-----------------------------------------------Introduction----------------------------------------------

1. INTRODUCTION
Most of the conventional drug delivery systems for treating the colon disorders
such as inflammatory bowel diseases (e.g. irritable bowel syndrome, ulcerative colitis,
Crohns disease etc.), infectious diseases (e.g. amoebiasis) and colon cancer are failing as
the drugs do not reach the site of action in appropriate concentrations. Thus, an effective
and safe therapy of these colonic disorders, using site-specific drug delivery systems is a
challenging task to the pharmaceutical technologists.

In the recent times, the colon-specific delivery systems are also gaining
importance for the systemic delivery of protein and peptide drugs. Due to negligible
activity of brush-border membrane peptidase activity and less activity of pancreatic
enzymes, the colon is considered to be more suitable for delivery of peptides and protein
2

in comparison to small intestine. Besides this low hostile environment, the colonic
transit time is long (20-30 hours) and the colonic tissue is highly responsive to the action
of absorption enhancers. The longer residence time, less peptidase activity, natural
absorptive characteristics and high response to absorption enhancers make the colon a
promising site for the delivery of protein and peptide drugs for systemic absorption.
Further, drug targeting to colon would prove useful where intentional delayed drug
absorption is desired from therapeutic point of view in the treatment of diseases that have
peak symptoms in the early morning such as nocturnal asthma, angina or arthritis.
Colonic drug delivery is also found useful for improving systemic absorption of drugs
like nitrendipine, metoprolol, theophylline, isosorbide mononitrate etc. However, a
substantial amount of research is needed in order to find out to what extent these
molecules can be absorbed after oral administration.

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ----------------

-----------------------------------------------Introduction---------------------------------------------Colonic delivery can be accomplished by oral or rectal administration. Rectal

dosage forms such as suppositories and enemas are not always effective since a high
variability in the distribution of these forms is observed. Suppositories are only effective
in the rectum because of the confined spread, and enema solutions can only offer topical
treatment to the sigmoid and descending colon. Therefore, oral administration is
preferred, but for this purpose, may physiological barriers have to be overcome.
Absorption or degradation of the active ingredient in the upper part of the GI tract is the
major obstacle and must be circumvented for successful colonic drug delivery.
Anatomy and Physiology of Colon:

5, 6, 7, 8, 9

The GI tract is divided into stomach, small intestine and large intestine. The large
intestine extending from the ileocaecal junction to the anus is divided into three main
parts. These are the colon, the rectum and the anal canal. The colon itself is made up of
the caecum, the ascending colon, the hepatic flexure, the transverse colon, the splenic
flexure, the descending colon and the sigmoid colon. It is about 1.5 m long, the transverse
colon being the longest and most mobile part, and has an average diameter of about 6.5
cm, although it varies in diameter from approximately 9 cm in the caecum to 2 cm in the
sigmoid colon.
The wall of the colon is composed of four layers: the serosa, the muscularis
externa, the submucosa and the mucosa. The serosa is the exterior coat of the large
intestine and consists of areolar tissue that is covered by a single layer of squamos
mesothelial cells. The major muscular coat of the large intestine is the muscularis
externa. This is composed of an inner circular layer of fibers that surrounds the bowel and

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ----------------

-----------------------------------------------Introduction---------------------------------------------of an outer longitudinal layer. The submucosa is the layer of connective tissue that lies
immediately beneath the mucosa. Lining the lumen of the colon, the mucosa is divided
into epithelium, lamina propria and muscularis mucosae. Closely spaced crypts extend
down into the surface of the mucosa. The muscularis mucosa consists of a layer of
smooth muscle and separates the submucosa from the lamina propria. The lamina propria
supports the epithelium, and occupies space between the crypts and beneath the crypts.
Within the lamina propria are located blood capillaries and lymphatic lacteals. The space
also acts as a reservoir for macrophages, neutrophils, eosinophils, lymphocytes and
plasma cells, which locally produce IgA antibodies.
The epithelium consists of a single layer of cells, which lines the crypts and
covers the surface of the mucosa. Three major cell types found in the epithelium are the
columnar absorptive cells, goblet (mucous) cells and enteroendocrine cells. Adjacent
columnar absorptive cells are attached to one another near their apical margins by a
junctional complex. Mucus production in the colon is a function of goblet cells and the
proportion of goblet cells increases in the elderly.
The arterial blood supply to the proximal colon is from the superior mesenteric
artery and the inferior mesenteric artery supplies the distal colon. The venous drainage is
via the superior (proximal colon) and inferior (distal colon) veins. The arterioles and
capillary branches pass to the epithelial surfaces between the crypts and form an
extensive network of capillary plexi.
The colon serves four major functions; (1) creation of suitable environment for
the growth of colonic microorganisms; (2) storage reservoir of faecal contents; (3)

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ----------------

-----------------------------------------------Introduction---------------------------------------------expulsion of the contents of the colon at an appropriate time and (4) absorption of
potassium and water from the lumen, concentrating the faecal content, and secretion and
excretion of potassium and bicarbonate. In vitro and in vivo electrophysiological studies
have demonstrated that the mechanism of sodium absorption is an active transport.
Furthermore, it is influenced by mucosal cyclic adenosine monophosphate level, pH,
osmolarity and compounds such as fatty acids, and bile acids. Water is absorbed
passively, while potassium and bicarbonate are actively secreted by colonic epithelium.
The active secretion of potassium is stimulated by mineral corticoids.
pH in the Colon:
The pH of the GI tract is subjected to both inter- and intra-subject variations.
Table gives an overview of the pH of the GI tract.
Average pH in the GI Tract
Location

pH

Oral Cavity
Oesophagus

6.2 7.4
5.0 6.0

Stomach

Fasted condition: 1.5 2.0

Small intestine

Fed condition: 3.0 5.0

Jejunum: 5.0 6.5
Ileum: 6.0 7.5

Large intestine

Right colon: 6.4

Mid colon and left colon: 6.0 7.6

Radiotelemetry has been used to measure the gastrointestinal pH in healthy

human subjects. The highest pH levels (7.5 0.5) were found to be in the terminal ileum.
On entry into the colon, the pH dropped to 6.4 0.6. The pH in the mid-colon was found

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ----------------

-----------------------------------------------Introduction---------------------------------------------to be 6.6 0.8 and in the left colon, 7.0 0.7. The presence or absence of food in the
stomach determines the gastric pH range, which varies from 1.5 to 3 in the fasted state
and rises to approximately 4 or 5 in the fed. In duodenum, the pH ranges from 1.7 to 4.3
in the fed state and from 3 to approximately 6 in fasted state. Passing from the jejunum
through the mid small bowel and ileum, the pH rises slightly from approximately 6.6 to
7.5 and this falls to about 6.4 in the right colon. The mid and left colon has pH values of
about 6.6 and about 7.0 respectively. Interspecies variability in pH is a major concern
when developing and testing colon-specific delivery systems in animals and applying the
information to humans. Colonic pH has been shown reduced in disease. The mean pH in
a group of 7 patients with untreated ulcerative colitis was 4.7 0.7 whereas in 5 patients
receiving treatment it was 5.5 0.4. The in vitro fermentation of the pharmaceutical
polysaccharides such as ispaghual and guar gum resulted in the reduction of pH in the
presence of faecal bacteria.
Gastrointestinal transit:
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 dosage
forms in GI tract are given in table.

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ----------------

-----------------------------------------------Introduction---------------------------------------------The Transit Time of Dosage Form in GI Tract

Organ
Stomach

Transit time (hr)

<1 (Fasting)
>3 (Fed)

Small intestine

3-4

Large intestine

20-30

The presence of food generally increases gastric residence and, in some cases,
with regular feeding, dosage forms have been shown to reside in the stomach for periods
in excess of 12 hours. Small intestinal transit is surprisingly constant at 3-4 hours and
appears to be independent of the dosage form and the subjects fasted or fed state.
Therefore, a dosage form could take from as little as 4 hours to longer than 12 hours to
arrive at the colon following oral administration. However, 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, diarrhea increases colonic transit and constipation decreases it. However, in
most disease conditions, transit time appears to remain reasonably constant.

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ----------------

-----------------------------------------------Introduction---------------------------------------------Colonic Microflora:
A large number of anaerobic and aerobic bacteria are present throughout the
entire length of the human GI tract. The microflora found in the GI tract of man is given
in below table.
The Microflora found in the GIT of Man
Bacterial counts (CFU/ml)
Stomach
Tota l b ac t e ri a l
count

0-10

Jejunum

Ileum

0-10

10 -10

Faeces

-3

10 -10

10

12

Aerobic or facultative anaerobic bacteria

Enterobacteria

0-10

0-10

10 -10

10 -10

10

Streptococci

0-10

0-10

10 -10

10 -10

10

Staphylococci

0-10

0-10

10 -10

10 -10

Lactobacillus

0-10

0-10

10 -10

10 -10

10

Fungi

0-10

0-10

10-10

10 -10

Bacteroides

Rare

0-10

10 -10

10 -10

Bifidobacteria

Rare

0-10

10 -10

10 -10

12

Gram-positive
cocci

Rare

0-10

10 -10

10 -10

11

Clostridia

Rare

Rare

10 -10

10 -10

11

Eubacteria

Rare

Rare

Rare

12

Anaerobic bacteria
10

10 -10

12

The upper region of the GIT has a very small number of bacteria and
predominantly consists of Gram-positive facultative bacteria. The concentration of
3

bacteria in the stomach is usually less than 10 colony-forming units/ml (CFU/ml) and
the most commonly isolated species are Streptococci, Staphylococci, Lactobacilli, and
various fungi. Under normal conditions, the microflora of the proximal small bowel are
-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ----------------

-----------------------------------------------Introduction---------------------------------------------3

similar to those of the stomach, the bacterial concentration being 10 -10 CFU/ml. In the
distal part of the small intestine, a higher concentration of anaerobic bacteria is found.
7

The lower ileum has a bacterial concentration of 10 -10 CFU/ml and the distal ileum
usually contains bacteria similar to those found in the colon.
In the ileocaecal sphincter, the bacterial concentration increased dramatically. The
11

concentration of bacteria in the human colon is 10 -10

12

CFU/ml. The bacterial flora of

the colon is predominantly anaerobic and composed of more than 400 strains. The
3

anaerobic bacteria outnumber the aerobic by a factor of 10 to 10 . The most important

anaerobic bacteria are Bacteroides, Bifidobacterium, Eubacterium, Peptococcus,
Peptostreptococcus, Ruminococcus, Propionibacterium and Clostridium. Important
facultative bacteria in the large intestine are Escherichia coli and Lactobacillus. The
faecal flora are representative of the flora of the large bowel. Approximately 30% of the
dry weight of faeces consists of bacteria. The influence of dietary factors appears to be of
little importance in terms of the composition of the microflora. Orally administered
antibiotics, however, can cause serious alterations in colonic flora.
A large number of compounds ingested orally are metabolized by gut bacteria. A
summary of the most important metabolic reactions carried out by intestinal bacteria is
given below.
Hydrolysis of glycosides, sulphate esters, amides, esters, sulphamates and nitrates.
Reduction of C=C, azo bonds, nitro groups, aldehydes, ketones, and N oxides.
Dehydroxylation (C&N dehydroxylation)
Decarboxylation
Dealkylation of O-alkyl groups and N-alkyl groups
-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ----------------

-----------------------------------------------Introduction---------------------------------------------Dehalogenation
Desamination
Heterocyclic ringfision
Acetylation
Esterification
The above metabolic actions of the microflora are influenced by numerous factors
such as age, gastrointestinal disease, intake of drugs and fermentation of dietary residues
and can lead to inactivation of drugs or the enhancement of the action and side effects of
the drugs.
Water absorption occurs secondary to the absorption of electrolytes and short
+

chain fatty acids (SCFA) by solvent drag. The human colon absorbs sodium (Na ) and


chloride (Cl ) and secretes bicarbonate (HCO

) and potassium (K ) against

electrochemical gradients. Bicarbonates in the lumen neutralize the acidity caused by

SCFA production. Carbohydrates that enter the colon, in any form but mostly as dietary
fiber or mucopolysaccharides are fermented to SCFA mainly acetic, propionic and
butyric. These SCFA are rapidly absorbed from the colon and are used by the colonic
epithelial cells or are transported to the liver. The absorption of SCFA enhances the
absorption of electrolytes and water. Sugars such as glucose and sucrose are poorly
absorbed in the adult human colon. Lipid soluble molecules are most readily absorbed by
passive diffusion. In general, organic acids, bases, and drugs are most rapidly absorbed in
their lipid soluble undissociated form. The equivalent pore size of the colon was
estimated as 2.3 when compared with jejunum (8 ) and ileum (4 ).

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ----------------

-----------------------------------------------Introduction---------------------------------------------Mucins are degraded by the colonic bacteria and hence the changes in the
intestinal flora may affect the mucosal environment. The mucus layer may also be
affected by disease and is thinned by the action of prostaglandins. Some dietary fibers
such as pectin have cation exchange properties that may bind charged molecules such as
bile acids. This binding is increased at the low pH encountered in the colon and may be a
factor in the immobilization of some drugs.
INTRODUCTION ON INFLAMMATORY BOWEL DISEASE
Ulcerative Colitis and Crohns Disease:
Inflammatory bowel disease (IBD) is a general term for group of chronic
inflammatory disorders of unknown etiology involving the gastrointestinal tract. Since
there are no pathognomonic features or specific diagnostic tests, in a strict sense, these
disorders remain diagnoses of exclusion. Their features are sufficiently characteristic.
However, to permit accurate diagnosis in the majority of cases, chronic IBD may be
divided into two major groupschronic non-specific ulcerative colitis and Crohns
disease.
Etiology and Pathogenesis:
While the cause of ulcerative colitis and Crohns disease remains unknown,
certain feature of these diseases have suggested several areas of possible etiologic
importance. These include familial or, genetic, infectious, immunological and
psychological factors.

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ---------------- 10

-----------------------------------------------Introduction---------------------------------------------Pathology:
In ulcerative colitis there is an inflammatory reaction primarily involving the
colonic mucosa. Grossly, the colon appears ulcerated, hyperemic, and usually
hemorrhagic. A striking feature of the inflammation is that it is uniform and continuous
with no intervening areas of normal mucosa. The return is usually involved (95% of
cases) and the inflammation extends proximally in a continuous fashion but for a variable
distance. The basic pathological features of Crohn's disease are the same the disease
involved the small bowel or colon.
Clinical Features:
Ulcerative Colitis: The major symptoms of ulcerative colitis are bloody diarrhea and
abdominal pain often with fever and weight loss in more severe cases. With mild disease,
there may be one or two semiformed stools containing little blood and with no systematic
manifestations in contrast the patient with severe disease may have frequent liquid stools
containing blood and pus, complain of severe cramps, and demonstrate symptoms and
signs of dehydration, anemia, fever, and weight loss. With predominantly rectal
involvement, constipation rather than diarrhea may be present, and trnesmus may be a
major complaint.
Crohn's Disease:
The major clinical features of Crohn's disease are fever, abdominal pain, diarrhea
often without blood, and generalized fatigability. This may be associated weight loss.
With colonic involvement diarrhea and pain are the most frequent symptoms.

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ---------------- 11

-----------------------------------------------Introduction---------------------------------------------Treatment:
In general, the treatment of ulcerative colitis and Crohn's disease shares certain
common principles. The principle drugs used in the therapy of ulcerative colitis are the
anti-inflammatory agents, sulphasalazine (azulfidine) and adrenal glucocorticoids or
ACTH. Sulfasalazine consists of a sulfonamide (sulfapyridine) moiety chemically bound
to solicylae (5-Amino-solicylate); it undergoes bacterial cleavage in the colon. The
liberated sulfapyridine is efficiently absorbed and largely excreted in the urine; the
liberated 5-amino-salicylate believed to be the active component, remains largely in the
colon and is excreted in the stool.

10

APPROCHES TO COLON-SPECIFIC DRUG DELIVERY

There are several ways in which colon-specific drug delivery has been attempted.
Prodrugs, coating with pH dependent polymers, design of timed-release dosage forms
and the use of carriers that are degraded exclusively by colonic bacteria are an array of
such attempts.

11, 12

The targeting of orally administered drugs to the colon is accomplished by:

i)

Coating with pH dependent polymers

ii)

Timed release dosage forms

iii)

Delivery systems based on the metabolic activity of colonic bacteria.

i) Coating with pH dependent polymers:

In these systems, drugs are formulated into solid dosage forms such as tablets,
capsules and pellets and coated with pH sensitive polymers as in enteric coating. Widely
used polymers are methacrylic resins (Eudragits), which are available in water-soluble
and water-insoluble forms. Eudragit L and S are copolymers of methacrylic acid and
-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ---------------- 12

-----------------------------------------------Introduction---------------------------------------------methyl methacrylate. Eudragit L is water soluble at pH 6 or above and is used as an

enteric coating polymer. Eudragit S is water soluble at pH 7 or above and is used to
deliver drugs to the end of the small bowel and large intestine. At present, 5-ASA is
commercially available as an oral dosage form coated with Eudragit L100 (Claversal,
Mesazal and Colitofalk) or Eudragit S (Asacol).

13

ii) Timed-release dosage forms:

Small intestinal transit time is relatively constant and is hardly influenced by the
nature of the formulation administered. Studies have shown that, once having left the
stomach, the formulation arrives at the ileocaecal junction about 3 to 4 hours after dosing.
An extension of the use of pH dependent polymers is the use of the Pulsincap System.
This delivery system consists of a capsule, half of which is non-disintegrating and other
half enteric coated. The enteric coat dissolves on entering the small intestine and a
hydrogel plug, stoppering the non-disintegrating part, swells at a rate determined by the
degree of cross-linking. After a predetermined time (e.g. 5 hours), the hydrogel plug
swells so much that it becomes ejected from the non-disintegrating bottom half of the
capsule thereby releasing the drug. It must be noted that the swelling of the hydrogel plug
is pH independent. Other reports also appear in the literature on the use of pH dependent
timed-release system for site-specific drug release in the colon. However, the sitespecificity of timed-release dosage forms is considered poor because of large variations
in gastric emptying times and passage across the ileo-caecal junction.

14, 15, 16

iii) Delivery Systems based on the metabolic activity of colonic bacteria:

The colonic bacteria carry out a variety of metabolic reactions and the most
important of them are reduction and hydrolysis. Different strategies were used to target

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ---------------- 13

-----------------------------------------------Introduction---------------------------------------------drugs to the colon based on these actions. The main feature of these systems is their sitespecificity. Different strategies are described below.
a) Coating with biodegradable azo polymers:
The intestinal microflora has a large metabolic capacity and it appears that
reduction of azo bonds is a general reaction of colonic bacteria. The azopolymers having
a high degree of hydrophilicity were degraded by colonic bacteria. It was also found that
the chain length of the azo aromatic group in the azo polymers had no much influence on
the rate of degradation. The developed copolymers of styrene and 2-hydroxyethyl
methacrylate which were cross-linked with divinyl azobenzene and N,N-bis(

-styrene

sulphonyl)-4,4-diaminoazo-benzene to coat oral dosage forms of insulin and

vasopressin. On entering the colon, the coating was degraded by bacterial azoreductases
thereby releasing the drug.

17

b) Prodrugs:
A well-known colon-specific prodrug, sulfasalazine, is used in the treatment of
ulcerative colitis and Crohns disease. Chemically, sulfasalazine is 5-aminosalicylic acid
(5-ASA) coupled with sulphapyridine by azo bonding. One reaching the colon, the azo
bond is reduced by colonic azoreductases to 5-ASA and sulphapyridine. The active
moiety is 5-ASA and sulphapyridine simply acts as a carrier to deliver 5-ASA intact to
the colon. Majority of side effects associated with the use of sulfasalazine are due to
systemic absorption of sulphapyridine from colon. Olsalazine, consisting of two 5-ASA
molecules linked by an azo bond, was developed for the purpose of delivering 5-ASA to
the colon without the use of sulphapyridine.

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ---------------- 14

-----------------------------------------------Introduction---------------------------------------------The polymeric prodrugs of 5-ASA were also developed by coupling 5-amino

group to a spacer group by means of an azo bond. The spacer 5-ASA conjugate is then
covalently linked to poly(methyl vinyl ether/ co-maleic anhydride) and also to
chloroformate-activated derivatives of dextran and poly[(2-hydroxyethyl)aspartamine]. A
very recent novel approach is the use of a water-soluble copolymer, N-(2-hydroxypropyl)
methacrylamide together with a bioadhesive sugar moiety complementary to mucus
lectins of the GI tract. In this approach, 5-ASA was linked through an azo bond to the
polymeric carrier and fucosylamine (sugar moiety) serves as bioadhesive material.

18

c) Hydrogels:
The synthesis and characterization of hydrogels for site-specific delivery of
peptide and protein drugs to the colon was described by Broadsted and Kopecek. The
hydrogels contain acidic co-monomers and enzymatically degradable azoaromatic crosslinks. In the acidic pH of the stomach, the gels have a low degree of swelling, which
protect the drug against degradation by digestive enzymes. As the gels pass down the GI
tract, the degree of swelling increases. On entering the colon, the gels reach a degree of
swelling which makes the cross-links accessible to enzymes (azoreductases) or mediators
(electron carriers). The cross-links are then degraded and the drug is released from the
disintegrated gels. The performance of the hydrogels for colon-specific drug delivery was
evaluated by conducting in vitro degradation studies in rat caecal content medium and in
vivo degradation studies by implanting (in a nylon bag) in the stomach and caecum of
male rats.

19,20,21

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ---------------- 15

-----------------------------------------------Introduction---------------------------------------------chondroitin sulfate in human colon. Colon-specific drug delivery systems based on

chondroitin sulfate and cross-linked chondroitin sulfate were reported by Rubinstein et al.
Insulin is a naturally occurring carbohydrate found in many plants such as onion,
garlic, artichoke and chicory. It consists of a mixture of oligomers and polymers
containing 2 to 60 or more D-fructose molecules which are linked by

(2-1) bonds. It is

generally accepted that insulin can resist hydrolysis and digestion in upper GI tract. In the
colon, it is fermented by the colonic microflora, more specifically by Bifidobacteria and
Bacteroides. Inulin HP (high degree of polymerization) incorporated in Eudragit RS film
was evaluated as a possible biodegradable coating for colonic drug delivery.
A delivery system based on glassy amylose for colon-specific drug delivery was
also reported. Chitosan is a high molecular weight cationic polysaccharide derived from
naturally occurring chitin in crab and shrimp shells by deacetylation. It has been
previously used as a pharmaceutical excipient in oral drug formulations to improve the
dissolution of poorly soluble drugs or for the sustained release of drugs. Tozaki et al have
used chitosan in the form of a small capsule (length 3.5 mm) to deliver insulin to the
colon for systemic absorption in rats. They also studied the effect of protease inhibitors
and absorption enhancers on the bioavailability of insulin. The findings of the study
suggested that chitosan capsules might be useful carriers for the colon-specific delivery
of peptides including insulin.
A suspension of natural polygalactomannans in polymethacrylate solutions to
form degradable coatings around the drug core was used to target the colon prepared by
Lehmann and Dreher (1991). The polygalactomannans form a swellable layer around the

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ---------------- 17

-----------------------------------------------Introduction---------------------------------------------drug core, thus delaying the release of the drug in the small bowel. They are destroyed
enzymatically in the colon with consequent drug release. Polymethacrylate copolymers
were used to improve the film forming properties of polygalactomannans. Block
polymers of polyurethanes with ethylated or acetylated galactomannan segments were
synthesized to form water-insoluble films. A significant change in the mechanical
properties of these films was observed when incubated in a suspension of human faeces
and pig caecal content in phosphate buffer indicating their potential use in colon-specific
drug delivery. In view of these reports, Krishnaiah et al (1998a; 1998b) carried out
investigations on the usefulness of guar gum, which also contains galactomannan, as a
carrier for colon-specific drug delivery.
Gura gum is a natural polysaccharide derived from the seeds of Cyamopsis
tetragonolobus, family Leguminosae. A novel tablet formulation for oral administration
using guar gum as the carrier and indomethacin as a model drug has been investigated for
colon-specific drug delivery using in vitro methods. Drug release studies under
conditions mimicking mouth to colon transit have shown that guar gum protects the drug
from being released completely in the physiological environment of stomach and small
intestine. Studies in pH 6.8 phosphate buffered saline (PBS) containing rat caecal
contents have demonstrated the susceptibility of guar gum to the colonic bacterial
enzyme action with consequent drug release. The pre-treatment of rats orally with 1 ml of
2% w/v aqueous dispersion of guar gum for 3 days induced enzymes specifically acting
on guar gum thereby increasing drug release. A further increase in drug release was
observed with rat caecal contents obtained after 7 days of pre-treatment. The presence of
4% w/v of caecal contents obtained after 3 days and 7 days of enzyme induction showed

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ---------------- 18

-----------------------------------------------Introduction---------------------------------------------biphasic drug release curves. The results illustrate the usefulness of guar gum as a
potential carrier for colon-specific drug delivery. The study also reveals that the use of
4% w/v of rat caecal contents in PBS, obtained after 7 days of enzyme induction provide
the best conditions for in vitro evaluation of guar gum.
In vivo gamma scintigraphic studies were carried out on the guar gum matrix
tablets, using Technetium-99m-DTPA (

99m

Tc-DTPA) as a tracer, in healthy subjects to

evaluate their in vivo performance. Scintigraphs taken at regular intervals have shown
that some amount of tracer present on the surface of the tablets was released in stomach
and small intestine. However, the bulk of the tracer present in the tablet mass was
delivered to the colon. The colonic arrival time of the tablets was found to vary from 2 to
4 hours. On entering the colon, the tablets degraded in five out of six volunteers thereby
releasing more amount of the tracer. The study clearly demonstrated that guar gum, in the
form of directly compressed matrix tablets, was a potential carrier for colon-specific drug
delivery.

-----------------Dr. H.L.T.College of Pharmacy, Channapatna, Bangalore ---------------- 19