Drug Delivery

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Design and Development of Multiparticulate

System for Targeted Drug Delivery to Colon

M. K. Chourasia & S. K. Jain

To cite this article: M. K. Chourasia & S. K. Jain (2004) Design and Development of
Multiparticulate System for Targeted Drug Delivery to Colon, Drug Delivery, 11:3, 201-207, DOI:
10.1080/10717540490445955

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Drug Delivery, 11:201–207, 2004
Copyright 
c Taylor & Francis Inc.
ISSN: 1071-7544 print / 1521-0464 online
DOI: 10.1080/10717540490445955
Design and Development of Multiparticulate System
for Targeted Drug Delivery to Colon
M. K. Chourasia and S. K. Jain
Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences,
Dr. Hari Singh Gour Vishwavidyalaya, Sagar (M.P.) 470 003, India
A multiparticulate system combining pH-sensitive property and
specific biodegradability for colon-targeted delivery of metron-
idazole has been investigated. Cross-linked chitosan microspheres
were prepared from an emulsion system using liquid paraffin as
the external phase and solution of chitosan in acetic acid as the dis-
perse phase. The multiparticulate system was prepared by coating
cross-linked chitosan microspheres exploiting Eudragit R
L-100
and S-100 as pH-sensitive polymers. Morphology and surface char-
acteristics of the formulations were determined by scanning elec-
tron microscopy. Particle size of the chitosan microspheres was de-
termined by optical microscopy while that of coated microspheres
was determined by particle size analyzer. In vitro drug-release stud-
ies were performed in conditions simulating stomach-to-colon tran-
sit in presence and absence of rat caecal contents. The size of the mi-
crospheres was small and they were efficiently microencapsulated
within Eudragit R
microspheres, forming a multireservoir system.
By coating the microspheres with Eudragit R
pH-dependant release
profiles were obtained. No release was observed at acidic pH; how-
ever, when it reached the pH where Eudragit R
starts solublizing
there was continuous release of drug from the formulation. Fur-
ther, the release of drug was found to be higher in the presence of
rat caecal contents, indicating the susceptibility of chitosan matrix
to colonic enzymes released from rat caecal contents.
Keywords Biodegradable Polymers, Colon-Targeted Drug Delivery,
Multiparticulate System, pH-Sensitive Polymers
INTRODUCTION
Targeting of drugs specifically to colon is advantageous in the
treatment of diseases associated with the colon such as amebi-
Received 12 April 2003; accepted 8 December 2003.
The author is grateful to M/s Broshell Pharmaceuticals, Sagar,
M. P., India for generously supplying metronidazole as gift sample
and Council of Scientific and Industrial Research, New Delhi, India for
providing financial assistance to carry out this work.
Address correspondence to S. K. Jain, Pharmaceutics Research
Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari
Singh Gour Vishwavidyalaya, Sagar (M.P.) 470003, India. E-mail:
drskjainin@yahoo.com
201
asis, Crohn’s diseases, ulcerative colitis, and colorectal cancer.
In addition, it has shown great potential in oral delivery of ther-
apeutic peptides and proteins, which are unstable in the upper
part of gastrointestinal tract. The colonic region is recognized as
having less diversity and intensity of enzymatic activities than
the stomach and small intestine (Davis 1990). Various strategies
are available for targeting drug release selectively to the colon
(Chourasia and Jain 2003). The designing of prodrugs is based
on the concept of preventing the release of drugs in the stomach
and small intestine, and drug release is triggered by the utiliza-
tion of some specific property at the target site such as altered
pH or high activity of certain enzymes in comparison to nontar-
get tissues (Davaran et al. 1999; Schacht et al. 1996). Since it is
known that azo function can be reduced in the colon (Chung et al.
1992), a lot of novel polymers containing azo groups either in the
polymeric backbone (Yamaoka et al. 2000) or in the crosslinks
(Shantha et al. 1995; Van den Mooter et al. 1992) have been
synthesized. In order to promote further selective degradation
in the vicinity of colonic environment, delivery systems have
been designed that contain both pH-sensitive acidic monomers
and degradable azo aromatic crosslinks (Chandehari et al. 1997;
Kakoulides et al. 1998). Polysaccharides such as chitosan, dex-
tran, inulin, and guar gum have been explored for their potential
in colon-specific drug delivery (Prasad et al. 1998; Shimono et al.
2002; Tozaki et al. 2002). The polysaccharides remain intact in
the hostile environment of the stomach and small intestine, and
upon arrival in the colon they are degraded by polysaccharidases
(Rubinstein et al. 1993).
pH-sensitive polymers, which dissolve at or above pH 7, may
also be used for colonic delivery (Cole et al. 2002; Khan et al.
1999). Ashford et al. (1993) showed that pH-sensitive polymers
are not suitable for colon-targeted drug delivery systems due to
poor site specificity. The long lag time at the ileocaecal junction
and fast transit indicate that a single unit may not be the best
dosage form for colon-targeted drug delivery system.
The proposed multiparticulate system combines pH-sensitive
property of enteric polymers as well as biodegradability of
202 M. K. CHOURASIA AND S. K. JAIN
chitosan in the colon. It consists of chitosan microspheres coated
using pH-sensitive polymers for the colon-targeted delivery of
metronidazole (MNZ) for the treatment of amebiasis. The drug
release is suppose to take place after dissolution of the enteric
coating in the small intestine and biodegradation of the chitosan
in the colon due to presence of polysaccharidases in the colonic
contents.
MATERIALS AND METHODS
Chitosan (purified viscosity grade 50) was obtained from
Central Institute of Fisheries Technology (Cochin, India). M/s
Broshell Pharmaceuticals (Sagar, M. P., India) generously sup-
plied metronidazole as a gift sample. Span-80 and Antifoam A
were procured from Sigma Chemicals (St.Louis, MO, USA).
Liquid paraffin heavy (viscosity 90 cp at 30◦ ) was from Central
Drug House (Mumbai, India). All other solvents and reagents
were of analytical grade.
Preparation of Cross-Linked Chitosan Microspheres
The microspheres were prepared using the emulsion method,
employing glutaraldehyde as cross-linker (Thanoo et al. 1992).
Chitosan solution (4% w/v) was prepared in 5% aqueous acetic
acid, and the drug was dispersed in this solution and mixed well.
This was dispersed in liquid paraffin (1:1 mixture of light and
heavy) containing span 80 (1% w/w) and antifoam A (0.1% w/w).
The dispersion was stirred using a stainless steel half moon
paddle stirrer at various speeds for 2 min and glutaraldehyde-
saturated toluene solution (1 ml to 3 ml) was added under stirring
and continued for 4 hr. After the stipulated stirring time, the mi-
crospheres were centrifuged, washed several times with hexane,
and dried in vacuum desiccator for 48 hr.
Coating of Cross-Linked Chitosan Microspheres
Coating of cross-linked chitosan microspheres containing
MNZ was performed using emulsion solvent evaporation tech-
nique. Chitosan microspheres were suspended in 10 ml of an
organic solvent (1:1, acetone:methanol) in which Eudragit
R
L-100 or S-100 was previously dissolved to give either 1:5 or
1:10 core/coating ratio. This organic phase was emulsified into
100 ml of liquid paraffin containing span 80 and antifoam A (1
and 0.1% w/v, respectively). The system was stirred at 1000 rpm
with two-blade mechanical stirrer for 4 hr at room temperature.
The Eudragit-coated microspheres were collected and rinsed
R
with n-hexane and dried in vacuum desiccator for 48 hr.
In Vitro Characterization of Microspheres
Determination of Particle Size and Shape
Morphology and surface characteristics of the microspheres
were determined using scanning electron microscopy (AIIMS,
New Delhi, India).
Particle size of the cross-linked chitosan microspheres was
determined by optical microscopy using calibrated ocular eye-
piece, whereas that of Eudragit-coated microspheres was de-
R
termined using particle size analyzer (Cilas 1064 L, Marcoussis,
France).
Determination of Drug Content
The amount of drug present in the microspheres was deter-
mined by a method reported by Thanoo et al. (1992). A weighed
quantity of the microspheres was extracted with methanol for
24 hr, and drug concentration in supernatant was determined
spectrophotometrically at 320.5 nm (UV 1601, Shimadzu,
Japan).
In Vitro Drug Release from Microspheres
In vitro drug release studies were carried out according to
Souder and Ellenbogen (1985) extraction technique using USP
dissolution test apparatus. The dissolution studies were carried
out in 100 ml dissolution medium, which was stirred at 100 rpm
at 37 ± 0.1◦ C.
The scheme of using the simulated fluids at different pH was
as follows:
1st hour: Simulated gastric fluid of pH 1.2.
2nd and 3rd hours: Mixture of simulated gastric and intestinal
fluid of pH 4.5.
4th and 5th hours: Simulated intestinal fluid of pH 6.8.
6th hour: Simulated intestinal fluid of pH 7.5.
Samples were withdrawn periodically and compensated with
an equal amount of fresh dissolution media. The samples were
analyzed for drug content by measuring absorbance at 320.5 nm
using UV spectrophotometer (UV 1601, Shimadzu, Japan).
In Vitro Drug Release in Presence of Rat Caecal Contents
In vitro drug release from coated microspheres was also car-
ried out in the presence of rat caecal contents to assess the
biodegradability of chitosan by colonic bacteria. Albino rats of
either sex weighing between 150–200 g were selected for the
present study and maintained on normal diet. In order to in-
duce the enzymes that specifically act on the chitosan during its
passage through the colon, the albino rats were intubated with
Teflon tubing and 1 ml of 1% w/v dispersion of chitosan in wa-
ter was administered directly into the stomach. This treatment
was continued for five days. Rats were dissected before release
rate studies, the caecum was isolated, ligated at both ends, cut
loose and immediately transferred into simulated intestinal fluid
of pH 7.5 previously bubbled with carbon dioxide. The caecal
contents were individually weighed, pooled, and suspended in
buffer to produce final caecal concentration of 3% w/v. Drug
release rate studies for the initial 5 hr were performed as de-
scribed above. From 6th hour and onwards it was carried out
in simulated intestinal fluid containing rat caecal contents. The
experiment was carried out with a continuous supply of car-
bon dioxide into dissolution media. Aliquots of samples were
withdrawn periodically and replaced with fresh buffer bubbled
with carbon dioxide. The volume was made up to 10 ml, cen-
trifuged, the supernatant was filtered through Whatman filter
paper, and drug content was determined spectrophotometrically
at 320.5 nm (UV 1601, Shimadzu, Japan).
 DESIGN AND DEVELOPMENT OF MULTIPARTICULATE SYSTEM 203

FIG. 1. Scanning electron photomicrograph of cross-linked chitosan microspheres.

RESULTS AND DISCUSSION
The multiparticulate systems for colon-targeted drug delivery
exhibit an advantage over single-unit dosage form, as they re-
main intact in the stomach and small intestine. Once they reach
in the colonic region, release of the drug is triggered due to
degradation of the system. Single unit dosage forms are based on
pH-sensitive polymers, which are not suitable for colon-targeted
drug delivery. These dosage forms exploit the enteric polymers
and maintain their integrity and do not cause the release of the
drug in the strongly acidic environment of the stomach. As they
arrive into the alkaline pH of the small intestine they start to
dissolve and release the drug.
This multiparticulate system combines a pH-sensitive prop-
erty and biodegradability in the colon. Colon-specific release of
the entrapped drug is achieved by dissolution of the enteric coat-
ing at the distal part of the small intestine and exposed chitosan
microspheres when reaches to the colon, release is effected by
swelling of the polymer as well as by the biodegradable effect
of polysaccharidases.
When aqueous glutaraldehyde is added to the dispersion of
chitosan in paraffin oil, an instantaneous reaction occurs and
the resultant product does not exhibit good sphericity and sur-
face texture. Therefore, slow and uniform cross-linking of the
droplets, particularly at the surface, is desirable to generate mi-
crospheres of good sphericity. Hence, glutaraldehyde-saturated
toluene was used, which by virtue of its solubility in oil
medium would help to uniformly cross-link the surface of
droplets.

TABLE 1
Average particle size, entrapment efficiency, and in vitro drug release of uncoated cross-linked chitosan microspheres

Formulation Particle Entrapment In vitro drug release

code Variables Values size (µm) efficiency (%) after 8 hr (%)
CCM1 Drug concentration 10% 14.5 ± 0.52 68.2 ± 2.56 98.8 ± 4.18
CCM2 15% 13.2 ± 0.43 71.3 ± 2.98 98.4 ± 3.92
CCM3 20% 12.1 ± 0.49 72.1 ± 2.94 99.3 ± 4.11
CCM4 Chitosan concentration 2% 14.1 ± 0.32 68.4 ± 2.36 90.8 ± 3.14
CCM5 4% 14.8 ± 0.58 78.3 ± 2.87 93.2 ± 3.42
CCM6 6% 15.2 ± 0.54 80.2 ± 3.21 96.0 ± 3.85
CCM7 Amount of glutaraldehyde 1 ml 13.9 ± 0.45 69.8 ± 3.10 99.5 ± 3.93
CCM8 2 ml 11.8 ± 0.30 64.3 ± 2.25 98.0 ± 3.76
CCM9 3 ml 12.4 ± 0.44 56.2 ± 2.58 91.4 ± 3.45
CCM10 Agitation speed 1000 rpm 14.3 ± 0.55 79.9 ± 3.34 91.7 ± 3.27
CCM11 2000 rpm 12.4 ± 0.39 74.5 ± 2.79 99.0 ± 3.68
CCM12 3000 rpm 10.2 ± 0.21 70.2 ± 2.96 99.4 ± 3.82
204 M. K. CHOURASIA AND S. K. JAIN

It is clearly seen from scanning electron photomicrograph TABLE 2

that microspheres possess a smooth surface and spherical shape Particle size and encapsulation efficiency of coated
(Figure 1). Particle size and entrapment efficiency of cross- cross-linked chitosan microspheres
linked chitosan microspheres bearing MNZ is shown in Table 1.
Due to the strong swelling and adhesive nature of the chitosan, Core/ Mean Entrapment
the particle size of cross-linked chitosan microspheres could not coating particle efficiency
be determined by particle size analyzer, and hence calibrated oc- Type of polymer ratio size (µm) (%)
ular eye piece was used for measurement of particle size by mi- Eudragit L-100 1:5 140.5 ± 5.21 74.1 ± 3.12
croscopic method. Mean particle size was found to be decreased 1:10 163.7 ± 6.34 78.5 ± 3.65
by increasing the amount of the drug while it was increased on Eudragit S-100 1:5 154.5 ± 4.56 80.7 ± 3.48
increasing the chitosan concentration. Mean particle size was 1:10 173.3 ± 5.85 76.3 ± 2.98
found to be 14.5 ± 0.52 µm at 10%, drug concentration, while it Eudragit L-100 & 1:5 148.8 ± 4.67 76.7 ± 2.76
was decreased to 12.1 ± 0.49 µm when the drug concentration Eudragit L-100 (1:1) 1:10 171.9 ± 6.59 81.2 ± 3.34
was increased to 20%. Increasing the concentration of chitosan
caused the viscosity to increase and led to an increase in the size
of emulsion droplet, and hence microspheres with bigger par- was increased (1 ml to 3 ml), which is due to the fact that as
ticles were produced. Particle size was decreased (14.3 ± 0.55 the amount of glutaraldehyde was increased it produced micro-
to 10.2 ± 0.21 µm) by increasing the agitation speed (1000 spheres with pronounced cross-linking between polymer chains
to 3000 rpm). When the agitation speed was increased above that retarded the release of drug (Table 1). Microspheres, which
3000 rpm the mean particle size was reduced, and microspheres were prepared at agitation speed of 3000 rpm, did not exhibit
did not exhibit good sphericity and surface appearance. good sphericity and released 99.4 ± 3.82% of MNZ, while those
The in vitro drug release studies were performed using gas- that were produced at 2000 rpm released 99.0 ± 3.68% of MNZ
trointestinal fluids of different pH. The effect of drug concentra- after 8 hr (Table 1). All the formulations released more than 90%
tion, chitosan concentration, glutaraldehyde concentration, and of the drug during dissolution studies for 8 hr.
agitation speed was observed on in vitro drug release. As the In the second part of this investigation cross-linked chitosan
microspheres were further coated with Eudragit L-100 and
R
amount of drug incorporated into cross-linked chitosan micro-
R
spheres was increased, the in vitro release was increased. In vitro Eudragit S-100 using esmulsion solvent evaporation
drug release after 4 hr was found to be 75.2 ± 3.41% in the case technique.
The shape of the Eudragit-coated cross-linked chitosan mi-
R
of microspheres having 10% drug, while it was 84.2±3.89% for
microspheres with 20% drug (Figure 2). The effect of chitosan crospheres was determined using scanning electron microscopy,
concentration on the release of drug was found to be meager and particle size was determined using laser diffraction particle
(Table 1). The drug release after 8 hr was decreased (99.5±3.94 size analyzer (Cilas 1064 L, France). The size after coating was
to 91.4 ± 3.45%) when the concentration of glutaraldehyde, considerably increased (140–175 µm) (Table 2 and Figure 3).

FIG. 2. Effect of drug concentration on drug release from cross-linked chitosan microspheres.
 DESIGN AND DEVELOPMENT OF MULTIPARTICULATE SYSTEM 205

FIG. 3. Scanning electron photomicrograph of coated cross-linked chitosan microspheres.

In the case of uncoated cross-linked chitosan microspheres,
nearly 80–90% of the drug was released in the initial 4–5 hr
release rate studies. This situation is not acceptable for those
drugs, which are required to be released locally in the colon.
Cross-linked chitosan microspheres were coated with Eudragit
R
was released during the initial 3 hr. Such release could be due
to the entrapped drug nearer to surface that was dissolved and
diffused out into the medium after swelling. Eudragit L-100
R
dissolves at pH above 6.0, and hence during 4th-hour study
at pH 6.8, 8.9 ± 0.39% and 6.7 ± 0.25% of the drug was re-

L-100, S-100, and a 1:1 mixture of both polymers to retard the
release of the drug until pH reaches above 6.0. In vitro release
studies revealed that no drug was released during first 3 hr stud-
ies except in case of Eudragit L-100 (core/coating ratio, 1:5),
R
where 1.4 ± 0.04% of the drug was released. In the case of
leased in the case of 1:5 and 1:10 core/coating ratio, respec-
tively, while no drug was released in case of Eudragit S-100
R
microspheres (1:10). Moreover, drug was continuously released
when the release studies were carried out above solubility pH
of the enteric polymers. Eudragit L-100 microspheres started
R

microspheres prepared from 1:1 mixture of Eudragit L-100 releasing drug at lower pH (6.8) than Eudragit S-100 (7.5),
R R

and S-100 (core/coating ratio, 1:5), 0.5 ± 0.02% of the drug while microspheres consisted of mixture of Eudragit L-100
R

FIG. 4. In vitro release of metronidazole from coated cross-linked chitosan microspheres.

206 M. K. CHOURASIA AND S. K. JAIN
FIG. 5. In vitro release of metronidazole from coated cross-linked chitosan microspheres in the presence of rat caecal contents.
and S-100 exhibited intermediate release pattern. The MNZ re-
lease from the microspheres was significantly affected by coat-
ing ratio (core/coating). The higher amount of drug release was
observed with microspheres prepared by 1:5 core/coating ra-
tio, while microspheres having 1:10 core/coating ratio exhib-
ited lower drug release (Figure 4). Drug release after 12 hr
in case of Eudragit L-100 with core/coating ratio of 1:5 and
R
1:10 was found to be 69.3 ± 3.12 and 62.7 ± 2.83%, respec-
tively, whereas microspheres of Eudragit S-100 with the same
R
core/coating ratio released 56.9 ± 2.65% and 50.4 ± 1.98%,
respectively.
The multiparticulate system successfully retarded the release
of drug until it enters into the colon. To assess the biodegrad-
ability of the chitosan to the colonic enzymes, in vitro release
studies in the presence of caecal contents were performed. The
albino rats were orally administered 1 ml of 1% w/v chitosan
dispersion in water continuously for 5 days in order to induce
the enzymes that specifically act on chitosan. Drug release rate
studies in the presence of rat caecal contents were carried out
from the 6th hour in simulated intestinal fluid of pH 7.4. Drug
release-rate studies for initial 5 hr were the same as described
previously.
The presence of rat caecal contents in the dissolution medium
resulted in improved drug release at different time intervals in
comparison to those that were carried out without using rat cae-
cal contents. In vitro drug release studies after 8 hr without rat
caecal contents released 32.8 ± 1.46% and 39.2 ± 1.29% of drug
in case of microspheres of 1:10 core/coating of Eudragit S-100
R
and L-100, respectively, while the presence of rat caecal con-
tents increased the release to 69.8 ± 3.17% and 82.4 ± 3.28%
(Figures 4 and 5). The release of drug from cross-linked chitosan
microspheres was supposed to take place after swelling, which
resulted in the formation of gel followed by the dissolution of
MNZ and diffusion through the gel. Cross-linking of the chi-
tosan with glutaraldehyde caused the swelling to decrease and
the consequent release of drug. This particular phenomenon is
helpful during the exposure of the chitosan microspheres to small
intestinal fluid. Drug release in presence of rat caecal contents
is triggered by the swelling behavior of chitosan as well as by
biodegradability due to colonic enzymes. More than 98% of
MNZ was released from all the formulations after 12 hr studies
in presence of rat caecal contents (Figure 5).
The release of a higher amount of drug in the presence of
rat caecal contents clearly reveals the susceptibility of chitosan
matrix to colonic enzymes released from rat caecal contents. A
considerably higher amount of caecal matter is present in the
human colon than the amount present in the in vitro studies. It
may not be necessary to induce the enzymes in case of admin-
istration of dosage form of chitosan, as considerable amount of
polysaccharidases would be present in the human colon.
REFERENCES
Ashford, M., Fell, J. T., Attwood, D., Sharma, H., and Woodhead, P. 1993. An
in vivo investigation into the suitability of pH-dependent polymers for colonic
targeting. Int. J. Pharm. 95:193–199.
Chandehari, H., Kopeckova, P., and Kopecek, J. 1997. In vitro degradation of
pH sensitive hydrogels containing aromatic azo bonds. Biomaterials 18:861–
872.
Chourasia, M. K., and Jain, S. K. 2003. Pharmaceutical approaches to colon
targeted drug delivery systems. J. Pharm. Pharmaceut. Sci. 6(1):33–66.
Chung, K. T., Stevens, S. E., and Cerniglia, C. E. 1992. The reduction of azo
dyes by the intestinal microflora. Crit. Rev. Microbiol. 18:175–190.
Cole, E. T., Scott, R. A., Connor, A. L., Wilding, I. R., Petereit, H. U., Schminke,
C., Beckert, T., and Cade, D. 2002. Enteric coated HPMC capsules designed
to achieve intestinal targeting. Int. J. Pharm. 231:83–95.
Davaran, S., Hanaee, J., and Khosravi, A. 1999. Release of 5-amino salicylic
acid from acrylic type polymeric prodrugs designed for colon-specific drug
delivery. J. Contrl. Rel. 58:279–287.
 DESIGN AND DEVELOPMENT OF MULTIPARTICULATE SYSTEM
Davis, S. S. 1990. Overcoming barriers to the oral administration of peptide
drugs. Trends Pharma. Sci. 11:353–355.
Kakoulides, E. P., Smart, J. D., and Tsibouklis, J. 1998. Azocrosslinked (poly-
acrylic acid) for colonic delivery and adhesion specificity: in vitro degradation
and preliminary ex vivo bioadhesion studies. J. Contrl. Rel. 54:95–109.
Khan, M. Z., Prebeg, Z., and Kurjakovic, N. A. 1999. A pH-dependent colon
targeted oral drug delivery system using methacrylic acid copolymers I. Ma-
R R
nipulation of drug release using Eudragit L100-55 and Eudragit S100
combinations. J. Contrl. Rel. 58:215–222.
Prasad, Y. V. R., Krishnaiah, Y. S. R., and Satyanarayana, S. 1998. In vitro
evaluation of guar gum as a carrier for colon-specific drug delivery. J. Control.
Rel. 51:281–287.
Rubinstein, A., Radai, R., Ezra, M., Pathak, S., and Rokem, J. M. 1993. In
vitro evaluation of calcium pectinate: A potential colon-specific drug delivery
carrier. Pharm. Res. 10:258–263.
Schacht, E., Gevaert, A., Kenawy, E. R., Molly, K., and Gelan, T. 1996. Polymers
for colon-specific drug delivery. J. Contrl. Rel. 39:327–338.
Shantha, K. L., Ravichandran, P., and Rao, K. P. 1995. Azo polymeric hydrogels
for colon targeted drug delivery. Biomaterials 16:1313–1318.
207
Shimono, N., Takatori, T., Masumi, T., Ueda, M., Mori, M., Higashi, Y., and
Nakamura, Y. 2002. Chitosan dispersed system for colon-specific drug deliv-
ery. Int. J. Pharm. 245:45–54.
Souder, J. C., and Ellenbogen, W. C. 1985. Control of d-amphetamine sulphate
sustained release capsule. Drug Standards 26:77–79.
Thanoo, B. C., Sunny, M. C., and Jayakrishnan, A. 1992. Cross linked
chitosan microspheres: Preparation and evaluation as a matrix for the
controlled release of pharmaceuticals. J. Pharm. Pharmacol. 44:283–
286.
Tozaki, H., Odoriba, T., Okada, N., Fujita, T., Terabe, A., Suzuki, T., Okabe, S.,
Murnishi, S., and Yamamoto, A. 2002. Chitosan capsules for colon-specific
drug delivery: Enhanced localization of 5-aminosalicylic acid in the large
intestine accelerates healing of TNBS-induced colitis in rats. J. Contrl. Rel.
82:51–61.
Van den Mooter, G., Samyn, C., and Kinget, R. 1992. Azo polymers for colon-
specific drug delivery. Int. J. Pharm. 87:37–46.
Yamaoka, T., Makita, Y., Sasatani, H., Kim, I., and Kimura, Y. 2000. Linear type
azo-conataining polyeurathane as drug coating material for colon-specific
delivery. J. Contrl. Rel. 66:187–197.