Review: Chitosan: Properties, Preparations and Application To Microparticulate Systems

J. MICROENCAPSULATION, 1997, VOL. 14, NO.
6, 689-711
REVIEW
Chitosan: properties, preparations and application to
microparticulate systems
H. S U H E Y L A KAS
Journal of Microencapsulation Downloaded from informahealthcare.com by University Of Wisconsin Madison on 05/02/13
Hacettepe University, Pharmacy Faculty, Pharmaceutical Technology

Department, 06100 Ankara, Turkey
(Received 8 November 1996; accepted 13 December 1996)
Chitosan, a hydrophilic biopolymer, is obtained industrially by hydrolysing the

aminoacetyl groups of chitin. I t is a natural, non-toxic, biodegradable poly-
saccharide available as solution, flake, fine powder, bead and fibre. The sources,
biochemical aspects, structure and chemical modification, physico-chemical and
functional properties, and applications of chitosan have been investigated
extensively in the literature. I n this paper, the attractive properties and broad
applications of chitosan-based microparticles, their versatile properties, differ-
ent preparation methods, and pharmaceutical and biopharmaceutical applica-
tions are reviewed.
Keywords: Chitosan, microparticles, preparation, pharmaceutical, biopharma-

For personal use only.
ceutical applications.
Introduction
Chitin, which is perhaps the second most important natural polysaccharide, is a

straight homopolymer composed of B (1,4)-linked GlcNAc units with a three-
dimensional a-helical configuration stabilized by intramolecular hydrogen
bonding. Chitosan, or B (1,4) 2-amino-2-deoxy-~-glucose, is a hydrophilic bio-
polymer obtained industrially by hydrolysing the aminoacetyl groups of chitin,
which is the main component of shells of crab, shrimp and krill, by an alkaline
treatment. After deacetylation of chitin, dry chitosan flakes are obtained. T h e y are
milled to get fine mesh chitosan and are blended with organic acids to give acid-
blend chitosan. After deacetylation of chitin, the chitosan obtained is dissolved in
acid, filtered and the precipitate is washed and dried to get amine free chitosan.
(Sanford 1989, 1990, Seo and Kinemura 1989, Versali 1993). T h e structural
formula of chitosan is shown in figure 1 . Its chemical formula is ( C 6 H 1 1 0 4 N ) , , .
Chitosan, a linear polyelectrolyte at acidic pHs, is soluble in variety of acids
and interacts with polyanionic counterions (Fukuda and Kikuchi 1978, Fukuda
1980). It forms gels with a number of multivalent anions and also with glutar-
aldehyde. I t has a high charge density i.e. one charge per glucosamine unit. Since
many minerals carry negative charges, the positive charge of chitosan interacts
strongly with negative surfaces.
Chitosan is a linear polyamine where amino groups are readily available for
chemical reactions and salt formation with acids. T h e important characteristics of
chitosan are its molecular weight, viscosity, deacetylation degree (DA) (Bodek
1994, Ferreira et al. 1994a, b), crystallinity index, number of monomeric units ( n ) ,
0265-2048/97 $12.00 0 1997 Taylor & Francis Ltd

690 H . Siiheyla K a j
r
-7....-
-.-.-.
tiH, CHPH
-
i ti H
water retention value, pk, and energy of hydration. T h e samples prepared are
characterized by their fraction of 2-acetylamino-~-glycose in the molecule.
Chitosan is soluble in acidic solutions but insoluble at p H > 6 * 5 and in most
organic solvents. It has gel forming properties in low pH range (Knapczyk et al.
1989a, b, Amiji and Pate1 1995). It has a high charge density, adheres to negatively
charged surfaces and chelates metal ions. Chitosan is known to chelate with heavy
metal ions by residual amino groups. Chitosan granules are utilized for the
separation of transition metals like cobalt (Dutkiewicz 1994). T h e results of
Dutkiewicz indicate that chitosan may be of potential use in the purification of
cobalt. The pharmaceutical requirements of chitosan are as follows: particle size

< 30pm, density between 1.35 and 1.4Og/cc, pH6.5-7.5, insoluble in water, and
partially soluble in acids (Knapczyk et al. 1989a).
Chitosan can also be characterized in terms of its quality, intrinsic properties
and physical forms (Sanford 1989). The quality characteristics of chitosan are
levels of heavy metals and proteins, pyrogenicity, bioburden, cytotoxicity and
clarity. Molecular weight, viscosity and degree of deacetylation are the intrinsic
properties. T h e type of acid for salt formation and the mesh size of chitosan are
also important characteristics. Its biological properties are: biocompatibility (e.g.
non-toxic, biodegradable, natural), bioactivity, wound healing acceleration,
reduced blood cholesterol levels, and immune system stimulant effect. Biomedical
properties, biological activity and biodegradation of chitosan are stated by
Knapczyk et al. (1989a, b, Muzzarelli et al. 1988, Struszczyk et al. 1994). T h e
chemical behaviour of chitosan and modified chitosan are given by Muzzarelli
(1990).
When lipid dispersions are placed in chitosan, flocculation and redispersion
mechanisms occur (Demarger-Andre and Domard 1994). T h e proposed mechanism
is shown in figure 2.
Sanford (1990) summarized the chemical and biological properties of chitosan
that relate to applications (tables 1 and 2). Sanford (1990) and Taravel and
Damard (1994) investigated the interaction of chitosan with alginate and collagen
respectively. Lehr et al. (1992) evaluated the mucoadhesive properties of the
cationic chitosan in comparison with polycarbophil as a reference. Although not
yet competitive in comparison with carbophil, they found the mucoadhesive
properties of chitosan significant. Miyazaki et al. (1995) studied mucoadhesive
properties of chitosan by release from oral mucosa. Leusen et al. (1994) compared
the anionic charged polyacrylic acid derivatives and the cationic charged chitosan.
Chitosan: properties, preparations and applications 69 1
rMo.uic iype flocculation Iiilerpmiculiu bridging

SLructure of flocs oht;uiied wiili 3 high inolccuLv inau chiimnri

Figure 2. Proposed mechanism of flocculation and redispersion of lipids in the presence of

chitosan (Demarger-Andre and Domard 1994).
Table 1 . Chemical properties of chitosan

(Sanford 1990).
Cationic polyamine
high charge density at pHs < 6.5
adheres to negatively charged surfaces
forms gels with polyanions
High molecular weight linear polyelectrolyte
viscosity, high to low
Chelates certain transitional metals
Amiable to chemical modification
reactive amino/hydroxyl groups
Aspden et al. (1995) showed the absence of chitosan toxicity when applied to nasal
mucosa. Genta et al. (1996) studied chitosan microspheres for nasal delivery.
Chitosan also shows mesophase formation ability (Terbojevic et al. 1991).
Chitosan, is now produced in different parts of the world (Japan, North
America, India, Norway, Poland, India, Italy, Russia) on a large scale. It is sold
commercially as solution, flaked and fine powder, and more recently in beads and
fibre forms. Chitosan’s ability to be made into films, fibers and beads as well as
powders and solutions lead to many commercial applications. It is mainly used for
pharmaceuticals, cosmetics, biomedicals, agricultural materials and food products.
Chitosan is used in personal care products (hair treatment, skin care, moisturizer,
wound healing), as food products (wine and juice clarification, protective fruit
692 H . Siiheyla Kaj
Table 2. Biological properties of chitosan

(Sanford, 1990)
Biocompatibility
natural polymer
biodegradable to normal body constituents
safe and non-toxic
Haemostatic
Bacteriostatic
Fungistatic
Spermicidal
Anticancerogen
Anticholesteremic
coating, hypocholosterolemic behaviour), for clarification and waste management

(treatment of sewage, sludge and brewers’ waste, chelation of toxic heavy metals
and radioactive materials), in agriculture (seed coating, increasing crop yield, as a
flocculating agent, as a controlled release agent for pesticides and herbicides), for
biotechnology products (to separate and purify biologicals and to immobilize
enzymes and cells) and in pharmaceuticals.
Although there are a number of books, numerous original papers and patents
concerning chitosan microparticles, there is a lack of a review on chitosan-related
microparticles. A recent review on microcapsules and microspheres of chitosan is
by Yao et al. (1995). Akbuga (1995) reviewed different biomedical, pharmaceutical

and other applications of chitin and chitosan. Chandy and Sharma (1990)
discussed the use of chitosan in the development of haemodialysis membranes,
artificial skin, drug targeting and other applications. Application of chitin and
chitosan to pharmaceutical preparations is reviewed by several authors (Miyazaki
et al. 1981, Nagai et al. 1984, Kanke et al. 1989, Brine 1989, Knapczyk 1989a,
Erden and Celebi 1990, Kristl et al. 1992, 1993, Kag 1995, Yin et al. 1996).
Biotechnology and food processing aspects of chitin and chitosan are presented by
Knorr (1986, 1991), Knorr et al. (1989), Groboillot et al. (1994) and Synowiecki et
al. (1994). Chitosan is also used in cosmetics and toiletries. This is reviewed by
Naidoo (1992) and Lang and Clausen (1989).
With the broad applications of chitosan-based microparticles, their properties,
preparation methods and pharmaceutical and bio-pharmaceutical applications are
reviewed in this study.
Preparation of chitosan microparticles
In this section different preparation methods of microparticulate systems such

as, beads, microspheres, microcapsules, ground mixtures, granules and kneaded
mixtures prepared using chitosan are reviewed.
Microparticles (beads, microspheres, microcapsules)

Ionotropic gelation. I n this method, chitosan solutions in acetic acid are prepared
and extruded dropwise through a needle into different concentrations of aqueous
solutions of magnetically stirred tripolyphosphate. T h e beads are removed from
the counter ion solution by filtration, washed with distilled water, dried by an air
Chitosan: properties, preparations and applications 693
jet and further air dried at ambient temperature (Sawayanagi et al. 1983a, b,
Kawashima et al. 1985a-d, Nishimura et al. 1986, Kim and Rha 1989; Bodmeier
and Paeratakul 1989, Bodmeier et al. 1989a, b, Chandy and Sharma 1991, 1993a, b,
Vural et al. 1991, 1994, Aqkgoz et al. 1992, 1993, 1995, 1996, Bodmeier and Wang
1993, Shiraishi et al. 1993, Mitani et al. 1995, Farivar et al. 1993, Wan et al. 1994,
Aydin and Akbuga, 1996, Sezer and Akbuga, 1995).
Extrusion-spheronization. Goskonda and Upadrashta (1993) prepared avicel

chitosan beads by extrusion-spheronization technology where the ingredients are

mixed and the wet mass is passed through an extruder. T h e cylindrical extrudate
obtained is immediately processed in a spheronizer. T h e beads are collected and
dried in a hot air oven at 40°C for 12 h (Tapia 1993, Prud’homme 1994).
Solvent evaporation technique. Chitosan is dissolved in an aqueous acetic acid

solution. T h e solution is added to toluene and sonicated to form a w/o emulsion.
Glutaraldehyde solution in toluene is added to the emulsion and stirred at room
temperature to give cross-linked microspheres. T h e suspension is centrifuged.
Following evaporation of the solvent, the microspheres are separated, washed with
distilled water and dried (Gallo and Hassan 1992, Hassan et al. 1992, Lin and Lin
1992a, b, Thanoo et al. 1992, Ohya et al. 1993, Akbuga and Durmaz 1994).
Li et al. (1991) modified the solvent evaporation method and named it ‘Dry-in-
Oil’ method. Here the chitosan solution in acetic acid is dropped into oil under
stirring. T h e system is warmed to 50°C and the pressure is reduced. When the
solvent is evaporated completely the microspheres are separated, washed with
sodium hydroxide solution, distilled water and diethyl ether and dried.
Multiple emulsion method. Multiphase emulsions are also prepared by the solvent
evaporation technique by a three step emulsification process (Pavenetto et al.
1995). Aqueous drug solution and oil phase containing emulsion stabilizers are
combined to give a water-in-oil emulsion (step 1). Later the w/o emulsion is
dispersed in the polymer solution (step 2). T h e solvent is evaporated under
reduced pressure (step 3).
Spray drying method. Chitosan microspheres are prepared by using a spray drier
apparatus. Microspheres have been prepared from solutions of different concen-
trations of chitosan in glacial acetic acid/water/acetone (Genta et al. 1994, 1995,
Ritthdej and Tiyaboonchai, 1995).
Precipitationlcoacervation method. Berthold et al. (1996a) prepared chitosan

microspheres by a novel precipitation method using sodium sulphate as pre-
cipitant. In this method chitosan is dissolved in acetic acid containing polysorbate
80. A solution of sodium sulphate is added dropwise during stirring and
ultrasonication. T h e formation of microspheres is indicated by turbidity. T h e
formed microspheres are purified by centrifugation and resuspended in deminer-
alized water. This method avoided the use of organic solvents and glutaraldehyde
for the preparation of chitosan microparticles with high loading capacity and
sustained release effect (Berthold et al. 1995, 199613).
Chitosan microparticles can also be prepared by complex coacervation. Sodium
alginate, sodium carboxymethylcellulose, kappa-carregeenan and sodium poly-
694 H . Siiheyla K a f
acrylic acid are used in the complex coacervation procedure with chitosan. Here
the micro-particles are formed by interionic interaction between oppositely
charged polymers. Formulation of coacervate capsules of chitosan-alginate and
chitosan-kappa-carrageenanis carried out by extruding either an aqueous solution
of kappa-carrageenan in a solution of sodium alginate through a hand-operated
syringe into potassium chloride or calcium chloride solution. T h e counterion
solution consisted of chitin. T h e obtained capsules were agitated to harden in the
counterion solution before washing and drying (Daly and Knorr 1988, Knorr and
Daly 1988, Ohtahara et al. 1989, Nishioka et al. 1990, Li et al. 1991, Pandya and
Knorr 1991, Ohya et al. 1993). Chitosan-alginate microparticles are also prepared
to control release characteristics and physicochemical properties (Kim and Rha
1989a, b). Chitosan-CMC complex microparticles are used to immobilize cell
culture (Shioya and Rha 1989). Adusumilli and Bolton (1991) evaluated chitosan
citrate complexes as matrices for controlled release formulations using factorial
design.
Coating by chitosan. In this method, previously formed microparticles are coated

with chitosan. HSA microspheres are prepared and added to various concentra-
tions of chitosan-acetic acid solutions and mixed. the chitosan treated micro-
particles are filtered and dried (Nishioka et al. 1989, Vural et al. 1990, 1991a, b,
1994a, b, Murata et al. 1993a, b, 1996, Meshali and Gabr 1993, Hari et al. 1996a, b,
Huguet et al. 1996, Knorr and Daly 1988, Takahashi et al. 1990). Murata et al.
(1993a, b) showed the suppression of alginate bead erosion and slower release of
the drug using chitosan reinforced alginate gel beads.
Granules
Spherical agglomeration technique. Granules of chitosan are prepared by the

spherical agglomeration technique. (Kawashima et al. 1985d). T h e granules
containing the active substance and sodium tripolyphosphate are dispersed in
ethyl cellulose with a propeller-type agitator. T h e dispersed particle mixtures are
agglomerated with water added to the system followed by agitation. T h e resultant
granules are separated and dried. T h e screened granules are dispersed in the acid
solution of chitosan by a propeller type agitation. During agitation the granules are
coated with a complex film of sodium tripolyphosphate and chitosan. T h e coated
granules are separated, washed with water and dried (Chandy and Sharma 1993b,
Kawashima et al. 1985a, b, Lee et al. 1990).
In other studies, the chitosan-drug mixture was extruded onto a glassplate.
After drying at room temperature, the chitosan gel cord was cut into pieces and
dried in vacuum at 50°C (Miyazaki et al. 1988, Hou et al. 1995).
Kneaded mixtures
T h e kneaded mixtures of the active substance with chitosan are prepared from
different weight ratios of the drug and the polymer. These mixtures are kneaded
with water, dried under vacuum at room temperature and screened through sieves
to obtain certain sized granules (Acarturk et al. 1993a, b, Shiraishi et al. 1990,
Sawayanagi et al. 1983a, b, Imai et al. 1991).
Chitosan : properties, preparations and applications 695
Ground mixtures
T h e ground mixtures of the active substance and chitosan were prepared by
cogrinding different weight ratios in a ball-mill for 24 hours (Shawayanagi et al.
1982, Shawayanagi et al. 1983a and b, Shiraishi et al. 1990). Nagai et al. (1984)
studied the dissolution properties and bio-availability of poorly soluble drugs from
ground mixtures with chitosan.
Physical mixtures
T h e physical mixtures of the drug with chitosan in different weight ratios are
prepared by simple blending in a ceramic mortar. (Nagai et al. 1984, Acarturk et
al. 1993a and b). Meshali and Gabr (1993) demonstrated the formation of
chitosan-pectin and acacia complexes. T h e physical mixtures showed that
increasing the concentration of the polymers retarded the release of chlorproma-
zine hydrochloride.
Immobilization by chitosan
In this section, immobilization and encapsulation of certain pharmaceuticals

and biopharmaceuticals in microparticulate forms are reviewed with examples
from literature.
Pharmaceuticals
Antiinjlammatory Drugs
Indomethacin ( I M ) . Bodmeier and Paeratakul (1989) prepared spherical
beads of IM, a poorly soluble drug, by dispersing the drug in a solution of
chitosan and dropping these dispersions into solutions of tripolyphosphate. Strong
spherical beads with a narrow particle size distribution could be prepared with
high yield and high drug content. T h e authors showed that the ionic character of
the polysaccharides allowed pH-dependent disintegration of the beads. They
proposed that the beads could be readily filled into capsules or could be com-
pressed into tablets. Shiraishi et al. (1 993) prepared chitosan gel beads containing
IM, an acidic drug, by a polyelectrolyte complexation of sodium tripolyphosphate
and chitosan. T h e effect of the molecular weight of chitosan on the release and
absorption rates of IM from gel beads were examined. T h e plasma concentration
of IM after oral administration of chitosan gel beads to beagle dogs exhibited a
sustained release pattern (figure 3).
Ritthidej et al. (1995) prepared sustained release microcapsules of I M
by spraying a drug containing C M C solution into a chitosan solution. T h e
effect of concentration of chitosan and the amount of glutaraldehyde were
investigated.
Vural et al. (1991b) produced a sustained relase form of indomethacin micro-
spheres by coating human serum albumin microspheres by chitosan, in order to
slow their clearance from the synovial fluid. They studied the effect of the type of
coating material and the chitosan concentration on I M release. T h e authors
attributed the decrease in the release rate to the viscosity of the chitosan, and
also to the swelling properties of the chitosan matrix (figure 4).
696 H . Siiheyla Ka,s
r
.O 2 4 6 8 10 12
Time (ti)
Figure 3. Plasma levels of IMC after oral administration of IMC (2mg/kg) and its
chitosan beads (equivalent to 4mg/kg IMC) to beagle dog. 0,IMC alone; A,C-3
beads; A, C-4 beads; I, C-5 beads; 0, C-6 beads (Shiraishi et al. 1993).
+Formula B
+Formula C
4 t - Formula 0
7
10
04
- 1 I
0 2 4 6 8 10
t(h)
Figure 4. Effect of chitosan concentration on in vitro release of indomethacin (Vural et al.
1991a). A, 0.5%chitosan; B, 1%chitosan; C, 1.5% chitosan; D, 2% chitosan.
Miyazaki et al. (1988) compared the release rate of IM from chitosan granules
with that of conventional commercial capsules and sustained release capsules. It
was shown that the release rate could be controlled by changing the mixing ratio of
drug and chitosan. T h e authors investigated the potential of chitosan granules as
an oral sustained release dosage form of I M in rabbit and pointed out that IM
granule preparations using chitosan may be useful as oral preparations with
reduced side effects and with prolonged action. In another study, Miyazaki et al.
(1981) dispersed I M in a chitosan gel to study the sustained release.
Chitosan : properties, preparations and applications 697
Table 3. Reduction of gastric mucosal injury by chitosan beads of diclofenac sodium

(Acikgoz et al. 1995).
Surface Gastric lesions
Group epithelial Ulceration
no. degeneration Oedema Bleeding Ulceration scale u1
1 - - - - 0.0 0.00
- - - - 0.0
2 + - - - 0.0 0.25
+ + + - 0.5
3 + + + + 1.5 1 .so
+ + + + 1.5
1, Empty chitosan; 2, DS microspheres; 3 , Plain drug. U I , ulceration index.
Sawayanagi et al. (1982a) investigated the application of chitosan to study the

permeation of I M through a chitosan membrane. These results suggested that the
permeation of drugs through the chitosan membrane is controlled mainly by
diffusion through pores. Imai et al. (1991) studied the interaction of IM with low
molecular weight chitosan. T h e data suggested that chitosan interacts with IM and
is useful for improvement of dissolution and absorption rates of IM. T h e oral
absorption rate of IM from kneaded mixtures was improved compared with I M
alone.
Hou et al. (1995) examined the sustained release effect of I M by chitosan
granules. T h e floating property of the granules on the acid medium is a unique
characteristic of the chitosan granules.
Diclofenac sodium ( D S ) . Murata et al. (1996) investigated the formation of a

complex between chondroitin sulphate and chitosan and also the influence of this
complex on the release pattern of DS incorporated in the beads. T h e complex
suppressed the disintegration of the gel beads and the release pattern of DS
incorporated in the beads.
Aqkgoz et al. (1992, 1996) performed an in vitro study to sustain the action of
DS and to show the effect of formulation variables on release kinetics. T h e
independent variables in the 33 factorial design were chitosan, tri-polyphosphate
concentrations and stabilization time. T h e dependent variable studied was t50%.
Aqkgoz et al. (1993, 1995) also determined the ulcerogenic index of the DS-
chitosan microspheres in rabbit. T h e authors showed that the optimum formula-
tion reduced gastric mucosal injury associated with DS and enhanced its antiin-
flammatory activity when compared to plain drug (table 3).
Tapia et al. (1993) prepared spheres from a wet mass by extrusion and
spheronization. Chitosan was included as a solution in the powder mix. T h e
addition of chitosan had a significant retardant effect on the drug release.
Dissolution testing at different stirring speeds did not alter the rate of drug
release, demonstrating that the diffusion process was controlled within, rather
than in the layer of liquid around the sphere.
Prednisolone (PDS). Berthold et al. (1996a) prepared chitosan microspheres as

a drug delivery system for PDS. They showed that drug release is dependent on
698 H . Siiheyla Kaf
the drug-polymer ratio. Sawayanagi et al. (1983a) prepared ground mixtures of

PDS with chitosan in order to improve the dissolution properties. Kanke et al.
(1989) formulated three types of chitosan films of PDS and studied the drug
release from the films. These results suggested that chitosan films could be
applicable for controlled release preparations of PDS. Drug release from the films
could be controlled by changing the thickness of the films.
Other anti-inflammatory agents. Bodmeier and Paeratakul (1989) prepared

spherical beads of the poorly soluble drug, ibuprofen, by dropping the chitosan
dispersion of the drug into a counter ion in order to sustain the release of the active
substance. Pavanetto et al. (1 995) prepared chitosan microspheres of ketoprofen,
by a multiple emulsion method. Results show that o/w/o emulsion provided a
suitable method for the production of microspheres with satisfactory yield.
Berthold et al. (1996a) developed a method which avoided the use of organic
solvents and glutaraldehyde for the preparation of chitosan microspheres of
steroids used as anti-inflammatory agents. T h e method provided high loading
capacity and sustained release. Sezer and Akbuga (1995) prepared chitosan beads
of piroxican by ionotropic gelation. They studied the effect of chitosan concentra-
tion and drying method on the release of piroxicam from beads.
Vural et al. (1991a, 1994a, b) investigated the effect of chitosan concentration
on a HSA based coating on the release of sulphasalazine. Chitosan of two different
molecular weights as constituents of microparticulate matrices loaded with the

water insoluble drug, dexamethasone were investigated by Genta et al. (1994,
1995). They prepared the microspheres by spray-drying and achieved an enhance-
ment of the dissolution rate of dexamethasone.
Anticancer drugs.
t5-Fluorouracil ( 5 - F U ) . Li et al. (1991) prepared chitosan microspheres of 5 -
F U using the ‘dry-in-oil’ method. The results suggested that chitosan is an
appropriate polymer for microspherical preparation and it is possible to slow
down the release rate of the drug by surface treatment. Ohya et al. (1993) prepared
chitosan microspheres of 5-FU coated by anionic polysaccharides, carboxymethyl
chitin, alginic acid and heparin. These polysaccharide chains on the surface of the
microspheres are expected to be recognized by the saccharide-specific receptor cell
surface. Ouchi et al. (1989) synthesized chitosan carrying 5-FU in order to provide
5-FU with reduced side effects having tumour cell affinity and exhibiting high
antitumour activity. T h e chitosan-5FU conjugates did not display acute toxicity in
the high dose range. Ouchi e t al. (1988) synthesized four kinds of chitosan 5-FU
systems. The results suggested that covalent attachment to chitosan depressed the
side effects. The carbonyl bonded 5-FU to chitosan had shown high antitumour
activity. Akbuga and Bergiaadi (1996) prepared crosslinked chitosan microspheres
containing 5-FU. Drug and chitosan concentration, crosslinking process, type of
oil, stirring rate and additives were examined. Release of 5-FU was altered by
changing the process factors and the addition of alginic acid, chitin, agar, sodium
caprylate and stearic acid.
Cisplatin ( C C D P ) . Cisplatin (CDDP) (Nishioka et al. 1989, 1990) containing

albumin microspheres and microcapsules incorporating the biodegradable macro-
molecules, chitin and chitosan were prepared and their C D D P content, release
profiles and susceptibility to various enzymes were examined. C D D P release was

suppressed by chitin and chitosan coating. Chitosan microspheres were shown to
undergo enzymatic degradation by lysozymes. Nishioka et al. (1992) coated
albumin microspheres of C D D P with chitin and chitosan and used these micro-
spheres to embolize the hepatic artery of dogs. They showed that release was
sustained and hepatic artery embolization was possible. These authors also showed
the increase of antitumor activity by the addition of chitin and chitosan. Kyotani et
al. (1992) showed the antitumour activity of cisdiamminedichloroplatinum albu-
min microspheres treated with chitin and chitosan on rabbit hepatic tumours.
Oxantrazole (0x2).Hassan et al. (1992) combined emulsion polymerization

and solvent evaporation techniques to prepare magnetic chitosan microspheres
containing the anticancer drug. A central composite experimental design was used
to evaluate the formulation factors and subsequent response-surface graphs
allowed optimal formulation conditions. Hassan and Gallo (1993) examined the
ability of O X 2 magnetic microspheres to enhance the delivery to brain. They
showed a 100-fold increase in O X 2 brain concentration when compared to OX2
solution.
Cytarabine and mitomycin-C. Chitosan-glutaric acid-cytarabine conjugates

were prepared and the in vitro release properties and in vivo antitumour
characteristics evaluated (Onishi et al. 1994). These conjugates prepared using

chitosan as drug carrier were demonstrated to be useful as macromolecular
antitumour agents.
Doxorubicin (DX).Ouchi et al. (1994) carried out the fixation of D X t o

carboxymethyl-chitin through covalent bonds in order to reduce the side effects
and to exhibit high antitumour activity.
Other pharmaceuticals.
Theophylline ( T F ) . Kawashima et al. (1985a) developed a novel method for
the preparation of TF granules coated with a polyelectrolyte complex of sodium
tripolyphosphate and chitosan. Kawashima et al. (1985b) studied the effect of
thickness and hardness of the coating film on the drug release rate of TF granules
coated with chitosan-tripolyphosphate complex. Lin and Lin (1992a) studied the
effect of acid type, acetic acid and sodium C M C concentration on the formulation,
dissolution and floating properties of TF chitosan microspheres (Lin and Lin
1992b). TF beads were prepared using the combination of Avicel and chitosan
using extrusion-spheronization technology (Goskonda and Upadrashta 1993).
Isosorbide-5-Mononitrate ( I S - 5 - M N ) . Farivar et al. (1993) investigated the

formulation and in vitro release profiles of IS-5-MN-chitosan beads. T h e authors
compared the release patterns with commercially available dosage forms.
Phenytoin ( P T ) . Murata et al. (1993a) prepared chitosan-reinforced alginate

gel beads containing P T by dropping the solution into calcium chloride using a
peristaltic pump. T h e diagrammatic representation of the formation of beads is
shown in figure 5 . Shiraishi et al. (1990) studied the dissolution behaviour of P T
from kneaded mixtures with low molecular weight chitosan. T h e results revealed a
I 1
ALGINATL
I '
I CHITOSAN
Figure 5. Diagrammatic representation of the formation of calcium induced alginate gel

beads in the presence of chitosan (Murata et al. 1993a).
significant increase of dissolution rate of drugs from kneaded mixtures. T h e

enhanced dissolution rate of kneaded mixtures may be due to the improvement
of wettability, changes in the crystallinity, crystal size and shape.
Sawayanagi et al. (1983b) also studied the dissolution properties and bioavail-
ability of P T from ground mixtures with chitosan. T h e dissolution rate of P T from
the ground mixtures was significantly greater than that from physical mixtures or
the powder form. It was also confirmed that the ground mixture gave enhanced
bioavailability in beagle dog.
Griseofulvin ( G R S ) . Bodmeier and Paeratakul (1989) prepared spherical beads

of the poorly soluble drug, GRS. Sawayanagi et al. (1982b) tried to increase the
enhancement of dissolution properties GRS from ground mixtures with chitosan.
The x-ray diffraction patterns and results of differential scanning calorimetry
suggested a decrease in the size of the crystals. T h e dissolution rate of GRS from
the ground mixtures was also studied. T h e ground mixtures with chitosan showed
fastest dissolution.
Sulfadiazine ( S R D ) . Bodmeier and Paeratakul (1989) improved significantly

the flow properties of S F D by preparing chitosan beads of SFD. I t resulted in
strong beads with high drug loading. S F D beads were prepared by dropping drug-
containing solutions of the positively charged polysaccharide, chitosan into T P P
solutions (Bodmeier e t al. 1989b). Chitosan beads showed pH-dependent swelling
and dissolution behaviour. Wan et al. (1994) prepared chitosan beads containing
SFD by ionotropic gelation with T P P ions. Beads containing u p to 90% drug
loading could be prepared by this method.
Spironolactone (SP). Acarturk et al. (1993a, b) studied the dissolution of SP

from kneaded mixtures with chitosan. According to the release experiments,
chitosan significantly increased the dissolution of SP.
Others. Chandy and Sharma (1993b) investigated the formulation and in vitro
release profiles of ampicillin-chitosan beads, and compared the release patterns
with commercially available dosage forms.
Goscondo et al. (1993) prepared beads using the combination of Avicel and
chitosan by extrusion/spheronization technology. T h e effect of different viscosities
of chitosan on bead formation and also on the release profiles were examined using
acethaminophen as a model drug. Incorporation of higher viscosity grades of
chitosan yielded beads with smooth surfaces and slower release characteristics.
Bodmeier and Paeratakul (1989) prepared spherical beads of the poorly soluble
drug tolbutamide.
Activated charcoal (Chandy and Sharma 1993a), furosemide (Akbuga and
Durmaz 1994), steroids (Chandy and Sharma 1991), nitrofurantoin (Hari et al.
1996) beads with chitosan were prepared and their release characteristics were
studied. Mitani et al. (1995) adsorbed benzoic acid and its derivatives onto swollen
chitosan beads. T h e presence of mannitol and glucose also stimulated the adsorp-
tion of benzoic acid. Remunan-Lopez et al. (1995) prepared free films of chitosan
by casting-solvent evaporation process. T h e cross-linked films with chlorphenir-
amine maleate were characterized by measuring their mechanical behaviour. Brine
(1989) studied the technical feasibility of chitosan for a direct compression dosage
form of a highly water soluble model drug, chlorpheniramine maleate. Brine
(1989) also demonstrated the application of chitosan to an analgesic drug, aspirin.
He showed that the only barrier to the application of chitosan wet granulation
system was the difficulties involved in handling and drying of acetic acid during
processing. Lee et al. (1990) sustained the release of aspirin from chitosan
granules. T h e drug release rate at high p H was delayed more than at the low
p H because of the swelling ability of chitosan granules at low p H . T h e authors
showed that the release rate was delayed more than 3-fold from crosslinked
granules. Miyazaki et al. (1990) described the release characteristics of chitosan
films both in vitro and in vivo, by using diazepam as an oral administration dosage
form.
Biopharmaceuticals
Proteins.
Bovine serum albumin ( B S A ) . BSA was loaded by passive absorption from
aqueous solutions into preformed glutaraldehyde cross-linked chitosan micro-
spheres (Jameela et al. 1994). T h e study demonstrated the possibility of incorpor-
ating biological macromolecules which are very sensitive to organic solvents, p H ,
temperature, and ultrasound by a passive absorption technique into degradable
biopolymer matrices, thereby preserving their biological integrity. I t was also
shown that drugs passively adsorbed into such matrices by taking advantage of
their swelling behaviour need not necessarily be released completely in the initial
burst and a sustained release may be possible for macromolecules.
Remunan-Lopez et al. (1995) used BSA as a model protein to prepare chitosan
gels for the controlled release of hydrophilic macromolecules. Several formulation
parameters (chitosan molecular weight, type of acid and salt) on the encapsulation
efficiency, particle size, morphology and BSA release were investigated. Polk et al.
(1994) controlled the release of HSA from chitosan-alginate microcapsules. This
work has demonstrated that chitosan-alginate membranes may be used as a vehicle

for the delayed release of a protein acid. T h e extrusion method used provides a
quick and effective method of producing membranes, and can be scaled up easily.
T h e release characteristics of BSA from chitosan alginate microcapsules
prepared using an electrostatic droplet generator were evaluated by Okhamafe et
al. (1996). Chitosan-alginate microcapsules showed unsatisfactory release proper-
ties.
Amino acids.
Methionine and lysine. Prud’homme (1994) investigated a new process using
chitosan as a pH sensitive agent in coating formulations for the preparation of
rumen-protected amino acids. Amino acid granules prepared by melt extrusion/
spheronization were coated by a laboratory scale fluid bed equipped with a
Wurster insert. In vitro and in vivo evaluation of the coated products showed
that it is a possible route for the preparation of rumen protected methionine and
lysine for ruminants.
Antithrombotic agents. Gallo and Hassan (1988) formulated a new magnetic

microsphere carrier that may localize drugs by both biochemical and physical
means. The microspheres prepared from chitosan are designed to bind to anionic
glycosaminoglycan receptors on the surface of the capillary endothelial cells. T h e
authors demonstrated the interaction of chitosan with heparin.
Chandy and Sharma (1989) immobilized the antithrombotic agents, hirudin,
PGEl , antithrombin-111, and heparin on liposome modified albumin blended
chitosan membranes and evaluated their antithrombotic effect. They showed that
chitosan membranes having biomolecules immobilized on them may have wider
applications in the hemodialysis of patients by offering improved permeability and
blood compatibility.
Fibroblast. Muzzarelli (1994) showed that chitosan is suitable as a matrix for

mammalian cell encapsulation. Chitosan prevented extensive cell clumping and
necrosis which is known to take place in other encapsulation materials. Encapsu-
lated cells were implanted into the basal ganglia of monkeys. Four weeks after
implantation in capsules containing chitosan matrix cells were still viable.
Berscht et al. (1994) incorporated basic fibroblast growth factor into chitosan
and studied the release by using an immunological assay, radioactivity measure-
ments and cell culture techniques. T h e release studies revealed a sustained release
of the biologically active basic fibroblast growth factor.
Toxoid. Jameela et al. (1994) loaded diphtheria toxoid (DT) by passive absorp-
tion into cross-linked chitosan microspheres. Preliminary immunization studies
carried out on rats using DT-loaded chitosan spheres have shown promise.
Glutaraldehyde crosslinked chitosan spheres were well tolerated by the living
tissue and were not found to be degraded completely in 6 months in vivo in rat
muscle.
Enzyme. Dextranase was immobilized on chitosan beads in a standard form

where the acidic solution was dropped into a sodium ion solution (Strusczyk 1995).
T h e effect of glutaraldehyde concentration on the binding of the enzyme to
chitosan was investigated. It was shown that the efficacy of immobilization by

chitosan was increased. Ohtakara et al. (1989) immobilized alfa-galactosidase and
glucoamylase in porous chitosan beads.
Znterleukin 2 (IL-2). In this study IL-2 was entrapped in an alginate/chitosan

porous microsphere complex and the immune activity of IL-2 released from the
microspheres was investigated. T h e controlled IL-2 release may result in an
improved tumour immunotherapy (Liu et al. 1995).
Monoclonal antibodies. Kim and Rha (1989a) have studied the effectiveness of
chitosan for encapsulation for mammalian cell culture. T h e cells were encapsu-
lated in a chitosan-alginate bi-polymer membrane. T h e concentration of the
monoclonal antibody in the capsule was 20 times higher than that of the free cell
culture. Shioya and Rha (1989) developed a microencapsulation method using

chitosan. T h e encapsulation method can be applied for encapsulated cell culture
under mild conditions. T h e encapsulation process was based on the electrostatic
interaction between chitosan and C M C .
Protein purification. Myers et al. (1994) investigated sources of chitosan for their
ability to exhibit a degree of dye adsorption which could be a preliminary step in
protein purification. These preliminary analyses on the adsorbent capacities of the
chitosan beads prepared by ionotropic gelation seemed promising.
Insulin. Hari et al. (1996a) loaded insulin into the chitosan/calcium alginate
system. Even though the load is very low, the results indicate the possibility of
modifying the formulation to obtain the desired controlled release of insulin for a
convenient G I tract delivery. Tohzaki et al. (1995, 1996) studied the colon specific
delivery of insulin from chitosan capsules in rats. They showed an improvement of
insulin absorption from the rat colon.
Others. Singh et al. (1995) incorporated Factor IX into chitosan gels and studied
the release. Aydin and Akbuga (1996) studied the release characteristics of salmon
calcitonin from chitosan beads. Neugebauer (1 994) synthesized solid phase peptide
as a potential synthetic vaccine on chitin and chitosan. Mao et al. (1996)
formulated chitosan nanospheres for gene delivery. Gursel (1995) encapsulated
the biologically active testosterone and B. subtilis spores within microcapsules
made of polyhydroxyalkanoates of bacterial origin. Covalent modification of the
biopolymer was achieved by conjugating chitosan and cellulose triacetate in order
to tailor the degradation and release rate pattern. This modification improved the
surface texture, size and shape of the microcapsules and gave spherical, porous and
less wrinkled microcapsules.
References
ACARTURK, F., SENCAN, A., and CELEBi, N., 1993a, Enhancement of the dissolution of
spironolactone with chitosan and low molecular weight gelatin. S .T . P .
Pharmaceutical Sciences, 3(5), 369-373.
ACARTURK, F., SENCAN, A,, and CELEBi, N., 1993b, Evaluation of the effect of low molecular
chitosan on the solubility and dissolution characteristics of spironolactone.
Pharmazie, 48(H.8), 605-607.
ACIKGBZ, M., KAS,H. S., ERCAN, M. T . , HASCELiK, Z., and HINCAL, A. A., 1993, Chitosan
microspheres of diclofenac sodium. 11. In vivo evaluation. Proceedings of the 9th

International Symposium on Microencapsulation, (Ankara, Turkey: Hacettepe
University Press) p. 45.
Z , KAS, H. s., HASCELiK, Z., MiLLi, u., and HINCAI.,A. A., 1995, Chitosan
A C I K G ~M.,
microspheres of diclofenac sodium. 11. In vitro and in vivo evaluation. Pharmazie, 50
(H.4), 275-277.
ACIKGOZ, M., KAS,H. S., and HINCAL, A. A., 1992, Chitosan microspheres of diclofenac
sodium. I. Formulation and release kinetics. Proceedings of the 6th International
Conference of Pharmaceutical Technology, (Chatenay Malabry, France: Association
de Pharmacie Galenique Industrielle) pp. 232-242.
ACIKGOZ, M., KAS,H. S., ORMAN, M., and HINCAL, A. A., 1996, Chitosan microspheres of
diclofenac sodium: I. Application of factorial design and evaluation of release
kinetics. Journal of Microencapsulation, 13(5), 141-160.
ADUSUMILLI, P. S. and BOLTON, S. M., 1991, Evaluation of chitosan citrate complexes as
matrices for controlled release formulations using a 3' full factorial design. Drug
Development and Industrial Pharmacy, 17(14), 193 1-1 945.
A K B U ~J.,
A ,1995, A biopolymer: chitosan, InternationalJournal of Pharmaceutical Advances,
1(1), 3-18.
AKBU~A J., and BERGiSADi, N., 1996, 5-Fluorouracil-loaded chitosan microspheres:
preparation and release characteristics. Journal of Microencapsulation, 13(5 ) ,
161-168.
A K B U ~J.A ,and DURMAZ, G., 1994, Preparation and evaluation of cross-linked chitosan
microspheres containing furosemide. International Journal of Pharmaceutics, 111,
21 7-222.
AMIII,M. M. and PATEL,V. R., 1995, Chitosan-polyethylene oxide hydrogels for pH-
sensitive oral drug delivery. Proceedings of the 22nd International Symposium of
Controlled Release Bioactive Materials, (Deerfield USA: Controlled Release Society,
Inc.), pp. 330-331.
ASPDEN, T. J., ILLUM,L., and SKAUGRUD, Q., 1995, T h e absence of chitosan toxicity when
applied to nasal mucosa. Proceedings of the 22nd International Symposium of
Controlled Release Bioactive Materials, (Deerfield USA: Controlled Release Society,
Inc.), pp. 550451.
AYDIN, 2. and A K B U ~J.,A , 1996, Chitosan beads for the delivery of salmon calcitonin:
preparation and release characteristics. International Journal of Pharmaceutics, 131,
101-103.
BERSCHT, P. C., NIES,B., L I E B E N D ~ RA,,
FER and
, KREUTER, J., 1994, Incorporation of basic
fibroblast growth factor into methylpyrolidinone chitosan fleeces and determination
of the in vitro release characteristics. Biomaterials, 15(8), 853-600.
BERTHOLD, A., CREMER, K., and KREUTER, J., 1995, Chitosan microspheres: preparation and
evaluation as delivery system for the controlled release of anti-inflammatory drugs.
Proceedings of the 10th International Symposium of Microencapsulation, (Austin, T X :
The University of Texas at Austin Press), p. 23.
BERTHOLD, A., CREMER, K., and KREUTER, J., 1996, Preparation and characterisation of
chitosan microspheres as drug carrier for prednisolone sodium phosphate as model
antiinflammatory drugs. Journal of Controlled Release, 39, 17-25.
BERTHOLD, A. and KREUTER, J., 1996, Chitosan microspheres: Improved acid stability and
change in physicochemical properties by crosslinking. Proceedings of the 23rd
International Symposium of Controlled Release Bioactive Materials, Kyoto, Japan.
(Deerfield, USA: Controlled Release Society), pp, 369-370.
Chitosan: properties, preparations a n d applications 705
BODEK, K. H., 1994, Potentiometric method for determination of the degree of acetylation of
chitosan. In Chitin World, edited by Z . S. Karnicki, A. Wojtasc-Pajak, M. M.,
Breziski and P. J . Bylowsky (Bremerhaven, Germany: Wirtschaftsverlag), pp. 456-
461.
BODMEIER, R., CHEN,H., and PAERATAKUL, O., 1989a, A novel approach to the oral delivery
of micro or nanoparticles. Pharmaceutical Research, 6(5),413-417.
BODMEIER, R., OH, K.-H., and PRAMAR, Y., 1989b, Preparation and evaluation of drug
containing chitosan beads. Drug Development and Industrial Pharmacy, 15(9), 1475-
1494.
BODMEIER, R. and PAERATAKUL, O., 1989, Spherical agglomerates of water insoluble drugs,
Journal of Pharmaceutical Sciences, 78(1l ) , 964-967.
BODMEIER, R, and WANG,J., 1995, Microencapsulation of drugs with aqueous colloidal
polymer dispersions, Journal of Pharmaceutical Sciences, 82(2), 191-1 94.
BRINE, C. J., 1989, Controlled release pharmaceutical applications of chitosan. In Chitin and
Chitosan-Sources, Chemistry, Biochemistry, Physical Properties and Applications,
edited by G . Skjak-Braek, T . Anthonsen and P. Sanford (London: Elsevier),
pp. 679-692.
CHANDY, T. and SHARMA, C. P., 1989, Bioactive molecules immobilized to liposome
modified albumin blended chitosan membranes-antithrombotic and permeability
properties. Journal of Colloid and Interfacial Science, 130(2), 331-340.
CIIANDY, T. and SHARMA, C. P., 1990, Chitosan-as a biomaterial. Biomat. A r t . Cells A r t .
Org., 18(1), 1-24.
CHANDY, T. and SHARMA, C. P., 1991, Biodegradable chitosan matrix for the controlled
release of steroids. Biomat. A r t . Cells Zmmob. Bioech., 19(4), 745-760.
CHANDY, T . and SHARMA, C. P., 1993a, Preparation and performance of chitosan
encapsulated activated charcoal (ACCB) adsorbents for small molecules. Journal of

Microencapsulation, 10(4), 47 5-486.
CHANDY, T . and SHARMA, C. P., 1993b, Chitosan matrix for oral sustained delivery of
ampicillin. Biomaterials, 14(12), 939-944.
D A I ~M.
Y , M. and KNORR, D., 1988, Chitosan-alginate coacervate capsules: effect of calcium
chloride, plasticizers and polyelectrolytes on mechanical stability, Biotechnology
Progress, 4, 76.
DEMARGER-ANDRE, S. and DOMARD, A., 1994, New properties of chitosan in lipid
dispersions. In Chitin World, edited by Z . S. Karnicki, A. Wojtasc-Pajak, M. M.
Breziski and P. J. Bylowsky, (Bremerhauser, Germany: Wirtschaftsverlag), pp. 153-
158.
DUTKIEWICZ, J., 1994, Possible applications of chitin based materials. In Chitin World,
edited by Z . S. Karnicki, A. Wojtasc-Pajak, M. M . Breziski and P. J. Bylowsky
(Bremerhaven, Germany: Wirtschaftsverlag), pp. 364373.
ERDEN, N. and (&mi, N., 1990, Kitin and kitozanin farmasotik teknolojideki uygulanigi.
Fabad Journal of Pharmacetical Science, 15, 277-287.
FARIVAR, M., K A ~H. , S., ONER,L., and HINCAL, A. A., 1993, Isosorbide-5-mononitrate
microspheres: formulation and evaluation of in witro release profiles by application of
factorial design. H. U . Ecz. Fak. Der., 13(2), 25-37.
FERREIRA, M. C., MARVAO, M. R., DUARTE, M. L., DOMARD, A., NUNES,T., and FEIO, G.,
1994a, Chitosan degree of acetylation: comparison of two specroscopic methods
(13C CP/MAS, NMR and dispersive IR). In Chitin World, edited by 2. S.
Karnicki, A. Wojtasc-Pajak, M. M. Breziski and P. J. Bylowsky, (Bremerhaven,
Germany: Wirtschaftsverlag), pp. 476-479.
FERREIRA, M. C., MARVAO, M. R., DUARTE, M. L., and NUNES,T., 1994b, Optimisation of
the measuring of chitin/chitosan degree of acetylation by FT-IR spectroscopy. In
Chitin World, edited by Z. S. Karnicki, A. Wojtasc-Pajak, M. M. Breziski and P. J .
Bylowsky (Bremerhaven, Germany: Wirtschaftsverlag), pp. 480-488.
FUKUDA, H., 1980, Polyelectrolyte complexes of chitosan carboxymethyl cellulose. Bulletin
of the Chemical Society ofJapan, 53, 837-840.
FUKUDA, H. and KIKUCHI, Y., 1978, Polyelectrolyte complexes of chitosan with sodium
carboxymethyl dextran. Bulletin of the Chemical Society ofJapan, 51, 1142-1 144.
706 H . Suheyla K a j
GALLO,J. M. and HASSAN, E. E., 1988, Receptor mediated magnetic carriers: basis for
targeting. Pharmaceutical Research, 5(5), 300-304.
GASCONDA, S. R. and UPADRASHTA, S. M., 1993, Avicel RC-59l/chitosan beads by extrusion-
spheronisation technology. Drug Development and Industrial Pharmacy, 19,
915-927.
GENTA,I., COSTANTINI, M., and MONTANAHI, L., 1996, Chitosan microspheres for nasal
delivery: Effect of crosslinking agents on release characteristics. Proceedings of the
23rd International Symposium Cont. Rel. Bioact. Muter., Kyoto, Japan (Deerfield,
USA: Controlled Release Society Inc.).
GENTA, I., PAVANETTO, F., COTI,B., GIUNCFIEDI, P., and CONTE,U., 1994, Spray drying for
the preparation of chitosan microspheres. Proc. 21st Int. Symp. Cont. Rel. Bioact.
Muter., Nice, France (Deerfield, USA: Controlled Release Society, Inc.) 616-617.
GENTA, I., PAVANETTO, F., COTI,B., GIUNCHEDI, P., and CONTE,U., 1995, Improvement of
dexamethasone dissolution rate from spray dried chitosan microspheres. S.T . P .
GROBOILLOT, A., BOADI, D. K., PONCELET, D., and NEUFELD, R. J., 1994, Immobilisation of
cells for application in the food industry. Biotechnology, 4(2), 75-108.
GORSEL, I., 1995, Use of microbial polyhydroxyalkanoates in the construction of biomedical
drug release systems. PhD thesis, Middle East Technical University, Ankara,
Turkey.
HARI,P. R., CHANDY, T., and SHARMA, C. P., 1996a, Chitosan/calcium-alginate beads for
oral delivery of insulin. Journal of Applied Polymer Science, 59(1 l ) , 1795-1 801.
HARI, P. R., CHANDY, T., and SHARMA, C. P., 1996b, Chitosan/calcium-alginate
microcapsules for intestinal delivery of nitrofurantoin. Journal of Micro-
encapsulation, 13(3), 3 19-330.
HASSAN, E. E. and GALLO, J. M., 1993, Targeting anticancer drugs to the brain I: Enhanced
brain delivery of oxantrazole following administration in magnetic cationic
microspheres. Journal of Drug Targeting, 1, 7-14.
HASSAN, E. E., PARISH, R. C., and GALLO, J. M., 1992, Optimised formulation of magnetic
chitosan microspheres containing the anticancer agent, oxantrazole. Pharmaceutical
Research, 9(3), 390-397.
Hou, W.-M., MIYAZAKI, S., TAKADA, M., and KOMAI,T., 1995, Sustained release of
indomethcin from chitosan granules. Chemical and Pharmaceutical Bulletin, 33(9),
3986-3993.
HUGUET, M. L., NEUFELD, R. J., and DEI.I.ACHERIE, E., 1996, Calcium alginate beads coated
with polycationic polymers: comparison of chitosan and DEAE-dextran. Process in
Biochemistry, 31(4), 347-353.
IMAI,T., SHIRAISHI, S., SAITO, H., and OTAGIRI, M., 1991, Interaction of indomethacin with
low molecular weight chitosan, and improvements of some pharmaceutical
properties of indomethacin by low molecular weight chitosans. International Journal
of Pharmaceutics, 67, 11-20.
JAMEELA, S. R., MISRA, A., and JAYAKRISHNAN, A., 1994, Crosslinked chitosan microspheres
as carriers for prolonged delivery of macromolecular drugs. Journal of Biomaterials
and Science Polymer Edn., 6(7), 621-632.
KANKE, M., KATAYAMA, H., TSUZUKI, S., and KURAMOTO, H., 1989, Application of chitin and
chitosan to pharmaceutical preparations. I. Film preparation and in vitro evaluation.
Chemical and Pharmaceutical Bulletin, 37(2), 523-525.
KAY,H. S., 1995, Chitosan-polymeric properties and applications. Proc. Nut. Symp.
Biomed. Sci. and Tech., (Ankara, Turkey: Middle East Technical University Press)
pp. 19-20.
KAWASHIMA, Y., HANDA, T., KASAI,A., TAKENAKA, H., and LIN,S. Y., 1985a, T h e effects of
thickness and hardness of the coating film on the drug release rate of theophylline
granules coated with chitosan sodium tripolyphosphate complex. Chemical and
Pharmaceutical Bulletin, 33(6), 2469-2474.
KAWASHIMA, Y., HANDA, T., KASAI,A., TAKENAKA, H., L I N ,S. Y., and ANDO,Y., 1985b,
Novel method for the preparation of controlled release theophylline granules coated
with a polyelectrolyte complex of sodium polyphosphate-chitosan. Journal of
KAWASHIMA, Y., LIN,S. Y., KASAI, A., HANDA, T., and TAKENAKA, H., 1985c, Preparation of
a prolonged release tablet of aspirin with chitosan. Chemical and Pharmaceutical
Bulletin, 33(5), 2107-21 13.
KAWASHIMA, Y., LIN,S. Y., OGAWA, M., HANDA, T., and TAKENAKA, H., 1985d, Preparation
of agglomerated crystals of polymeric mixtures and a new complex of indomethacin-
epirizole by the spherical crystallisation technique. Journal of Pharmaceutical
Sciences, 74(11), 1152-1156.
KIM,S.-K. and RHA,C., 1989a, Chitosan for the encapsulation of mammalian cell culture.
In Chitin and Chitosan-Sources, Chemistry, Biochemistry, Physical Properties and
Applications, edited by G. Skjak-Braek, T. Anthonsen and P. Sanford (London:
Elsevier), pp. 617-626.

K I M ,S.-K. and RHA,C., 1989b, Transdermal permeation of proteins in chitosan capsules.
Applications, edited by G. Skjak-Braek, T . Anthonsen and P. Sanford (London:
KNAPCZYK, J., KROWCZYNSKI, L., KRZEK, J., BRZESKI, M., NURNBERG, E., SCHENK, D., and
STRUSZCZYK, H., 1989a, Requirements of chitosan for pharmaceutical and
biomedical applications. In Chitin and Chitasan-Sources, Chemistry, Biochemistry,
Physical Properties and Applications, edited by G. Skjak-Braek, T. Anthonsen and
P. Sanford (London: Elsevier), pp. 757-664.
KNAPCZYK, J., KROWCZYNSKI, L., MARCHUT, E., BRZOZOWSKI, T., MARUNKIEWICZ, J.,
GUMINSKA, H., KoNrURER, S. J., and PTAK,W., 1989b, Some biomedical properties
of chitosan. In Chitin and Chitosan-Sources, Chemistry, Biochemistry, Physical
Properties and Applications, edited by G. Skjak-Braek, T. Anthonsen and P. Sanford
(London: Elsevier), pp. 605-616.
J., KROWCZYNSKI,
KNAPCZYK, L., SCHENK, D., and LIBER, Z., 1989c, Pharmaceutical dosage
forms with chitosan. In Chitin and Chitosan-Sources, Chemistry, Biochemistry,
Physical properties and Applications, edited by G. Skjak-Braek, T. Anthonsen and
KNORR, D, 1986, Nutritional quality, food processing and biotechnology aspects of chitin
and chitosan: a review. Processes in Biochemistry, 21, 90-92.
KNORR, D., 1991, Recovery and utilisation of chitin and chitosan in food processing waste
management. Food Technology, Jan., 114-122.
KNORR, D., BEAUMONT, M. D., and PANOYA, Y., 1989, Potential of acid soluble and water
soluble chitosans in biotechnology. In Chitin and Chitosan-Sources, Chemistry,
Biochemistry, Physical Properties and Applications, edited by G. Skjak-Braek,
T . Anthonsen and P. Sanford (London: Elsevier), pp. 101-118.
KNORR, D. and DALY,M., 1988, Mechanics and diffusional changes observed in multilayer
chitosan/alginate coacervate capsules. Processesses in Biochemistry, 23(2), 48-50.
KRISTL, J., SMID-KORRAR, J., and SrRuc, E., 1992, Hydrocolloids and gels of chitosan as
drug carriers. European Journal of Pharmacology and Biopharmacology, 38, 95.
KRISTL,J., SMID-KORBAR, J., STRUC,E., SCHARA, M., and RUPPRECHT, H., 1993,
Hydrocolloid and gels of chitosan drug carriers, International Journal of
Pharmaceutics, 99, 13-19.
KYOTANI, S., NISHIOKA, Y., OKAMURA, M., TANAKA, T., MIYAZAKI, M., OHNISHI, S., TANAKA,
S., and TERAO, M., 1992, A Study of embolising materials for embolization therapy
of hepatocellular carcinoma. Chemical and Pharmaceutical Bulletin, 40, 2814-2816.
LANC,G. and CLAUSEN, T., 1989, The use of chitosan in cosmetics. In Chitin and Chitosan-
Sources, Chemistry, Biochemistry, Physical Properties and Applications, edited by
G. Skjak-Braek, T. Anthonsen and P. Sanford (London: Elsevier), pp. 139-150.
LEE,Y. C., Yoo, Y. M., K I M ,K. S., and SHIN, J. S., 1990, Sustained release aspirin from
chitosan granules, Pollimo, 14(4), 342-345 (Chemical Abstract, 115, 1542h).
LEHR,C.-M., BouwsrR~,J. A., SCHACHT, E. H., and JUNGINGER, H. E., 1992, In vitro
evaluation of mucoadhesive properties of chitosan and some other natural polymers.
International Journal of Pharmaceutics, 78, 43-48.
LI, Y. P., MACHIDA, Y., SANNAN, T., and NAGAI,T., 1991, Preparation of chitosan
microspheres containing fluorouracil using the ‘dry-in-oil’ method and its release
characteristics. S . T . P . Pharmaceutical Science, 1(6), 363-368.
708 H . Siiheyla Kag
L I N ,S. Y. and LIN,P. C., 1992a, Effect of acid type, acetic acid and sodium carboxy methyl
cellulose concentration on the formulation, micromeritic, dissolution and floating
properties of theophyllin chitosan microcapsules. Chemical and Pharmaceutical
Bulletin, 40(9), 2491-2497.
LIN, S. Y. and LIN, P. C., 1992b, T h e influence of sodium bicarbonate and sodium
tripolyphosphate and the adding sequence on the formation and dissolution of
theophylline chitosan microcapsules. S.T . P . Pharmaceutical Science., 2(6), 500-505.
L I U , L.-S., LIU, S.-Q., NG, S. H. HELLER,J., and FROIX, M., 1995, T h e potential
application of alginate chitosan porous microspheres loaded with interleukin-2 in
tumour immunotherapy. Proc. 22nd Int. Symp. Control. Rel. Broact. Muter., Seattle,
USA (Deerfield, USA: Controlled Release Society, Inc.), 542-543.

LUEBEN, H. L., LEHR,C.-M., RENTEL, C.-O., NOACH, A. B. J., DE BOER,A. G., VERHOEF,
J. C., and JUNGINGER, H. E., 1994, Bioadhesive polymers for the peroral delivery of
peptide drugs. Journal of Controlled Release, 29, 329-338.
MAO,H., ROY,K., WALSH,S., AUGUST, J., and LEONG,K., DNA-chitosan nanospheres for
gene delivery. Proc. 23rd Int. Symps. Contr. Rel. Bioact. M a t . , Kyoto-Japan,
(Deerfield: Controlled Release Society, Inc.).
MESHALI, M. M. and GARR,K. E., 1993, effect of interpolymer complex formation of
chitosan with cection or acacia on the release behavior of clorpromazine HCI.
International Journal of Pharmaceutics, 89, 177-1 81.
MYERS, T. A., HEALY, M. G., and MURPHY, W. R., 1994, Chitosan beads as support matrices
in dye-ligand affinity chromatography. In Chitin World, edited by Z. S. Karnicki,
A. Wojtasc-Pajak, M. M. Breziski and P. J. Bylowsky (Bremerhaven Germany:
Wirtschaftsverlag), pp. 276-283.
MITANI, T., TAMASHITA, T., OKUMURA, C., ISHII, H., 1995, Adsorption of benzoic acid and
its derivatives to swollen chitosan beads. Biosci. Biotech. Biochem., 59, 927-928.
MIYAZAKI, S., ISHII,K., and NADAI,T . , 1981, T h e use of chitin and chitosan as drug
carriers. Chemical and Pharmaceutics Bulletin, 29( lo), 3067-3069.
MIYAZAKI, S., NAKAYAMA, A., ODA,M., TAKADA, M., and ATTWOOD, D., 1995, Drug release
from oral mucosal adhesive tablets of chitosan and sodium alginate. International
Journal of Pharmaceutics, 118, 257-263.
MIYAZAKI, S., YAMAGUCHI, H., and TAKADA, M., 1990, Pharmaceutical application of
biomedical polymers XXIX. Preliminary Study on film dosage form prepared
chitosan for oral drug delivery. Acta Pharrnaceutica Nordica, 2(6), 401-406.
MIYAZAKI, S., YAMAGUCHI, H., YOKOUCHI, C., TAKADA, M., and Hou, W.-M., 1988,
Sustained release and introgastric floating granules of indomethacin using chitosan
in rabbits. Chemical and Pharmaceutical Bulletin, 36( lo), 4033-4038.
MURATA, Y., MAEDA, T., MIYOMOTO, E., and KAWASHIMA, S., 1993a. Preparation of chitosan-
reinforced alginate gel beads pharmaceutics effects of chitosan on gel matrix erosion.
MURATA, Y., MIYOMOTO, E., and KAWASHIMA, S., 1996, Additive effect of chondroitin sulfate
and chitosan on drug release from calcium induced alginate gel beads. Journal of
Controlled Release, 38, 101-108.
MURATA, Y., NAKADA, K., MIYOMAJO, E., and KAWASHIMA, S., 1993b, Influence of erosion of
calcium-induced alginate gel matrix on release of coloning matter, Journal of
Controlled Release, 23, 21-26.
MUZZARELLI, R. A. A., 1990, Modified chitosan and their chemical behaviors, American
Chemical Society Div. Polym. Chem., 31(17), 626.
MUZZARELLI, R. A. A., 1994, Morphogenetic actions of chitosan and growth factors-
fibroblast encapsulation in chitosan gel. Workshops on Cell Cultures, Italy.
MUZZARELLI, R., BALDASSARRE, V., CONTI,F., FERRARA, P., BIAGINI,G., GAZZANELLI, G., and
VASI,V., 1988. Biological activity of chitosan: Ultrastructural Study, Biomaterials,
9, 247-252.
NAGAI,T., SAWAYANAGI, Y., and NAMBU, N., 1984, Application of chitin and chitosan to
pharmaceutical preparation. In Chitin, Chitosan and Related Enzymes (Academic),
pp. 21-39.
NAIDOO, N. T., 1992, Natural cosmetic constituents: seaweeds, chitosan and rice, South
Africaan Farming Journal, 59, 131-132.
NEUGEBAUER, W., BRZEZINKI, R., and WILLICK, G., 1994, Solid phase peptide synthesis on
chitin/chitosan support: potential synthetic vaccine. In Chitin World, edited by Z. S.
Karnicki, A. Wojtasz-Pojak, M. M. Brezeski and P. J. Bylowski (Bremerhaven,
Wirtschaftsverlag), pp. 153-158, 342-349.
NISHIMURA, K., N I S I ~ I M Us.,
R ASEO,
, H., NISHI,N., TOKURA, S., and AZUMA,I., 1986,
Macrophage attraction with multiporous beads prepared from partially deacetylated
chitin. Journal of Biomed. Muter. Res., 20, 1359-1372.
NISHIOKA, Y., KYOTANI, S., OKAMURA, M., MIYAZAKI, M., OKAZAKI, K., OHNISHI, S.,
YAMAMOTO, Y., and ITO, K., 1990, Release characteristics of cisplatin chitosan
microspheres and effect of containing chitin. Chemical and Pharmaceutical Bulletin,
38( lo), 2871-2873.

NISHIOKA, Y . , KYOTANI, S., NASUI,H., OKAMURA, M., MIYAZAKI, M., OKAZAKI, K.,
OHNISHI,S., YAMAMOTO, Y., and ITO, K., 1989, Preparation and release
characteristics of cisplatin albumin microspheres containing chitin and treated
with chitosan. Chemical and Pharmaceutical Bulletin, 37( 1 l ) , 3074-3077.
OHTAKARA, A., MLJKERJEE, G., and MITSUTOMI, M., 1989, Immobilization of alpha-
galactosidase and glucoamylases on crosslined chitosan beads. In Chitin and
Chitosan-Sources, Chemistry, Biochemistry, Physical Properties and Applicatios,
edited by G. Skjak-Braek, T . Anthonsen and P. Sanford (London: Elsevier),
pp. 643-652.
OHYA,Y., TAKEI, T., KOBAYASHI, H., and OUCHI, T., 1993, Release behaviour of 5-FU from
chitosan gel microspheres immobilizing 5-FU derivative coated with polysacchar-
ides and their cell specific recognition. Journal of Microencapsulation, 10( l ) , 1-9.
OKHAMAFE, A. o., AhISDEN, B., CHU,w., and GOOSEN, M. F. A., 1996, Modulation of
protein release from chitosan-alginate microcapsules using the pH sensitive polymer
hydroxypropyl methyl-cellulose acetate succinate, Journal of Microencapsulation,

13(5), 497-508.
ONISHI,H., SONG, Y., ICHIKAWA,H., MACHIDA, Y., and NAGAI, T . , 1994, Macromolecular
products of cytarabine and mitomycin C with chitosan, n-succinyl-chitosan and 6-
0-carboxymethyl-chitin as drug carriers, 301-310.
T. and BANBA,
OLJCHI, T . , 1988, Fixation of 5 Auonousaic to chitosan and its antitumour
activity, Trans. SOC.Biomed. XI,232.
OUCHI,T., BANBA, T., FUJIMOTO, M., and HAM,S., 1989, Synthesis and antitumour activity
of chitosan carrying 5-FU. Makromol. Chem., 190, 1817-1825.
OUCHI,T . , NONOMURA, K., HIRAI,K., and OHYA,Y., 1994, Synthesis of CM-chitin/
doxorubicin conjugate attached through tetrapeptide spacer groups and release
behavior of doxorubicin from itself in vitro. In Chitin World, edited by 2. S .
Karnicki, A. Wojtasc-Pajak, M. M. Breziski and P. J. Bylowsky (Bremerhaven
Germany: Wirtschaftsverlag), pp. 350-358.
PANDYA, Y. and KNORR,D., 1991, Diffusion characteristics and properties of chitosan
coacervate capsules. Processes in Biochemistry, 26, 75-81.
PAVANETTO, F., GENTA,I., CONTI,B., MODENA, T . , and PERUGINI, P., 1995, multiple
emulsion O/W/O as preparation method for hydrophobic drug loaded chitosan
microspheres. Proc. 20th Int. Symp. Microencap. Austin-USA, (Austin: T h e
University of Texas at Austin Press), 49.
POLK,A,, A., AMSDEN, B., DE YAO,K., PENG,T., and GOOSEN, M. F. A., 1984, Controlled
release of albumin from chitosan-alginate microcapsules. Journal of Pharmaceutical
Sciences, 83(2), 178-185.
PRUD’HOMME, C., 1994, Chitosan in PH sensitive coatings for rumen protected amino acids.
Proc. Int. Symp. Contr. Rel. Bioac. Muter., 21, 112-113.
REMUNAN-LOPEZ, C., LORENZO, M. L., and ALONSO, M. J., 1995, development of new
microencapsulated chitosan gel cores for the controlled release of hydrophilic
macromolecules. Proc. 20th Int. Symp. Microencap. Austin-USA, (Austin: T h e
University of Texas at Austin Press), 54.
RITTTHIDEJ, G . C. and TIYABOONCHAI, W., 1995, Development of indomethocin sustained
release microcapsules using chitosan-carboxymethylcellulosecomplex coacervation.
Proc. 10th Int. Symp. Microencap., U S A , 26.
SANFORD, P. A,, 1989, Chitosan: commercial uses and potential applications. In Chitin and
Chitosan-Sources, Chemistry, Biochemistry, Physical Properties and Applications,

edited by G. Skjak-Braek, T. Anthonsen and P. Sanford (London: Elsevier),
pp. 51-70.
SANFORD, P. A., 1990, Chitosan and alginate: new forms of commercial interest, Amer.
Chem. SOC.Div. Polym. Chem., 31(1), 628.
SAWAYANACI, Y., NAMBU, N., and NAGAI, T., 1982a, Permeation of drugs through chitosan
membranes. Chemical and Pharmaceutical Bulletin, 30(9), 3297-3301.
SAWAYANACI, Y., NAMBU,N., and NACAI,T., 1982b, Enhancement of dissolution properties
of griseofulvin from ground mixtures with chitin or chitosan. Chemical and
SAWAYANAGI, Y., NAMBU, N., and NAGAI, T., 1983, Enhancement of dissolution properties of
prednisolone from ground mixtures with chitin or chitosan. Chemical and
SAWAYANAGI, Y., NAMBU,N., and NAGAI,T., 1983b, Dissolution properties and
bioavailability of phenytoin from ground mixtures with chitin and chitosan.
Chemical and Pharmaceutical Bulletin, 31(6), 2064-2068.
SEO,H . and KINEMURA, Y., 1989, Preparation and some properties of chitosan porous beads.
Applications, edited by G. Skjak-Braek, T. Anthonsen and P. Sanford (London:
SEZER,A. D. and AKBUGA, J., 1996, Controlled release of piroxicam from chitosan beads,
International Journal of Pharmaceutics, 121, 1 1 3-1 16.
SHIOYA, T. and RHA,C., 1989, Transmembrane permeability of chitosan/carboxymethyl
cellulose capsules. In Chitin and Chitosan-Sources, Chemistry, Biochemistry,
Physical properties and Applications, edited by G . Skjak-Braek, T. Anthonsen and
SINGH,M., JAMESON, T., MACPHEE, M., RDOHAN, W., and MIEKKA, S., 1995, Factor I X
release from chitosan hydrogels. Proc. ZZnd Int. Symp. Control. Rel. Bioact. Mater.,
Seattle-USA, (Deerfield: Controlled Release Society, Inc.), 21 -22.
SHIRAISHI, S., ARAHIRA, M., IMAI,T . , and OTAGIRI, M., 1990, Enhancement of dissolution
rates of several drugs by low molecular chitosan and alginate. Chemical and
SHIRAISHI, S., IMAI,T., and OTAGIRI, M., 1993, Controlled release of indomethacin by
chitosan polyelectrolyte complex: optimization and in vivolin nitro evaluation.
Journal of Controlled Release, 25, 217-225.
STRUSZCYK, M. H., 1995, Immobilization of dextranase on chitosan. MSc dissertation,
Poland.
STRLJSZCZYK, H., NIEKRASZEWICZ, A. OWCZAREK, K., and WISNIEWSKA-WRONA, M., 1994,
Biodegradation of chitosan. In Chitin World, edited by Z. S. Karnicki, A. Wojtasc-
Pajak, M. M. Breziski and P. J. Bylowsky (Bremerhaven Wirtschaftsverlag), pp.
550-554.
SYNOWIECKI, J., HAN,X. Q., and SHAHIDI, F., 1994, Application of chitin immobilized
proteolytic enzymes in food processing operations. In Chitin World, edited by Z. S.
Karnicki, A. Wojtasc-Pajak, M. M. Breziski and P. J. Bylowsky (Bremerhaven,
TAPIA, C., BUCKTON, G., and NEWTON, J. M., 1993, factors influencing the mechanism of
release from sustained release matrix pellets, produced by extrusion/spheronization.
International Journal of Pharmaceutics, 92, 21 1-21 8.
TARAVEL, M. N. and DAMARD, A,, 1994, New aspects of the interaction between collagen and
chitosan. In Chitin World, edited by Z . S. Karnicki, A. Wojtasc-Pajak, M. M.
Breziski and P. J. Bylowsky (Wirtschaftsverlag), pp. 462-468.
TERBOJEVICH, M., COSAN, A,, CONIO,G., MARSANO, E., and BIANCHI, E., 1991, Chitosan:
chain rigidity and mesophase formation. Carbohydrate Research, 25 1-260.
THANOO, B. C., SUNNY, M. C., and JAYAKRISHNAN, A., 1992, Crosslinked chitosan
microspheres: Preparation and evaluation as a matrix for the controlled release of
pharmaceuticals. Journal of Pharmacy and Pharmacology, 44, 283-286.
TOHZAKI, H . , FUJITA,
T., MURAKAMI, M., YAMAMOTO, A., MURANISHI, S., 1995, Metabolism
of peptide drugs by the microorganisms in rat cecal contents and colon specific
Chitosan: properties, preparations and applications 71 1
delivery of insulin from chitosan capsules in rats. Proc. 22nd Int. Symp. Cont. Rel.
Bioact. Mater., Seattle-USA, (Deerfield: Controlled Release Soceity, Inc.),
498-499.
TOHZAKI, H., FUJITA, T., YAMAMOTO, A., MURANISHI, S., SUGIYAMA, T., TERABE, A.,
MA~SLJMOTO, T., and SUZUKI, I., 1966, Chitosan capsules for colon specific drug
delivery: Improvement of insulin absorption from the rat colon. Proc. 23rd Int.
Symp. Cont. Rel. Bioact. Mater., Kyoto-Japan, (Deerfield: Controlled Release
Society, Inc.).
TAKAHASHI, T., TAKAYAMA, K., MACHIDA, Y., and NAGAI,T . , 1990, Characteristics of
polyion complexes of chitosan with sodium alginate and sodium polyacrylate.

VERSALI, M. F., 1993, An alternative technology of chitosan production, European Chitin
Society Newsletter, 28.
Z , K A ~H.
VURAI.,I., A C I K G ~M., , S., ERCAN, M. T., HASCEl,iK, Z., and HINCAL,A. A . , 1994a,
In vitro and in vivo evaluation of antiinflammatory drugs. In Chitin World, edited by
Z . S. Karnicki, A. Wojtasc-Pajak, M. M. Breziski and P. J. Bylowsky (Bremerhaven,
I., KAQ,H . S., and HINCAL,
VURAI., A. A., 1990, Chitosan treated albumin microspheres of
indometlasine: I. Formulation and in vitro release profiles. Proc. Liposomes in Drug
Delivery-21 Years On, 12-1 5 December, London-United Kingdom, (London:
University of London Press), p.45.
VURAL,I., KAQ,H. S., and HINCAL, A. A., 1991a, Chitosan treated albumin microspheres of
sulphasalazine: I. Formulation and in vitro release characteristics. Proc. 10th
Pharma. Technol. Conf., 16-18 April, Bologna, Italy, vol. I, part 2, (Liverpool: Solid
Dosage Research Unit), pp. 491-504.
VURAI., I., KAQ, H. S., and HINCAL, A. A., 1991b, Indomethacin microspheres I.
Formulation and in vitro evaluation. Chimica-Oggi, 9( 1l), 49-52.
VURAL,I., KAQ,H. S., and HINCAL, A. A., 1994b, Chitosan treated albumin microspheres of
sulphasalazine: I. Formulation and in vitro release profiles. H . U . J . Fac. Pharm.,
14(2), 57-65.
WAN,L. S. C., L I M ,L. Y., and SOH,B. L., 1994, drug release from chitosan beads, S . T . P .
Pharma. Sci., 4(3), 195-200.
YIN,Y., SHAO, L., GUAN,Y., and YAO,K., 1996, pH sensitive drug delivery carriers of
chitosan based hydrogels. Proc. 23rd Int. Symp. Cont. Rel. Bioact. Mater., Kyoto-
Japan, (Deerfield: Controlled Release Society, Inc.).
YAO,K.-DE,PENG,T., YIN,Y.-J., Xu, M.-X., and GOOSEN, M. F. A., 1995, Microcapsules/
microspheres related to chitosan. J.M.S.-Rev. Macromol. Chem. Phys., C , 35( l ) ,
155-180.

Review: Chitosan: Properties, Preparations and Application To Microparticulate Systems

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Review: Chitosan: Properties, Preparations and Application To Microparticulate Systems

Uploaded by

Copyright:

Available Formats

J. MICROENCAPSULATION, 1997, VOL. 14, NO.

Hacettepe University, Pharmacy Faculty, Pharmaceutical Technology

(Received 8 November 1996; accepted 13 December 1996)

Chitosan, a hydrophilic biopolymer, is obtained industrially by hydrolysing the

Keywords: Chitosan, microparticles, preparation, pharmaceutical, biopharma-

Chitin, which is perhaps the second most important natural polysaccharide, is a

0265-2048/97 $12.00 0 1997 Taylor & Francis Ltd

cobalt. The pharmaceutical requirements of chitosan are as follows: particle size

rMo.uic iype flocculation Iiilerpmiculiu bridging

SLructure of flocs oht;uiied wiili 3 high inolccuLv inau chiimnri

Figure 2. Proposed mechanism of flocculation and redispersion of lipids in the presence of

Table 1 . Chemical properties of chitosan

Table 2. Biological properties of chitosan

coating, hypocholosterolemic behaviour), for clarification and waste management

by Yao et al. (1995). Akbuga (1995) reviewed different biomedical, pharmaceutical

Preparation of chitosan microparticles

In this section different preparation methods of microparticulate systems such

Microparticles (beads, microspheres, microcapsules)

Extrusion-spheronization. Goskonda and Upadrashta (1993) prepared avicel

chitosan beads by extrusion-spheronization technology where the ingredients are

Solvent evaporation technique. Chitosan is dissolved in an aqueous acetic acid

Precipitationlcoacervation method. Berthold et al. (1996a) prepared chitosan

Coating by chitosan. In this method, previously formed microparticles are coated

Spherical agglomeration technique. Granules of chitosan are prepared by the

In this section, immobilization and encapsulation of certain pharmaceuticals

Table 3. Reduction of gastric mucosal injury by chitosan beads of diclofenac sodium

Sawayanagi et al. (1982a) investigated the application of chitosan to study the

Diclofenac sodium ( D S ) . Murata et al. (1996) investigated the formation of a

Prednisolone (PDS). Berthold et al. (1996a) prepared chitosan microspheres as

the drug-polymer ratio. Sawayanagi et al. (1983a) prepared ground mixtures of

Other anti-inflammatory agents. Bodmeier and Paeratakul (1989) prepared

molecular weights as constituents of microparticulate matrices loaded with the

Cisplatin ( C C D P ) . Cisplatin (CDDP) (Nishioka et al. 1989, 1990) containing

profiles and susceptibility to various enzymes were examined. C D D P release was

Oxantrazole (0x2).Hassan et al. (1992) combined emulsion polymerization

Cytarabine and mitomycin-C. Chitosan-glutaric acid-cytarabine conjugates

characteristics evaluated (Onishi et al. 1994). These conjugates prepared using

Doxorubicin (DX).Ouchi et al. (1994) carried out the fixation of D X t o

Isosorbide-5-Mononitrate ( I S - 5 - M N ) . Farivar et al. (1993) investigated the

Phenytoin ( P T ) . Murata et al. (1993a) prepared chitosan-reinforced alginate

Figure 5. Diagrammatic representation of the formation of calcium induced alginate gel

significant increase of dissolution rate of drugs from kneaded mixtures. T h e

Griseofulvin ( G R S ) . Bodmeier and Paeratakul (1989) prepared spherical beads

Sulfadiazine ( S R D ) . Bodmeier and Paeratakul (1989) improved significantly

Spironolactone (SP). Acarturk et al. (1993a, b) studied the dissolution of SP

work has demonstrated that chitosan-alginate membranes may be used as a vehicle

Antithrombotic agents. Gallo and Hassan (1988) formulated a new magnetic

Fibroblast. Muzzarelli (1994) showed that chitosan is suitable as a matrix for

Enzyme. Dextranase was immobilized on chitosan beads in a standard form

chitosan was investigated. It was shown that the efficacy of immobilization by

Znterleukin 2 (IL-2). In this study IL-2 was entrapped in an alginate/chitosan

culture. Shioya and Rha (1989) developed a microencapsulation method using

microspheres of diclofenac sodium. 11. In vivo evaluation. Proceedings of the 9th

encapsulated activated charcoal (ACCB) adsorbents for small molecules. Journal of

Elsevier), pp. 617-626.

USA (Deerfield, USA: Controlled Release Society, Inc.), 542-543.

38( lo), 2871-2873.

hydroxypropyl methyl-cellulose acetate succinate, Journal of Microencapsulation,

Chitosan-Sources, Chemistry, Biochemistry, Physical Properties and Applications,

polyion complexes of chitosan with sodium alginate and sodium polyacrylate.

You might also like