Microparticles
Powder
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Insuline
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bilaminated films
palavered tablets
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Nifedipine and
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Ipriflavon
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granuls
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Glipizide
Melatonin
Prednisolone
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Drug Delivery
Chitosan beads
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and Buserelin,
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Delivery
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Acriflavine
I J PA S

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