Pulsatile Drug Delivery System for Colon – A Review - International ...

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
___________________________________________Review Paper
Pulsatile Drug Delivery System for Colon – A Review
Moin K. Modasiya* and Vishnu M. Patel
APMC College of Pharmaceutical Education and Research, Himatnagar, Gujarat, India.
__________________________________________________________________________________
ABSTRACT
Conventionally, drugs are released in an instant or absolute manner. Nevertheless, in current days, Pulsatile
Drug Release Systems (PDRS) are gaining upward attention. In PDRS, where the drug is released quickly
following a well defined lag-time, could be beneficial for many drugs or treatments. PDRS can be classified in
single and multiple pulse systems. The colon is a location where both local and systemic delivery of drugs can
take place. Local delivery allows topical treatment of inflammatory bowel disease (IBD). On the other hand,
healing can be made efficient if the drugs can be embattled directly into the colon, by this means reducing the
systemic side effects. Consequently PDRS is one of such systems that, deliver the drug at the exact time,
correct place and in precise amounts, holds superior promise of benefit to the patients suffering from
unending troubles like arthritis, asthma, hypertension, inflammation. This assessment covers both the primary
approaches namely prodrugs, pH - time dependent systems, microbially triggered systems and newer
approaches namely pressure controlled colonic delivery capsules, osmotic controlled drug delivery of PDRS for
colon.
Key Words: Pulsatile Drug Release Systems, Lag-time and Colon.
1, 2
1. INTRODUCTION
Oral controlled drug delivery systems offer
temporal and spatial control over the release of
drug. Such systems represent the most popular
form of controlled drug delivery for the obvious
advantage of oral route of drug administration. The
spatial targeting of the drug to the colon generally
follows pulsatile release. Pulsatile release profile is
characterized by the initial lag time followed by the
rapid and complete drug release.
Fig. 1: Drug release profile of pulsatile drug
delivery system 1,2
________________________________________
*Address for correspondence:
E-mail: m_chandni2004@yahoo.co.in
A: Ideal sigmoidal release B & C: Delayed
release after initial lag time
The first pulsed delivery formulation that released
the active substance at a precisely defined time
point was developed in the early 1990s. In this
context, the aim of the research was to achieve a
so-called sigmoidal release pattern (pattern A in
Figure).
The characteristic feature of the formulation was a
defined lag time followed by a drug pulse with the
enclosed active quantity being released at once.
Thus, the major challenge in the development of
pulsatile drug delivery system is to achieve a rapid
drug release after the lag time. Often, the drug is
released over an extended period of time (patterns
B & C in Figure 1).
Pulsatile drug delivery system is desirable for the
drugs acting or having an absorption window in the
gastro-intestinal tract or for the drugs with an
extensive first pass metabolism Ex, B-blockers or
for the drugs, which develop biological tolerance,
where the constant presence of drug at the site of
action diminishes the therapeutic effect or for drugs
with special pharmacokinetic features designed
according to the circadian rhythm of human.
Pulsatile drug delivery system is generally
classified into time controlled and site specific
controlled systems. The release from the former
group is primarily controlled by the system while
the release in the second group is primarily
Vol. 2 (3) Jul – Sep 2011 www.ijrpbsonline.com 934

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
controlled by the biological environment in the
gastro intestinal tract such as pH or enzyme 3 .
Delivery of drugs to colon has been extensively
investigated during the last decade. A number of
diseases such as Crohn's disease, Ulcerative colitis,
Irritable bowel syndrome and carcinoma of colon
can be treated by local delivery of drugs. Colon
targeting is also been used for systemic absorption
of peptides, oral vaccines, growth hormones,
interleukins, insulin as colon provides friendly
environment which may be due to lower activity of
proteases.
Various diseases that exhibit diurnal rhythms may
also be treated by using colon specific
formulations. Colonic drug delivery can be
achieved by oral or rectal administration. With
regard to rectal route, the drugs do not always
reach the specific sites of the colonic diseases and
the sites of colonic absorption 4,5 .
Colon targeting of orally administered drugs can be
achieved by various techniques such as pH
triggered approach, time dependent approach,
pressure dependent approach, microbially
controlled delivery, osmotic controlled approach ,
prodrug approach and bioadhesive system 6 .
1.1. Advantages: (1,2)
Many body functions that follow circadian
rhythm. A number of hormones like
rennin, aldosterone, and cortisol show
daily fluctuations in their blood levels.
Circadian effects are also observed in case
of pH and acid secretion in stomach,
gastric emptying, and gastro-intestinal
blood transfusion.
Diseases like bronchial asthma,
myocardial infarction, angina pectoris,
rheumatic disease, ulcer, and hypertension
display time dependence. Sharp increase
in asthmatic attacks during early morning
hours. Such a condition demands
considerations of diurnal progress of the
disease rather than maintaining constant
plasma drug level. A drug delivery system
administered at bedtime, but releasing
drug well after the time of administration
(during morning hours), would be ideal in
this case. It is true for preventing heart
attacks in the middle of the night and the
Fig. 3: Anatomy of the colon
morning stiffness typical of people
suffering from arthritis.
Drugs that produce biological tolerance
demand for a system that will prevent
their continuous presence at the biophase,
as this tends to reduce their therapeutic
effect.
The lag time is essential for the drugs that
undergo degradation in gastric acidic
medium (e.g., peptide drugs) irritate the
gastric mucosa or induce nausea and
vomiting. These conditions can be
satisfactorily handled by enteric coating,
and in this sense, enteric coating can be
considered as a pulsatile drug delivery
system.
Targeting a drug to distal organs of gastrointestinal
tract (GIT) like the colon
requires that the drug release be prevented
in the upper two-third portion of the GIT.
The drugs that undergo extensive firstpass
metabolism (-blockers) and those
that are characterized by idiosyncratic
pharmacokinetics or pharmacodynamics
resulting in reduced bioavailability,
altered drug/metabolite ratios, altered
steady state levels of drug and metabolite,
and potential food-drug interactions
require delayed release of the drug to the
extent possible.
1.2. Classification of pulsatile drug delivery
1, 2
systems
Pulsatile drug delivery systems (PDDS) can be
classified in site-specific and time-controlled
systems. Drug release from site-specific systems
depends on the environment in the gastro intestinal
track, e.g., on pH, presence of enzymes, and the
pressure in the gastro intestinal track. In contrast,
time-controlled DDS are independent of the
biological environment. The drug release is
controlled only by the system. Time-controlled
pulsatile delivery has been achieved mainly with
drug-containing cores, which are covered with
release-controlling layers Figure 2.
Vol. 2 (3) Jul – Sep 2011 www.ijrpbsonline.com 935

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
1.2.1. Single unit system
Capsular system
Different single-unit capsular pulsatile drug
delivery systems have been developed. A general
architecture of such systems consists of an
insoluble capsule body housing a drug and a plug.
The plug is removed after a predetermined lag time
owing to swelling, erosion, or dissolution.
Tablets system
Most of the pulsatile drug delivery systems are
reservoir devices coated with a barrier layer. This
barrier erodes or dissolves after a specific lag
period, and the drug is subsequently released
rapidly. The lag time depends on the thickness of
the coating layer.
1.2.2. Multiparticulate systems
Multiparticualte systems (e.g., pellets) offer various
advantages over single-unit systems. These include
no risk of dose dumping, flexibility of blending
units with different release patterns, and
Pulsatile Drug Delivery System
Time Controlled System Site Specific System
Single unit system Multiple unit system
Tablet
E.g. Time clock system
Capsule
E.g.: Pulsincap system
Pellets
E.g. Time-Controlled Explosion
System
Fig. 2: Classification of pulsatile drug delivery system 1,2
reproducible and short gastric residence time. But
the drug-carrying capacity of multiparticulate
systems is lower due to presence of higher quantity
of excipients. Such systems are invariably a
reservoir type with either rupturable or altered
permeability coating
1.3 Factors to be considered in the design of
colon-specific drug delivery system
1.3.1 Anatomy and physiology of colon
The large intestine extends from the distal end of
the ileum to the anus. Human large intestine is
about 1.5 m long (Table 1) 7 . The colon is upper
five feet of the large intestine and mainly situated
in the abdomen. The colon is a cylindrical tube that
is lined by moist, soft pink lining called mucosa,
the pathway is called the lumen and is
approximately 2-3 inches in diameter 8 . The cecum
forms the first part of the colon and leads to the
right colon or the ascending colon (just under the
liver) followed by the transverse colon, the
descending colon, sigmoidal colon, rectum and the
anal canal (Figure 3) 9 . The physiology of the
Vol. 2 (3) Jul – Sep 2011 www.ijrpbsonline.com 936

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
proximal and distal colon differs in several respects
that have an effect on drug absorption at each site.
The physical properties of the luminal content of
the colon also change, from liquid in the cecum to
semisolid in the distal colon.
Table 1: Summary of anatomical and physiological features of
small intestine and colon.
Region of Gastrointestinal Tract Characteristics
Entire gastrointestinal tract 500-700
Duodenum 20-30
Small intestine Jejunum 150-250
Ileum 200-350
Cecum 6-7
Length (cm)
Large intestine
Ascending colon
Transverse colon
20
45
Descending colon 30
Sigmoid colon 40
Rectum 12
Anal canal 3
Internal diameter
Small intestine 3-4
(cm)
Large intestine 6
Stomach
Fasted 1.5-3
Fed 2-5
Small intestine
Duodenum(fasted)
Duodenum(fed)
6.1
5.4
pH
Ileum 7-8
Cecum and colon 5.5-7
Large intestine
Rectum 7
The major functions of the colon are 1) the
consolidation of the intestinal contents into feaces
by the absorption of the water and electrolytes and
to store the feaces until excretion. The absorptive
capacity is very high, each day about 2000 ml of
fluid enters the colon through the ileocecal valve
from which more than 90% of the fluid is absorbed.
2) creation of a suitable environment for the growth
of colonic microorganisms such as Bacteroides,
Eubacterium, and Enterobacteriaceae; 3) expulsion
of the contents of the colon at a suitable time; and
4) absorption of water and Na + from the lumen,
concentrating the fecal content, and secretion of K +
and (HCO3 - ) 9 .
1.3.2. pH in the colon
The pH of the gastrointestinal tract is subject to
both inter and intra subject variations. Diet,
diseased state, and food intake influence the pH of
the gastrointestinal fluid. The change in pH along
the gastrointestinal tract has been used as a means
for targeted colon drug delivery 10,11 . There is a pH
gradient in the gastrointestinal tract with value
ranging from 1.2 in the stomach through 6.6 in the
proximal small intestine to a peak of about 7.5 in
the distal small intestine (Table 1). The pH
difference between the stomach and small intestine
has historically been exploited to deliver the drug
to the small intestine by way of pH sensitive enteric
coatings. There is a fall in pH on the entry into the
colon due to the presence of short chain fatty acids
arising from bacterial fermentation of
polysaccharides. For example lactose is fermented
by colonic bacteria to produce large amounts of
lactic acid resulting in drop in the pH to about
5.0 12 .
1.3.3. Colonic microflora and their enzymes
Intestinal enzymes are used to trigger drug release
in various parts of the GIT. Usually, these enzymes
are derived from gut microflora residing in high
number in the colon. These enzymes are used to
degrade coatings/matrices as well as to break bonds
between an inert carrier and an active agent (i.e.,
release of a drug from a prodrug). Over 400 distinct
bacterial species have been found, 20-30% of
which are of the genus Bacteroides 13 . The upper
region of the GIT has very small number of
bacteria and predominantly consists of Grampositive
facultative bacteria. The concentration of
bacteria in the human colon is 10 11 - 10 12 CFU/ml.
The most important anaerobic bacteria are
Bacteroides, Bifidobacterium, Eubacterium,
Peptococcus, Peptostreptococcus, Ruminococcus,
Propionibacterium, and Clostridium 14 . Sammary of
the most important metabolic reaction carried out
by intestinal bacteria are given in table 2 15 .
Vol. 2 (3) Jul – Sep 2011 www.ijrpbsonline.com 937

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
Table 2: Drug metabolizing enzymes in the colon that catalyze reactions
Enzymes Microorganism Metabolic reaction catalyzed
Nitroreductase E. coli, Bacteroides
Reduce aromatic and heterocyclic nitro
compounds
Azoreductase
Clostridia, Lactobacilli,
E. coli
Reductive cleavage of azo compounds
N-Oxide reductase,
sulfoxide reductase
E. coli Reduce N-Oxides and sulfoxides
Hydrogenase Clostridia, Lactobacilli
Reduce carbonyl groups and aliphatic double
bonds
Esterases and amidases
E. coli, P. vulgaris,
B. subtilis, B. mycoides
Cleavage of esters or amidases of carboxylic
acids
Glucosidase Clostridia, Eubacteria
Cleavage of β-glycosidases of alcohols and
phenols
Glucuronidase E. coli, A. aerogenes
Cleavage of β-glucuronidases of alcohols and
phenols
Sulfatase Eubacteria, Clostridia, Streptococci Cleavage of O-sulfates and sulfamates
1.3.4. Transit of material in the colon
Gastric emptying of dosage forms is highly
variable and depends primarily on whether the
subject is fed or fasted and on the properties of the
dosage form such as size and density. The arrival
of an oral dosage form at the colon is determined
by the rate of gastric emptying and the small
intestinal transit time. The transit times of small
oral dosage forms in GIT are given in table 3.
The movement of materials through the colon is
slow and tends to be highly variable and influenced
by a number of factors such as diet, dietary fiber
content, mobility, stress, disease and drugs. In
healthy young and adult males, dosage forms such
as capsules and tablets pass through the colon in
approximately 20-30 hours, although the transit
time of a few hours to more than 2 days can occur.
Diseases affecting colonic transit have important
implications for drug delivery: diarrhoea increases
colonic transit and constipation decreases it.
However, in most disease conditions, transit time
appears to remain reasonably constant.
Table 3: The transit time of
dosage form in GIT
Organ Transit time (hr)
Stomach
3 (Fed)
Small intestine 3-4
Large intestine 20-30
1.4. Drug candidates suitable for colonic drug
delivery
Drug delivery selectively to the colon through oral
route is becoming increasingly popular for the
treatment of large intestinal diseases and for
systemic absorption of peptide and protein drugs.
It is well recognized that peptides and proteins are
well absorbed intact from the gastrointestinal tract,
but the bioavailability is invariably extremely low,
with exceptions, such as di and tripeptide
analogues, cyclosporin 16,17 . A variety of protein and
peptide drugs like calcitonin, interferon,
interleukins, erythropoietin, growth hormones and
even insulin are being investigated for their
systemic absorption using colon-specific delivery 18 .
Inflammatory bowel disease (IBD) such as
ulcerative colitis and Crohn’s disease require
selective local delivery of the drug to the colon.
Sulfasalazine is the most commonly prescribed
medication for such diseases. The other drugs used
in IBD are steroids such as dexamethasone,
prednisolone and hydrocortisone. In Colonic
cancer, anticancer drugs like 5-flurouracil,
doxorubicin and nimustine are to be delivered
specifically to the colon. The site-specific delivery
of drugs like, metronidazole, mebendazole and
albendazole are used in the treatment of infectious
diseases such as amoebiasis and helmenthiasis.
Because of the small extent of paracellular
transplant, the colon is a more selective site for
drug absorption that the small intestine. Drug
shown to be well absorbed include glibenclamide,
diclofenac, theophylline, ibuprofen, metoprolol and
oxprenolol 14 .
1.5. Strategies for colon-specific drug delivery
1.5.1 Prodrugs
Prodrug is pharmacologically inactive derivative of
a parent drug molecule that requires spontaneous or
enzymatic transformation in vivo to release the
active drug. For colonic delivery of drugs, prodrugs
are designed to undergo minimal absorption and
hydrolysis in the tracts of the upper GIT and
undergo enzymatic hydrolysis in the colon, there
by releasing the active drug moiety from the
carrier. A number of other linkages susceptible to
bacterial hydrolysis specifically in the colon have
been prepared where the drug is attached to
hydrophilic moieties like amino acid, glucuronic
Vol. 2 (3) Jul – Sep 2011 www.ijrpbsonline.com 938

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
acid, glucose, galactose, cellulose, coating
materials over drug cores etc.
Polysaccharides are used as glucuronic prodrugs,
which are specifically degraded by colonic
glucuronidases 19 and glycosidic prodrugs, which
are specifically degraded by colonic glycosidases 20 .
Back et.al. (1942) was realized that sulphasalazine
given for the treatment of rheumatoid arthritis was
also useful in patients with inflammatory bowel
disease (IBD). Furthermore, Khan et.al. (1977)
found that the active moiety effective in IBD was
5-amino- 3-salicylic acid (5-ASA) and
sulphapyridine (SP) only acted as a carrier 21 .The
high site specificity of prodrugs clearly indicates
the involvement of the colon for the prodrug to
drug conversion.
Anti- inflammatory glucocorticoids do not possess
carboxylic acid groups and must be chemically
transformed in order to react with dextran.
Dexamethasone and methyl prednisolone were
attached to dextran using succinic acid as a
spacer 22,23 and the resultant prodrug were incubated
with rat GIT contents, but were rapidly degraded in
caecal and colonic contents. This illustrates the
usefulness of the conjugates for selective delivery
of glucocorticoids to the large intestine.
1.5.2 pH- Dependent System
The pH-dependent systems exploit the generally
accepted view that pH of the human GIT increases
progressively from the stomach (pH 1-2 which
increases to 4 during digestion), small intestine (pH
6-7) at the site of digestion and it increases to 7-8
in the distal ileum. The coating of pH-sensitive
polymers to the tablets, capsules or pellets provide
delayed release and protect the active drug from
gastric fluid. The polymers used for colon
targeting, however, should be able to withstand the
lower pH values of the stomach and of the
proximal part of the small intestine and also be able
to disintegrate at the neutral of slightly alkaline pH
of the terminal ileum and preferably at the ileocecal
junction. Widely used polymers are methacrylic
resins (Eudragits), which are available in watersoluble
and water-insoluble forms. Eudragit L and
S are copolymers of methacrylic acid and methyl
methacrylate. Colon targeted drug delivery systems
based on methacrylic resins has described for
insulin, prednisolone, quinolones, salsalazine,
cyclosporine, beclomethasone dipropionate and
naproxane 14 . In fact, the pH in the distal small
intestine is usually around 7.5, while the pH in the
proximal colon is closer to 6.0. These delivery
systems therefore have a tendency to release their
drug load prior to reaching the colon. To overcome
the problem of premature drug release, a
copolymer of methacrylic acid, methylmethacrylate
and ethylmethacrylate (Eudragit FS), which
dissolve at a slower rate and at a higher threshold
pH (7-7.5), has been developed recently 24 .
1.5.3 Time-dependent system
Time-dependent delivery has also been proposed as
a means of targeting to the colon. Time-dependent
systems release their drug load after a
preprogrammed time delay. To attain colonic
release, the lag time should equate the time taken
for the system to reach the colon. This time is
difficult to predict in advance, although a lag time
of five hours is usually considered sufficient, given
that small intestine transit time is reported to be
relatively constant at three to four hours 25 . A
number of systems have been developed based on
this principle, with one of the earliest being the
somewhat complex Pulsincap device 26 .
1.5.4 Microflora-activated system
The bioenvironment inside the human GIT is
characterized by the presence of complex
microflora especially the colon that is rich in
microorganisms that are involved in the process of
reduction of dietary component or other materials.
Drugs that are coated with the polymers, which are
showing degradability due to the influence of
colonic micro- organisms, can be exploited in
designing drugs for colon targeting.
Polysaccharides offer an alternative substrate for
the bacterial enzymes present in the colon. Many of
these polymers are already used as excipients in
drug formulations or are constituents of the human
diet and are therefore generally regarded as safe. A
large number of polysaccharides have already been
studied for their potential as colon-specific
drug carrier systems, such as chitosan, pectin,
chondroitin sulphate, cyclodextrin, dextrans, guar
gum, inulin, amylose, sodium alginate and locust
bean gum 27,28 .
1.6. Evaluation of colon-specific drug delivery
systems
A successful colon-specific drug delivery system is
one that remains intact in the physiological
environment of stomach and small intestine, but
releases the drug in the colon. Different in-vitro
and in-vivo methods are used to evaluate the
colonic drug delivery systems.
1.6.1 In-vitro method
The ability of the coats/ carriers to remain intact in
the physiological environment of the stomach and
small intestine is generally assessed by conducting
drug release studies in 0.1N HCl for 2 hours (mean
gastric emptying time) and in pH 7.4 Sorensen’s
phosphate buffer for 3 hours (mean small intestinal
transit time) using USP dissolution rate test
apparatus or flow through dissolution apparatus.
Currently, four dissolution apparatus are
Vol. 2 (3) Jul – Sep 2011 www.ijrpbsonline.com 939

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
recommended in the USP to accommodate
different actives and dosage forms: basket method,
paddle method, Bio-Dis method and flow-through
cell method.
The ability of the delivery system to release the
drug in the colon is tested in-vitro by incubating it
in a buffer medium in the presence of either
enzymes (e.g. pectinase, dextranase) or rat/ guinea
pig/ rabbit caecal contents 14 . The amount of drug
released at different time intervals during the
incubation is estimated to find out the degradation
of the carrier under study. Rama Prasad et.al.
(1998) reported the usefulness of guar gum as a
carrier for colon-specific delivery established that a
buffer medium with rat caecal contents (4%w/v)
obtained after 7 days of enzyme induction provides
the best conditions for in-vitro evaluation.
USP Dissolution apparatus III (reciprocating
cylinder) was employed to assess in-vitro
performance of guar-based colonic formulations 28 .
Because of the unique setup of dissolution
apparatus III (i.e. the dissolution tubes can be
programmed to move along successive rows of
vessels), drug release can be evaluated in different
medium successively. Wong et.al. evaluated
several guar-based colonic formulations using
apparatus III in simulated gastric fluid (pH 1.2),
simulated intestinal fluid (pH 7.5) and simulated
colonic fluids containing galactomannanase. As
expected, when compared with drug release in
simulated gastric and intestinal fluids, results
showed that drug release was accelerated in the
colonic fluid due to the presence of the
galactomannanase that could hydrolyse the guar
gum.
1.6.2. In vivo methods 14
1.6.2.1 Animal Models
Different animal models are used for evaluating invivo
performance of colon-specific drug delivery
systems. Guinea pigs were used to evaluate colonspecific
drug delivery from a glucoside prodrug of
dexamethasone. Other animal models used for the
in-vivo evaluation of colon-specific drug delivery
systems include the rat and pig.
1.6.2.2 Techniques for monitoring the in-vivo
behaviour of colon-specific delivery systems in
humans
A variety of techniques like (i) string technique, (ii)
endoscopy, (iii) radiotelemetry, (iv)
roentgenography and (v) gamma scintigraphy were
used for monitoring the in-vivo behavior of the oral
dosage forms.
1.7 REFERENCES
1. Gothoskar AV, Joshi AM and Joshi NH.
Pulsatile Drug Delivery Systems: A
Review, Drug Delivery Technology,
2004;4(5).
2. Shivakumar HG, Pramod kumar TM and
Kashppa Goud Desai. Pulsatile drug
delivery system. Indian J Pham Educ.
2003;37(3):125.
3. Sungthonngjeen S, Satit P, Ornlaksana P,
Andrei D and Roland B. Development of
pulsatile release tablets with swelling and
rupturable layers. J Control Release.
2004;95:147-159.
4. Hardy JG, Lee SW, Clark AG and
Reynolds JR. Enema volume and
spreading. Int J Pharm. 1986;35:85-90.
5. Wood E, Wilson CG and Harday JG. The
spreading of foam and solution enemas.
Int J Pharm. 1985;25:191-197.
6. Vyas SP and Khar RK. Controlled Drug
delivery concepts and advances. 1 ed.
2002: Vallabh Prakashan.
7. Vandamme THF, Lenourry A, Charrueau
C and Chaumeil JC. The use of
polysaccharides to target drugs to the
colon. Carbo Poly. 2002;48:219-231.
8. Sarasija S and Hota A. Colon- specific
drug delivery systems. Ind J Pharm Sci.
2002;62(1):1-8.
9. Macfarlane GT and Cummings JH. The
colonic flora, fermentation and large
bowel digestive function. In Phillips S F,
Pemberton J H, Shorter R G. The large
intenstine: physiology, pathophysiology
and disease. New York: Raven press.
1991:51.
10. Vandamme THF, Lenourry A, Charrueau
C and Chaumeil JC. The use of
polysaccharides to target drugs to the
colon. Carbo Poly. 2002;48:219-231.
11. Thomas P, Richards D, Richards A,
Rojers L, Evans B K, Drew M J and
Rhodes J. Absorption of delayed-release
prednisolone in ulcerative colitis and
crohn's Disease. Int J Pharm. 1985;37:757.
12. Tomlin J and Read NW. The relation
between bacterial degradation of viscous
polysaccharides and stool output in human
beings. Brit J Nutr. 1988;60:476.
13. Sarasija S and Hota A. Colon- specific
drug delivery systems. Ind J Pharm Sci.
2002;62(1):1-8.
14. Krishnaiah YSR and Styanarayana S.
Colon- specific drug delivery systems. In
Jain NK. Advances in controlled and
novel drug delivery. CBS publishers and
distributors. 2000;89-119.
15. Lee Vincent HL and Mukherjee SK. Drug
Delivery- Oral colon- specific. Ency
Pharm Tech. Dekker Encyclopedia.
2002;871-885.
Vol. 2 (3) Jul – Sep 2011 www.ijrpbsonline.com 940

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
16. Smith PL, Wall DA, Gochoco CH and
Wilson G. Routes of delivery: Case
studied: (5) Oral absorption of peptides
and proteins. Adv drug deliv Rev.
1992;8:253.
17. Reynolds JEF, Eds Martindale. The Extra
Pharmacopoeia. 31 st Edn. Royal
Pharmaceutical Society. London.
1996;1279.
18. Mackay M and Tomlinson E. Colonic
delivery of therapeutic peptides and
proteins. In: Colonic drug absorption and
metabolism. Bieck P(Ed). Marcel Dekker.
New York. 1933;159-176.
19. Haeberlin B, Empey L, Fedorak R, Nolen
H and Friend DR. In vivo studies in the
evaluation of glucuronide prodrug for
novel therapy of ulcerative colitis.
Proceedings of the International
Symposium on Controlled Release of
Bioactive Materials. 1993;20:174-175.
20. Friend DR and Chang GW. Drug
glycosides: potential prodrug for colon-
specific drug delivery. J Med Chem.
1985;28:51-57.
21. McDowell RH. Properties of alginates.
London, Alginate Industries Ltd., 4th ed.
1977;67.
22. Dusel R, McGinity J, Harris MR, Vadino
WA and Cooper J. Sodium alginate,
Handbook of Pharmaceutical Excipients,
Published by American pharmaceutical
Society: USA and The Pharmaceutical
Society of Great Britain, London.
1986:257-258.
23. McGinity JW, Harris MR, Vadino WA
and Cooper J. Alginic acid, Handbook of
Pharmaceutical excipient, published by
American pharmaceutical Society: USA
and The Pharmaceutical Society of Great
Britain, London. 1986:5
24. Dew MJ, Hughes PJ, Lee MG, Evans BK
and Rhodes J. An oral preparation to
release drugs in the human colon. British
Journal of Clinical Pharmacology.
1982;14:405-408.
25. Hebden JM, Wilson CG, Spiller RC,
Gilchrist PJ, Blackchaw E, Frier ME and
Perkin AC. Regional difference in quinine
absorption from the undistributed human
colon assessed using a timed release
delivery system. Pharma Res.
1999;16:1087-1092.
26. Wilding IR, Davice SS, Bakhshaee M,
Stevens HNE, Sparrow RA and Brennanj.
Pharma Res. 1992;9:645-657.
27. Hovgaard L and Brondsted H. Current
application of polysaccharides in colon
targeting. Crit Rev Ther Drug Carrier
Syst. 1996;13:185-223.
28. Sinha VR and Kumaria R. polysaccharide
in colon specific drug delivery. Int J
Pharm. 2001;224:19-23.
Vol. 2 (3) Jul – Sep 2011 www.ijrpbsonline.com 941